ANTI-KLK5 ANTIBODIES AND METHODS OF USE

Abstract

The invention provides anti-KLK5 antibodies and methods of using the same.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. .sctn. 119(e) to U.S. Provisional Patent Application Ser. No. 62/643,034 filed on Mar. 14, 2018, the entire contents of which are incorporated herein by reference.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing submitted via EFS-Web and hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 12, 2019, is named P34707-US-1_SL.txt, and is 424,527 bytes in size.

FIELD OF THE INVENTION

[0003] The present invention relates to anti-KLK5 antibodies and methods of using the same.

BACKGROUND

[0004] Human kallikrein-related peptidases (KLKs) are (chymo)-trypsin-like serine proteases that are expressed in a variety of tissues such as prostate, ovary, breast, testis, brain, and skin. KLKs belong to a subgroup of the chymotrypsin-like serine protease family S1A of clan PA(S). The 15 human KLK genes are located on chromosome 19q13.4 and constitute the largest contiguous serine protease cluster in the human genome. These genes, generally composed of five coding exons and in some cases one or two 5' non-coding exons, encode the kallikrein-related peptidases KLK1 to KLK15. All KLK genes encode single-chain pre-pro-proteins containing a chymotrypsin- or trypsin-like catalytic domain of 224-237 residues with an amino acid sequence identity of approximately 40% among KLK4 to KLK15. KLK1 and its close homologs KLK2 and KLK3 form a clade of their own, KLK4, 5, and 7 belong to another subgroup, whereas KLK6 shares more similarity with KLK13 and KLK14. See Debela et al., Biol Chem 389, 623-632 (2008).

[0005] KLK5 appears to be most abundantly expressed in human skin, specifically in the upper spinous and granular layers of the skin, where keratinocytes undergo terminal differentiation and are transformed into flattened brick-like structures that form the stratum corneum, the outermost epidermal layer and the barrier to the outside environment. See Debela et al., J Mol Biol, 373, 1017-1031 (2007); and Tan et al., J Med Chem. 2015 Jan. 22; 58(2):598-612 (2014). KLK5 is described to play pathological roles in skin disorders such as Netherton Syndrome. See Furio et al., PLOS Genet 11(9), e1005389 (2015). Netherton Syndrome is caused by loss-of-function mutations in the SPINK5 gene, encoding the serine protease inhibitor Kazal-type 5 (SPINK5). See Descargues et al., Nat Genet. 2005 January; 37(1):56-65 (2004). SPINK5 has been shown to inhibit several members of the KLK serine protease family (e.g. KLK5 and KLK7). See Wang et al., Exp Dermatol. July; 23(7):524-6 (2014). The absence of SPINK5 in Netherton Syndrome results in unopposed KLKs activities. KLK5 hyperactivity is thought to be a key element in the pathophysiology of Netherton Syndrome as KLK5 is a regulator of proteolysis in the epidermis. Ablation of KLK5 and KLK7 rescues lethality of Netherton Syndrome-like phenotype. See Briot et al., J Exp Med. May 11; 206(5):1135-47 (2009); Furio et al., J Exp Med. March 10; 211(3):499-513 (2014); and Kasparek et al., PLoS Genet. 2017 Jan. 17; 13(1):e1006566 (2017). Netherton Syndrome is a complex systemic disease with multiple effects for which currently no satisfactory treatment is available.

[0006] Asthma is a clinically heterogeneous disorder associated with both genetic and environmental risk factors. Estimates of heritability from asthma twin studies vary from 35% to 80%, indicating an important role for genetic risk. See e.g., Ullemar et al., Allergy 71, 230-238 (2016). Several large scale GWAS have been performed for asthma and asthma related phenotypes, and many of the loci identified such as those near ORMDL3, IL13, IL1RL1 and TSLP genes have been confirmed in multiple study populations. See e.g., Bonnelykke et al., Nat Genet 46, 51-55 (2014). Recent studies identified a SNP at the KLK4/5 locus which is protective for the risk regarding periostin low, or type 2 low inflammation asthma. In the same study, KLK5 levels were found to be elevated in bronchoalveolar lavage of severe asthma patients supporting the hypothesis that KLK5 plays a role in bronchial obstruction and asthma pathogenesis.

[0007] Despite the advances in the field of diseases such as Netherton Syndrome and asthma, there remains a need to identify targets and develop means that can supplement or enhance the efficacy of existing therapies.

SUMMARY

[0008] Provided herein are anti-KLK5 antibodies and methods of using the same.

[0009] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:28; (b) HVR-H2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:38, SEQ ID NO:45, and SEQ ID NO:54; (c) HVR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:65, SEQ ID NO:69, and SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:96; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:109; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:127.

[0010] In some embodiments, the antibody comprises (a) HVR-H1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:22, and SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53; (c) HVR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:65, SEQ ID NO:69, and SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:82, SEQ ID NO:87, and SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:101, and SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:115, SEQ ID NO:119, and SEQ ID NO:122.

[0011] In some embodiments of any of the antibodies, the antibody comprises (i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115; (ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119; or (iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0012] In some embodiments of any of the antibodies, the antibody comprises a) a VH sequence of SEQ ID NO:202 and a VL sequence of SEQ ID NO:140; b) a VH sequence of SEQ ID NO:225 and a VL sequence of SEQ ID NO:151; or c) a VH sequence of SEQ ID NO:257 and a VL sequence of SEQ ID NO:162.

[0013] In some embodiments of any of the antibodies, the antibody comprises a) a VH sequence of SEQ ID NO:201 and a VL sequence of SEQ ID NO:139; b) a VH sequence of SEQ ID NO:221 and a VL sequence of SEQ ID NO:149; or c) a VH sequence of SEQ ID NO:248 or SEQ ID NO:254, and a VL sequence of SEQ ID NO:160.

[0014] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody comprises a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:201 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:139; b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:221 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:149; or c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:248 or SEQ ID NO:254, and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:160.

[0015] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody comprises (i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112; (ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113; (iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114; (iv) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116; (v) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117; (vi) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118; (vii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118; (viii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120; (ix) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118; or (x) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

[0016] In some embodiments, the antibody comprises a VH sequence selected from the group consisting of SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:226, SEQ ID NO:227, and SEQ ID NO:228, and a VL sequence selected from the group consisting of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:152, SEQ ID NO:153, and SEQ ID NO:154.

[0017] In some embodiments, the antibody comprises (a) a VH sequence of SEQ ID NO:170 and a VL sequence of SEQ ID NO:131; (b) a VH sequence of SEQ ID NO:171 and a VL sequence of SEQ ID NO:132; (c) a VH sequence of SEQ ID NO:172 and a VL sequence of SEQ ID NO:133; (d) a VH sequence of SEQ ID NO:203 and a VL sequence of SEQ ID NO:141; (e) a VH sequence of SEQ ID NO:204 and a VL sequence of SEQ ID NO:142; (f) a VH sequence of SEQ ID NO:205 and a VL sequence of SEQ ID NO:143; (g) a VH sequence of SEQ ID NO:206 and a VL sequence of SEQ ID NO:144; (h) a VH sequence of SEQ ID NO:226 and a VL sequence of SEQ ID NO:152; (i) a VH sequence of SEQ ID NO:227 and a VL sequence of SEQ ID NO:153; or (j) a VH sequence of SEQ ID NO:228 and a VL sequence of SEQ ID NO:154.

[0018] Further provided herein is an isolated antibody that binds to KLK5, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:170 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:131; (b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:171 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:132; (c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:172 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:133; (d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:203 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:141; (e) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:204 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:142; (f) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:205 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:143; (g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:206 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:144; (h) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:226 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:152; (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:227 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:153; or (j) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:228 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:154.

[0019] In some embodiments of any of the antibodies, the antibody is an IgG1 or IgG4.

[0020] In some embodiments of any of the antibodies, the antibody inhibits the biological activity of KLK5 by at least 50% as measured by one or more methods as described in the Examples herein below. In some embodiments, the one or more methods is selected from the group consisting of a recombinant KLK5 direct activity assay, coupled pro-KLK1 fluorescent peptide assay, a coupled pro-KLK7 fluorescent peptide assay, a pro-KLK1 LC/MS assay, a pro-KLK7 LC/MS assay, and a K.sub.i(app) assay. In some embodiments, the biological activity is the serine protease activity of KLK5.

[0021] In some embodiments of any of the antibodies, the antibody is a monoclonal antibody.

[0022] In some embodiments of any of the antibodies, the antibody is a human, humanized, or chimeric antibody.

[0023] In some embodiments of any of the antibodies, the antibody is an antibody fragment that binds KLK5.

[0024] Further provided herein is an antibody that forms a thermodynamic epitope when bound to KLK5 comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0025] Further provided herein is an antibody that competes for binding with any of the antibodies described herein.

[0026] Further provided herein is an antibody that binds to the same epitope as any of the antibodies described herein.

[0027] Further provided herein is an isolated nucleic acid encoding any of the antibodies described herein.

[0028] Further provided herein is a host cell comprising the nucleic acid described herein.

[0029] Further provided herein is a method of producing an antibody comprising culturing the host cell described herein so that the antibody is produced.

[0030] Further provided herein is an immunoconjugate comprising the antibody described herein.

[0031] Further provided herein is a pharmaceutical formulation comprising the antibody described herein and a pharmaceutically acceptable carrier.

[0032] Further provided herein is the antibody as described herein for use as a medicament.

[0033] Further provided herein is the antibody as described herein for use in treating a disease selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0034] Further provided is the antibody as described herein for use in inhibiting the biological activity of KLK5.

[0035] Further provided is the use of the antibody as described herein in the manufacture of a medicament. In some embodiments, the medicament is for treating a disease selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0036] Further provided is the use of the antibody described herein in the manufacture of a medicament for inhibiting the biological activity of KLK5.

[0037] Further provided is a method of treating an individual having a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea comprising administering to the individual an effective amount of the antibody described herein. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is Th2-low asthma.

[0038] Further provided is a method of inhibiting the biological activity of KLK5 in an individual comprising administering to the individual an effective amount of the antibody described herein to inhibit the biological activity of KLK5.

[0039] Further provided herein is an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233 according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, and Lys233 according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225 according to standard protease numbering.

[0040] Further provided herein is an antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5.

BRIEF DESCRIPTION OF THE FIGURES

[0041] FIG. 1A-1N show the evaluation of each of the KLK5 inhibitors using fluorescent peptide substrate in the direct assay. 5 nM recombinant human KLK5 and 0.19-100 nM KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 50 .mu.M Boc-VPR-AMC. Plates were examined every 102 s for 30-60 minute using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. The results for the KLK5 inhibitors are depicted as follows: FIG. 1A: Spink9.SRE.Fc (Spink9), FIG. 1B: mAb1108, FIG. 1C: 3-3F5, FIG. 1D: 1008, FIG. 1E: 9B6, FIG. 1F: 9F2, FIG. 1G: 9H3, FIG. 1H: 9H5, FIG. 1I: 8B7, FIG. 1J: 2B11, FIG. 1K: 8F5, FIG. 1L: 10C5, FIG. 1M: 10H3, and FIG. 1N: 2-3F4.

[0042] FIG. 2A-2N show the evaluation of KLK5 inhibitors in pro-KLK7 coupled assay. 5 nM recombinant human KLK5 and 0.19-100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 125 nM pro-KLK7 and 100 .mu.M suc-LLVY-AMC. After 24 hours, fluorescent readings were made every 102 s for 30-60 min and the RFU endpoint value was calculated by averaging the last 5 readings. The results for the KLK5 inhibitors are depicted as follows: FIG. 2A: Spink9.SRE.Fc, FIG. 2B: mAb1108, FIG. 2C: 3-3F5, FIG. 2D: 1008, FIG. 2E: 9B6, FIG. 2F: 9F2, FIG. 2G: 9H3, FIG. 2H: 9H5, FIG. 2I: 8B7, FIG. 2J: 2B11, FIG. 2K: 8F5, FIG. 2L: 10C5, FIG. 2M: 10H3, and FIG. 2N: 2-3F4.

[0043] FIG. 3A-3N show the evaluation of KLK5 inhibitors in pro-KLK1 coupled assay. 0.5 nM recombinant human KLK5 and 0.019-10 nM KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 31.25 nM pro-KLKland 50 .mu.M PFR-AMC. Plates were examined every 102 s for 120 minute using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. The results for the KLK5 inhibitors are depicted as follows: FIG. 3A: Spink9.SRE.Fc, FIG. 3B: mAb1108, FIG. 3C: 3-3F5, FIG. 3D: 1008, FIG. 3E: 9B6, FIG. 3F: 9F2, FIG. 3G: 9H3, FIG. 3H: 9H5, FIG. 3I: 8B7, FIG. 3J: 2B11, FIG. 3K: 8F5, FIG. 3L: 10C5, FIG. 3M: 10H3, and FIG. 3N: 2-3F4.

[0044] FIG. 4A-4N shows the results of an LC/MS assay measuring the inhibition of proteolysis of pro-KLK7 by recombinant KLK5 by monitoring the KLK5-derived cleavage product peptides. A pre-incubation of SPINK9.SRE.Fc, mAb1108 and the 12 selected antibodies and KLK5 preceded a two-hour incubation of 5 nM KLK5 with 15 nM pro-KLK7. The results for the KLK5 inhibitors are depicted as follows: FIG. 4A: SPINK9.SRE.Fc, FIG. 4B: mAb1108, FIG. 4C: 10C8, FIG. 4D: 9B6, FIG. 4E: 2B11, FIG. 4F: 9F2, FIG. 4G: 2-3F4, FIG. 4H: 10H3, FIG. 4I: 9H3, FIG. 4J: 8B7, FIG. 4K: 8F5, FIG. 4L: 3-3F5, FIG. 4M: 10C5, and FIG. 4N: 9H5.

[0045] FIG. 5A-4N shows the results of an LC/MS assay measuring the inhibition of proteolysis of pro-KLK1 by recombinant KLK5 by monitoring the KLK5-derived cleavage product peptides. A pre-incubation of SPINK9.SRE.Fc, mAb1108 and 12 selected antibodies and KLK5 preceded a 20 minute incubation of 0.5 nM KLK5 with 300 nM pro-KLK1 (FIG. 5A-N). The results for the KLK5 inhibitors are depicted as follows: FIG. 5A: SPINK9.SRE.Fc, FIG. 5B: mAb1108, FIG. 5C: 10C8, FIG. 5D: 9B6, FIG. 5E: 2B11, FIG. 5F: 9F2, FIG. 5G: 2-3F4, FIG. 5H: 10H3, FIG. 5I: 9H3, FIG. 5J: 8B7, FIG. 5K: 8F5, FIG. 5L: 3-3F5, FIG. 5M: 10C5, and FIG. 5N: 9H5.

[0046] FIG. 6A-6N shows the Specificity of KLK5 inhibitors on KLK7 activity. 5 nM recombinant human KLK7 and 0.19-100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 100 .mu.M suc-LLVY-AMC. Plates were examined every 102 s for 75 minutes using a PHERAstar Plus reader using a 340 nm excitation/460 nm emission module. IC.sub.50 values are summarized in Table 6. The results for the KLK5 inhibitors are depicted as follows: FIG. 6A: Spink9.SRE.Fc, FIG. 6B: mAb1108, FIG. 6C: 3-3F5, FIG. 6D: 10C8, FIG. 6E: 9B6, FIG. 6F: 9F2, FIG. 6G: 9H3, FIG. 6H: 9H5, FIG. 6I: 2B11, FIG. 6J: 8B7, FIG. 6K: 8F5, FIG. 6L: 10C5, FIG. 6M: 10H3 and FIG. 6N: 2-3F4.

[0047] FIG. 7A-7N shows the specificity of KLK5 inhibitors on KLK1 activity. 3 nM recombinant human KLK1 and 0.19-100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 100 .mu.M PFR-AMC. Plates were examined every 102 s for 60 minutes using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. IC.sub.50 values are summarized in Table 7. The results for the KLK5 inhibitors are depicted as follows: FIG. 7A: Spink9.SRE.Fc, FIG. 7B: mAb1108, FIG. 7C: 3-3F5, FIG. 7D: 10C8, FIG. 7E: 9B6, FIG. 7F: 9F2, FIG. 7G: 9H3, FIG. 7H: 9H5, FIG. 7I: 8B7, FIG. 7J: 2B11, FIG. 7K: 8F5, FIG. 7L: 10C5, FIG. 7M: 10H3 and FIG. 7N: 2-3F4.

[0048] FIG. 8A-8N shows the specificity of KLK5 inhibitors on KLK4 activity. 2 nM recombinant human KLK4 and 0.19-100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 50 .mu.M Boc-VPR-AMC. Plates were examined every 102 s for 60 minutes using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. IC.sub.50 values are summarized in Table 8. The results for the KLK5 inhibitors are depicted as follows: FIG. 8A: Spink9.SRE.Fc, FIG. 8B: mAb1108, FIG. 8C: 3-3F5, FIG. 8D: 10C8, FIG. 8E: 9B6, FIG. 8F: 9F2, FIG. 8G: 9H3, FIG. 8H: 9H5, FIG. 8I: 8B7, FIG. 8J: 2B11, FIG. 8K: 8F5, FIG. 8L: 10C5, FIG. 8M: 10H3 and FIG. 8N: 2-3F4.

[0049] FIG. 9A-9N shows the specificity of KLK5 inhibitors on Trypsin activity. 0.25 nM trypsin isolated from bovine pancreas and 0.19-100 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 50 .mu.M Boc-VPR-AMC. Plates were examined every 102 s for 60 minutes using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. IC.sub.50 values for selected antibodies (FIG. 9C-N) are summarized in Table 9. The results for the KLK5 inhibitors are depicted as follows: FIG. 9A: Spink9.SRE.Fc, FIG. 9B: mAb1108, FIG. 9C: 3-3F5, FIG. 9D: 10C8, FIG. 9E: 9B6, FIG. 9F: 9F2, FIG. 9G: 9H3, FIG. 9H: 9H5, FIG. 9I: 8B7, FIG. 9J: 2B11, FIG. 9K: 8F5, FIG. 9L: 10C5, FIG. 9M: 10H3 and FIG. 9N: 2-3F4.

[0050] FIG. 10A-10AB shows the analysis of KLK5 inhibitor potency by determination of Ki.sub.app. KLK5 at various concentrations (0.5, 0.25, 0.125, and 0.0625 nM) and 0.0019-10 nM anti-KLK5 inhibitors were pre-incubated for 30 minutes prior to addition of 300 .mu.M Z-VPR-pNA. Plates were read in a Versamax tunable microplate reader with measurements at 405 nm taken every 102 seconds for 3 hours. The derived Ki.sub.app values are summarized in Table 10. The results for the KLK5 inhibitors are depicted as follows (respective left panels show IC.sub.50 values of KLK5 inhibitors at various KLK5 concentrations (0.5, 0.25, 0.125, and 0.0625 nM); respective right panels show IC.sub.50 values determined and plotted as a function of KLK5 concentration): FIG. 10A and FIG. 10B: Spink9.SRE.Fc, FIG. 10C and FIG. 10D: mAb1108, FIG. 10E and FIG. 10F: 3-3F5, FIG. 10G and FIG. 10H: 10C8, FIG. 10I and FIG. 10J: 9B6, FIG. 10K and FIG. 10L: 9F2, FIG. 10M and FIG. 10N: 9H3, FIG. 10O and FIG. 10P: 9H5, FIG. 10Q and FIG. 10R: 8B7, FIG. 10S and FIG. 10T: 2B11, FIG. 10U and FIG. 10V: 8F5, FIG. 10W and FIG. 10X: 10C5, FIG. 10Y and FIG. 10Z: 10H3, FIG. 10AA and FIG. 10AB: 2-3F4.

[0051] FIG. 11 shows a table summarizing the IC.sub.50 values as evaluated and shown in FIGS. 1-10.

[0052] FIGS. 12A and 12B. FIG. 12A shows sequence regions that are identified by hydrogen exchange measurements to be affected when in complex with each antibody, these sequence regions (underlined) are: region 1 (56-68, pH.sub.exp 8.0), region 2 (107-124, pH.sub.exp 6.0), region 3 (184-195, pH.sub.exp 8.0), region 4 (232-246, pH.sub.exp 6.0), effective time correction uses pH.sub.ref=7.5. FIG. 12B shows the actual hydrogen exchange data for a representative peptide for each sequence region underlined in FIG. 12A.

[0053] FIGS. 13A and 13B. FIG. 13A shows alignment of the light chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 1008, 8F5, 3-3F5, 9E3, 10D10, 12B3, 1D10. FIG. 13B shows alignment of the heavy chain variable sequences of anti-KLK5 antibody clones 14C8, 14E12, 8E11, 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 1008, 8F5, 3-3F5, 9E3, 10D10, 12B3, 1D10. Shown are also the CDR regions according to Kabat numbering.

[0054] FIGS. 14A and 14B. FIG. 14A shows alignment of the light chain variable sequences of the anti-KLK5 antibody clone 10C5 and six humanized 10C5 clones. FIG. 14B shows alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 10C5 and 28 humanized 10C5 clones. The amino acid residues highlighted in black are the residues which were changed. Shown are also the CDR regions according to Kabat numbering.

[0055] FIGS. 15A and 15B. FIG. 15A shows alignment of the light chain variable sequences of the anti-KLK5 antibody clone 9H5 and four humanized 9H5 clones. FIG. 15B shows alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 9H5 and 17 humanized 9H5 clones. The amino acid residues highlighted in black are the residues which were changed. Shown are also the CDR regions according to Kabat numbering.

[0056] FIGS. 16A and 16B. FIG. 16A shows alignment of the light chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and five humanized 3-3F5 clones. FIG. 16B shows alignment of the heavy chain variable sequences of the anti-KLK5 antibody clone 3-3F5 and 27 humanized 3-3F5 clones. The amino acid residues highlighted in black are the residues which were changed. Shown are also the CDR regions according to Kabat numbering.

[0057] FIG. 17 shows the evaluation of KLK5 inhibitors in the A549 cell-based IL-8 secretion assay. The KLK5-induced IL-8 secretion level (gray star) was set at 100% residual activity while the buffer (starvation media) alone (gray circle) was set at 0% residual activity. Dose response curves are shown for Spink5.Fc (black circle and dotted black line), humanized 3.3F5 (black diamond and solid black line) anti-KLK5 antibody, humanized 9H5 anti-KLK5 antibody (open gray square and solid gray line), and humanized 10C5 anti-KLK5 antibody (black open circle and dotted gray line). The data shown are the mean.+-.standard deviation of at least three independent experiments.

[0058] FIGS. 18A and 18B. FIG. 18A shows an overlay of human KLK5 with KLK5-10C5 Fab complex. FIG. 18B shows the interface between human KLK5 and 10C5 Fab. The numbering of the amino acid residues of human KLK5 is based on the standard numbering for proteases. See Debela et al., J Mol Biol, 373, 1017-1031 (2007). The numbering of the amino acid residues of the Fab fragments is based on Kabat.

[0059] FIGS. 19A and 19B. FIG. 19A shows an overlay of human KLK5 with KLK5-9H5 Fab complex. FIG. 19B shows the interface between human KLK5 and 9H5 Fab. The numbering of the amino acid residues of human KLK5 is based on the standard numbering for proteases. The numbering of the amino acid residues of the Fab fragments is based on Kabat.

[0060] FIGS. 20A and 20B. FIG. 20A shows an overlay of human KLK5 with KLK5-3-3F5 Fab complex. FIG. 20B shows the interface between human KLK5 and 3-3F5 Fab. The numbering of the amino acid residues of human KLK5 is based on the standard numbering for proteases. The numbering of the amino acid residues of the Fab fragments is based on Kabat.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

I. Definitions

[0061] The terms "anti-KLK5 antibody" and "an antibody that binds to KLK5" refer to an antibody that is capable of binding KLK5 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting KLK5. In some embodiments, the extent of binding of an anti-KLK5 antibody to an unrelated polypeptide (polypeptide other than KLK5) is less than about 10% of the binding of the antibody to KLK5 as measured, e.g., by a radioimmunoassay (RIA). In some embodiments, an antibody that binds to KLK5 has a dissociation constant (Kd) of .ltoreq.1 .mu.M, .ltoreq.100 nM, .ltoreq.10 nM, .ltoreq.1 nM, .ltoreq.0.1 nM, .ltoreq.0.01 nM, or .ltoreq.0.001 nM (e.g., 10.sup.-8M or less, e.g., from 10.sup.-8 M to 10.sup.-13 M, e.g., from 10.sup.-9M to 10.sup.-13 M). In some embodiments, an antibody that binds to KLK5 has an IC.sub.50 value (concentration of an inhibitor, e.g. an antibody or fragment thereof, required to reduce the rate of an enzymatic reaction by 50%) of .ltoreq.1 .mu.M, .ltoreq.100 nM, .ltoreq.10 nM, .ltoreq.1 nM, .ltoreq.0.1 nM, .ltoreq.0.01 nM, or .ltoreq.0.001 nM (e.g., 10.sup.-8 M or less, e.g., from 10.sup.-8M to 10.sup.-13M, e.g., from 10.sup.-9 M to 10.sup.-13 M). In some embodiments, an anti-KLK5 antibody binds to a binding region (e.g. an epitope) of KLK5 that is conserved among different species of KLK polypeptides.

[0062] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0063] The term "isolated" as used in reference to antibody, binding polypeptide, polynucleotide or small molecule is one which has been separated from a component of its natural environment. In some embodiments, an antibody, binding polypeptide, polynucleotide or small molecule is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0064] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same binding region (e.g., epitope), except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies described herein may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies.

[0065] A "blocking antibody" or an "antagonist antibody" is one which inhibits or reduces biological activity of the antigen it binds. Preferred blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

[0066] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

[0067] The terms "full length antibody," "intact antibody," and "whole antibody" are used herein interchangeably to refer to an antibody (e.g., an anti-KLK5 antibody) having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region.

[0068] A "human antibody" is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

[0069] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In some embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0070] "Native antibodies" refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (.kappa.) and lambda (.lamda.), based on the amino acid sequence of its constant domain.

[0071] The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called .alpha., .delta., .epsilon., .gamma., and .mu., respectively.

[0072] An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab').sub.2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multi specific antibodies formed from antibody fragments.

[0073] An "antibody that binds to the same epitope" or an "antibody that binds to the same binding region" as a reference antibody refers to an antibody that blocks binding of the reference antibody to its binding partner (e.g., an antigen) in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its binding partner in a competition assay by 50% or more.

[0074] The term "thermodynamic epitope", e.g. in the context of epitope mapping using hydrogen exchange mass spectrometry, refers to those portions of a protein whose backbone structural dynamics or local free energy of unfolding is altered in response to a specific binding event such as becoming bound by an antibody. The structural epitope may or may not be partially or entirely contained within the thermodynamic epitope.

[0075] The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence ("complementarity determining regions" or "CDRs") and/or form structurally defined loops ("hypervariable loops") and/or contain the antigen-contacting residues ("antigen contacts"). Generally, antibodies comprise six HVRs: three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). Exemplary HVRs herein include:

[0076] (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

[0077] (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991));

[0078] (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); and

[0079] (d) combinations of (a), (b), and/or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

[0080] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra, e.g. as set out in FIGS. 13-16 as well as in the Table of Sequences herein below. Unless otherwise indicated, the CDRs are determined according to Kabat et al., supra.

[0081] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6.sup.th ed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0082] The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0083] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0084] An "acceptor human framework" for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0085] A "human consensus framework" is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), vols. 1-3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra.

[0086] "Affinity" or "Binding Affinity" refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., antibody, binding polypeptide, polynucleotide, small molecule) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., either of antibody, binding polypeptide, polynucleotide, small molecule and the antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.

[0087] An "affinity matured" antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.

[0088] A "binding region" is the portion of the binding partner (e.g., an antigen) to which a KLK5 antibody selectively binds. For a binding polypeptide binding partner, a linear binding region can be a peptide portion of about 4-15 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) amino acid residues. A non-linear, conformational binding region may comprise residues of a polypeptide sequence brought to close vicinity in the three-dimensional (3D) structure of the binding polypeptide binding partner.

[0089] "Effector functions" refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.

[0090] The terms "KLK5" and "Kallikrein-5," as used herein, refers to any native KLK5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length," unprocessed KLK5 as well as any form of KLK5 that results from processing in the cell. The term also encompasses naturally occurring variants of KLK5, e.g., splice variants or allelic variants. In some embodiments, the amino acid sequence of an exemplary human KLK5 is UNIPROT Q9Y337. In some embodiments, the amino acid sequence of an exemplary human KLK5 is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus signal peptide) of UNIPROT Q9Y337 (G55, D153 variant) and is shown in SEQ ID NO:2. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus signal peptide) of the G55, N153 variant shown in SEQ ID NO:4. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus signal peptide) of the R55, N153 variant shown in SEQ ID NO:6. In some embodiments, the amino acid sequence of an exemplary human KLK5 is amino acid residues 23-293 (minus signal peptide) of the R55, D153 variant shown in SEQ ID NO:8.

[0091] The numbering in this paragraph below, relates to full-length unprocessed KLK5. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid N at position 153. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid D at position 153. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid G at position 55. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid R at position 55. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid G at position 55 and the amino acid N at position 153. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid G at position 55 and the amino acid D at position 153. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid R at position 55 and the amino acid N at position 153. In some embodiments, the amino acid sequence of the human KLK5 comprises the amino acid R at position 55 and the amino acid D at position 153.

[0092] The numbering in this paragraph below, relates to full-length unprocessed KLK5. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding an N at position 153. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding a D at position 153. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding a G at position 55. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding an R at position 55. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding a G at position 55 and an N at position 153. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding G at position 55 and a D at position 153. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding R at position 55 and an N at position 153. In some embodiments, the nucleic acid sequence of the human KLK5 comprises a sequence encoding an R at position 55 and a D at position 153.

[0093] The terms "SPINK5" and "Serine protease inhibitor Kazal-type 5," as used herein, refers to any native SPINK5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length," unprocessed SPINK5 as well as any form of SPINK5 that result from processing in the cell. The term also encompasses naturally occurring variants of SPINK5, e.g., splice variants or allelic variants. In some embodiments, the amino acid sequence of an exemplary human SPINK5 is UNIPROT Q9NQ38 and is shown in SEQ ID NO:9. In some embodiments, the amino acid sequence of an exemplary human SPINK5 is amino acid residues 23-1064 (minus signal peptide) of UNIPROT Q9NQ38 and is shown in SEQ ID NO:10.

[0094] The term "SPINK fusion polypeptide" as used herein refers to a fusion polypeptide in which a SPINK polypeptide or a fragment thereof (e.g., certain domains of the SPINK polypeptide (e.g., SPINK5 and/or SPINK9) is linked, directly or indirectly, to another polypeptide (e.g., non-SPINK polypeptide).

[0095] The term "SPINK Fc fusion polypeptide" as used herein refers to a fusion polypeptide in which a SPINK polypeptide or a fragment thereof (e.g., certain domains of the SPINK polypeptide (e.g., SPINK5 and/or SPINK9) is linked, directly or indirectly, to an Fc region. In some embodiments, the Fc region is selected from the group consisting of an IgG1 Fc region, IgG2a Fc region and IgG4 Fc region. In some embodiments, the Fc region is an IgG2a Fc region. In some embodiments, the IgG2a Fc region is a mouse IgG2a Fc region. In some embodiments, the Fc region is an IgG1 Fc region. In some embodiments, the IgG1 Fc region is a human IgG1 Fc region. In some embodiments, the Fc region is an IgG4 Fc region. In some embodiments, the IgG4 Fc region is a human IgG4 Fc region. In some embodiments, the SPINK polypeptide or a fragment thereof is a human SPINK polypeptide or a fragment thereof. In some embodiments, the SPINK polypeptide or a fragment thereof is a mouse SPINK polypeptide or a fragment thereof. It is understood that minor sequence variations such as insertions, deletions, substitutions, especially conservative amino acid substitutions of the SPINK polypeptide, the SPINK domains or the Fc that do not affect the function and/or activity of the SPINK polypeptide, the SPINK domains or the SPINK Fc fusion polypeptide are provided herein. In some embodiments, the SPINK Fc fusion polypeptide provided herein can bind to KLK5, which can lead to inhibition of KLK5. In some embodiments, the SPINK polypeptide or a fragment thereof is SPINK 9. In some embodiments, the SPINK Fc fusion polypeptide is SPINK9.SRE.Fc (SEQ ID NO:320).

[0096] The term "polypeptide" as used herein, refers to any native polypeptide of interest (e.g., KLK5, or SPINK5) from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length," unprocessed polypeptide as well as any form of the polypeptide that results from processing in the cell. The term also encompasses naturally occurring variants of the polypeptide, e.g., splice variants or allelic variants.

[0097] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0098] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0099] "Polynucleotide," or "nucleic acid," as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, .alpha.-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), "(O)NR.sub.2 ("amidate"), P(O)R, P(O)OR', CO or CH.sub.2 ("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (--O--) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

[0100] An "isolated" polynucleotide or nucleic acid refers to a molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0101] "Isolated nucleic acid encoding an anti-KLK5 antibody" refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.

[0102] The term "KLK5 genomic sequence" as used herein, refers to either the cDNA and/or the genomic form of the KLK5 gene, which may include introns as well as upstream and downstream regulatory sequences.

[0103] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0104] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0105] A "reference sample", "reference cell", "reference tissue", "control sample", "control cell", or "control tissue", as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject. For example, healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of another subject. In even another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of another subject.

[0106] The term "sample," as used herein, refers to a formulation that is obtained or derived from a subject of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics. For example, the phrase "disease sample" and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, perspiration, mucus, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cellular extracts, and combinations thereof.

[0107] By "tissue sample" or "cell sample" is meant a collection of similar cells obtained from a tissue of a subject. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a disease tissue/organ. The tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.

[0108] An "effective amount" of an agent, e.g., a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.

[0109] A "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the subject is a human.

[0110] The term "patient" as used herein, refers to an animal, such as a mammal. In one embodiment, patient refers to a human.

[0111] The term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0112] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0113] The term "Th2-high asthma" as used herein, refers to asthma that exhibits high levels of one or more Th2 cell-related cytokines, for example, IL13, IL4, IL9, IL5, or that exhibits Th2 cytokine-associated inflammation. In some embodiments, the term Th2-high asthma may be used interchangeably with eosinophil-high asthma. In some embodiments, the Th2-high asthma is Th2 driven asthma. In some embodiments, the asthma patient has been determined to be Eosinophilic Inflammation Positive (EIP). See, e.g., International Patent Application Publication No. WO 2015/061441, which is incorporated by reference herein in its entirety. In some embodiments, the subject has been determined to have elevated levels of at least one of the eosinophilic signature genes as compared to a control or reference level. See WO2015/061441. In some embodiments, the Th2-high asthma is periostin-high asthma. In some embodiments, the subject has high serum periostin. In some embodiments, the subject is eighteen years or older. In some embodiments, the subject has been determined to have an elevated level of serum periostin as compared to a control or reference level. In some embodiments, the control or reference level is the median level of periostin in a population. In some embodiments, the subject has been determined to have 20 ng/ml or higher serum periostin. In some embodiments, the subject has been determined to have 25 ng/ml or higher serum periostin. In some embodiments, the subject has been determined to have 50 ng/ml or higher serum periostin. In some embodiments, the control or reference level of serum periostin is 20 ng/ml, 25 ng/ml, or 50 ng/ml. In some embodiments, the asthma is eosinophil-high asthma. In some embodiments, the subject has been determined to have an elevated eosinophil count as compared to a control or reference level. In some embodiments, the control or reference level is the median level of a population. In some embodiments, the subject has been determined to have 150 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 200 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 250 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 300 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 350 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 400 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 450 or higher eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have 500 or higher eosinophil count/.mu.l blood. In some preferred embodiments, the subject has been determined to have 300 or higher eosinophil count/.mu.l blood. In some embodiments, the eosinophils are peripheral blood eosinophils. In some embodiments, the eosinophils are sputum eosinophils. In some embodiments, the subject exhibits elevated level of FeNO (fractional exhaled nitric acid) and/or elevated level of IgE. For example, in some instances, the subject exhibits a FeNO level above any of about 5 ppb (parts per billion), 10 ppb, 15 ppb, 20 ppb, 25 ppb, 30 ppb, 35 ppb, 40 ppb, 45 ppb, 50 ppb, 60 ppb, 70 ppb, 80 ppb, 90 ppb and 100 ppb. In some instances, the subject has an IgE level that is above 50 IU/ml.

[0114] The term "Th2-low asthma", "non-Th2-high asthma", "type 2-low asthma", "T2-low asthma", "non-eosinophilic asthma", pauci-granulocytic asthma", or "pauci-inflammatory asthma", as used herein, refers to asthma that exhibits low levels of one or more Th2 cell-related cytokines, for example, IL13, IL4, IL9, IL5, or exhibits non-Th2 cytokine-associated inflammation. In some embodiments, the term Th2-low asthma may be used interchangeably with eosinophil-low asthma. In some embodiments, the asthma patient has been determined to be Eosinophilic Inflammation Negative (EIN). See, e.g., WO 2015/061441. In some embodiments, the Th2-low asthma is Th17-driven asthma. In some embodiments, the Th2-low asthma is periostin-low asthma. In some embodiments, the subject is eighteen years or older. In some embodiments, the subject has been determined to have a reduced level of serum periostin as compared to a control or reference level. In some embodiments, the control or reference level is the median level of periostin in a population. In some embodiments, the subject has been determined to have less than 20 ng/ml serum periostin. In some embodiments, the asthma is eosinophil-low asthma. In some embodiments, the subject has been determined to have a reduced eosinophil count as compared to a control or reference level. In some embodiments, the control or reference level is the medium level of a population. In some embodiments, the subject has been determined to have less than 150 eosinophil count/.mu.l blood. In some embodiments, the subject has been determined to have less than 100 eosinophil count/.mu.l blood. In certain preferred embodiments, the subject has been determined to have less than 300 eosinophil count/.mu.l blood.

[0115] "Treatment" (and variations such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the subject or cell being treated. Desirable effects of treatment include one or more of preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and improved prognosis.

[0116] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.

[0117] The use of the terms "a" and "an" and "the" and similar terms in the context of describing embodiments herein are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. It is understood that aspects and embodiments provided herein include "consisting" and/or "consisting essentially of" aspects and embodiments.

[0118] As is understood by one skilled in the art, reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0119] The phrase "substantially different," refers to a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference/comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values (e.g., Kd values). The difference between said two values may be, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and/or greater than about 50% as a function of the value for the reference/comparator molecule.

II. Compositions and Methods

[0120] In one aspect, the invention is based, in part, on the discovery of KLK5 antibodies that inhibit the biological activity of KLK5. In some embodiments, antibodies that bind to KLK5 are provided. In some embodiments, an isolated antibody that binds to KLK5 is provided, i.e. an anti-KLK5 antibody. In some embodiments, the anti-KLK5 antibody inhibits the biological activity of KLK5. In some embodiments, the anti-KLK5 antibody substantially or completely inhibits the biological activity of KLK5. In some embodiments, the biological activity of KLK5 is serine protease activity. In some embodiments, the biological activity of KLK5 is tryptic-like serine protease activity. In some embodiments, the biological activity of KLK5 is KLK5 promoted human smooth muscle cell proliferation and contraction. In some embodiments, the biological activity of KLK5 is KLK5 induced epithelial expression of inflammatory cytokines, chemokines, and adhesion molecules. In some embodiments, the biological activity of KLK5 is KLK5 induced epithelium production of neutrophil chemotactic cytokines and neutrophil influx into the lung tissues. In some embodiments, the biological activity of KLK5 is inhibited by at least about any of 40%, 50%, 60%, 70%, 80%, 90% and/or more. In some embodiments, the biological activity of the KLK5 is inhibited by about any of 40%, 50%, 60%, 70%, 80%, 90% and/or more. In some embodiments, the biological activity of the KLK5 is inhibited by between any of 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, and/or 90-100%.

[0121] In some embodiments of any of the anti-KLK5 antibodies, the anti-KLK5 antibody substantially or completely inhibits binding of SPINK5 to KLK5. In some embodiments, binding of SPINK5 to KLK5 is inhibited by at least about any of 40%, 50%, 60%, 70%, 80%, 90% and/or more. In some embodiments, binding of SPINK5 to KLK5 is inhibited by about any of 40%, 50%, 60%, 70%, 80%, 90% and/or more. In some embodiments, binding of SPINK5 to KLK5 is inhibited by between any of 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, and/or 90-100%.

[0122] In some embodiments of any of the anti-KLK5 antibodies, the anti-KLK5 antibody has an IC.sub.50 value of less than about any of 1000 nM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 100 pM, 50 pM, 10 pM, 5 pM, and/or 1 pM. In some embodiments, the anti-KLK5 antibody has an IC.sub.50 value of less than any of 1000 nM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 100 pM, 50 pM, 10 pM, 5 pM, and/or 1 pM. In some embodiments, the anti-KLK5 antibody has an IC.sub.50 value of between about any of 50 .mu.M-1 .mu.M, 1-500 nM, 500 nM-100 nM, 100 nM-10 nM, 10 nM-1 nM, 1000 pM-500 pM, 500 pM-200 pM, 200 pM-150 pM, 150 pM-100 pM, 100 pM-10 pM, and/or 10 pM-1 pM.

[0123] Antibodies provided herein are useful, e.g., for the diagnosis or treatment of disease selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is persistent chronic severe asthma with acute events of worsening symptoms (exacerbations or flares) that can be life threatening. In some embodiments, the asthma is atopic (also known as allergic) asthma, non-allergic asthma (e.g., often triggered by infection with a respiratory virus (e.g., influenza, parainfluenza, rhinovirus, human metapneumovirus, and respiratory syncytial virus) or inhaled irritant (air pollutants, smog, diesel particles, volatile chemicals and gases indoors or outdoors, or even by cold dry air). In some embodiments, the asthma is intermittent or exercise-induced, asthma due to acute or chronic primary or second-hand exposure to "smoke" (typically cigarettes, cigars, pipes), inhaling or "vaping" (tobacco, marijuana or other such substances), or asthma triggered by recent ingestion of aspirin or related NSAIDS. In some embodiments, the asthma is mild, or corticosteroid naive asthma, newly diagnosed and untreated asthma, or not previously requiring chronic use of inhaled topical or systemic steroids to control the symptoms (cough, wheeze, shortness of breath/breathlessness, or chest pain). In some embodiments, the asthma is chronic, corticosteroid resistant asthma, corticosteroid refractory asthma, asthma uncontrolled on corticosteroids or other chronic asthma controller medications. In some embodiments, the asthma is moderate to severe asthma. In some embodiments, the asthma is Th2-high asthma. In some embodiments, the asthma is severe asthma. In some embodiments, the asthma is atopic asthma, allergic asthma, non-allergic asthma (e.g., due to infection and/or respiratory syncytial virus (RSV)), exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids. In some embodiments, the asthma is T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma. In some embodiments, the asthma is eosinophilic asthma. In some embodiments, the asthma is allergic asthma. In some embodiments, the subject has been determined to be Eosinophilic Inflammation Positive (EIP). See WO2015/061441. In some embodiments, the asthma is periostin-high asthma (e.g., having periostin level at least about any of 20 ng/mL, 25 ng/mL, or 50 ng/mL serum). In some embodiments, the asthma is eosinophil-high asthma (e.g., at least about any of 150, 200, 250, 300, 350, 400 eosinophil counts/ml blood). In some embodiments, the asthma is Th2-low asthma or nonTh2-driven asthma. In some embodiments, the subject has been determined to be Eosinophilic Inflammation Negative (EIN). See WO2015/061441. In some embodiments, the asthma is periostin-low asthma (e.g., having periostin level less than about 20 ng/mL serum). In some embodiments, the asthma is eosinophil-low asthma (e.g., less than about 150 eosinophil counts/.mu.l blood or less than about 100 eosinophil counts/.mu.l blood).

[0124] A. Exemplary Anti-KLK5 Antibodies

[0125] Provided herein are isolated antibodies that bind to KLK5. In one embodiment, the antibody inhibits the biological activity of KLK5 by at least 50%. KLK5 is a (chymo)-trypsin-like serine proteases that is expressed in human skin, specifically in the upper spinous and granular layers of the skin. KLK5 is known to play pathological roles in skin disorders such as Netherton Syndrome.

[0126] An exemplary naturally occurring human KLK5 precursor protein sequence, with signal peptide (amino acids 1-22) is provided in SEQ ID NO:1. The corresponding mature KLK5 protein sequence corresponding to amino acids 23-293 of SEQ ID NO:1 is provided in SEQ ID NO:2. Exemplary variants of human KLK5 precursor proteins with signal peptides containing either one or both of the amino acid exchanges R55 and N153 are provided in SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, respectively.

[0127] In certain embodiments, an anti-KLK5 antibody has one or more of the following characteristics, in any combination:

[0128] a) inhibits the biological activity of KLK5 by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%;

[0129] b) inhibits the serine protease activity of KLK5;

[0130] c) binds specifically to human KLK5;

[0131] d) has an IC.sub.50 value of less than 10 nM, less than 5 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM; and/or

[0132] e) has an IC.sub.50 value of less than 500 pM, less than 200 pM, less than 100 pM, less than 50 pM, less than 25 pM, less than 10 pM, less than 5 pM, less than 1 pM.

[0133] Antibody 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 1008, 8F5, 3-3F5 and Other Embodiments

[0134] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence selected from any one of SEQ ID NOs:14-24; (b) HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53; (c) HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72; (d) HVR-L1 comprising the amino acid sequence selected from any one of SEQ ID NOs:79-91; (e) HVR-L2 comprising the amino acid sequence selected from any one of SEQ ID NOs:99-106; and (f) HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122.

[0135] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence selected from any one of SEQ ID NOs:14-24; (b) HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53; (c) HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72 and HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72, HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122, and HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence selected from any one of SEQ ID NOs:14-24; (b) HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53; and (c) HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72.

[0136] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence selected from any one of SEQ ID NOs:79-91; (b) HVR-L2 comprising the amino acid sequence selected from any one of SEQ ID NOs:99-106; and (c) HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence selected from any one of SEQ ID NOs:79-91; (b) HVR-L2 comprising the amino acid sequence selected from any one of SEQ ID NOs:99-106; and (c) HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122.

[0137] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence selected from any one of SEQ ID NOs:14-24, (ii) HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53, and (iii) HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence selected from any one of SEQ ID NOs:79-91, (ii) HVR-L2 comprising the amino acid sequence selected from any one of SEQ ID NOs:99-106, and (c) HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122.

[0138] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence selected from any one of SEQ ID NOs:14-24; (b) HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53; (c) HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72; (d) HVR-L1 comprising the amino acid sequence selected from any one of SEQ ID NOs:79-91; (e) HVR-L2 comprising the amino acid sequence selected from any one of SEQ ID NOs:99-106; and (f) HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122.

[0139] In any of the above embodiments, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0140] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence selected from any one of SEQ ID NO:170-257. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence selected from any one of SEQ ID NO:170-257 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in any one of SEQ ID NO:170-257. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence selected from any one of SEQ ID NO:170-257, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence selected from any one of SEQ ID NOs:14-24; (b) HVR-H2 comprising the amino acid sequence selected from any one of SEQ ID NOs:32-53; (c) HVR-H3 comprising the amino acid sequence selected from any one of SEQ ID NOs:62-72.

[0141] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence selected from any one of SEQ ID NO:131-161. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence selected from any one of SEQ ID NO:131-162 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in the amino acid sequence selected from any one of SEQ ID NO:131-162. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence of the amino acid sequence selected from any one of SEQ ID NO:131-162, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence selected from any one of SEQ ID NOs:79-91; (b) HVR-L2 comprising the amino acid sequence selected from any one of SEQ ID NOs:99-106; and (c) HVR-L3 comprising the amino acid sequence selected from any one of SEQ ID NOs:112-122.

[0142] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:170 and SEQ ID NO:131, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:171 and SEQ ID NO:132, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:172 and SEQ ID NO:133, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:201 and SEQ ID NO:139, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:203 and SEQ ID NO:141, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:204 and SEQ ID NO:142, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:205 and SEQ ID NO:143, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:206 and SEQ ID NO:144, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:221 and SEQ ID NO:149, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:226 and SEQ ID NO:152, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:227 and SEQ ID NO:153, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:228 and SEQ ID NO:154, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:248 and SEQ ID NO:160, respectively, including post-translational modifications of those sequences.

[0143] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of the amino acid sequence selected from any one of SEQ ID NO:170-257. In certain embodiments, an antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0144] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a HC sequence of the amino acid sequence selected from any one of SEQ ID NO:288-306. In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a LC sequence of the amino acid sequence selected from any one of SEQ ID NO:265-280.

[0145] In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:288 and SEQ ID NO:265, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:289 and SEQ ID NO:266, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:290 and SEQ ID NO:267, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:292 and SEQ ID NO:269, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:293 and SEQ ID NO:269, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:294 and SEQ ID NO:270, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:295 and SEQ ID NO:271, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:296 and SEQ ID NO:272, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:297 and SEQ ID NO:273, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:299 and SEQ ID NO:275, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:300 and SEQ ID NO:275, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:301 and SEQ ID NO:276, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:302 and SEQ ID NO:277, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:303 and SEQ ID NO:278, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:305 and SEQ ID NO:280, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the HC and LC sequences in SEQ ID NO:306 and SEQ ID NO:280, respectively, including post-translational modifications of those sequences.

[0146] Provided herein are antibodies comprising a light chain variable domain comprising the HVR1-LC, HVR2-LC and HVR3-LC sequence according to Kabat numbering as depicted in FIGS. 14A, 15A and/or 16A and a heavy chain variable domain comprising the HVR1-HC, HVR2-HC and HVR3-HC sequence according to Kabat numbering as depicted in FIGS. 14B, 15B and/or 16B. In some embodiments, the antibody comprises a light chain variable domain comprising the HVR1-LC, HVR2-LC and/or HVR3-LC sequence, and the FR1-LC, FR2-LC, FR3-LC and/or FR4-LC sequence as depicted in FIGS. 14A, 15A and/or 16A. In some embodiments, the antibody comprises a heavy chain variable domain comprising the HVR1-HC, HVR2-HC and/or HVR3-HC sequence, and the FR1-HC, FR2-HC, FR3-HC and/or FR4-HC sequence as depicted in FIGS. 14B, 15B and/or 16B.

[0147] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein.

[0148] In a further aspect, an anti-KLK5 antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0149] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework. In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab').sub.2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0150] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0151] Antibody 10C5, 9H5, 3-3F5 and Other Embodiments

[0152] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:28; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:45, or SEQ ID NO:54; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:96; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:109; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:127.

[0153] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, SEQ ID NO:22, or SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, SEQ ID NO:87, or SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:101, or SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115, SEQ ID NO:119, or SEQ ID NO:122.

[0154] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, SEQ ID NO:22, or SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:115, SEQ ID NO:119, or SEQ ID NO:122. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72, HVR-L3 comprising the amino acid sequence of SEQ ID NO:115, SEQ ID NO:119, or SEQ ID NO:122, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, SEQ ID NO:22, or SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, SEQ ID NO:69, or SEQ ID NO:72.

[0155] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, SEQ ID NO:87, or SEQ ID NO:91; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99, SEQ ID NO:101, or SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115, SEQ ID NO:119, or SEQ ID NO:122.

[0156] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0157] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0158] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0159] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0160] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0161] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0162] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having SEQ ID NO:202. In another aspect, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence having SEQ ID NO:140.

[0163] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence selected from any one of SEQ ID NOs:173-201. In another aspect, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence selected from any one of SEQ ID NOs:134-139 and SEQ ID NO:321.

[0164] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:201. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:201. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:201, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65.

[0165] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:139. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:139. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:139, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0166] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:201 and SEQ ID NO:139, respectively, including post-translational modifications of those sequences.

[0167] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:201 and a VL sequence of SEQ ID NO:139. In certain embodiments, an antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0168] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having SEQ ID NO:225. In another aspect, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence having SEQ ID NO:151.

[0169] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence selected from any one of SEQ ID NOs:207-224. In another aspect, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence selected from any one of SEQ ID NOs:145-150.

[0170] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:221. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:221. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:221, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0171] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:149. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:149. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:149, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0172] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:221 and SEQ ID NO:149, respectively, including post-translational modifications of those sequences.

[0173] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:221 and a VL sequence of SEQ ID NO:149. In certain embodiments, an antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0174] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having SEQ ID NO:257. In another aspect, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence having SEQ ID NO:162.

[0175] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence selected from any one of SEQ ID NOs:229-256. In another aspect, an anti-KLK5 antibody is provided comprising a light chain variable domain (VL) sequence selected from any one of SEQ ID NOs:155-161.

[0176] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:248. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:248. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:248, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72.

[0177] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:160. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:160. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:160, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0178] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:248 and SEQ ID NO:160, respectively, including post-translational modifications of those sequences.

[0179] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:248 and a VL sequence of SEQ ID NO:160.

[0180] Provided herein are antibodies comprising a light chain variable domain comprising the HVR1-LC, HVR2-LC and HVR3-LC sequence according to Kabat numbering as depicted in FIGS. 14A, 15A and/or 16A and a heavy chain variable domain comprising the HVR1-HC, HVR2-HC and HVR3-HC sequence according to Kabat numbering as depicted in FIGS. 14B, 15B and/or 16B. In some embodiments, the antibody comprises a light chain variable domain comprising the HVR1-LC, HVR2-LC and/or HVR3-LC sequence, and the FR1-LC, FR2-LC, FR3-LC and/or FR4-LC sequence as depicted in FIGS. 14A, 15A and/or 16A. In some embodiments, the antibody comprises a heavy chain variable domain comprising the HVR1-HC, HVR2-HC and/or HVR3-HC sequence, and the FR1-HC, FR2-HC, FR3-HC and/or FR4-HC sequence as depicted in FIGS. 14B, 15B and/or 16B.

[0181] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0182] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0183] Further provided herein is an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233 according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, and Lys233 according to standard protease numbering. In some embodiments, the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225 according to standard protease numbering.

[0184] Further provided herein is an antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5.

[0185] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0186] Antibody 8G10 and Other Embodiments

[0187] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112.

[0188] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:62. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:62 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:112. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:62, HVR-L3 comprising the amino acid sequence of SEQ ID NO:112, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:32. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62.

[0189] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112.

[0190] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112.

[0191] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112.

[0192] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:170. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:170. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:170, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62.

[0193] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:131. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:131. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:131, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112.

[0194] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:170 and SEQ ID NO:131, respectively, including post-translational modifications of those sequences.

[0195] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:170 and a VL sequence of SEQ ID NO:131.

[0196] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0197] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0198] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0199] Antibody 9B6 and Other Embodiments

[0200] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113.

[0201] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:63. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:63 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:113. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:63, HVR-L3 comprising the amino acid sequence of SEQ ID NO:113, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:33. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63.

[0202] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113.

[0203] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113.

[0204] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113.

[0205] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:171. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:171. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:171, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63.

[0206] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:132. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:132. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:132, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113.

[0207] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:171 and SEQ ID NO:132, respectively, including post-translational modifications of those sequences.

[0208] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:171 and a VL sequence of SEQ ID NO:132.

[0209] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0210] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0211] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0212] Antibody 2-3F4 and Other Embodiments

[0213] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114.

[0214] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:64. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:64 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:114. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:64, HVR-L3 comprising the amino acid sequence of SEQ ID NO:114, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:34. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64.

[0215] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114.

[0216] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114.

[0217] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114.

[0218] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:172. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:172. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:172, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64.

[0219] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:133. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:133. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:133, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114.

[0220] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:172 and SEQ ID NO:133, respectively, including post-translational modifications of those sequences.

[0221] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:172 and a VL sequence of SEQ ID NO:133.

[0222] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0223] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0224] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0225] Antibody 10C5 and Other Embodiments

[0226] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0227] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:65. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:65 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:115. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:65, HVR-L3 comprising the amino acid sequence of SEQ ID NO:115, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:35. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65.

[0228] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0229] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0230] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0231] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:201. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:201. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:201, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65.

[0232] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:139. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:139. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:139, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115.

[0233] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:201 and SEQ ID NO:139, respectively, including post-translational modifications of those sequences.

[0234] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:201 and a VL sequence of SEQ ID NO:139. In certain embodiments, an antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0235] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0236] In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) a heavy chain frame work region 1 (HC-FR1) of SEQ ID NO:333, (b) a heavy chain frame work region 2 (HC-FR2) of SEQ ID NO:334, (c) a heavy chain frame work region 3 (HC-FR3) of SEQ ID NO:335, and (d) a heavy chain frame work region 4 (HC-FR4) of SEQ ID NO:336.

[0237] In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR1 of SEQ ID NO:333. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR2 of SEQ ID NO:334. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR3 of SEQ ID NO:335. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR4 of SEQ ID NO:336.

[0238] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) a light chain frame work region 1 (LC-FR1) of SEQ ID NO:329, (b) a light chain frame work region 2 (LC-FR2) of SEQ ID NO:330, (c) a light chain frame work region 3 (LC-FR3) of SEQ ID NO:331, and (d) a light chain frame work region 4 (LC-FR4) of SEQ ID NO:332.

[0239] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR1 of SEQ ID NO:329. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR2 of SEQ ID NO:330. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR3 of SEQ ID NO:331. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR4 of SEQ ID NO:332.

[0240] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0241] Further provided herein is an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering. In one embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:201 and SEQ ID NO:139

[0242] Further provided herein is an antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5. In one embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:201 and SEQ ID NO:139.

[0243] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0244] Antibody 2B11 and Other Embodiments

[0245] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116.

[0246] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:66. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:66 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:116. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:66, HVR-L3 comprising the amino acid sequence of SEQ ID NO:116, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:39. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66.

[0247] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116.

[0248] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116.

[0249] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116.

[0250] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:203. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:203. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:203, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66.

[0251] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:141. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:141. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:141, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116.

[0252] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:203 and SEQ ID NO:141, respectively, including post-translational modifications of those sequences.

[0253] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:203 and a VL sequence of SEQ ID NO:141.

[0254] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0255] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0256] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0257] Antibody 10H3 and Other Embodiments

[0258] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117.

[0259] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:67. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:67 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:117. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:67, HVR-L3 comprising the amino acid sequence of SEQ ID NO:117, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:40. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67.

[0260] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117.

[0261] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117.

[0262] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117.

[0263] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:204. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:204. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:204, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67.

[0264] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:142. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:142. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:142, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117.

[0265] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:204 and SEQ ID NO:142, respectively, including post-translational modifications of those sequences.

[0266] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:204 and a VL sequence of SEQ ID NO:142. In certain embodiments, an antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0267] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0268] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0269] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0270] Antibody 9H3 and Other Embodiments

[0271] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0272] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:68. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:68 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:118. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:68, HVR-L3 comprising the amino acid sequence of SEQ ID NO:118, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:33. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68.

[0273] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0274] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0275] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0276] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:205. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:205. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:205, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68.

[0277] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:143. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:143. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:143, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0278] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:205 and SEQ ID NO:1143, respectively, including post-translational modifications of those sequences.

[0279] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:205 and a VL sequence of SEQ ID NO:143.

[0280] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0281] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab').sub.2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0282] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0283] Antibody 8B7 and Other Embodiments

[0284] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0285] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:118. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:68, HVR-L3 comprising the amino acid sequence of SEQ ID NO:118, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:41. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0286] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0287] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0288] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0289] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:206. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:206. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:206, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0290] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:144. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:144. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:144, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0291] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:206 and SEQ ID NO:144, respectively, including post-translational modifications of those sequences.

[0292] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:206 and a VL sequence of SEQ ID NO:144.

[0293] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0294] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab').sub.2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0295] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0296] Antibody 9H5 and Other Embodiments

[0297] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0298] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:119. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69, HVR-L3 comprising the amino acid sequence of SEQ ID NO:119, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:42. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0299] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0300] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0301] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0302] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:221. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:221. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:221, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0303] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:149. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:149. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:149, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119.

[0304] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:221 and SEQ ID NO:149, respectively, including post-translational modifications of those sequences.

[0305] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:221 and a VL sequence of SEQ ID NO:149. In certain embodiments, an antibody is provided that, when bound to KLK5 results in a thermodynamic epitope comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

[0306] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0307] In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) a heavy chain frame work region 1 (HC-FR1) of SEQ ID NO:341, (b) a heavy chain frame work region 2 (HC-FR2) of SEQ ID NO:342, (c) a heavy chain frame work region 3 (HC-FR3) of SEQ ID NO:343, and (d) a heavy chain frame work region 4 (HC-FR4) of SEQ ID NO:344.

[0308] In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR1 of SEQ ID NO:341. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR2 of SEQ ID NO:342. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR3 of SEQ ID NO:343. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR4 of SEQ ID NO:344.

[0309] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) a light chain frame work region 1 (LC-FR1) of SEQ ID NO:337, (b) a light chain frame work region 2 (LC-FR2) of SEQ ID NO:338, (c) a light chain frame work region 3 (LC-FR3) of SEQ ID NO:339, and (d) a light chain frame work region 4 (LC-FR4) of SEQ ID NO:340.

[0310] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR1 of SEQ ID NO:337. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR2 of SEQ ID NO:338. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR3 of SEQ ID NO:339. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR4 of SEQ ID NO:340.

[0311] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0312] Further provided herein is an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, and Lys233 according to standard protease numbering. In one embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:221 and SEQ ID NO:149.

[0313] Further provided herein is an antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5. In one embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:221 and SEQ ID NO:149.

[0314] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0315] Antibody 9F2 and Other Embodiments

[0316] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120.

[0317] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:120. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:69, HVR-L3 comprising the amino acid sequence of SEQ ID NO:120, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:46. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0318] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120.

[0319] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120.

[0320] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120.

[0321] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:226. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:226. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:226, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69.

[0322] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:152. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:152. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:152, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120.

[0323] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:226 and SEQ ID NO:152, respectively, including post-translational modifications of those sequences.

[0324] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:226 and a VL sequence of SEQ ID NO:152.

[0325] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0326] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0327] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0328] Antibody 1008 and Other Embodiments

[0329] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0330] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:70. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:70 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:118. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:70, HVR-L3 comprising the amino acid sequence of SEQ ID NO:118, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:42. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70.

[0331] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0332] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0333] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0334] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:227. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:227. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:227, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70.

[0335] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:153. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:153. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:153, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118.

[0336] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:227 and SEQ ID NO:153, respectively, including post-translational modifications of those sequences.

[0337] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:227 and a VL sequence of SEQ ID NO:153.

[0338] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0339] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab').sub.2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0340] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0341] Antibody 8F5 and Other Embodiments

[0342] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

[0343] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:71. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:71 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:121. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:70, HVR-L3 comprising the amino acid sequence of SEQ ID NO:121, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:47. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71.

[0344] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

[0345] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

[0346] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

[0347] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:228. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:228. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:228, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71.

[0348] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:154. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:154. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:154, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

[0349] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:228 and SEQ ID NO:154, respectively, including post-translational modifications of those sequences.

[0350] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:228 and a VL sequence of SEQ ID NO:154.

[0351] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0352] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0353] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0354] Antibody 3-3F5 and Other Embodiments

[0355] In one aspect, an anti-KLK5 antibody is provided comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0356] In one aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:72. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:72 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:122. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:72, HVR-L3 comprising the amino acid sequence of SEQ ID NO:122, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:52. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72.

[0357] In another aspect, an anti-KLK5 antibody is provided comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0358] In another aspect, an anti-KLK5 antibody is provided comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0359] In another aspect, an anti-KLK5 antibody is provided comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24 (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0360] In another aspect, an anti-KLK5 antibody is provided comprising a heavy chain variable domain (VH) sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:248. In certain embodiments, a VH sequence having at least any of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:248. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VH sequence in SEQ ID NO:248, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72.

[0361] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:160. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-KLK5 antibody comprising that sequence retains the ability to bind to KLK5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:160. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-KLK5 antibody comprises the VL sequence in SEQ ID NO:160, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

[0362] In another aspect, an anti-KLK5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:248 and SEQ ID NO:160, respectively, including post-translational modifications of those sequences.

[0363] In a further aspect, an anti-KLK5 antibody is provided that binds to the same epitope as an anti-KLK5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-KLK5 antibody comprising a VH sequence of SEQ ID NO:248 and a VL sequence of SEQ ID NO:160.

[0364] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-KLK5 antibody is humanized. In one embodiment, an anti-KLK5 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g. a human immunoglobulin framework or a human consensus framework.

[0365] In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) a heavy chain frame work region 1 (HC-FR1) of SEQ ID NO:349, (b) a heavy chain frame work region 2 (HC-FR2) of SEQ ID NO:350, (c) a heavy chain frame work region 3 (HC-FR3) of SEQ ID NO:351, and (d) a heavy chain frame work region 4 (HC-FR4) of SEQ ID NO:352.

[0366] In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR1 of SEQ ID NO:349. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR2 of SEQ ID NO:350. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR3 of SEQ ID NO:351. In one embodiment, the anti-KLK5 antibody comprises a VH domain comprising a HC-FR4 of SEQ ID NO:352.

[0367] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) a light chain frame work region 1 (LC-FR1) of SEQ ID NO:345, (b) a light chain frame work region 2 (LC-FR2) of SEQ ID NO:346, (c) a light chain frame work region 3 (LC-FR3) of SEQ ID NO:347, and (d) a light chain frame work region 4 (LC-FR4) of SEQ ID NO:348.

[0368] In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR1 of SEQ ID NO:345. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR2 of SEQ ID NO:346. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR3 of SEQ ID NO:347. In one embodiment, the anti-KLK5 antibody comprises a VL domain comprising a LC-FR4 of SEQ ID NO:348.

[0369] In one embodiment, an anti-KLK5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab').sub.2 fragment. In another embodiment, the antibody is a full length antibody, e.g an intact IgG1 antibody or an intact IgG4 antibody or other antibody class or isotype as defined herein.

[0370] Further provided herein is an antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225 according to standard protease numbering. In one embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24 (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:248 and SEQ ID NO:160.

[0371] Further provided herein is an antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5. In one embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24 (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:248 and SEQ ID NO:160.

[0372] In a further aspect, an anti-KLK5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described below.

[0373] 2. Antibody Affinity

[0374] In some embodiments of any of the anti-KLK5 antibodies, the anti-KLK5 antibody has a binding affinity (dissociation constant Kd) to KLK5 of .ltoreq.1 .mu.M, .ltoreq.100 nM, .ltoreq.10 nM, .ltoreq.1 nM, .ltoreq.0.1 nM, .ltoreq.0.01 nM, or .ltoreq.0.001 nM (e.g. 10.sup.-8 M or less, e.g. from 10.sup.-8 M to 10.sup.-13 M, e.g., from 10.sup.-9 M to 10.sup.-13 M).

[0375] In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (.sup.125I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)). To establish conditions for the assay, MICROTITER.RTM. multi-well plates (Thermo Scientific) are coated overnight with 5 .mu.g/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23.degree. C.). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [.sup.125I]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20.RTM.) in PBS. When the plates have dried, 150 .mu.l/well of scintillant (MICROSCINT-20.TM.; Packard) is added, and the plates are counted on a TOPCOUNT.TM. gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.

[0376] According to another embodiment, Kd is measured using a BIACORE.RTM. surface plasmon resonance assay. For example, an assay using a BIACORE.RTM.-2000 or a BIACORE.RTM.-3000 (BIAcore, Inc., Piscataway, N.J.) is performed at 25.degree. C. with immobilized antigen CM5 chips at .about.10 response units (RU). In one embodiment, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NETS) according to the supplier's instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 .mu.g/ml (.about.0.2 .mu.M) before injection at a flow rate of 5 .mu.l/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20.TM.) surfactant (PBST) at 25.degree. C. at a flow rate of approximately 25 .mu.l/min. Association rates (k.sub.on) and dissociation rates (k.sub.off) are calculated using a simple one-to-one Langmuir binding model (BIACORE.RTM. Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (Kd) is calculated as the ratio k.sub.off/k.sub.on. See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 106 M-1 s-1 by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation=295 nm; emission=340 nm, 16 nm band-pass) at 25.degree. C. of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO.TM. spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0377] 3. Antibody Fragments

[0378] In some embodiments, the anti-KLK5 antibody provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab').sub.2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458. For discussion of Fab and F(ab').sub.2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Pat. No. 5,869,046.

[0379] Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0380] Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516 B1).

[0381] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coli or phage), as described herein.

[0382] 4. Chimeric and Humanized Antibodies

[0383] In some embodiments, the anti-KLK5 antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0384] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0385] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the "guided selection" approach to FR shuffling).

[0386] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0387] 5. Human Antibodies

[0388] In some embodiments, the anti-KLK5 antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0389] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 describing XENOMOUSE.TM. technology; U.S. Pat. No. 5,770,429 describing HUMAB.RTM. technology; U.S. Pat. No. 7,041,870 describing K-M MOUSE.RTM. technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE.RTM. technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

[0390] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Pat. No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0391] Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

[0392] 6. Library-Derived Antibodies

[0393] Anti-KLK5 antibodies may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N.J., 2001) and further described, e.g., in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, N.J., 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J Immunol. Methods 284(1-2): 119-132(2004).

[0394] In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO J, 12: 725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

[0395] Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

[0396] 6. Multispecific Antibodies

[0397] In some embodiments, the anti-KLK5 antibody provided herein is a multispecific antibody, e.g. a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for KLK5 and the other is for any other antigen. In certain embodiments, bispecific antibodies may bind to two different epitopes of KLK5. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express KLK5. Bispecific antibodies can be prepared as full length antibodies or antibody fragments.

[0398] Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10: 3655 (1991)), and "knob-in-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using "diabody" technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g. Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991).

[0399] Engineered antibodies with three or more functional antigen binding sites, including "Octopus antibodies," are also included herein (see, e.g. US 2006/0025576A1).

[0400] The antibody or fragment herein also includes a "Dual Acting FAb" or "DAF" comprising an antigen binding site that binds to KLK5 as well as another, different antigen (see, US 2008/0069820, for example).

[0401] 7. Antibody Variants

[0402] In some embodiments, amino acid sequence variants of the anti-KLK5 antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.

[0403] a) Substitution, Insertion, and Deletion Variants

[0404] In some embodiments, anti-KLK5 antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Conservative substitutions are shown in Table 1 under the heading of "preferred substitutions." More substantial changes are provided in Table 1 under the heading of "exemplary substitutions," and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

TABLE-US-00001 TABLE 1 Original Exemplary Preferred Residue Substitutions Substitutions Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His; Asp, Lys; Arg Gln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; Norleucine Leu Leu (L) Norleucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; Norleucine Leu

[0405] Amino acids may be grouped according to common side-chain properties:

[0406] (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;

[0407] (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;

[0408] (3) acidic: Asp, Glu;

[0409] (4) basic: His, Lys, Arg;

[0410] (5) residues that influence chain orientation: Gly, Pro;

[0411] (6) aromatic: Trp, Tyr, Phe.

[0412] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0413] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g. a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity).

[0414] Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR "hotspots," i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N.J., (2001).) In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0415] In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may, for example, be outside of antigen contacting residues in the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.

[0416] A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.

[0417] Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0418] b) Glycosylation Variants

[0419] In certain embodiments, the anti-KLK5 antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0420] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.

[0421] In some embodiments, anti-KLK5 antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about .+-.3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107).

[0422] Anti-KLK5 antibody variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

[0423] c) Fc Region Variants

[0424] In some embodiments, one or more amino acid modifications may be introduced into the Fc region of the anti-KLK5 antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.

[0425] In some embodiments, the invention contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks Fc.gamma.R binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII and Fc(RIII FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Pat. No. 5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI.TM. non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, Calif.; and CytoTox 96.RTM. non-radioactive cytotoxicity assay (Promega, Madison, Wis.). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). Clq binding assays may also be carried out to confirm that the antibody is unable to bind Clq and hence lacks CDC activity. See, e.g., Clq and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M. S. et al., Blood 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S. B. et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0426] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutant with substitution of residues 265 and 297 to alanine (U.S. Pat. No. 7,332,581).

[0427] Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U U.S. Pat. No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).)

[0428] In certain embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

[0429] In some embodiments, alterations are made in the Fc region that result in altered (i.e., either improved or diminished) Clq binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[0430] Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (U.S. Pat. No. 7,371,826).

[0431] See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Pat. Nos. 5,648,260; 5,624,821; and WO 94/29351 concerning other examples of Fc region variants.

[0432] d) Cysteine Engineered Antibody Variants

[0433] In some embodiments, it may be desirable to create cysteine engineered anti-KLK5 antibodies, e.g., THIOMAB.TM. antibodies in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and 5400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, e.g., in U.S. Pat. No. 7,521,541.

[0434] e) Antibody Derivatives

[0435] In some embodiments, the anti-KLK5 antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

[0436] In some embodiments, conjugates of the anti-KLK5 antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one embodiment, the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody-nonproteinaceous moiety are killed.

[0437] B. Recombinant Methods and Compositions

[0438] Anti-KLK5 antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No. 4,816,567. In one embodiment, isolated nucleic acid encoding an anti-KLK5 antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making an anti-KLK5 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0439] For recombinant production of an anti-KLK5 antibody, nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

[0440] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp. 245-254, describing expression of antibody fragments in E. coli.). After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0441] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[0442] Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0443] Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES.TM. technology for producing antibodies in transgenic plants).

[0444] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR.sup.- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).

[0445] C. Assays

[0446] Anti-KLK5 antibodies provided herein may be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art.

[0447] 1. Binding Assays and Other Assays

[0448] In one aspect, an antibody of the invention is tested for its antigen binding activity, e.g., by known methods such as ELISA, BIACore.RTM., FACS, or Western blot, etc.

[0449] In another aspect, competition assays may be used to identify an antibody that competes with any of the antibodies described herein for binding to KLK5. In certain embodiments, such a competing antibody binds to the same epitope (e.g., a linear or a conformational epitope) that is bound by any of the antibodies described herein. Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, N.J.).

[0450] In an exemplary competition assay, immobilized KLK5 is incubated in a solution comprising a first labeled antibody that binds to KLK5 (e.g., any of the antibodies described herein) and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to KLK5. The second antibody may be present in a hybridoma supernatant. As a control, immobilized KLK5 is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to KLK5, excess unbound antibody is removed, and the amount of label associated with immobilized KLK5 is measured. If the amount of label associated with immobilized KLK5 is substantially reduced in the test sample relative to the control sample, then that indicates that the second antibody is competing with the first antibody for binding to KLK5. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).

[0451] 2. Activity Assays

[0452] In one aspect, assays are provided for identifying anti-KLK5 antibodies having biological activity. Biological activity may include, e.g. inhibition of KLK5. In one embodiment, the anti-KLK5 antibodies inhibit the serine protease activity of KLK5. Antibodies having such biological activity in vivo and/or in vitro are also provided.

[0453] In some embodiments, the anti-KLK5 antibodies are tested for such biological activity. In some embodiments, the biological activity is tested by one or more methods selected from the group consisting of a direct activity assay, fluorescent peptide assay, an LC/MS assay, and a K.sub.i(app) assay. In some embodiments, the biological activity is measured by one or more methods selected from the group consisting of a recombinant KLK5 direct activity assay, coupled pro-KLK1 fluorescent peptide assay, a coupled pro-KLK7 fluorescent peptide assay, a pro-KLK1 LC/MS assay, a pro-KLK7 LC/MS assay, and a K.sub.i(app) assay. In some embodiments, the IC.sub.50 values are measured by the assays described herein above and in detail in the Examples below.

[0454] D. Immunoconjugates

[0455] The invention also provides immunoconjugates comprising an anti-KLK5 antibody provided herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

[0456] In one embodiment, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Pat. No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

[0457] In another embodiment, an immunoconjugate comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

[0458] In another embodiment, an immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At.sup.211, I.sup.131, I.sup.125, Y.sup.90, Re.sup.186, Re.sup.188, Sm.sup.153, Bi.sup.212, P.sup.32, Pb.sup.212 and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or I123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

[0459] Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026. The linker may be a "cleavable linker" facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020) may be used.

[0460] The immunuoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, Ill., U.S.A).

[0461] E. Methods and Compositions for Diagnostics and Detection

[0462] In some embodiments, any of the anti-KLK5 antibodies provided herein is useful for detecting the presence of KLK5 in a biological sample. The term "detecting" as used herein encompasses quantitative or qualitative detection. In some embodiments, a biological sample comprises a cell or tissue, such as skin epidermis, lung parenchyma, bronchial sub-epithelium. In some embodiments, a biological sample comprises bronchial alveolar lavage.

[0463] In one embodiment, an anti-KLK5 antibody for use in a method of diagnosis or detection is provided. In a further aspect, a method of detecting the presence of KLK5 in a biological sample is provided. In certain embodiments, the method comprises contacting the biological sample with an anti-KLK5 antibody as described herein under conditions permissive for binding of the anti-KLK5 antibody to KLK5, and detecting whether a complex is formed between the anti-KLK5 antibody and KLK5. Such method may be an in vitro or in vivo method. In one embodiment, an anti-KLK5 antibody is used to select subjects eligible for therapy with an anti-KLK5 antibody, e.g. where KLK5 is a biomarker for selection of patients.

[0464] Exemplary disorders that may be diagnosed using an anti-KLK5 antibody of the invention include Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0465] In certain embodiments, labeled anti-KLK5 antibodies are provided. Labels include, but are not limited to, labels or moieties that are detected directly (such as fluorescent, chromophoric, electron-dense, chemiluminescent, and radioactive labels), as well as moieties, such as enzymes or ligands, that are detected indirectly, e.g., through an enzymatic reaction or molecular interaction. Exemplary labels include, but are not limited to, the radioisotopes .sup.32P, .sup.14C, .sup.125I, .sup.3H, and .sup.131I, fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luceriferases, e.g., firefly luciferase and bacterial luciferase (U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, .beta.-galactosidase, glucoamylase, lysozyme, saccharide oxidases, e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase, coupled with an enzyme that employs hydrogen peroxide to oxidize a dye precursor such as HRP, lactoperoxidase, or microperoxidase, biotin/avidin, spin labels, bacteriophage labels, stable free radicals, and the like.

[0466] F. Pharmaceutical Formulations

[0467] Pharmaceutical formulations of an anti-KLK5 antibody as described herein are prepared by mixing such antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX.RTM., Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

[0468] Exemplary lyophilized antibody formulations are described in U.S. Pat. No. 6,267,958. Aqueous antibody formulations include those described in U.S. Pat. No. 6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer.

[0469] The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.

[0470] Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0471] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules.

[0472] The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0473] G. Therapeutic Methods and Compositions

[0474] Any of the anti-KLK5 antibodies provided herein may be used in therapeutic methods.

[0475] In one aspect, an anti-KLK5 antibody for use as a medicament is provided. In further aspects, an anti-KLK5 antibody is provided for use in treating a disease selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0476] In certain embodiments, an anti-KLK5 antibody for use in a method of treatment is provided. In certain embodiments, the invention provides an anti-KLK5 antibody for use in a method of treating an individual having a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea comprising administering to the individual an effective amount of the anti-KLK5 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described below. In some embodiments, provided is an anti-KLK5 antibody for use in inhibiting the biological activity of KLK5. In some embodiments, provided is an anti-KLK5 antibody for use in a method of inhibiting the biological activity of KLK5 in an individual comprising administering to the individual an effective of the anti-KLK5 antibody to inhibit the biological activity of KLK5. An "individual" according to any of the above embodiments is preferably a human. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0477] In a further aspect, the invention provides for the use of an anti-KLK5 antibody in the manufacture or preparation of a medicament. In one embodiment, the medicament is for treatment a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In a further embodiment, the medicament is for use in a method of treating a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea comprising administering to an individual having said disease an effective amount of the medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described below. In a further embodiment, the medicament is for inhibiting the biological activity of KLK5. In a further embodiment, the medicament is for use in a method of inhibiting the biological activity of KLK5 in an individual comprising administering to the individual an amount effective of the medicament to inhibiting the biological activity of KLK5. An "individual" according to any of the above embodiments may be a human. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0478] In a further aspect, the invention provides a method for treating a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, and rosacea. In some embodiments, the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, rosacea and eosinophilic esophagitis. In one embodiment, the method comprises administering to an individual having such Netherton Syndrome, asthma, atopic dermatitis, psoriasis, or rosacea an effective amount of an anti-KLK5 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. An "individual" according to any of the above embodiments may be a human. In some embodiments, the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma. In some embodiments, the asthma is TH2-low asthma.

[0479] In a further aspect, the invention provides a method for inhibiting the biological activity of KLK5 in an individual. In one embodiment, the method comprises administering to the individual an effective amount of an anti-KLK5 antibody to inhibiting the biological activity of KLK5. In one embodiment, an "individual" is a human.

[0480] In a further aspect, the invention provides pharmaceutical formulations comprising any of the anti-KLK5 antibodies provided herein, e.g., for use in any of the above therapeutic methods. In one embodiment, a pharmaceutical formulation comprises any of the anti-KLK5 antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical formulation comprises any of the anti-KLK5 antibodies provided herein and at least one additional therapeutic agent, e.g., as described below.

[0481] Antibodies of the invention can be used either alone or in combination with other agents in a therapy. For instance, an antibody of the invention may be co-administered with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is an IL-13 axis binding antagonist, an IL-5 axis binding antagonist, an IL-33 axis binding antagonist, an M1 prime antagonist, an IgE antagonist, a TRPA1 antagonist, a CRTH2 antagonist, a broncodilator or asthma symptom controller medication, an immunomodulator, a corticosteroid, a Th2 pathway inhibitor, a tyrosine kinase inhibitor, or a phosphodiesterase inhibitor. In some embodiments, the IL-13 axis binding antagonist is an anti-IL-13 antibody. In some embodiments, the anti-IL-13 antibody is lebrikizumab. In some embodiments, the IL-5 axis binding antagonist is an IL-5 binding antagonist or an IL-5 receptor binding antagonist. In some embodiments, the IL-33 axis binding antagonist is an IL-33 binding antagonist or an ST2 binding antagonist. In some embodiments, the IL-33 binding antagonist is an anti-IL-33 antibody. In some embodiments, the M1 prime antagonist is quilizumab.

[0482] Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the antibody of the invention can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent or agents. In one embodiment, administration of the anti-KLK5 antibody and administration of an additional therapeutic agent occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other. Antibodies of the invention can also be used in combination with radiation therapy.

[0483] An antibody of the invention (and any additional therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.

[0484] Antibodies of the invention would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The antibody need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically/clinically determined to be appropriate.

[0485] For the prevention or treatment of disease, the appropriate dosage of an antibody of the invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 .mu.g/kg to 15 mg/kg (e.g. 0.1 mg/kg-10 mg/kg) of antibody can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. One typical daily dosage might range from about 1 .mu.g/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the antibody would be in the range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, e.g. every week or every three weeks (e.g. such that the patient receives from about two to about twenty, or e.g. about six doses of the antibody). An initial higher loading dose, followed by one or more lower doses may be administered.

[0486] It is understood that any of the above formulations or therapeutic methods may be carried out using an immunoconjugate of the invention in place of or in addition to an anti-KLK5 antibody.

[0487] H. Articles of Manufacture

[0488] In another aspect of the invention, an article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above is provided. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an antibody of the invention. The label or package insert indicates that the composition is used for treating the condition of choice. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody of the invention; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0489] It is understood that any of the above articles of manufacture may include an immunoconjugate of the invention in place of or in addition to an anti-KLK5 antibody.

III. Examples

[0490] The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided above.

Example 1--Material and Methods

Generation of Anti-KLK5 Antibodies

[0491] New Zealand White rabbits were immunized with human KLK5 and single B cells were isolated using a modified protocol related to published literature, e.g. see Offner et al., PLoS ONE 9(2), 2014. This modified workflow included direct FACS sorting of IgG+ huKLK5+ B cells into single wells. The B cell culture supernatants were assayed by ELISA for binding to human KLK5 and an irrelevant control protein. KLK5 specific B cells were lysed and immediately frozen in -80.degree. C. for storage until molecular cloning. Variable regions (VH and VL) of each monoclonal antibody from rabbit B cells were cloned into expression vectors from extracted mRNA as previously described, e.g. see Offner et al., PLoS ONE 9(2), 2014. Individual recombinant rabbit antibodies were expressed in Expi293 cells and subsequently purified with protein A. Purified anti-KLK5 antibodies were then subjected to functional activity assays and kinetic screening.

[0492] Rats were immunized in a similar manner and hybridomas were generated using a modified fusion partner (e.g. see Price et al., J Immunol Methods 31; 343(1):28-41 (2009)). Various conditions were optimized to enable sorting of individual IgG+ huKLK5+ hybridomas into single wells followed by additional culturing after sorting. The resulting hybridoma supernatants were assayed by ELISA and positive samples were purified using protein A for subsequent functional and kinetic characterization.

BIAcore.TM. Experiments

[0493] The binding affinity of the antibodies in this section was determined by BIAcore.TM. T200 machine. Briefly, BIAcore.TM. research grade CM5 chips were activated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) reagents according to the supplier's instructions. Goat anti-human Fc IgGs were coupled to the chips to achieve approximately 10,000 response units (RU) in each flow cell. Unreacted coupling groups were blocked with 1M ethanolamine. For kinetics measurements, antibodies were captured to achieve approximately 300 RU. Ten-fold serial dilutions of human KLK5 were injected in HBS-P buffer at 37.degree. C. with a flow rate of 30 .mu.L/min. Association rates (ka) and dissociation rates (kd) were calculated using a 1:1 Langmuir binding model (BIAcore.TM. T200 Evaluation Software version 2.0). The equilibrium dissociation constant (KD) was calculated as the ratio kd/ka.

Assays for Determination of KLK5 Inhibition

[0494] The inhibition of human KLK5 by anti-KLK5 antibodies was measured using a recombinant KLK5 direct activity assay. Recombinant human KLK5 (Genentech) was diluted to 5 nM in direct assay buffer (75 mM Tris (pH 8.0), 150 mM NaCl and 0.01% TWEEN.RTM. 20) and combined with anti-KLK5 antibodies in 384-well assay plate (384 Well Low Volume, Black, Round Bottom, Corning, Catalog No. 4514). Antibodies were supplied in either phosphate sample buffer (70 mM sodium phosphate (pH 6), 200 mM NaCl and 0.01% TWEEN.RTM. 20) or citrate/Tris sample buffer (10 mM citric acid, 30 mM Tris (pH 6) and 0.01% TWEEN.RTM. 20). Antibody dilutions were made in the appropriate sample buffer or in direct assay buffer. Plates were incubated for 30 minutes at ambient temperature. Fluorescent peptide substrate, Boc-VPR-AMC (Bachem, Part No. 1-1120) was added directly to the assay plate. Final in-well concentrations were 50 .mu.M Boc-VPR-AMC, 5 nM recombinant human KLK5, and 0.19-100 nM anti-KLK5 antibodies. Plates were examined every 102 s for 30-60 minute using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. The Reaction rate (expressed as RFU) was calculated by linear regression of readings in the linear range, typically beginning at 204 s and continuing until the end of the assay. Buffer alone and 100 nM final SPINK9.SRE.Fc (Genentech) were used as 100% and 0% activity controls, respectively. The IC.sub.50 value of the anti-KLK5 antibodies were determined from a four-parameter fit for their respective curves.

[0495] The inhibition of human KLK5 by anti-KLK5 antibodies was measured using a coupled pro-KLK7 fluorescent peptide assay. Recombinant human KLK5 (Genentech) was diluted to 5 nM in pro-KLK7 citrate/Tris coupled buffer (50 mM Tris (pH 7.5), 150 mM NaCl and 0.01% TWEEN.RTM. 20) if antibody samples were in citrate/Tris sample buffer or pro-KLK7 phosphate coupled buffer (50 mM Tris (pH 8.0), 150 mM NaCl and 0.01% TWEEN.RTM. 20) if antibody samples were in phosphate sample buffer. Diluted KLK5 was then combined with anti-KLK5 antibodies in 384-well assay plate (384 Well Low Volume, Black, Round Bottom, Corning, Catalog No. 4514). Antibody dilutions were made as described for the direct KLK5 assay. Plates were incubated for 30 minutes at ambient temperature. Fluorescent peptide substrate, suc-LLVY-AMC (Bachem, Part No. I-1395) and pro-KLK7 (Genentech) were added directly to the assay plate and incubated at ambient temperature. Final in-well concentrations were 100 .mu.M suc-LLVY-AMC, 125 nM pro-KLK7, 5 nM recombinant human KLK5, and 0.19-100 nM anti-KLK5 antibodies. After 24 hours, fluorescent readings were made every 102 s for 30-60 min and the RFU endpoint value was calculated by averaging the last 5 readings. Buffer alone and 100 nM final SPINK9.SRE.Fc (Genentech) were used as 100% and 0% activity controls, respectively. The IC.sub.50 value of the anti-KLK5 antibodies were determined from a four-parameter fit for their respective curves.

[0496] IC.sub.50 value of the anti-KLK5 antibodies was determined using a pro-KLK7 Assay by KLK5-derived cleavage peptide detection using LC/MS (pro-KLK7 LC/MS assay). The product peptide EEAQGDK from reaction between the enzyme KLK5 and substrate proKLK7 was detected by mass spectrometry coupled to liquid chromatography. All compounds were diluted with 50 mM ammonium bicarbonate buffer (Powder/Certified, Fisher Chemical, A643-500) with final concentrations in the assay at 5 nM KLK5 (Genentech) and antibodies ranging from 0.02 to 65 nM, diluted in 96-well plates (Bio-Rad, Hard-Shell 96-Well PCR Plates, low profile, thin wall, skirted, blue/clear # HSP9631). Plates were incubated at room temperature for 30 minutes. Afterward, 15 nM of substrate proKLK7 (Genentech) was added to the enzyme plus inhibitors. After 2 hours, the reaction was quenched using 0.5 .mu.L of Formic Acid (99.5+%, Optima.TM. LC/MS Grade, Fisher Chemical, A117-10X1AMP). Peptide was detected using the combination of the following masses: Q1, 388.7 m/z and Q3, 319.0 m/z, in a QTRAP.RTM. 6500 LC-MS/MS mass spectrometer (Sciex, Framingham, Mass.). Quantitation of generated peptide was measured using a synthetic KLK7 peptide calibration curve. The IC.sub.50 values were determined using Prism 6 Software (GraphPad Software, La Jolla, Calif.).

[0497] The inhibition of human KLK5 by anti-KLK5 antibodies was measured using a coupled pro-KLK1 fluorescent peptide assay. Recombinant human KLK5 (Genentech) was diluted to 0.5 nM in pro-KLK1 coupled assay buffer (100 mM Tris (pH 8.5) and 0.01% TWEEN.RTM. 20) and combined with anti-KLK5 antibodies in 384-well assay plate (384 Well Low Volume, Black, Round Bottom, Corning, Catalog No. 4514). Antibody dilutions were made as described for the direct KLK5 assay. Plates were incubated for 30 minutes at ambient temperature. Fluorescent peptide substrate, PFR-AMC (Bachem, Part No. I-1295) and pro-KLK1 (Genentech) were added directly to the assay plate and incubated at ambient temperature. Final in-well concentrations were 50 .mu.M PFR-AMC, 31.25 nM pro-KLK1, 0.5 nM recombinant human KLK5, and 0.19-100 nM anti-KLK5 antibodies. Plates were examined every 102 s for 120 minute using a PHERAstar.RTM. Plus reader using a 340 nm excitation/460 nm emission module. The endpoint RFU values were calculated by averaging readings around a time dictated by the inflection point of a plot of RFU versus time for the no inhibitor controls. Buffer alone and 100 nM final SPINK9.SRE.Fc (Genentech) was used as 100% and 0% activity controls, respectively. The IC.sub.50 values of the anti-KLK5 antibodies were determined from a four-parameter fit for their respective curves.

[0498] IC.sub.50 values of the anti-KLK5 antibodies was determined using a pro-KLK1 Assay by KLK5-derived cleavage peptide detection using LC/MS (pro-KLK1 LC/MS Assay). The product peptide APPIQSR from reaction between the enzyme KLK5 and substrate proKLK1 was detected by mass spectrometry coupled to liquid chromatography. All compounds were diluted with 50 mM ammonium bicarbonate buffer (Powder/Certified, Fisher Chemical, A643-500) with final concentrations in the assay at 0.5 nM KLK5 (Genentech) and antibodies ranging from 0.01 to 29 nM, diluted in 96-well plates (Bio-Rad, Hard-Shell 96-Well PCR Plates, low profile, thin wall, skirted, blue/clear # HSP9631). Plates were incubated at room temperature for 60 minutes. Afterward, 300 nM of substrate proKLK1 (Genentech) was added to the enzyme plus inhibitors. After 20 minutes, the reaction was quenched using 0.5 .mu.L of Formic Acid (99.5+%, Optima.TM. LC/MS Grade, Fisher Chemical, A117-10X1AMP). Peptide was detected using the combination of the following masses: Q1, 384.7 m/z and Q3, 600.3 m/z, in a QTRAP.RTM. 6500 LC-MS/MS mass spectrometer (Sciex, Framingham, Mass.). IC.sub.50 value were determined using peak areas and Prism 6 Software (GraphPad Software, La Jolla, Calif.).

[0499] K.sub.i(app) assay using Z-VPR-pNA as substrate was performed at room temperature in a 96-well half-area plate (white with clear, flat bottom, Corning #3884). Inhibitor samples were diluted to 3.times. final concentration in assay buffer (100 mM Tris, pH 8.0, 100 mM NaCl, 0.01% TWEEN.RTM. 20). Buffer alone and 100 nM final SPINK9.SRE.Fc (Genentech) were used as 100% and 0% activity controls, respectively. Inhibitor or control samples (20 .mu.L) were added to the plate followed by 20 .mu.L KLK5 (Genentech) in assay buffer at final concentrations of 0.5, 0.25, 0.125, and 0.0625 nM. After 30 minutes, 20 .mu.L of Z-VPR-pNA substrate (California Peptide, #876-08, prepared as a 30 mM stock solution in DMSO) in assay buffer was added at a final concentration of 300 .mu.M. In some initial assays the final DMSO concentration was increased to 10% by making an initial dilution of the substrate to 3 mM in DMSO before diluting to 900 .mu.M (i.e., 3.times. final) in assay buffer. After addition of substrate, the plate was read in a Versamax tunable microplate reader with measurements at 405 nm taken every 102 seconds for 3 hours. Reaction rates (expressed as .mu.AU/s) were calculated by linear regression in the range 4182-10710 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values. In the case of a bivalent inhibitor, the raw IC.sub.50 value was multiplied by two. The IC.sub.50 value was then plotted versus KLK5 enzyme concentration, yielding the K.sub.i(app) from the y-intercept value. In addition, if the inhibitor was potent enough, the combined purity of both enzyme and inhibitor could be judged by comparing the slope of the plot to the theoretical value of 0.5.

Assays for Determination of Antibody Selectivity

[0500] KLK1 selectivity assay was performed at room temperature in a 384-well plate (black, low-volume round bottom, Corning #4514) with a final reaction volume of 15 .mu.L. Inhibitor samples were diluted to 3.times. final concentration in assay buffer (75 mM Tris, pH 8.0, 150 mM NaCl, 0.01% TWEEN.RTM. 20). Reactions lacking inhibitor and reactions lacking enzyme were used as 100% and 0% activity controls, respectively. Inhibitor or control samples (5 .mu.L) were added to the plate followed by 5 .mu.L KLK1 (R&D Systems, 2337-SE, Lot NLY0315111, activated according to R&D systems protocol) in assay buffer at a final concentration of 3 nM. After 30 minutes, 5 .mu.L of H-Pro-Phe-Arg-AMC acetate salt (Bachem I-1295, 10 mM stock solution in water) in assay buffer was added at a final concentration of 100 .mu.M. After addition of substrate, the plate was read in PHERAstar.RTM. microplate reader using optic module FI 340 460 with the gain set to 85%. Measurements were taken every 102 seconds for 1 hour. Reaction rates (expressed as RFU/s) were calculated by linear regression in the range 204-918 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values. In the case of bivalent inhibitors, the raw IC.sub.50 value was multiplied by two.

[0501] KLK4 selectivity assay was performed at room temperature in a 384-well plate (black, low-volume round bottom, Corning #4514) with a final reaction volume of 15 .mu.L. Inhibitor samples were diluted to 3.times. final concentration in assay buffer (75 mM Tris, pH 8.0, 150 mM NaCl, 0.01% TWEEN.RTM. 20). Reactions lacking inhibitor and reactions lacking enzyme were used as 100% and 0% activity controls, respectively. Inhibitor or control samples (5 .mu.L) were added to the plate followed by 5 .mu.L KLK4 (R&D Systems, 1719-SE, Lot MSY0116011, activated according to R&D systems protocol) in assay buffer at a final concentration of 2 nM. After 30 minutes, 5 .mu.L of Boc-Val-Pro-Arg-AMC (Bachem I-1120, 31.3 mM stock solution in water) in assay buffer was added at a final concentration of 50 .mu.M. After addition of substrate, the plate was read in PHERAstar.RTM. microplate reader using optic module FI 340 460 with the gain set to 85%. Measurements were taken every 102 seconds for 1 hour. Reaction rates (expressed as RFU/s) were calculated by linear regression in the range 510-3570 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values. In the case of bivalent inhibitors, the raw IC.sub.50 value was multiplied by two.

[0502] Trypsin selectivity assay was performed at room temperature in a 384-well plate (black, low-volume round bottom, Corning #4514) with a final reaction volume of 15 .mu.L. Inhibitor samples were diluted to 3.times. final concentration in assay buffer (75 mM Tris, pH 8.0, 150 mM NaCl, 0.01% TWEEN.RTM. 20). Reactions lacking inhibitor and reactions lacking enzyme were used as 100% and 0% activity controls, respectively. Inhibitor or control samples (5 .mu.L) were added to the plate followed by 5 .mu.L trypsin (Sigma Aldrich T8003, Lot SLBM2321V, 42.0 .mu.M stock solution in 1 mM HCl) in assay buffer at a final concentration of 0.25 nM. After 30 minutes, 5 .mu.L of Boc-Val-Pro-Arg-AMC (Bachem I-1120, 31.3 mM stock solution in water) in assay buffer was added at a final concentration of 50 .mu.M. After addition of substrate, the plate was read in PHERAstar microplate reader using optic module FI 340 460 with the gain set to 85%. Measurements were taken every 102 seconds for 1 hour. Reaction rates (expressed as RFU/s) were calculated by linear regression in the range 204-3570 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values. In the case of bivalent inhibitors, the raw IC.sub.50 value was multiplied by two.

[0503] KLK7 selectivity assay was performed at room temperature in a 384-well plate (black, low-volume round bottom, Corning #4514) with a final reaction volume of 15 .mu.L. Inhibitor samples were diluted to 3.times. final concentration in assay buffer (75 mM Tris, pH 8.0, 150 mM NaCl, 0.01% TWEEN.RTM. 20). Reactions lacking inhibitor and reactions lacking enzyme were used as 100% and 0% activity controls, respectively. Inhibitor or control samples (5 .mu.L) were added to the plate followed by 5 .mu.L KLK7 (Genentech) in assay buffer at a final concentration of 5 nM. After 30 min, 5 .mu.L of Suc-Leu-Leu-Val-Tyr-AMC (Bachem I-1395, 25 mM stock solution in water) in assay buffer was added at a final concentration of 100 .mu.M. After addition of substrate, the plate was read in PHERAstar.RTM. microplate reader using optic module FI 340 460 (AMC Module) with the gain set to 85%. Measurements were taken every 102 seconds for 1 hour 15 minute. Reaction rates (expressed as RFU/s) were calculated by linear regression in the range 2040-4488 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values.

PHERAstar.RTM. Experiments

[0504] Pre MCA PHERAstar Module: After 30 min, 5 .mu.L of Suc-Leu-Leu-Val-Tyr-AMC (Bachem I-1395, 25 mM stock solution in water) in assay buffer was added at a final concentration of 100 .mu.M. After addition of substrate, the plate was read in PHERAstar.RTM. microplate reader using optic module FI 340 460 (AMC Module) with the gain set to 85%. Measurements were taken every 102 seconds for 1 hour 15 minute. Reaction rates (expressed as RFU/s) were calculated by linear regression in the range 2040-4488 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values.

[0505] Post MCA PHERAstar.RTM. Module: After 30 min, 5 .mu.L of Mca-RPKPVE-Nval-WRK(Dnp)-NH2 Fluorogenic MMP Substrate (R&D Systems ES002, 4.3 mM stock solution in DMSO) in assay buffer was added at a final concentration of 10 .mu.M. After addition of substrate, the plate was read in PHERAstar microplate reader using optic module FI 320 405 (MCA Module) with the gain set to 85%. Measurements were taken every 102 seconds for 1 hour 15 minute. Reaction rates (expressed as RFU/s) were calculated by linear regression in the range 204-1020 seconds. Reaction rates were normalized to the values of the 0% and 100% activity controls and fit with a 4-parameter equation to calculate IC.sub.50 values.

Wasatch Experiments

[0506] An array-based SPR imaging system (Carterra.TM., USA) was used to epitope bin a panel of 288 monoclonal antibodies. Purified antibodies were diluted at 10 .mu.g/ml in 10 mM sodium acetate buffer pH 4.5. Using amine coupling, antibodies were directly immobilized onto a SPR sensorprism CMD 200M chip (XanTec Bioanalytics GmbH, Germany) using a Continuous Flow Microspotter (Carterra.TM., USA) to create an array of 288 antibodies. For analysis, the IBIS MX96 SPRi (Carterra.TM., USA) was used to evaluate analytes binding to the immobilized ligands. For kinetic analyses, human, cyno and murine KLK5 were injected for 3 minutes from 0 to 300 nM at 3-fold dilution followed by a dissociation period of 10 minutes. Human KLK1, KLK4, and KLK7 were injected at a single concentration of 500 nM to ensure the specificities of the antibodies. For epitope binning against SPINK9-Fc-SRE, human KLK5 was first injected for 4 minute at 100 nM and was followed by a second 4 minute injection of SPINK9-Fc-SRE at 10 .mu.g/ml. The surface was regenerated with 10 mM glycine pH1.5 between cycles. The experiment was performed at 25.degree. C. in a running buffer of HBS-T buffer (0.01M HEPES pH 7.4, 0.15M NaCl, 0.05% surfactant P20). The kinetic data was processed using Scrubber 2.0 (BioLogic.TM. Software) and the epitope binning data was processed using Wasatch binning software tool (Carterra.TM., USA).

Hydrogen Exchange Mass Spectrometry

[0507] Experimental starting material compositions are listed in Table 2. Two labeling solutions were prepared with .sup.2H.sub.2O (heavy water) having a pH of either 6.0 or 8.0, and consisting of a mixture of anhydrous monobasic sodium phosphate and dibasic sodium phosphate dehydrate combined in an appropriate ratio to achieve the stated deuterium activity at a total concentration 10 mM with 140 mM NaCl. Starting materials (Table 2) were diluted approximately 1:10 with labeling solutions using a leap robotics platform and incubated for various times before being diluted 1:1 with quench buffer (4M GdmCl, 0.5 M TCEP, 200 mM Citric acid), to a final pH of 2.5, and then prepared quickly for mass measurement. Quenched material was injected into an online flow system where it was digested using pepsin, buffer exchanged while bound to a trap column, separated by reversed-phase chromatography, and introduced into the gas phase by electrospray where individual peptides are assessed for the amount of carried deuterium.

TABLE-US-00002 TABLE 2 Starting Material Exp. Composition Sample Mab:KLK5 Ratio [Mab] .mu.M [KLK5] .mu.M KLK5.10C5 0.70 23.10 33.00 KLK5.10H3 0.65 20.98 33.00 KLK5.9H5 0.55 18.07 33.00 KLK5 0.00 0.00 33.00

[0508] At either pH 6.0 or 8.0, samples were labeled for 0.5, 5.0, 56.0, and 600.0 minutes. Independent experimental replicates were included; on plots shown, error bars represent the range of measurements, whose average shown by markers in FIG. 12B. Feature abstraction and data analysis involved custom in-house software.

[0509] Effective labeling time at a reference pH was defined by both experimental pH and actual labeling time: t.sub.eff=t.sub.exp*10{circumflex over ( )}(PH.sub.ref-pH.sub.exp). The reference pH in FIG. 12B is 6.0. To correct for a well-known proton activity offset that occurs as a result of .sup.2H.sub.2O, the following relationship connects pH measurements with pH values referred herein:

pH=pH.sub.measure+([.sup.2H.sub.2O/.sup.2H.sub.2O+.sup.1H.sub.2O]*0.4).

[0510] The sequence and retention time of experimental peptides derived from KLK5 was determined in initial experiments where the same procedural workflow described above was followed but with a labeling buffer in .sup.1H.sub.2O solvent. This provides a starting mass from which the amount of deuterium contained in each peptide during the labeling experiments may be determined; additionally, these experiments utilize tandem-MS for de novo sequencing by MS.

IL-8 Secretion Assay

[0511] IL-8 is secreted by several cell types in response to inflammatory stimuli. KLK5 stimulates A459 cells, resulting in the secretion of IL-8. Adenocarcinomic human alveolar basal epithelial cells constitute the A549 cell-line. A549 cells were cultured with media containing RPMI, 10% FBS, L-glutamine, and supplemented with penicillin and streptomycin. Cells were plated into TC-treated 96-well plates (Corning, Cat.#3997) at 50,000 cells per well and starved of serum for 18 hours before KLK5 challenge. Human KLK5 was first incubated with KLK5 inhibitors or starvation media for 1 hour at room temperature prior to addition to plate (200 nM in-well concentration) for 24 hr at 37.degree. C. in a humid environment in the presence of 5% CO.sub.2. Endotoxin inhibitor (1 .mu.M) was also added to each well. After incubation, the cell supernatants were collected and either analyzed immediately or stored at -20.degree. C. Cell supernatants were serially diluted in sample diluent (PBS/0.5% BSA/0.05% polysorbate-20/5 mM EDTA/0.25% CHAPS/0.2% BGG/10 ppM Proclin) for analysis in an IL-8 sandwich ELISA using a standard protocol with mouse anti-human IL-8 monoclonal antibody for capture (R&D Systems, Cat # MAB208) and biotinylated mouse anti-human IL-8 monoclonal antibody for detection (R&D Systems, Cat # BAF208). The cell stimulation activity of KLK5 was analyzed by normalizing the IL-8 concentrations to 100% for KLK5 treatment alone and to 0% for starvation media alone treatment. IC.sub.50 values were determined using a 4-parameter fit with GraphPad Prism software.

KLK5 and Fab Expression, Purification and Crystallization

[0512] Recombinant human KLK5 residues I67-S293 (SEQ ID NO:328) was expressed in a Baculovirus expression system as a C-terminal fusion of ubiquitin with an Enterokinase cleavage site engineered between ubiquitin and KLK5. Sf9 cells were coexpressed with EndoH with 1 mg/mL of Kifunensine. Protein was purified on a HiTrap.TM. Heparin column. The column was washed with 25 mM TRIS pH 7.5 for 5 CV (column volumes), and then eluted with 0-750 mM NaCl over a gradient of 20 CV. Resultant protein pool was then further purified over 5200 by SEC in 25 mM Tris pH 7.5, 300 mM NaCl. The Ubiquitin was then cleaved using Enterokinase, and sample further purified by SEC again. Mass spectrometry and SDS PAGE revealed a pure KLK5 sample, which was confirmed to be active. Fab fragments including heavy and light chains were expressed and purified as described. See Carter et al., Biotechnology 10(2), 163-167 (1992). KLK5 was then mixed with each of the Fabs separately, 10C5, 9H5, and 3-3F5, and the complex was purified by SEC in 25 mM HEPES pH 7.2, 100 mM NaCl. The crystallization conditions for the 3 Fab-KLK5 complexes were as follows: 3-3F5 complex--15% PEG 4K, 0.1 M MgCl2, 0.1 M Na Citrate pH 5.0; 10C5 Complex: 20% PEG4K, 0.2M Ammonium Sulfate, 25% Glycerol; 9H5 Complex: 15% PEG4K, 10% Isopropanol, 0.1M HEPES pH 7.5. Crystal for the 10C5 and 9H5 complexes were only obtained when the lysine residues in the protein complexes were methylated. See Walter et al., Structure, 14(11), 1617-1622 (2006).

Data Collection and Structure Solution

[0513] X-ray diffraction data was collected under cryo-cooled conditions at 100 Kelvin using various synchrotron X-ray radiation at the Advanced Light Source (Berkeley, Calif.) or Advanced Photon Source (Argonne, Ill.) according to standard methods. Diffraction images were processed and reduced using the data processing software XDS. See Kabsch W, Acta Crystallogr D Biol Crystallogr, 66 (Pt 2), 125-132 (2010). Models were generated using the molecular replacement technique with the program PHASER. The structure of human TIGIT (see Debala et al., J Mol Biol, 373:1017-1031 (2007)) and Fab antibody model (See Nakamura et al., Cell Host Microbe, 14(1), 93-103 (2013)) were used as search models. The structures underwent iterative rounds of model adjustment using the program COOT and refinement using the Phenix.refine or BUSTER programs. Models were refined to acceptable R and R free values and Ramachandran statistics (calculated by Molprobity). The crystal structures of KLK5 complexed with each of the Fabs, 10C5, 9H5 and 3-3F5 as well as the details of interactions and epitopes can be found in FIGS. 18-20 and Tables 5-13.

Example 2--Humanization of Anti-KLK5 Antibodies

[0514] By immunization of animals with human KLK5 as described herein above, as set of 540 monoclonal anti-KLK5 antibodies was obtained. As this set contained anti-KLK5 antibodies with highly variable characteristics, the antibodies were screened for desired characteristics, such as a certain 1050 values and selectivity to human KLK5. This screening revealed a large number of antibodies with low affinity to human KLK5, no selectivity with respect to human KLK5, and/or insufficient functional activity. For example, some of the obtained anti-KLK5 antibodies were partial inhibitors, i.e. inhibition by .ltoreq.50% (e.g. clones 12B3, 1D10) or inhibition by .ltoreq.90% (e.g. clones 14C8, 14E12, 8E11). Some of the obtained anti-KLK5 antibodies inhibited human KLK5 only in one of the assays described herein (e.g. clones 9E3, 10D10). Only 13 anti-KLK5 antibodies were selected based on their characteristics (clones 8G10, 9B6, 2-3F4, 10C5, 2B11, 10H3, 9H3, 8B7, 9H5, 9F2, 10C8, 8F5, 3-3F5). The three anti-KLK5 antibodies with the highest inhibitory activities (clones 9H5, 10C5, 3-3F5) were then selected for humanization.

[0515] Rabbit monoclonal antibodies 9H5, 10C5, and 3-3F5 were humanized as described below. Residue numbers are according to Kabat et al., Sequences of proteins of immunological interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991).

[0516] Variants constructed during the humanization of 9H5, 10C5, and 3-3F5 were assessed in the form of human IgG1. Hypervariable regions from each of the rabbit antibodies (namely positions 24-34 (L1), 50-56 (L2) and 89-97 (L3) in VL domain, and 26-35 (H1), 50-65 (H2) and 95-102 (H3) in VH domain) were grafted into various acceptor frameworks. Specifically, for 9H5, VL CDRs were grafted into KV1D-39*01 and VH CDRs were grafted into HV3-53*01. For 10C5, VL CDRs were grafted into KV1-8*01 and VH CDRs were grafted into HV3-64*01. For 3-3F5, VL CDRs were grafted into KV1-8*01 and VH CDRs were grafted into HV3-23*01. All VL and VH Vernier positions from rabbit antibodies were also grafted into their respective human germline frameworks. The grafts with all rabbit amino acids in Vernier positions are referred to as L1H1 (hu9H5.L1H1, hu10C5.L1H1 and hu3-3F5.L1H1) (FIGS. 14-16).

[0517] The binding affinity of the antibodies in this section was determined using BIAcore.TM. T200 as described herein above. The binding affinity of humanized 9H5, 10C5 and 3-3F5 version L1H1 (hu9H5.L1H1, hu10C5.L1H1 and hu3-3F5.L1H1) antibodies were compared to their chimeric parental clones. Rabbit Vernier positions of version L1H1 antibodies were converted back to human residues to evaluate the contribution of each rabbit Vernier positions to binding affinity to hKLK5.

[0518] For 9H5, three additional light chains (L2: L1+Ala43, L3: L1+Tyr49, and L4: L1+Ala43+Tyr49 (CDR graft)) and sixteen additional heavy chains (H2: H1+Ala24, H3: H1+Trp47, H4: H1+Val48, H5: H1+Ser49, H6: H1+Phe67, H7: H1+Asn73, H8: H1+Leu78, H9: H1+Tyr91, H10: H1+Gln105, H11: no rabbit residues in Vernier positions (CDR graft), H12: H1+Asp61+Ser62+Val63+Gly65, H13: CDR graft+Asp61+Ser62+Val63+Gly65, H14: CDR graft+Tyr47+Gly49, H15: H14+Gln2, H16: H14+Asn72+Thr73+Asn74+Leu75, and H17: H14+Phe62) were made (FIG. 15). Tyr47 and Gly49 on the heavy chain (H14) were determined to be the key rabbit Vernier residues based on binding affinity evaluation of the variant antibodies described above (data not shown). Chimeric 9H5 bound with a KD of 1.9E.sup.-1.degree. M, while hu9H5.L4H14, bound with a KD of 6.9E.sup.-10 M.

[0519] For 10C5, four additional light chain variants L2-L5 (L2: L1+Ile2, L3: L1+Ala43, L4: L1+Ile2+Ala43 (CDR graft), L5: CDR graft+Ser77+Pro80, L6: CDR graft+Ser77+Pro80+Glu103+Val105+Val106) and twenty-seven additional heavy chain variants H2 to H28 (H2: H1+Ala24, H3: H1+Tyr47, H4: H1+Val48, H5: H1+Ser49, H6: H1+Phe67, H7: H1+Asn73, H8: H1+Leu78, H9: H1+Tyr91, H10: H1+Gln105, H11: H1+Asn61+Ser62+Val63+Gly65, H12: no rabbit residues in Vernier positions (CDR graft), H13: CDR graft+Asn61+Ser62+Val63+Gly65, H14: CDR graft+Trp47+Gly49, H15: H14+Gln2, H16: H14+Asn72+Leu73+Asn74+Thr75, H17: H14+Phe62, H18: H14+Asn72+Thr73+Asn74+Leu75, H19: H14+Asn72, H20: H14+Asn74, H21: H14+Asn72+Asn74, H22: H14+Ile48, H23: H14+Ser67, H24: H22+Ser67, H25: H14+Thr73, H26: H14+Thr78, H27: H25+Thr78, H28: H22+Ser67+Thr73+Thr78) were made (FIG. 14). Trp47, Ile48, Gly49, Ser67, Thr73, and Val78 on the heavy chain (H28) were determined to be the key rabbit Vernier residues based on binding affinity evaluation of the variant antibodies described above (data not shown). Chimeric 10C5 bound with a KD of 1.65E.sup.-11M, while hu10C5.L5H28, bound with a KD of 5.70E''.sup.11 M.

[0520] For 3-3F5, four additional light chain variants L2-L5 (L2: L1+Ile2, L3: L1+Ala43, L4: L1+Ile2+Ala43 (CDR graft), L5: CDR graft+Ser77+Pro80) and twenty-six additional heavy chain variants H2 to H27 (H2: H1+Ala24, H3: H1+Val48, H4: H1+Ser49, H5: H1+Phe67, H6: H1+Asn73, H7: H1+Leu78, H8: H1+Tyr91, H9: H1+Arg105, H10: H1+Phe58, H11: H1+Asp61+Ser62+Val63, H12: CDR graft+Phe58, H13: CDR graft+Phe58+Asp61+Ser62+Val63, H14: CDR graft+Gly49, H15: H14+Phe58, H16: H14+Gln2, H17: H14+Asn72+Thr73+Asn74+Leu75, H18: H14+Phe62, H19: H18+Val24, H20: H18+Ile48, H21: H18+Ser67, H22: H18+Ile48+Ser67, H23: H18+Thr73, H24: H18+Val78, H25: H18+Thr73+Val78, H26: H18+Ile148+Ser67+Thr73+Val78, H27: CDRs graft+Ala24+Ile48+Gly49+Phe58+Phe62+Ser67, H28: H19+Phe58+Thr73+Thr78) were made (FIG. 16). Val24, Gly49, Thr73, and Val78 on the heavy chain (H28) were determined to be the key rabbit Vernier residues based on binding affinity evaluation of the variant antibodies described above (data not shown). Chimeric 3-3F5 bound with a KD of <1E.sup.-12M (KD is below the detection limit of 10E.sup.-6 s.sup.-1 for the instrument), while hu3-3F5.L5H19 bound with a KD of 4.1E.sup.-12 M and hu3-3F5.L5H25 bound with a KD of 9.1E.sup.-12 M.

[0521] The hu9H5.L4H14, hu10C5.L5H28, hu3-3F5.L5H19, hu3-3F5.L5H25 and their chimeric counterparts were tested for their ability to bind human KLK5 as described herein above. Binding properties for the humanized antibodies are shown in Table 3.

TABLE-US-00003 TABLE 3 Ligand Sample ka (1/Ms) kd (1/s) KD (M) human KLK5 9H5 7.05E.sup.+5 1.37E.sup.-4 1.93E.sup.-10 hu9H5.L4H14 8.10E.sup.+5 5.62E.sup.-4 6.94E.sup.-10 human KLK5 10C5 1.78E.sup.+7 2.92E.sup.-4 1.65E.sup.-11 hu10C5.L5H28 1.90E.sup.+7 1.08E.sup.-3 5.70E.sup.-11 human KLK5 3-3F5 2.93E.sup.+7 <1.00E.sup.-5 <1.00E.sup.-12 hu3-3F5.L5H19 4.84E.sup.+7 2.01E.sup.-4 4.14E.sup.-12 hu3-3F5.L5H25 2.57E.sup.+7 2.35E.sup.-4 9.14E.sup.-12

Example 3--Evaluation of IC.sub.50 Values and Specificity of Anti-KLK5 Antibodies

Evaluation of KLK5 Inhibitor IC.sub.50 Values Using Fluorescent Peptide Substrates

[0522] The ability of Spink9.SRE.Fc, mAb1108 or 12 selected antibodies to inhibit the proteolysis of the substrate, Boc-VPR-AMC, by human KLK5 was assessed using an enzymatic assay. In this assay the three-mer fluorogenic peptide substrate contains a highly fluorescent 7-amino4-methylcoumarin (AMC) group that is quenched by resonance energy transfer to the t-Butyloxycarbonyl (Boc). The cleavage of the peptide substrate by human KLK5 resulted in an increased fluorescent signal and the inhibition or absence of KLK5 resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum KLK5 activity (% control). The results of a single experiment run in duplicate are shown in FIG. 1. The calculated IC.sub.50 value for Spink9.SRE.Fc (FIG. 1A) was 1.23 nM and the range of IC.sub.50 values for the 12 selected antibodies (FIGS. 1 C-N) was 0.89 to 1.32 nM. Spink0.SRE.Fc as well as all 12 selected antibodies fully inhibited KLK5 activity, although mAb1108 (FIG. 1B) only demonstrated .about.20% inhibition of KLK5 activity. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 1).

Evaluation of KLK5 Inhibitor IC.sub.50 Values Using Coupled Macromolecular Substrate Activity

[0523] As demonstrated in FIG. 1, Spink9.SRE.Fc as well as the identified 12 anti-KLK5 antibodies are potent inhibitors of KLK5 activity as monitored using a peptide based substrate. To further evaluate the inhibitory profiles of these inhibitors, two assays were developed utilizing macromolecular substrates, pro-KLK7 (FIG. 2) and pro-KLK1 (FIG. 3), in combination with KLK specific fluorescent peptide substrates.

[0524] In FIG. 2, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected anti-KLK5 antibodies to inhibit KLK5 mediated activation of pro-KLK7 was assessed using a coupled enzymatic assay. In this assay, human KLK5 is incubated with human pro-KLK7 resulting in cleavage, release of the KLK7 pro-domain and activation of KLK7. Activated human KLK7 can proteolyze a KLK7 specific substrate, Suc-LLVY-AMC, resulting in an increased fluorescent signal. The cleavage of pro-KLK7 by human KLK5 results in active KLK7 and an increased fluorescent signal whereas the inhibition or absence of KLK5 resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum human KLK5 activity (% control). The results of a single experiment run in duplicate are shown in FIG. 2.

[0525] Similar to data using the peptide-based substrate (FIG. 1), Spink9.SRE.Fc (FIG. 2A) was a potent inhibitor of KLK5 activation of pro-KLK7 with an IC.sub.50 value of 2.07 nM. Additionally, mAb1108 (FIG. 2B) had an IC.sub.50 value of 1.21 nM whereas the range of IC.sub.50 values for the 12 selected anti-KLK5 antibodies (FIGS. 2 C-N) was 0.58 to 1.53 nM. In the KLK5 pro-KLK7 coupled assay all of inhibitors, Spink9.SRE.Fc as well as antibodies, fully inhibited KLK5 activity. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 2).

[0526] In FIG. 3, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected anti-KLK5 antibodies to inhibit KLK5 mediated activation of pro-KLK1 was assessed using a coupled enzymatic assay. In this assay, human KLK5 is incubated with human pro-KLK1 resulting in cleavage, release of the KLK7 pro-domain and activation of KLK1. Activated human KLK1 can proteolyze a KLK1 specific substrate, PFR-AMC, resulting in an increased fluorescent signal. The cleavage of pro-KLK1 by human KLK5 results in active KLK1 and an increased fluorescent signal whereas the inhibition or absence of KLK5 resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum human KLK5 activity (% control). The results of a single experiment run in duplicate are shown in FIG. 3. The IC.sub.50 value for Spink9. SRE.Fc (FIG. 3A) was 0.325 nM and the range of IC.sub.50 for the 12 selected anti-KLK5 antibodies (FIGS. 2 C-N) was 0.074 to 0.151 nM. Spink0.SRE.Fc as well as all 12 selected anti-KLK5 antibodies fully inhibited KLK5 activity, although mAb1108 (FIG. 1B) only demonstrated .about.40% inhibition of KLK5 activity. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 3).

KLK5-Derived Cleavage Peptide Detection by LC/MS for IC.sub.50 Value Determination

[0527] The ability of Spink9.SRE.Fc, mAb1108 or 12 selected anti-KLK5 antibodies to inhibit proteolysis of pro-KLK7 or pro-KLK1 by recombinant KLK5 was assessed using an LC/MS assay that monitors the KLK5-derived cleavage product peptides. For both assays, the cleavage of the pro-peptide KLK7 or KLK1 by human KLK5 results in a specific MS signal and the inhibition of KLK5 activity results in a measurable decrease of the peptide signal. The results of a single experiment for pro-KLK7 are shown in FIG. 4 and they are expressed as area of pro-peptide KLK7. The calculated IC.sub.50 value for Spink9.SRE.Fc (FIG. 4A) was 1.13 nM, for MAb1108 (FIG. 4B) was 1.86 nM and the range of IC.sub.50 values for the 12 selected anti-KLK5 antibodies (FIG. 4 C-N) was 0.31 to 1.72 nM. Spink9.SRE.Fc as well as all 12 selected anti-KLK5 antibodies fully inhibited KLK5 activity, and mAb1108 (FIG. 4B) demonstrated .about.80% inhibition of KLK5 activity. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 4). FIG. 5 shows the results of three experiments for pro-KLK1 and they are expressed as area of pro-peptide KLK1. The IC.sub.50 value for Spink9.SRE.Fc (FIG. 5A) was 0.58 nM, for MAb1108 (FIG. 5B) was 0.34 nM and the range of IC.sub.50 values for the 12 selected anti-KLK5 antibodies (FIG. 5 C-N) was 0.08 to 0.48 nM. Spink9.SRE.Fc as well as all 12 selected anti-KLK5 antibodies fully inhibited KLK5 activity, although mAb1108 (FIG. 5B) demonstrated .about.40% inhibition of KLK5 activity. The ICso values from the curve fittings are presented in FIG. 11 (Column 5).

Specificity of KLK5 Antibodies

[0528] To evaluate the specificity the anti-KLK5 antibodies characterized in FIGS. 1-5, the 12 anti-KLK5 antibodies were assayed against activated human KLK7 (FIG. 6), human KLK1 (FIG. 7), human KLK4 (FIG. 8) and trypsin (FIG. 9) monitored by the cleavage of specific fluorescent peptide substrates. As these 12 anti-KLK5 antibodies were generated to selectively interact with KLK5, it was anticipated that these molecules should not inhibit other KLKs (FIGS. 6-9) or trypsin (FIG. 9).

[0529] In FIG. 6, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected anti-KLK5 antibodies to inhibit the proteolysis of the substrate, Suc-LLVY-AMC, by human KLK7 was assessed using an enzymatic assay. The cleavage of the peptide substrate by human KLK7 resulted in an increased fluorescent signal and the inhibition or absence of KLK7 resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum KLK7 activity (% control). The results of a single experiment run in duplicate are shown in FIG. 6. Spink9.SRE.Fc (FIG. 6A) and mAb1108 (FIG. 6B) did not inhibit KLK7 up to 100 nM. As seen in FIG. 6, the 12 selected anti-KLK5 antibodies (FIGS. 6C-N) also do not inhibit KLK7 activity up to 100 nM. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 6).

[0530] In FIG. 7, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected anti-KLK5 antibodies to inhibit the proteolysis of the substrate, PFR-AMC, by human KLK1 was assessed using an enzymatic assay. The cleavage of the peptide substrate by human KLK1 resulted in an increased fluorescent signal and the inhibition or absence of KLK1 resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum KLK1 activity (% control). The results of a single experiment run in duplicate are shown in FIG. 7. Spink9.SRE.Fc (FIG. 7A) and mAb1108 (FIG. 7B) did not inhibit KLK1 up to 100 nM. As seen in FIG. 7, the 12 selected anti-KLK5 antibodies (FIGS. 7C-N) also do not inhibit KLK1 activity up to 100 nM. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 7).

[0531] In FIG. 8, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected anti-KLK5 antibodies to inhibit the proteolysis of the substrate, Boc-VPR-AMC, by human KLK4 was assessed using an enzymatic assay. The cleavage of the peptide substrate by human KLK4 resulted in an increased fluorescent signal and the inhibition or absence of KLK4 resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum KLK4 activity (% control). The results of a single experiment run in duplicate are shown in FIG. 8. Spink9.SRE.Fc (FIG. 8A) and mAb1108 (FIG. 8B) did not inhibit KLK4 up to 100 nM. As seen in FIG. 8, the 12 selected anti-KLK5 antibodies (FIGS. 8C-N) also do not inhibit KLK4 activity up to 100 nM. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 8).

[0532] In FIG. 9, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected antibodies to inhibit the proteolysis of the substrate, Boc-VPR-AMC, by bovine trypsin was assessed using an enzymatic assay. The cleavage of the peptide substrate by trypsin resulted in an increased fluorescent signal and the inhibition or absence of trypsin resulted in a quenched fluorescent signal. The results were expressed as a percentage of maximum trypsin activity (% control). The results of a single experiment run in duplicate are shown in FIG. 9. Spink9.SRE.Fc (FIG. 9A) and mAb1108 (FIG. 9B) did not inhibit trypsin up to 100 nM. As seen in FIG. 9, the 12 selected antibodies (FIG. 9C-N) also do not inhibit trypsin activity up to 100 nM. The IC.sub.50 values from the curve fittings are presented in FIG. 11 (Column 9).

[0533] Taken together, these studies using KLK7 (FIG. 6 and Table 6), KLK1 (FIG. 7 and Table 7), KLK4 (FIG. 8 and Table 8) and trypsin (FIG. 9 and Table 9) show that Spink9.SRE.Fc, mAb1108 or the 12 selected antibodies specifically interact and inhibit only KLK5 activity.

Ranking of Antibodies by Ki.sub.app

[0534] In characterizing the 12 selected antibodies in either the direct (FIG. 1) or coupled assays (FIGS. 2-5), it was observed that the selected antibodies have similar or greater inhibitory potency than Spink9.SRE.Fc for KLK5. However, several of the antibodies have similar IC.sub.50 values in each of the assays (Tables 1-5) making it difficult to rank the potency of the antibodies.

[0535] In FIG. 10, the ability of Spink9.SRE.Fc, mAb1108 or 12 selected antibodies to inhibit the proteolysis of the substrate, z-VPR-pNA, by human KLK5 at various concentrations was assessed using an enzymatic assay. In this assay the three-mer chromogenic peptide substrate contains a p-nitroanilide (pNA) group that is quenched by the terminal amino acid. The cleavage of the chromogenic peptide substrate by KLK5 resulted in an increased absorbance at 405 nm and the inhibition or absence of KLK5 resulted in a low absorbance 405 nm. The results were expressed as a percentage of maximum KLK5 activity (% control).

[0536] The IC.sub.50 values of Spink9.SRE.Fc at various KLK5 concentrations (FIG. 10A) is determined and plotted as a function of KLK5 concentration (FIG. 10B) where the Ki.sub.app value is determined as the y-intercept. From this analysis, the Ki.sub.app value for Spink9.SRE.Fc is 1.28 nM. This analysis was also performed for mAb1108 (FIGS. 10 C-D) that has a Ki.sub.app value of 1.53 nM as well as the 12 selected antibodies (FIGS. 10 E-AB), which have a range of Ki.sub.app values of less than 0.01 nM to 6.35 nM. The Ki.sub.app values from this analysis are presented in FIG. 11 (Column 10).

Example 4--Kinetic Analysis and Epitope Binning with Wasatch

[0537] The results of the epitope binning and off-rates against human KLK5 for a subset of the most potent antibodies are shown in Table 4. Variable levels of binding were observed to mouse and cyno KLK5. Importantly, no binding was observed to human KLK1, human KLK4, or human KLK7, confirming that these antibodies are specific. Most clones, except for 8E11 and 8G10, compete with SPINK9 for binding to human KLK5, suggesting that they either bind the same epitope (i.e., the active site) at SPINK9 or allosterically alter human KLK5 so that SPINK9 can no longer bind.

TABLE-US-00004 TABLE 4 Clone ID SPINK9 competition (Y/N) human KLK5 kd (1/s) 14C8 Y 3.76E.sup.-04 14E12 Y 4.14E.sup.-04 2B11 Y 5.74E.sup.-04 8B7 Y 5.47E.sup.-04 8E11 N 2.02E.sup.-04 8F5 Y 3.16E.sup.-04 8G10 N 2.45E.sup.-04 9B6 Y 1.78E.sup.-04 9F2 Y 3.39E.sup.-04 9H3 Y 1.43E.sup.-04 9H5 Y 3.67E.sup.-04 10C5 Y 1.26E.sup.-04 10C8 Y 6.16E.sup.-05 10H3 Y 5.89E.sup.-04 2.3F4 Y 1.84E.sup.-04 SPINK9-SRE-Fc Y 4.70E.sup.-04

Example 5--Epitope Mapping by Hydrogen Exchange Mass Spectrometry

[0538] Hydrogen exchange measurements as completed herein measure the exchange of protons bound to backbone amide residues with those bound to molecules of the solvent. When a protiated (.sup.1H) sample is diluted into deuterated solvent, difference in mass between a proton and deuteron can be measured by mass spectrometry. Upon a series of increasing incubation times in deuterated solvent (.sup.2H.sub.2O), rate of exchange can be measured. In this way, KLK 5 (SEQ ID NO:353) complexed to one of three anti-KLK5 antibodies (10C5, 10H3 and 9H5) over three separate experiments was measured and then compared to results obtained from performing the experiment on KLK5 alone. A differential analysis of mass differences was then performed and overlapping peptides utilized to narrow in on a common thermodynamic epitope shared between all three anti-KLK5 antibodies (10C5, 10H3 and 9H5) (FIG. 12 A). The term "thermodynamic epitope" refers to those portions of a protein whose backbone structural dynamics, or local free energy of unfolding is altered in response to a specific binding event such as becoming bound by an antibody. The structural epitope may be contained within the thermodynamic epitope.

[0539] Interpretation of data used the rule of N-2 whereby each peptide cannot carry deuterium on the first two sites due to back exchange. In addition, when there are many unique overlapping peptides, this information may be used to narrow in on those affected residues within each peptide. The four sequence regions of KLK5 identified to comprise a common thermodynamic epitope between are LRPNQL (FIG. 12 B, Region 1), QGVKSI (FIG. 12 B, Region 2), KRCEDAYPRQIDDT (FIG. 12 B, Region 3), and DYPCARPNRPGVY (FIG. 12 B, Region 4), a common structural epitope between all three antibodies tested is contained within these regions.

[0540] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Example 6--Evaluation of KLK5 Inhibitor IC.sub.50 Values in a Cell-Based IL-8 Secretion Assay

[0541] KLK5 stimulates A549 cells to secrete IL-8. The ability of Spink5.Fc, Spink9.SRE.Fc, or humanized anti-KLK5 antibodies 3-3F5, 9H5, or 10C5, to inhibit KLK5-induced IL-8 secretion was evaluated in the A549 cell-based IL-8 secretion assay. In this assay, serum-starved A549 cells were stimulated with 200 nM KLK5 for 24 hr (KLK5 alone or KLK5 pre-incubated with inhibitors for 1 hour). The IL-8 concentration was measured with a sandwich ELISA and IC.sub.50s of the inhibitors were determined. The results were expressed as a percentage of maximum KLK5 activity and the averages.+-.standard deviations of at least three independent experiments are shown in FIG. 17. All inhibitors fully inhibited KLK5-induced IL-8 secretion to within 5% of the level of buffer alone (starvation media), which was within the error of the assay. All inhibitors showed potent inhibition of KLK5-induced IL-8 secretion and the average IC.sub.50s for at least three independent experiments were as follows: Spink5.Fc (21 nM); 10C5 (28 nM); 9H5 (15 nM); 3-3F5 (1.2 nM). The residual activity observed when KLK5 is incubated with 360 nM Spink9.SRE.Fc is 2% (data not shown).

Example 7--Structure of 10C5, 9H5 and 3-3F5 Bound to Human KLK5

[0542] For crystal structure experiments described herein, human KLK5 residues I67-S293 (SEQ ID NO:328) were used. The numbering of the amino acid residues of human KLK5 used in this Example 7 and as shown in corresponding FIGS. 18-20 and Tables 5-13 is based on the standard numbering for proteases. See Debela et al., J Mol Biol, 373, 1017-1031 (2007). The numbering of the amino acid residues of the Fab fragments used in this Example 7 and as shown in corresponding FIGS. 18-20 and Tables 5-13 is based on Kabat.

The Structure of 10C5 Bound to Human KLK5

[0543] The 10C5 Fab/KLK5 complex structure shows that the binding of 10C5 to KLK5 results in conformational changes that allosterically result in disruption of the substrate binding site as well as the active site of KLK5, including the catalytic triad, rendering the protease unable to bind substrates and losing activity. The most distinct element of KLK5 that is recognized by the 10C5 fab is the helix encompassing residues 163-174A. The loop/turn immediately following the helix, made up by the residues 173-174A is flipped up by the antibody binding which results in a steric clash with residues in the 220s loop as well as the 90s loop (standard protease convention), that are important for substrate binding as well as positioning of the catalytic triad in the active site that cleaves peptides (FIG. 18A).

[0544] The buried surface area between KLK5 and 10C5 Fab is .about.860 .ANG..sup.2. In the 10C5 fab light chain, CDR-L1, residues Q24-S34 contact residues 5131, A132, 5164 and R167 in KLK5; Y50 from CDR-L2 contacts R167 in KLK5; CDR-L3 contacts A132, L163, 5164, Q165, K166, E169, I176, D177 and D178 in KLK5. In the 10C5 heavy chain, CDRH1, residues S31-T35 contact only D170 in KLK5; CDRH2, residues Y50-A63, contacts residues K166, E169, D170, A171, Y172, P173, R174, Q174A and 1176 in KLK5; CDRH3, E95-Y100c contacts residues 5164, K166, R167 and D170 in KLK5 (Tables 5-7, FIG. 18B).

[0545] The sequences of the 10C5 Fab HC and LC used for the crystallization with human KLK5 is depicted in SEQ ID NO:322 and SEQ ID NO:323, respectively.

TABLE-US-00005 TABLE 5 Interface Interface residues in residues KLK5 in KLK5 Interface residues in (Standard Interface residues in (Standard 10C5 Heavy Chain Protease 10C5 Light Chain Protease (Kabat Numbering) Numbering) (Kabat Numbering) Numbering) Ser 31 Ser 164 Glu 27 Pro 130 Gly 33 Lys 166 Ser 28 Ser 131 Tyr 50 Arg 167 Ser 30 Ala 132 Thr 52 Glu 169 Glu 32 Val 162 Ser 52A Asp 170 Tyr 50 Leu 163 Asn 53 Ala 171 Gly 91 Ser 164 Tyr 54 Tyr 172 Phe 92 Gln 165 Val 56 Pro 173 Gly 93 Lys 166 Ser 57 Arg 174 Ser 94 Arg 167 Tyr 58 Gln 174A Ser 95 Glu 169 Tyr 59 Ile 176 Val 97 Gln 174A Lys 64 Arg 224 Ile 176 Glu 95 Asp 177 Pro 97 Asp 178 Gly 100 Lys 233 Tyr 100A Tyr 100C

TABLE-US-00006 TABLE 6 Hydrogen Bonds Bond Bond Heavy Chain Length Light Chain Length Residue (Angstrom) KLK5 residue Residue (Angstrom) KLK5 residue Tyr 50 [OH] 2.8 Glu 169 [OE2] Tyr 50 [OH] 2.6 Arg 167 [NH1] Ser 52A [OG] 2.6 Asp 170 [OD1] Phe 92 [O] 2.9 Gln 165 [N] Ser 52A [N] 3.4 Asp 170 [OD2] Phe 92 [O] 3.2 Lys 166 [N] Tyr 58 [OH] 3.8 Arg 174 [O] Ser 95 [OG] 3.7 Asp 178 [N] Ser 57 [O] 2.6 Gln 174A Ser 94 [N] 2.7 Glu 169 [OE1] [NE2] Tyr 58 [OH] 3.0 Ile 176 [N]

TABLE-US-00007 TABLE 7 Salt Bridges Bond Heavy Chain Length Residue (Angstrom) KLK5 residue Glu 95 [OE1] 2.3 Lys 166 [NZ] Glu 95 [OE1] 3.4 Lys 166 [NZ]

The Structure of 9H5 Bound to Human KLK5

[0546] The 9H5 Fab/KLK5 complex structure shows that the binding of 9H5 to KLK5 results in conformational changes, similar to 10C5 fab, result in allosteric disruption of the substrate binding site as well as the active site of KLK5, including the catalytic triad, rendering the protease unable to bind substrates and losing activity. The most distinct element of KLK5 that is recognized by the 9H5 fab is the helix encompassing residues 163-174A. The loop/turn immediately following the helix, made up by the residues 173-174A is flipped up by the antibody binding which results in a steric clash with residues in the 220s loop as well as the 90s loop (standard protease convention), that are important for substrate binding as well as positioning of the catalytic triad in the active site that cleaves peptides. Overall, more of the KLK5 protein is disordered in the 9H5:KLK5 complex crystal structure, compared to 10C5 bound KLK5, and is likely a direct result of the Fab binding and the induced conformational changes (FIG. 19A).

[0547] The buried surface area between KLK5 and 9H5 Fab is 805 .ANG..sup.2. In the 9H5 light chain, CDRL1, residues Q24-S34 contacts residues 5131, A132, G133, L163, 5164, R167 in KLK5; CDRL2, residues S50-S56, does not contact any residues in KLK5; CDRL3, residues H89-T97 contact residues A132, 5164, Q165, K166, E169, Q174A, 1176 and D177 in KLK5. In the 9H5 heavy chain, CDRH1, residues S31-S35 do not contact KLK5; CDRH2, residues F50-A63 contacts residues K166, E169, D170, Y172, P173, R174, Q174A and 1176 in KLK5; CDRH3, residues D95-1102 contacts residues K166, R167 and D170 in KLK5 (Tables 8-10, FIG. 19B).

[0548] The sequences of the 9H5 Fab HC and LC used for the crystallization with human KLK5 is depicted in SEQ ID NO:324 and SEQ ID NO:325, respectively.

TABLE-US-00008 TABLE 8 Interface Interface residues residues in KLK5 in KLK5 Interface residues in (Standard Interface residues (Standard 9H5 Heavy Chain Protease in 9H5 Light Chain Protease (Kabat Numbering) Numbering) (Kabat Numbering) Numbering) Ser 31 Ser 164 Gln 27 Pro 130 Gly 33 Lys 166 Ser 28 Ser 131 Ser 35 Arg 167 Ser 30 Ala 132 Phe 50 Glu 169 Tyr 32 Gly 133 Gly 52 Asp 170 His 89 Val 162 Ser 53 Ala 171 Gln 90 Leu 163 Gly 54 Tyr 172 Asp 91 Ser 164 Phe 56 Pro 173 Tyr 92 Gln 165 Tyr 58 Arg 174 Thr 93 Lys 166 Lys 64 Gln 174A Ser 94 Arg 167 Asp 95 Ile 176 Ser 95 Glu 169 Val 97 Asp 177 Asn 95A Gln 174A Gly 98 Thr 97 Ile 176 Ser 100B Asp 177 Leu 100C Lys 233

TABLE-US-00009 TABLE 9 Hydrogen Bonds Bond Bond Heavy Chain Length Light Chain Length Residue (Angstrom) KLK5 residue Residue (Angstrom) KLK5 residue Ser 53 [N] 2.3 Asp 170 [OD2] Tyr 92 [O] 3.2 Gln 165 [N] Ser 53 [N] 3.5 Asp 170 [O] Tyr 92 [O] 2.8 Lys 166 [N] Ser 53 [OG] 2.2 Asp 170 [OD2] Ser 30 [OG] 3.1 Ala 132 [O] Ser 53 [OG] 3.7 Asp 170 [O] Thr 93 [OG1] 2.9 Glu 169 [OE1] Gly 54 [N] 3.5 Asp 170 [OD2] Ser 95 [OG] 3.4 Glu 169 [OE1] Gly 54 [N] 2.8 Asp 170 [O] Ser 94 [N] 3.0 Glu 169 [OE2] Tyr 58 [OH] 3.1 Ile 176 [O] Ser 95 [OG] 3.6 Ile 176 [O] Gly 98 [O] 3.6 Arg 167 [NH2] Asn 95A 2.5 Asp 177 [OD1] [ND2] Tyr 58 [OH] 2.7 Ile 176 [N]

TABLE-US-00010 TABLE 10 Salt Bridges Bond Heavy Chain Length Residue (Angstrom) KLK5 residue Asp 95 [OD1] 2.5 Lys 166 [NZ] Asp 95 [OD2] 3.7 Lys 166 [NZ]

The Structure of 3F5.5 Fab Bound to Human KLK5

[0549] The 3-3F5 Fab/KLK5 complex structure shows that the binding of the 3-3F5 to KLK5 results in slight conformational changes, although not as drastic as observed with the 10C5 or the 9H5 complexes with KLK5. The substrate recognition pocket is altered, where the Asp 189 in KLK5, (which forms a salt bridge and thereby recognizing positively charged P1-residue (Arg/Lys) before proteolysis) becomes disordered. The catalytic triad in KLK5 appears intact, although the fab binding renders the catalytic pocket more open, resulting in KLK5 losing catalytic activity. The 140s loop and 70s loop are disordered in the crystal structure (FIG. 20A).

[0550] The buried surface area between KLK5 and 3F5.5 Fab is 956 .ANG..sup.2. In the 3-3F5 light chain, CDRL1, residues Q24-A34 contact 5131, A132 and G133 in KLK5; CDRL2, residues D50-S56 does not contact any residues in KLK5; CDRL3, residues Q89-I97 contact residues S164, Q165, K166 and E169 in KLK5. In the 3F5.5 heavy chain, CDRH1 residues D31-E46 does not interact with KLK5 at all, neither does CDRH2; CDRH3, residues D95-G100i contact residues L163, 5164, K166, R167, D170, G184, D185, K186, A187, N224, R225 and P225 in KLK5 (Tables 11-13, FIG. 20B).

[0551] The sequences of the 3-3F5 Fab HC and LC used for the crystallization with human KLK5 is depicted in SEQ ID NO:326 and SEQ ID NO:327, respectively.

TABLE-US-00011 TABLE 11 Interface Interface residues residues in KLK5 in KLK5 Interface residues in (Standard Interface residues in (Standard 3-3F5 Heavy Chain Protease 3-3F5 Light Chain Protease (Kabat Numbering) Numbering) (Kabat Numbering) Numbering) Asp 31 Leu 163 Ile2 Ser 131 Trp 47 Ser 164 Ser 28 Ala 132 Gly 52 Lys 166 Ile 29 Gly 133 Ser 53 Arg 167 Gly 30 Ser 164 Ser 54 Glu 169 Asn 31 Gln 165 Val 56 Asp 170 Ala 32 Lys 166 Trp 58 Ala 171 Asp 50 Arg 167 Asp 95 Pro 173 Gly 68 Glu 169 Arg 96 Arg 174 Gln 89 Asp 170 Asp 97 Gly 184 Gln 90 Tyr 98 Asp 185 Gly 91 Gly 99 Lys 186 Asp 92 Tyr 100 Ala 186A Ser 93 Arg 100A Arg 188 His 94 Ala 100B Asn 223 Asn 95 Asp 100C Arg 224 Ile 97 Ala 100E Pro 225 Thr 100F Ser 100G Met 100I

TABLE-US-00012 TABLE 12 Hydrogen Bonds Bond Bond Heavy Chain Length Light Chain Length KLK5 Residue (Angstrom) KLK5 residue Residue (Angstrom) residue Ser 53 [N] 3.0 Asp 170 [OD1] Ser 28 [OG] 2.9 Ser 131 [OG] Ser 54 [N] 3.0 Asp 170 [OD1] Asp 92 [OD1] 3.7 Gln 165 [N] Ser 54 [OG] 2.8 Asp 170 [OD1] Asp 92 [O] 3.1 Gln 165 [N] Gly 99 [N] 3.1 Asp 170 [OD2] Asp 92 [O] 3.0 Lys 166 [N] Ser 53 [N] 3.1 Asp 170 [OD2] Asn 31 [N] 3.6 Ala 132 [O] Ser 53 [OG] 3.0 Asp 170 [OD2] Asn 95 [ND2] 3.1 Gln 165 [OE] Ala 100B [N] 2.8 Asn 223 [OD1] Thr 100F [O] 3.9 Arg 167 [NH1] Arg 96 [O] 2.8 Arg 167 [NH1] Ser 100G [OG] 2.8 Arg 167 [NH2] Tyr 100 [OH] 2.9 Asp 185 [N] Tyr 100 [OH] 3.7 Lys 186 [N] Arg 100A [O] 2.8 Lys 186 [NZ] Tyr 100 [O] 3.0 Asn 223 [ND2]

TABLE-US-00013 TABLE 13 Salt Bridges Bond Heavy Chain Length Residue (Angstrom) KLK5 residue His 94 [NE2] 2.8 Glu 169 [OE1] His 94 [NE2] 3.9 Glu 169 [OE2]

TABLE-US-00014 Table of Sequences SEQ NAME SEQUENCE ID NO Human KLK5 MATARPPWMWVLCALITALLLGVTEHVLANNDVSCDHPSNTVPSGSNQDLGAGAGE 1 Q9Y337 DARSDDSSSRIINGSDCDMHTQPWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKK G55, D153 VFRVRLGHYSLSPVYESGQQMFQGVKSIPHPGYSHPGHSNDLMLIKLNRRIRPTKD (incl. signal VRPINVSSHCPSAGTKCLVSGWGTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQ peptide IDDTMFCAGDKAGRDSCQGDSGGPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCK (underlined)) FTKWIQETIQANS Human KLK5 ##STR00001## 2 G55, D153 PWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKKVFRVRLGHYSLSPVYESGQQMF (mature form) ##STR00002## GTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQIDDTMFCAGDKAGRDSCQGDSG GPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCKFTKWIQETIQANS Human KLK5 ##STR00003## 3 G55, N153 DARSDDSSSRIINGSDCDMHTQPWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKK (incl. signal ##STR00004## peptide (under VRPINVSSHCPSAGTKCLVSGWGTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQ lined)) IDDTMFCAGDKAGRDSCQGDSGGPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCK FTKWIQETIQANS Human KLK5 ##STR00005## 4 G55, N153 PWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKKVFRVRLGHYSLSPVYESGQQMF (mature form) ##STR00006## GTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQIDDTMFCAGDKAGRDSCQGDSG GPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCKFTKWIQETIQANS Human KLK5 ##STR00007## 5 R55, N153 DARSDDSSSRIINGSDCDMHTQPWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKK (incl. signal ##STR00008## peptide (under VRPINVSSHCPSAGTKCLVSGWGTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQ lined)) IDDTMFCAGDKAGRDSCQGDSGGPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCK FTKWIQETIQANS Human KLK5 ##STR00009## 6 R55, N153 PWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKKVFRVRLGHYSLSPVYESGQQMF (mature form) ##STR00010## GTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQIDDTMFCAGDKAGRDSCQGDSG GPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCKFTKWIQETIQANS Human KLK5 ##STR00011## 7 R55, D153 DARSDDSSSRIINGSDCDMHTQPWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKK (incl. signal ##STR00012## peptide (under VRPINVSSHCPSAGTKCLVSGWGTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQ lined)) IDDTMFCAGDKAGRDSCQGDSGGPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCK FTKWIQETIQANS Human KLK5 ##STR00013## 8 R55, D153 PWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKKVFRVRLGHYSLSPVYESGQQMF (mature form) ##STR00014## GTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQIDDTMFCAGDKAGRDSCQGDSG GPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCKFTKWIQETIQANS Human SPINK5 MKIATVSVLLPLALCLIQDAASKNEDQEMCHEFQAFMKNGKLFCPQDKKFFQSLDG 9 Q9NQ38 IMFINKCATCKMILEKEAKSQKRARHLARAPKATAPTELNCDDFKKGERDGDFICP (incl. signal DYYEAVCGTDGKTYDNRCALCAENAKTGSQIGVKSEGECKSSNPEQDVCSAFRPFV peptide RDGRLGCTRENDPVLGPDGKTHGNKCAMCAELFLKEAENAKREGETRIRRNAEKDF (underlined)) CKEYEKQVRNGRLFCTRESDPVRGPDGRMHGNKCALCAEIFKQRFSEENSKTDQNL GKAEEKTKVKREIVKLCSQYQNQAKNGILFCTRENDPIRGPDGKMHGNLCSMCQAY FQAENEEKKKAEARARNKRESGKATSYAELCSEYRKLVRNGKLACTRENDPIQGPD GKVHGNTCSMCEVFFQAEEEEKKKKEGKSRNKRQSKSTASFEELCSEYRKSRKNGR LFCTRENDPIQGPDGKMHGNTCSMCEAFFQQEERARAKAKREAAKEICSEFRDQVR NGTLICTREHNPVRGPDGKMHGNKCAMCASVFKLEEEEKKNDKEEKGKVEAEKVKR EAVQELCSEYRHYVRNGRLPCTRENDPIEGLDGKIHGNTCSMCEAFFQQEAKEKER AEPRAKVKREAEKETCDEFRRLLQNGKLFCTRENDPVRGPDGKTHGNKCAMCKAVF QKENEERKRKEEEDQRNAAGHGSSGGGGGNTQDECAEYREQMKNGRLSCTRESDPV RDADGKSYNNQCTMCKAKLEREAERKNEYSRSRSNGTGSESGKDTCDEFRSQMKNG KLICTRESDPVRGPDGKTHGNKCTMCKEKLEREAAEKKKKEDEDRSNTGERSNTGE RSNDKEDLCREFRSMQRNGKLICTRENNPVRGPYGKMHINKCAMCQSIFDREANER KKKDEEKSSSKPSNNAKDECSEFRNYIRNNELICPRENDPVHGADGKFYTNKCYMC RAVFLTEALERAKLQEKPSHVRASQEEDSPDSFSSLDSEMCKDYRVLPRIGYLCPK DLKPVCGDDGQTYNNPCMLCHENLIRQTNTHIRSTGKCEESSTPGTTAASMPPSDE Human SPINK5 KNEDQEMCHEFQAFMKNGKLFCPQDKKFFQSLDGIMFINKCATCKMILEKEAKSQK 10 (mature form) RARHLARAPKATAPTELNCDDFKKGERDGDFICPDYYEAVCGTDGKTYDNRCALCA ENAKTGSQIGVKSEGECKSSNPEQDVCSAFRPFVRDGRLGCTRENDPVLGPDGKTH GNKCAMCAELFLKEAENAKREGETRIRRNAEKDFCKEYEKQVRNGRLFCTRESDPV RGPDGRMHGNKCALCAEIFKQRFSEENSKTDQNLGKAEEKTKVKREIVKLCSQYQN QAKNGILFCTRENDPIRGPDGKMHGNLCSMCQAYFQAENEEKKKAEARARNKRESG KATSYAELCSEYRKLVRNGKLACTRENDPIQGPDGKVHGNTCSMCEVFFQAEEEEK KKKEGKSRNKRQSKSTASFEELCSEYRKSRKNGRLFCTRENDPIQGPDGKMHGNTC SMCEAFFQQEERARAKAKREAAKEICSEFRDQVRNGTLICTREHNPVRGPDGKMHG NKCAMCASVFKLEEEEKKNDKEEKGKVEAEKVKREAVQELCSEYRHYVRNGRLPCT RENDPIEGLDGKIHGNTCSMCEAFFQQEAKEKERAEPRAKVKREAEKETCDEFRRL LQNGKLFCTRENDPVRGPDGKTHGNKCAMCKAVFQKENEERKRKEEEDQRNAAGHG SSGGGGGNTQDECAEYREQMKNGRLSCTRESDPVRDADGKSYNNQCTMCKAKLERE AERKNEYSRSRSNGTGSESGKDTCDEFRSQMKNGKLICTRESDPVRGPDGKTHGNK CTMCKEKLEREAAEKKKKEDEDRSNTGERSNTGERSNDKEDLCREFRSMQRNGKLI CTRENNPVRGPYGKMHINKCAMCQSIFDREANERKKKDEEKSSSKPSNNAKDECSE FRNYIRNNELICPRENDPVHGADGKFYTNKCYMCRAVFLTEALERAKLQEKPSHVR ASQEEDSPDSFSSLDSEMCKDYRVLPRIGYLCPKDLKPVCGDDGQTYNNPCMLCHE NLIRQTNTHIRSTGKCEESSTPGTTAASMPPSDE HVR-H1 Sequences HVR-H1 DYNMA 11 14C8 HVR-H1 DYYMA 12 14E12 HVR-H1 SSYWIC 13 8E11 HVR-H1 TSYWIC 14 8G10 HVR-H1 NYGVT 15 9B6 HVR-H1 NYGVS 16 2.3F4 HVR-H1 SYGVT 17 10C5, hu10C5-H1 to hu10C5-H28 HVR-H1 NYGVS 18 2B11 HVR-H1 TFAIN 19 10H3 HVR-H1 GYGVS 20 9H3 HVR-H1 NYGVT 21 8B7 HVR-H1 SYGVS 22 9F2, 10C8, 9H5, hu9H5-H1 to hu9H5-H17 HVR-H1 SYPIS 23 8F5 HVR-H1 DYGVS 24 3-3F5, hu3-3F5-H1 to hu3-3F5-H27 HVR-H1 NNYVNFVMC 25 9E3 HVR-H1 DNYVMS 26 10D10 HVR-H1 GGGIY 27 12B3, 1D10 HVR-H1 X.sub.1YGVX.sub.2 wherein X.sub.1 is S or D, X.sub.2 is T or S 28 10C5, hu10C5-H1 to hu10C5-H28, 9H5, hu9H5-H1 to hu9H5-H17, 3-3F5, hu3-3F5-H1 to hu3-3F5-H27 (consensus) HVR-H2 Sequences HVR-H2 TISYDAGRTYYRDSVKG 29 14C8 HVR-H2 SISYDGDTTYYRDSVKG 30 14E12 HVR-H2 CVYGLDVNIYYASWTK 31 8E11 HVR-H2 CVYGLDVNIYYASWTE 32 8G10 HVR-H2 FIGSGGSAYYASWAKS 33 9B6, 9H3 HVR-H2 FIGYGGSTYYASWAKS 34 2.3F4 HVR-H2 YITSNYGVSYYASWAKS 35 10C5, hu10C5-H1 to hu10C5-H10, hu10C5-H12, hu10C5-H14 to hu10C5-H16, hu10C5-H18 to hu10C5-H28 HVR-H2 YITSNYGVSYYANSVKG 36 hu10C5-H11, hu10C5-H13 HVR-H2 YITSNYGVSYYASFAKS 37 hu10C5-H17 HVR-H2 YITSNYGVSYYAX.sub.1X.sub.2X.sub.3KX.sub.4 wherein X.sub.1 is S or N, X.sub.2 is W, S or 38 hu10C5-H1 to F, X.sub.3 is A or V, X.sub.4 is S or G hu10C5-H28 (consensus) HVR-H2 YIGSAGSTYYATWAKS 39 2B11 HVR-H2 AIGRGGSAYYASWAKS 40 10H3 HVR-H2 FIGSSGSAYYASWAKS 41 8B7 HVR-H2 FIGSGGFAYYASWAKS 42 10C8, 9H5, hu9H5-H1 to hu9H5-H10, hu9H5-H12, hu9H5-H14 to hu9H5-H16 HVR-H2 FIGSGGFAYYADSVKG 43 hu9H5-H11, hu9H5-H13 HVR-H2 FIGSGGFAYYASFAKS 44 hu9H5-H17 HVR-H2 FIGSGGFAYYAX.sub.1X.sub.2X.sub.3KX.sub.4 wherein X.sub.1 is S or D, X.sub.2 is W, S or 45 hu9H5-H1 to F, X.sub.3 is A or V, X.sub.4 is S or G hu9H5-H17 (consensus) HVR-H2 FIGSGGSPYYASWAKS 46 9F2 HVR-H2 YITSEYGVAYYATWAES 47 8F5

HVR-H2 AIGSSGVAWYANWAKG 48 3-3F5, hu3-3F5-H1 to hu3-3F5-H9, hu3-3F5-H14, hu3-3F5-H16, hu3-3F5-H17 HVR-H2 AIGSSGVAFYANWAKG 49 hu3-3F5-H10, hu3-3F5-H12, hu3-3F5-H15 HVR-H2 AIGSSGVAWYADSVKG 50 hu3-3F5-H11, HVR-H2 AIGSSGVAFYADSVKG 51 hu3-3F5-H13 HVR-H2 AIGSSGVAWYANFAKG 52 hu3-3F5-H18 to hu3-3F5-H26 HVR-H2 AIGSSGVAFYANFAKG 53 hu3-3F5-H27 HVR-H2 AIGSSGVAX.sub.1YAX.sub.2X.sub.3X.sub.4KG wherein X.sub.1 is W or F, X.sub.2 is N or D, X.sub.3 54 hu3-3F5-H1 to is W, S or F, X.sub.4 is A or V hu3-3F5-H27 (consensus) HVR-H2 SIDPGDDSTDYASWAT 55 9E3 HVR-H2 CIDPGDDSTYYASWAT 56 10D10 HVR-H2 SIYPDHGSVDYANWVNG 57 12B3 HVR-H2 YIYPDHGSADYATWVNG 58 1D10 HVR-H2 X.sub.1IGSX.sub.2GX.sub.3AX.sub.4YAX.sub.5X.sub.6X.sub.7KX.sub.8 wherein X.sub.1 is F or A, X.sub.2 is G or S, 59 9H5, X.sub.3 is F or V, X.sub.4 is Y, W, or F, X.sub.5 is S, D, or N, X.sub.6 is W, hu9H5-H1 to S, or F, X.sub.7 is A or V, X.sub.8 is S or G hu9H5-H17, 3-3F5, hu3-3F5-H1 to hu3-3F5-H27 (consensus) HVR-H3 Sequences HVR-H3 GIFNYGTDYFDY 60 14C8 HVR-H3 DGTIPAGSWFAY 61 14E12 HVR-H3 GGGSADFGFDL 62 8E11, 8G10 HVR-H3 DDVGGGKSLDI 63 9B6 HVR-H3 LCGVDCADALDS 64 2.3F4 HVR-H3 ENPDYGYAYDA 65 10C5, hu10C5-H1 to hu10C5-H28 HVR-H3 AAYSAGSADAEDI 66 2B11 HVR-H3 ENAGSGWGELDI 67 10H3 HVR-H3 DNVGGDMSLDI 68 9H3 HVR-H3 DDVGGGKSLDI 69 8B7, 9F2, 9H5, hu9H5-H1 to hu9H5-H17 HVR-H3 DDVGGGRSLDI 70 10C8 HVR-H3 ENPTYGYAYDA 71 8F5 HVR-H3 DRDYGYRADDATSGMDL 72 3-3F5, hu3-3F5-H1 to hu3-3F5-H27 HVR-H3 GDAGTSYSFNF 73 9E3 HVR-H3 GDAAASYSFNF 74 10D10 HVR-H3 ESGGSYYDL 75 12B3 HVR-H3 ETGGSWYDL 76 1D10 HVR-Ll Sequences HVR-L1 RASEDIYSGLA 77 14C8 HVR-L1 LASKNIYRNLA 78 14E12 HVR-L1 QASENIYSLLA 79 8E11, 8G10 HVR-L1 QASQNIGDYLS 80 9B6 HVR-L1 QASEDIGSYCS 81 2.3F4 HVR-Ll QASESISNELS 82 10C5, hu10C5-L1 to hu10C5-L6 HVR-Ll QASQSISNYVA 83 2B11 HVR-L1 QASESISSDLA 84 10H3 HVR-L1 QASQNINNYLS 85 9H3 HVR-L1 QASQSIGSYLS 86 8B7 HVR-L1 QASQSISSYLS 87 9H5, hu9H5-L1 to hu9H5-L4 HVR-L1 QASQSISNYLS 88 9F2 HVR-L1 QASQSISTYLS 89 10C8 HVR-L1 QASESIGNELS 90 8F5 HVR-L1 QASESIGNALA 91 3-3F5, hu3-3F5-L1 to hu3-3F5-L5 HVR-L1 QASESISRYLS 92 9E3 HVR-L1 QASESISTYLS 93 10D10 HVR-L1 QASQSISTYLA 94 12B3 HVR-L1 QASQSISSYLA 95 1D10 HVR-L1 QASX.sub.1SIX.sub.2X.sub.3X.sub.4LX.sub.5 wherein X.sub.1 is E or Q, X.sub.2 is S or G, X.sub.3 is 96 10C5, N or S, X.sub.4 is E, Y or A, X.sub.5 is S or A hu10C5-L1 to hu10C5-L6, 9H5, hu9H5-L1 to hu9H5-L4, 3-3F5, hu3-3F5-L1 to hu3-3F5-L5 (consensus) HVR-L2 Sequences HVR-L2 GATTLHD 97 14C8 HVR-L2 DASRLQD 98 14E12 HVR-L2 DASDLAS 99 8E11, 8G10, 2.3F4, 9E3, 10D10, 3-3F5, hu3-3F5-L1 to hu3-3F5-L5 HVR-L2 SASTLAS 100 9B6 HVR-L2 YASTLAS 101 10C5, hu10C5-L1 to hu10C5-L6 HVR-L2 RASTLAS 102 2B11 HVR-L2 AASTLAS 103 10H3, 9H3 HVR-L2 DASNLAS 104 8B7 HVR-L2 SASTLAS 105 9F2 10C8 9H5, hu9H5-L1 to hu9H5-L4 HVR-L2 QASTLAS 106 8F5 HVR-L2 KTSTLAS 107 12B3 HVR-L2 KASTLAS 108 1D10 HVR-L2 X.sub.1ASX.sub.2LAS wherein X.sub.1 is Y, S or D, X.sub.2 is T or D 109 10C5, hu10C5-L1 to hu10C5-L6

9H5, hu9H5-L1 to hu9H5-L4, 3-3F5, hu3-3F5-L1 to hu3-3F5-L5 (consensus) HVR-L3 Sequences HVR-L3 HQGLSFPYT 110 14C8 HVR-L3 QQYHDYPYT 111 14E12 HVR-L3 QATAYGSSGNA 112 8E11, 8G10 HVR-L3 HQDYTSNDVENT 113 9B6 HVR-L3 QQDYTGNNVDNT 114 2.3F4 HVR-L3 AQGFGSSGVENV 115 10C5, hu10C5-L1 to hu10C5-L6 HVR-L3 HQGYSSSNVDNI 116 2B11 HVR-L3 QQGYTWNNVDNV 117 10H3 HVR-L3 HQDYTSNNVDNT 118 9H3, 8B7, 10C8 HVR-L3 HQDYTSSNVDNT 119 9H5, hu9H5-L1 to hu9H5-L4 HVR-L3 HQDYTSNSVDNT 120 9F2 HVR-L3 AQGFSSSGVENV 121 8F5 HVR-L3 QQGDSHNNVDNI 122 3-3F5, hu3-3F5-L1 to hu3-3F5-L5 HVR-L3 QQDYSRSNIVNS 123 9E3 HVR-L3 QQDYSSSNIVNS 124 10D10 HVR-L3 QQGYSGSSVENT 125 12B3 HVR-L3 QQGYSGSNVENT 126 1D10 HVR-L3 X.sub.1QX.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7VX.sub.8NX.sub.9 wherein X.sub.1 is A, H or Q, X.sub.2 is G or D, 127 10C5, X.sub.3 is F, Y or D, X.sub.4 is G, T or S, X.sub.5 is S or H, X.sub.6 is S hu10C5-L1 to or N, X.sub.7 is G or N, X.sub.8 is E or D, X.sub.9 is V, T or I hu10C5-L6 9H5, hu9H5-L1 to hu9H5-L4, 3-3F5, hu3-3F5-L1 to hu3-3F5-L5 (consensus) VL Sequences (HVRs underlined) VL DIQMTQSPASLSASLGETVTIQCRASEDIYSGLAWYQQKPGKSPQLLIYGATTLHD 128 14C8 GVPSRFSGSGSGTQYSLKISSMHSEDEGIYFCHQGLSFPYTFGAGTKLELK VL DIQMTQSPASLSASLGETVTIECLASKNIYRNLAWYQQKPGKSPQFLISDASRLQD 129 14E12 GVPSRFTGSDSGSQYSLKINSLQSEDVATYFCQQYHDYPYTFGAGTKLELK VL DVVMTQTASPVSAAVGGTVTIKCQASENIYSLLAWYQQKPGQPPKVLIYDASDLAS 130 8E11 GVPSRFKGSGSGTQFTLTISDLECADAATYYCQATAYGSSGNAFGGGTEVVVK VL DVVMTQTPASVSEPVGGTVTIKCQASENIYSLLAWYQQKPGQPPKVLIYDASDLAS 131 8G10 GVPSRFKGSGSGTQFTLTISDLECADAATYYCQATAYGSSGNAFGGGTEVVVK VL NIVMTQTPASVEVAVGGTVVIKCQASQNIGDYLSWYQQKPGQRPKLLIYSASTLAS 132 9B6 GVPSRFKGSGSGTQFTLTISDLECADAATYYCHQDYTSNDVENTFGGGTEVVVK VL AYYMTQTPASVEVAVGGTVTIKCQASEDIGSYCSWYQQKPGQPPKLLIYDASDLAS 133 2.3F4 GVPSRFKGSGSGTDFTLTISGVQCDDAATYYCQQDYTGNNVDNTFGGGSEVVVK VL AYDMTQTPASLEAAVGGTVTINCQASESISNELSWYQQKPGQPPDLLIYYASTLAS 134 10C5 GVPSRFKGSGSGTEFTLTISDLECADAATYYCAQGFGSSGVENVFGGGTEVVVK VL AYRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKPPKLLIYYASTLAS 135 hu10C5-L1 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCAQGFGSSGVENVFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKPPKLLIYYASTLAS 136 hu10C5-L2 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCAQGFGSSGVENVFGGGTKVEIK VL AYRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKAPKLLIYYASTLAS 137 hu10C5-L3 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCAQGFGSSGVENVFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKAPKLLIYYASTLAS 138 hu10C5-L4 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCAQGFGSSGVENVFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKAPKLLIYYASTLAS 139 hu10C5-L5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGFGSSGVENVFGGGTKVEIK VL AX.sub.1RMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKX.sub.2PKLLIYYASTLA 140 10C5, SGVPSRFSGSGSGTDFTLTISX.sub.3LQX.sub.4EDFATYYCAQGFGSSGVENVFGGGTX.sub.- 5VX.sub.6 hu10C5-L1 to X.sub.7K hu10C5-L6 wherein X.sub.1 is Y or I, X.sub.2 is P or A, X.sub.3 is C or S, X.sub.4 is S (consensus) or P, X.sub.5 is E or K, X.sub.6 is E or V, X.sub.7 is I or V VL AYYMTQTPASVEAAVGGTVTIKCQASQSISNYVAWYQQKPGQPPKLLIYRASTLAS 141 2B11 GVSSRFSGSGSGTEFTLTISDLECADAATYYCHQGYSSSNVDNIFGGGTEVVVK VL AYEMTQTPASVEVAVGGTVTINCQASESISSDLAWYQQKPGQRPKLLIYAASTLAS 142 10H3 GVPSRFKGSGSGTEFTLSISGVQCADAATYYCQQGYTWNNVDNVFGGGTEVVVK VL DIVMTQTPASVSEPVGGTVTIKCQASQNINNYLSWYQQKPGQPPKQLIYAASTLAS 143 9H3 GVPSRFKGSGSGTQFTLTISDLECADAATYYCHQDYTSNNVDNTFGGGTEVVVK VL NIVMTQTPASVEVAVGGTVTIKCQASQSIGSYLSWYQQKPGQPPKLLIYDASNLAS 144 8B7 GVPSRFKGSGSGTQFTLSISDLECADAATYYCHQDYTSNNVDNTFGGGTEVVIK VL NIVMTQTPASVEAAVGGTVTINCQASQSISSYLSWYQQKSGQRPKLLIFSASTLAS 145 9H5 GVPSRFTGSGSGTQFTLTISDLQCADAATYYCHQDYTSSNVDNTFGGGTEVVVK VL DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKRPKLLIFSASTLAS 146 hu9H5-L1 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTKVEIK VL DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKAPKLLIFSASTLAS 147 hu9H5-L2 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTKVEIK VL DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKRPKLLIYSASTLAS 148 hu9H5-L3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTKVEIK VL DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKAPKLLIYSASTLAS 149 hu9H5-L4 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTKVEIK VL DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKAPKLLIYSASTLAS 150 hu9H5-L5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTEVVVK VL DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKX.sub.1PKLLIX.sub.2SASTLA 151 9H5, SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTX.sub.3VX.sub.4X.su- b.5 hu9H5-L1 to K hu9H5-L5 wherein X.sub.1 is R or A, X.sub.2 is F or Y, X.sub.3 is E or K, X.sub.4 is E (consensus) or V, X.sub.5 is V or I VL NIVMTQTPASVEVAVGGTVIIKCQASQSISNYLSWYHQKSGQRPRLLIYSASTLAS 152 9F2 GVPSRFKGSGSGTQFTLTISDLECADAATYYCHQDYTSNSVDNTFGGGTEVVVK VL NIVMTQTPASVEVAMGGTVIIKCQASQSISTYLSWYQQKPGQPPKLLIYSASTLAS 153 10C8 GVSSRFEGSGSGTQFTLTISGVQCADAATYYCHQDYTSNNVDNTFGGGTEVVVK VL AYDLTQTPASVEAAVGGTVTINCQASESIGNELSWYQQKSGQPPKLLIYQASTLAS 154 8F5 GVPSRFKGSGSGTDFTLTISDLECADAATYYCAQGFSSSGVENVFGGGTEVVVK VL AYDMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYDASDLAS 155 3-3F5 GVPSRFKGSGSGTQFTLTISGVECADAATYYCQQGDSHNNVDNIFGGGTEVVVK VL AYRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKPPKLLIYDASDLAS 156 hu3-3F5-L1 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCQQGDSHNNVDNIFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKPPKLLIYDASDLAS 157 hu3-3F5-L2 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCQQGDSHNNVDNIFGGGTKVEIK VL AYRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKAPKLLIYDASDLAS 158 hu3-3F5-L3 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCQQGDSHNNVDNIFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKAPKLLIYDASDLAS 159 hu3-3F5-L4 GVPSRFSGSGSGTDFTLTISCLQSEDFATYYCQQGDSHNNVDNIFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKAPKLLIYDASDLAS 160 hu3-3F5-L5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGDSHNNVDNIFGGGTKVEIK VL AIRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKAPKLLIYDASDLAS 161 hu3-3F5-L6 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGDSHNNVDNIFGGGTEVVVK VL AX.sub.1RMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKX.sub.2PKLLIYDASDLA 162 3-3F5, SGVPSRFSGSGSGTDFTLTISX.sub.3LQX.sub.4EDFATYYCQQGDSHNNVDNIFGGGTX.sub- .5VX.sub.6 hu3-3F5-L1 to X.sub.7K hu3-3F5-L6 wherein X.sub.1 is Y or I, X.sub.2 is P or A, X.sub.3 is C or S, X.sub.4 is S (consensus) or P X.sub.5 is E or K, X.sub.6 is E or V, X.sub.7 is V or I VL AIEMTQTPSSASEPVGGTVTIKCQASESISRYLSWYQQKPGQPPKLLIYDASDLAS 163 9E3 GVSSRFKGSGSGTQFTLIISDVECADAATYYCQQDYSRSNIVNSFGGGTEVVVK VL AYDMTQTPSSASEPVGGTVTIKCQASESISTYLSWYQQKPGQPPKLLIYDASDLAS 164 10D10 GVSSRFKGSGSGTQFTLTISDVECADAATYYCQQDYSSSNIVNSFGGGTEVVVK VL AYDMTQTPASVEVAVGGTVTIKCQASQSISTYLAWYQQKPGQRPNLLIYKTSTLAS 165 12B3 GVPSRFRGSGSGTQFTLTISGVECADAATYYCQQGYSGSSVENTFGGGTEVVVK VL AYDMTQTPVSVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYKASTLAS 166 1D10 GVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSGSNVENTFGGGTEVVVK VH Sequences (HVRs underlined) VH EVQLVESGGGLVQPGRSLKLSCTASGFTFSDYNMAWVRQAPKGGLEWVTTISYDAG 167 14C8 RTYYRDSVKGRFTISRDNAKRTLSLQMDSLRSEDTATYYCATGIFNYGTDYFDYWG QGVMVTVSS VH EVQLVESGGGLVRPGRSLRLSCAASGFTFSDYYMAWVRQAPTKGLEWVASISYDGD 168 14E12 TTYYRDSVKGRFTISRDNARSSLYLQMDSLRSDDTANYFCTTDGTIPAGSWFAYWG QGTLVTVSS VH QEQLEESGGDLVKPEGSLTLTCTASGFSFSSSYWICWVRQAPGKGLEWIACVYGLD 169 8E11 VNIYYASWTKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGGGSADEGFDLWGP GTLVTVSS VH QSLEESGGDLVKPEGSLTLTCTASGFSFSTSYWICWVRQAPGKGLEWIACVYGLDV 170 8G10 NIYYASWTEGRFTISKTSSTTVTLQVTSLTAADTATYFCARGGGSADFGFDLWGPG TLVTVSS VH QSVKESEGGLFKPTDNLTLTCTVSGFSLSNYGVTWVRQAPGNGLEYIGFIGSGGSA 171 9B6 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT LVTVSS VH QSVEESRGGLIKPTDTLTLTCTASGFSLSNYGVSWVRQAPGNGLEYIGFIGYGGST 172 2.3F4 YYASWAKSRSTITRNTNLNTVTLQMTSLTAADTATYFCARLCGVDCADALDSWGPG TLVTVSS VH QSLEESGGGLVKPTDTLTLTCTVSGFSLSSYGVTWVRQAPGRGLEWIGYITSNYGV 173 10C5 SYYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARENPDYGYAYDAWGPG TLVTVSV

VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 174 hu10C5-H1 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 175 hu10C5-H2 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEYIGYITSNYG 176 hu10C5-H3 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 177 hu10C5-H4 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWISYITSNYG 178 hu10C5-H5 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 179 hu10C5-H6 VSYYASWAKSRFTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 180 hu10C5-H7 VSYYASWAKSRSTISRDNSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 181 hu10C5-H8 VSYYASWAKSRSTISRDTSKNTLYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 182 hu10C5-H9 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 183 hu10C5-H10 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 184 hu10C5-H11 VSYYANSVKGRSTISRDTSKNTVYLQMGSLRAEDMAVYFCARENPDYGYAYDAWGP GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEYVSYITSNYG 185 hu10C5-H12 VSYYASWAKSRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEYVSYITSNYG 186 hu10C5-H13 VSYYANSVKGRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 187 hu10C5-H14 VSYYASWAKSRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EQQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 188 hu10C5-H15 VSYYASWAKSRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 189 hu10C5-H16 VSYYASWAKSRFTISRNLNTNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 190 hu10C5-H17 VSYYASFAKSRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYCYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 191 hu10C5-H18 VSYYASWAKSRFTISRNTNLNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 192 hu10C5-H19 VSYYASWAKSRFTISRNNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 193 hu10C5-H20 VSYYASWAKSRFTISRDNNKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 194 hu10C5-H21 VSYYASWAKSRFTISRNNNKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 195 hu10C5-H22 VSYYASWAKSRFTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 196 hu10C5-H23 VSYYASWAKSRSTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 197 hu10C5-H24 VSYYASWAKSRSTISRDNSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 198 hu10C5-H25 VSYYASWAKSRFTISRDTSKNTLYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWVGYITSNYG 199 hu10C5-H26 VSYYASWAKSRFTISRDNSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 200 hu10C5-H27 VSYYASWAKSRSTISRDNSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 201 hu10C5-H28 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ GTTVTVSS VH EX.sub.1QLVESGGGLVQPGGSLRLSCAX.sub.2SGFSLSSYGVTWVRQAPGKGLEX.sub.3X.sub.- 4X.sub.5YITS 202 10C5, NYGVSYYAX.sub.6X.sub.7X.sub.8KX.sub.9RX.sub.10TISRX.sub.11X.sub.12X.- sub.13X.sub.14NTX.sub.15YLQMGSLRAEDMAVYX.sub.16CA hu10C5-H1 to RENPDYGYAYDAWGX.sub.17GTTVTVSS hu10C5-H28 wherein X.sub.1 is V or Q, X.sub.2 is V or A, X.sub.3 is W or Y, X.sub.4 is I (consensus) or V, X.sub.5 is G or S, X.sub.6 is S or N, X.sub.7 is W, S or F, X.sub.8 is A or V, X.sub.9 is S or G, X.sub.10 is S or F, X.sub.11 is D or N, X.sub.12 is T, L or N, X.sub.13 is S or N, X.sub.14 is K, T or L, X.sub.15 is V or L, X.sub.16, is F or Y, X.sub.17 is P or Q VH QSVKESEGGLFKPTDTLTLTCTVSGFSLINYGVSWVRQAPGKGLEWIGYIGSAGST 203 2B11 YYATWAKSRATITRNTNLNTVTLKMTSLTAADTATYFCARAAYSAGSADAEDIWGP GTLVTVSS VH QSVKESEGGLIKPTDTLTLTCTVSGFSLSTFAINWVRQAPGNGLEWIGAIGRGGSA 204 10H3 YYASWAKSRSTITKNTNLNTVTLKMTRPTAADTATYFCARENAGSGWGELDIWGPG TLVTVSS VH QSVKESEGGLFKPTDTLTLTCTVSGFSLSGYGVSWVRQAPGKGLEYIGFIGSGGSA 205 9H3 YYASWAKSRSTITRNTNLNTVTLKMTRLTAADTATYFCARDNVGGDMSLDIWGPGT LVTVSS VH QSVKESEGGLFKPTDNLTLTCTVSGFSLSNYGVTWVRQAPGNGLEYIGFIGSSGSA 206 8B7 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT LVTVSS VH QSVKESEGGLFKPTDNLTLTCTVSGFSLSSYGVSWVRQAPGNGLEYIGFIGSGGFA 207 9H5 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT VVTVSV VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 208 hu9H5-H1 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 209 hu9H5-H2 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEWIGFIGSGGF 210 hu9H5-H3 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 211 hu9H5-H4 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYISFIGSGGF 212 hu9H5-H5 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 213 hu9H5-H6 AYYASWAKSRFTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 214 hu9H5-H7 AYYASWAKSRSTISRDNSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 215 hu9H5-H8 AYYASWAKSRSTISRDTSKNTLYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 216 hu9H5-H9 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 217 hu9H5-H10 AYYASWAKSRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGQG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAVSGFSLSSYGVSWVRQAPGKGLEYIGFIGSGGF 218 hu9H5-H11 AYYADSVKGRSTISRDTSKNTVYLQMNSLRAEDTAVYFCARDDVGGGKSLDIWGPG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEWVSFIGSGGF 219 hu9H5-H12 AYYASWAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEWVSFIGSGGF 220 hu9H5-H13 AYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 221 hu9H5-H14 AYYASWAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG TLVTVSS VH EQQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 222 hu9H5-H15 AYYASWAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 223 hu9H5-H16 AYYASWAKSRFTISRNTNLNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG TLVTVSS VH EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 224 hu9H5-H17 AYYASFAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG TLVTVSS VH EX.sub.1QLVESGGGLIQPGGSLRLSCAX.sub.2SGFSLSSYGVSWVRQAPGKGLEX.sub.3X.sub.- 4X.sub.5FIGS 225 9H5, GGFAYYAX.sub.6X.sub.7X.sub.8KX.sub.9RX.sub.10TISRX.sub.11X.sub.12X.su- b.13X.sub.14NTX.sub.15YLQMNSLRAEDTAVYX.sub.16CAR hu9H5-H1 to DDVGGGKSLDIWGX.sub.17GTLVTVSS hu9H5-H17 wherein X.sub.1 is V or Q, X.sub.2 is V or A, X.sub.3 is Y or W, X.sub.4 is I (consensus) or V, X.sub.5 is G or S, X.sub.6 is S or D, X.sub.7 is W, S or F, X.sub.8 is A or V, X.sub.9 is S or G, X.sub.10 is S or F, X.sub.11 is D or N, X.sub.12 is T or N, X.sub.13 is S or N, X.sub.14 is K or L, X.sub.15 is V or L, X.sub.16 is F or Y, X.sub.17 is P or Q VH QSVKESEGGLFKPTDNLTLTCTVSGFSLSSYGVSWVRQAPGNGLEYIGFIGSGGSP 226 9F2 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT LVTVSS VH QSVKESEGGLFKPTDNLTLTCTVSGFSLSSYGVSWVRQAPGNGLEYIGFIGSGGFA 227 10C8 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGRSLDIWGPGT VVTVSS VH QSVKESEGGLFKPTDTLTLTCTVSGFSLSSYPISWVRQAPGNGLEWIGYITSEYGV 228 8F5 AYYATWAESRSTITRNTNLNTVTLKMTSLTAADTATYFCVRENPTYGYAYDAWGPG TLVTVSS VH QSVKESEGGLFKPTDTLTLTCTVSGFSLNDYGVSWVRQAPGNGLEWIGAIGSSGVA 229 3-3F5 WYANWAKGRSTITRNTNLNTVTLKMASLTAADTATYFCARDRDYGYRADDATSGMD LWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 230 hu3-3F5-H1 AWYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 231

hu3-3F5-H2 AWYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 232 hu3-3F5-H3 AWYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWISAIGSSGV 233 hu3-3F5-H4 AWYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 234 hu3-3F5-H5 AWYANWAKGRFTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 235 hu3-3F5-H6 AWYANWAKGRSTISRHNSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 236 hu3-3F5-H7 AWYANWAKGRSTISRHTSKNTLYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 237 hu3-3F5-H8 AWYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 238 hu3-3F5-H9 AWYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 239 hu3-3F5-H10 AFYANWAKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 240 hu3-3F5-H11 AWYADSVKGRSTISRHTSKNTVYLQMNSLRAEDTAVYFCARDRDYGYRADDATSGM DLWGPGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVSAIGSSGV 241 hu3-3F5-H12 AFYANWAKGRFTISRHNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLVESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVSAIGSSGV 242 hu3-3F5-H13 AFYADSVKGRFTISRHNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 243 hu3-3F5-H14 AWYANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 244 hu3-3F5-H15 AFYANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EQQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 245 hu3-3F5-H16 AWYANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 246 hu3-3F5-H17 AWYANWAKGRFTISRNTNLNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 247 hu3-3F5-H18 AWYANFAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 248 hu3-3F5-H19 AWYANFAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 249 hu3-3F5-H20 AWYANFAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 250 hu3-3F5-H21 AWYANFAKGRSTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 251 hu3-3F5-H22 AWYANFAKGRSTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 252 hu3-3F5-H23 AWYANFAKGRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 253 hu3-3F5-H24 AWYANFAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 254 hu3-3F5-H25 AWYANFAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 255 hu3-3F5-H26 AWYANFAKGRSTISRDTSKNTVYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EVQLLESGGGLVQPGGSLRLSCAASGFSLNDYGVSWVRQAPGKGLEWIGAIGSSGV 256 hu3-3F5-H27 AFYANFAKGRSTISRDTSKNTVYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM DLWGRGTLVTVSS VH EX.sub.1QLX.sub.2ESGGGLVQPGGSLRLSCAX.sub.3SGFSLNDYGVSWVRQAPGKGLEWX.sub.- 4X.sub.5AIGS 257 3-3F5, SCVAX.sub.6YAX.sub.7X.sub.8X.sub.9KGRX.sub.10TISRX.sub.11X.sub.12X.- sub.13X.sub.14NTX.sub.15YLQMNSLRAEDTAVYX.sub.16CAR hu3-3F5-H1 to DRDYGYRADDATSGMDLWGX.sub.17GTLVTVSS hu3-3F5-H27 wherein X.sub.1 is V or Q, X.sub.2 is V or L, X.sub.3 is V or A, X.sub.4 is I (consensus) or V, X.sub.5 is G or S, X.sub.6 is W or F, X.sub.7 is N or D, X.sub.8 is W, S or F, X.sub.9 is A or V, X.sub.10 is S or F, X.sub.11 is H, N or D, X.sub.12 is T or N, X.sub.13 is S or N, X.sub.14 is K or L, X.sub.15 is V or L, X.sub.16 is F or Y, X.sub.17 is P or R VH QEQLEESGGGLVKPGASLTLTCTVSGFSLTNNYVNFVMCWVRQAPGKGLEWIASID 258 9E3 PGDDSTDYASWATGRFTISKASSTTVTLQVTSLTAADTATYFCARGDAGTSYSFNF WGPGTLVTVS VH QEQLVESGGGLVKPGASLTLTCTASGFSLTDNYVMSWVRQAPGKGLEWIACIDPGD 259 10D10 DSTYYASWATGRFTISRASSTTVTLQVTSLTAADTATYFCARGDAAASYSFNFWGP GTLVTVSS VH QSLEESGGGLVKPGGTLTLTCKASGIDFNGGGIYWVRQAPGKGLEWIASIYPDHGS 260 12B3 VDYANWVNGRFTISLDNAQNTVFLQLTSLTVADTATYFCARESGGSYYDLWGPGTL VTVSS VH QSLEESGGGLVKPGGTLTLTCTASGFDFNGGGIYWVRQAPGKGLEWIAYIYPDHGS 261 1D10 ADYATWVNGRFTISLDNAQNTVFLQMTSLTVADTATYFCARETGGSWYDLWGPGTL VTVSS LC Sequences LC DIQMTQSPASLSASLGETVTIQCRASEDIYSGLAWYQQKPGKSPQLLIYGATTLHD 262 14C8 GVPSRFSGSGSGTQYSLKISSMHSEDEGIYFCHQGLSFPYTFGAGTKLELKRADAA PTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDS KDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC DIQMTQSPASLSASLGETVTIECLASKNIYRNLAWYQQKPGKSPQFLISDASRLQD 263 14E12 GVPSRFTGSDSGSQYSLKINSLQSEDVATYFCQQYHDYPYTFGAGTKLELKRADAA PTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDS KDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC DVVMTQTASPVSAAVGGTVTIKCQASENIYSLLAWYQQKPGQPPKVLIYDASDLAS 264 8E11 GVPSRFKGSGSGTQFTLTISDLECADAATYYCQATAYGSSGNAFGGGTEVVVKRAD AAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQ DSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC DVVMTQTPASVSEPVGGTVTIKCQASENIYSLLAWYQQKPGQPPKVLIYDASDLAS 265 8G10 GVPSRFKGSGSGTQFTLTISDLECADAATYYCQATAYGSSGNAFGGGTEVVVKRAD AAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQ DSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC NIVMTQTPASVEVAVGGTVVIKCQASQNIGDYLSWYQQKPGQRPKLLIYSASTLAS 266 9B6 GVPSRFKGSGSGTQFTLTISDLECADAATYYCHQDYTSNDVENTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYYMTQTPASVEVAVGGTVTIKCQASEDIGSYCSWYQQKPGQPPKLLIYDASDLAS 267 2.3F4 GVPSRFKGSGSGTDFTLTISGVQCDDAATYYCQQDYTGNNVDNTFGGGSEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYDMTQTPASLEAAVGGTVTINCQASESISNELSWYQQKPGQPPDLLIYYASTLAS 268 10C5 GVPSRFKGSGSGTEFTLTISDLECADAATYYCAQGFGSSGVENVFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AIRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKAPKLLIYYASTLAS 269 10C5-L5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGFGSSGVENVFGGGTKVEIKRT huKappa VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC LC AYYMTQTPASVEAAVGGTVTIKCQASQSISNYVAWYQQKPGQPPKLLIYRASTLAS 270 2B11 GVSSRFSGSGSGTEFTLTISDLECADAATYYCHQGYSSSNVDNIFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYEMTQTPASVEVAVGGTVTINCQASESISSDLAWYQQKPGQRPKLLIYAASTLAS 271 10H3 GVPSRFKGSGSGTEFTLSISGVQCADAATYYCQQGYTWNNVDNVFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC DIVMTQTPASVSEPVGGTVTIKCQASQNINNYLSWYQQKPGQPPKQLIYAASTLAS 272 9H3 GVPSRFKGSGSGTQFTLTISDLECADAATYYCHQDYTSNNVDNTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC NIVMTQTPASVEVAVGGTVTIKCQASQSIGSYLSWYQQKPGQPPKLLIYDASNLAS 273 8B7 GVPSRFKGSGSGTQFTLSISDLECADAATYYCHQDYTSNNVDNTFGGGTEVVIKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC NIVMTQTPASVEAAVGGTVTINCQASQSISSYLSWYQQKSGQRPKLLIFSASTLAS 274 9H5 GVPSRFTGSGSGTQFTLTISDLQCADAATYYCHQDYTSSNVDNTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKAPKLLIYSASTLAS 275 9H5-L4 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTKVEIKRT huKappa VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC LC NIVMTQTPASVEVAVGGTVIIKCQASQSISNYLSWYHQKSGQRPRLLIYSASTLAS 276 9F2 GVPSRFKGSGSGTQFTLTISDLECADAATYYCHQDYTSNSVDNTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC NIVMTQTPASVEVAMGGTVIIKCQASQSISTYLSWYQQKPGQPPKLLIYSASTLAS 277 10C8 GVSSRFEGSGSGTQFTLTISGVQCADAATYYCHQDYTSNNVDNTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYDLTQTPASVEAAVGGTVTINCQASESIGNELSWYQQKSGQPPKLLIYQASTLAS 278 8F5 GVPSRFKGSGSGTDFTLTISDLECADAATYYCAQGFSSSGVENVFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYDMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYDASDLAS 279 3-3F5 GVPSRFKGSGSGTQFTLTISGVECADAATYYCQQGDSHNNVDNIFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AIRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKAPKLLIYDASDLAS 280 3-3F5-L5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGDSHNNVDNIFGGGTKVEIKRT huKappa VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC LC AIEMTQTPSSASEPVGGTVTIKCQASESISRYLSWYQQKPGQPPKLLIYDASDLAS 281 9E3 GVSSRFKGSGSGTQFTLIISDVECADAATYYCQQDYSRSNIVNSFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYDMTQTPSSASEPVGGTVTIKCQASESISTYLSWYQQKPGQPPKLLIYDASDLAS 282 10D10 GVSSRFKGSGSGTQFTLTISDVECADAATYYCQQDYSSSNIVNSFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYDMTQTPASVEVAVGGTVTIKCQASQSISTYLAWYQQKPGQRPNLLIYKTSTLAS 283 12B3 GVPSRFRGSGSGTQFTLTISGVECADAATYYCQQGYSGSSVENTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC LC AYDMTQTPVSVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYKASTLAS 284 1D10 GVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSGSNVENTFGGGTEVVVKRA DAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC HC Sequences

HC EVQLVESGGGLVQPGRSLKLSCTASGFTFSDYNMAWVRQAPKGGLEWVTTISYDAG 285 14C8 RTYYRDSVKGRFTISRDNAKRTLSLQMDSLRSEDTATYYCATGIFNYGTDYFDYWG QGVMVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLS SGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPT IKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQIS WFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPI ERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTE LNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRT PGK HC EVQLVESGGGLVRPGRSLRLSCAASGFTFSDYYMAWVRQAPTKGLEWVASISYDGD 286 14E12 TTYYRDSVKGRFTISRDNARSSLYLQMDSLRSDDTANYFCTTDGTIPAGSWFAYWG QGTLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLS SGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPT IKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQIS WFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPI ERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTE LNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRT PGK HC QEQLEESGGDLVKPEGSLTLTCTASGFSFSSSYWICWVRQAPGKGLEWIACVYGLD 287 8E11 VNIYYASWTKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGGGSADFGFDLWGP GTLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSS GVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISW FVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTEL NYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTP GK HC QSLEESGGDLVKPEGSLTLTCTASGFSFSTSYWICWVRQAPGKGLEWIACVYGLDV 288 8G10 NIYYASWTEGRFTISKTSSTTVTLQVTSLTAADTATYFCARGGGSADFGFDLWGPG TLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSG VHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWF VNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELN YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG K HC QSVKESEGGLFKPTDNLTLTCTVSGFSLSNYGVTWVRQAPGNGLEYIGFIGSGGSA 289 9B6 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT LVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC QSVEESRGGLIKPTDTLTLTCTASGFSLSNYGVSWVRQAPGNGLEYIGFIGYGGST 290 2.3F4 YYASWAKSRSTITRNTNLNTVTLQMTSLTAADTATYFCARLCGVDCADALDSWGPG TLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSG VHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWF VNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELN YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG K HC QSLEESGGGLVKPTDTLTLTCTVSGFSLSSYGVTWVRQAPGRGLEWIGYITSNYGV 291 10C5 SYYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARENPDYGYAYDAWGPG TLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSG VHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWF VNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELN YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG K HC EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 292 10C5-H28 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ hIgG1 GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS N297G GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW ##STR00015## KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK HC EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 293 10C5-H28 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ hIgG4 GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS 5228P GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP ##STR00016## GVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK HC QSVKESEGGLFKPTDTLTLTCTVSGFSLINYGVSWVRQAPGKGLEWIGYIGSAGST 294 2B11 YYATWAKSRATITRNTNLNTVTLKMTSLTAADTATYFCARAAYSAGSADAEDIWGP GTLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSS GVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISW FVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTEL NYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTP GK HC QSVKESEGGLIKPTDTLTLTCTVSGFSLSTFAINWVRQAPGNGLEWIGAIGRGGSA 295 10H3 YYASWAKSRSTITKNTNLNTVTLKMTRPTAADTATYFCARENAGSGWGELDIWGPG TLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSG VHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWF VNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELN YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG K HC QSVKESEGGLFKPTDTLTLTCTVSGFSLSGYGVSWVRQAPGKGLEYIGFIGSGGSA 296 9H3 YYASWAKSRSTITRNTNLNTVTLKMTRLTAADTATYFCARDNVGGDMSLDIWGPGT LVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC QSVKESEGGLFKPTDNLTLTCTVSGFSLSNYGVTWVRQAPGNGLEYIGFIGSSGSA 297 8B7 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT LVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC QSVKESEGGLFKPTDNLTLTCTVSGFSLSSYGVSWVRQAPGNGLEYIGFIGSGGFA 298 9H5 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT VVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 299 9H5-H14 AYYASWAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG hIgG1 TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG N297G VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY ##STR00017## TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVESCSVMHEALHNHYTQKSLSLSPG K HC EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 300 9H5-H14 AYYASWAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG hIgG4 TLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG S228P VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP ##STR00018## VEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK HC QSVKESEGGLFKPTDNLTLTCTVSGFSLSSYGVSWVRQAPGNGLEYIGFIGSGGSP 301 9F2 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGKSLDIWGPGT LVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC QSVKESEGGLFKPTDNLTLTCTVSGFSLSSYGVSWVRQAPGNGLEYIGFIGSGGFA 302 10C8 YYASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCARDDVGGGRSLDIWGPGT VVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC QSVKESEGGLFKPTDTLTLTCTVSGFSLSSYPISWVRQAPGNGLEWIGYITSEYGV 303 8F5 AYYATWAESRSTITRNTNLNTVTLKMTSLTAADTATYFCVRENPTYGYAYDAWGPG TLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSG VHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWF VNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELN YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG K HC QSVKESEGGLFKPTDTLTLTCTVSGFSLNDYGVSWVRQAPGNGLEWIGAIGSSGVA 304 3-3F5 WYANWAKGRSTITRNTNLNTVTLKMASLTAADTATYFCARDRDYGYRADDATSGMD LWGPGTLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSG SLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPR GPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDV QISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLP APIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNG KTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSF SRTPGK HC EVQLLESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 305 3-3F5-H19 AWYANFAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM hIgG1 DLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS N297G GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE ##STR00019## PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK HC EVQLLESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 306 3-3F5-H19 AWYANFAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM hIgG4 DLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS S228P GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE ##STR00020## NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSS IEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLGK HC QEQLEESGGGLVKPGASLTLTCTVSGFSLTNNYVNFVMCWVRQAPGKGLEWIASID 307 9E3 PGDDSTDYASWATGRFTISKASSTTVTLQVTSLTAADTATYFCARGDAGTSYSFNF WGPGTLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGS LSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRG PTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQ ISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPA PIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGK TELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFS RTPGK HC QEQLVESGGGLVKPGASLTLTCTASGFSLTDNYVMSWVRQAPGKGLEWIACIDPGD 308 10D10 DSTYYASWATGRFTISRASSTTVTLQVTSLTAADTATYFCARGDAAASYSFNFWGP GTLVTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSS GVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISW FVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTEL NYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTP GK HC QSLEESGGGLVKPGGTLTLTCKASGIDFNGGGIYWVRQAPGKGLEWIASIYPDHGS 309 12B3 VDYANWVNGRFTISLDNAQNTVFLQLTSLTVADTATYFCARESGGSYYDLWGPGTL VTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVH TFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVN NVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTI SKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYK NTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HC QSLEESGGGLVKPGGTLTLTCTASGFDFNGGGIYWVRQAPGKGLEWIAYIYPDHGS 310 1D10 ADYATWVNGRFTISLDNAQNTVFLQMTSLTVADTATYFCARETGGSWYDLWGPGTL VTVSSASTKGPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVH TFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVN NVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTI SKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYK NTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK Constant Regions

huKappa RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 311 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC hIgG1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV 312 N297 LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH ##STR00021## QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK hIgG1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV 313 G297 LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH ##STR00022## QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK hIgG4 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV 314 S228 ##STR00023## EFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK hIgG4 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV 315 P228 ##STR00024## EFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Miscellaneous Sequences KLK5 thermo- LRPNQL 316 dynamic epitope Region 1 KLK5 thermo- QGVKSI 317 dynamic epitope Region 2 KLK5 thermo- KRCEDAYPRQIDDT 318 dynamic epitope Region 3 KLK5 thermo- DYPCARPNRPGVY 319 dynamic epitope Region 4 Hu SPINK9 IESAKQTKQMVDCSHYKKLPPGQQRFCHREYDPICGSDGKTYKNDCFFCSK 320 (I20-C86. VKKTDGTLKFVHFGKCGNSVTDKTHTCPPCPAPELLGGPSVFLFPPKPKDT C22S.H48R. LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR M49E); Fc VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP human IgG1 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS E356.M358 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK VL AIRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKAPKLLIYYASTLAS 321 hu10C5-L6 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGFGSSGVENVFGGGTEVVVK Fab HC EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYGVTWVRQAPGKGLEWIGYITSNYG 322 10C5 VSYYASWAKSRSTISRDTSKNTVYLQMGSLRAEDMAVYYCARENPDYGYAYDAWGQ Humanized GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD Fab LC AIRMTQSPSSFSASTGDRVTITCQASESISNELSWYQQKPGKAPKLLIYYASTLAS 323 10C5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGFGSSGVENVFGGGTKVEIKRT Humanized VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Fab HC EVQLVESGGGLIQPGGSLRLSCAASGFSLSSYGVSWVRQAPGKGLEYVGFIGSGGF 324 9H5 AYYASWAKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDVGGGKSLDIWGQG Humanized TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD Fab LC DIQMTQSPSSLSASVGDRVTITCQASQSISSYLSWYQQKPGKAPKLLIYSASTLAS 325 9H5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQDYTSSNVDNTFGGGTKVEIKRT Humanized VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Fab HC EVQLLESGGGLVQPGGSLRLSCAVSGFSLNDYGVSWVRQAPGKGLEWVGAIGSSGV 326 3-3F5 AWYANFAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRDYGYRADDATSGM Humanized DLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCD Fab LC AIRMTQSPSSFSASTGDRVTITCQASESIGNALAWYQQKPGKAPKLLIYDASDLAS 327 3-3F5 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGDSHNNVDNIFGGGTKVEIKRT Humanized VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Human KLK5 IINGSDCDMHTQPWQAALLLRPNQLYCGAVLVHPQWLLTAAHCRKKVFRVRLGHYS 328 Crystal LSPVYESGQQMFQGVKSIPHPGYSHPGHSNDLMLIKLNRRIRPTKDVRPINVSSHC Structure PSAGTKCLVSGWGTTKSPQVHFPKVLQCLNISVLSQKRCEDAYPRQIDDTMFCAGD Experiments KAGRDSCQGDSGGPVVCNGSLQGLVSWGDYPCARPNRPGVYTNLCKFTKWIQETIQ ANS Framework Sequences FR-L1 AX.sub.1RMTQSPSSFSASTGDRVTITC 329 10C5 wherein X.sub.1 is Y or I (consensus) FR-L2 WYQQKPGKX.sub.1PKLLIY 330 10C5 wherein X.sub.1 is P or A (consensus) FR-L3 GVPSRFSGSGSGTDFTLTISX.sub.1LQX.sub.2EDFATYYC 331 10C5 wherein X.sub.1 is C or S, X.sub.2 is S or P (consensus) FR-L4 FGGGTX.sub.1VX.sub.2X.sub.3K 332 10C5 wherein X.sub.1 is E or K, X.sub.2 is E or V, X.sub.3 is I or V (consensus) FR-H1 EX.sub.1QLVESGGGLVQPGGSLRLSCAX.sub.2SGFSLS 333 10C5 wherein X.sub.1 is V or Q, X.sub.2 is V or A (consensus) FR-H2 WVRQAPGKGLEX.sub.1X.sub.2X.sub.3 334 10C5 wherein X.sub.1 is W or Y, X.sub.2 is I or V, X.sub.3 is G or S (consensus) FR-H3 RX.sub.1TISRX.sub.2X.sub.3X.sub.4X.sub.5NTX.sub.6YLQMGSLRAEDMAVYX.su- b.7CAR 335 10C5 wherein X.sub.1 is S or F, X.sub.2 is D or N, X.sub.3 is T, L or N, X.sub.4 (consensus) is S or N, X.sub.5 is K, T or L, X.sub.6 is V or L, X.sub.7 is F or Y FR-H4 WGX.sub.1GTTVTVSS 336 10C5 wherein X.sub.1 is P or Q (consensus) FR-L1 DIQMTQSPSSLSASVGDRVTITC 337 9H5 FR-L2 WYQQKPGKX.sub.1PKLLIX.sub.2 338 9H5 wherein X.sub.1 is R or A, X.sub.2 is F or Y (consensus) FR-L3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 339 9H5 FR-L4 FGGGTX.sub.3VX.sub.4X.sub.5K 340 9H5 wherein X.sub.3 is E or K, X.sub.4 is E or V, X.sub.5 is V or I (consensus) FR-H1 EX.sub.1QLVESGGGLIQPGGSLRLSCAX.sub.2SGFSLS 341 9H5 wherein X.sub.1 is V or Q, X.sub.2 is V or A (consensus) FR-H2 WVRQAPGKGLEX.sub.1X.sub.2X.sub.3 342 9H5 wherein X.sub.1 is Y or W, X.sub.2 is I or V, X.sub.3 is G or S (consensus) FR-H3 RX.sub.1TISRX.sub.2X.sub.3X.sub.4X.sub.5NTX.sub.6YLQMNSLRAEDTAVYX.su- b.7CAR 343 9H5 wherein X.sub.1 is S or F, X.sub.2 is D or N, X.sub.3 is T or N, X.sub.4 is S (consensus) or N, X.sub.5 is K or L, X.sub.6 is V or L, X.sub.7 is F or Y FR-H4 WGX.sub.1GTLVTVSS 344 9H5 wherein X.sub.1 is P or Q (consensus) FR-L1 AX.sub.1RMTQSPSSFSASTGDRVTITC 345 3-3F5 wherein X.sub.1 is Y or I (consensus) FR-L2 WYQQKPGKX.sub.1PKLLIY 346 3-3F5 wherein X.sub.1 is P or A (consensus) FR-L3 GVPSRFSGSGSGTDFTLTISX.sub.1LQX.sub.2EDFATYYC 347 3-3F5 wherein X.sub.1 is C or S, X.sub.2 is S or P (consensus) FR-L4 FGGGTX.sub.1VX.sub.2X.sub.3K 348 3-3F5 wherein X.sub.1 is E or K, X.sub.2 is E or V, X.sub.3 is V or I (consensus) FR-H1 EX.sub.1QLX.sub.2ESGGGLVQPGGSLRLSCAX.sub.3SGFSLN 349 3-3F5 wherein X.sub.1 is V or Q, X.sub.2 is V or L, X.sub.3 is V or A (consensus) FR-H2 WVRQAPGKGLEWX.sub.1X.sub.2 350 3-3F5 wherein X.sub.1 is I or V, X.sub.2 is G or S (consensus) FR-H3 RX.sub.1TISRX.sub.2X.sub.3X.sub.4X.sub.5NTX.sub.6YLQMNSLRAEDTAVYX.su- b.7CAR 351 3-3F5 wherein X.sub.1 is S or F, X.sub.2 is H, N or D, X.sub.3 is T or N, X.sub.4 is (consensus) S or N, X.sub.5 is K or L, X.sub.6 is V or L, X.sub.7 is F or Y FR-H4 WGX.sub.1GTLVTVSS 352 3-3F5 wherein X.sub.1 is P or R (consensus) Human KLK5 NNDVSCDHPSNTVPSGSNQDLGAGAGEDARSDDSSSRIINGSDCDMHTQPWQAALL 353 HDX LRPNQLYCGAVLVHPQWLLTAAHCRKKVFRVRLGHYSLSPVYESGQQMFQGVKSIP Experiments HPGYSHPGHSNDLMLIKLNRRIRPTKDVRPINVSSHCPSAGTKCLVSGWGTTKSPQ VHFPKVLQCLNISVLSQKRCEDAYPRQIDDTMFCAGDKAGRDSCQGDSGGPVVCNG SLQGLVSWGDYPCARPNRPGVYTNLCKFTKWIQETIQANSGNSDYKDDDDK

Sequence CWU 1

1

3561293PRTHomo sapiens 1Met Ala Thr Ala Arg Pro Pro Trp Met Trp Val Leu Cys Ala Leu Ile1 5 10 15Thr Ala Leu Leu Leu Gly Val Thr Glu His Val Leu Ala Asn Asn Asp 20 25 30Val Ser Cys Asp His Pro Ser Asn Thr Val Pro Ser Gly Ser Asn Gln 35 40 45Asp Leu Gly Ala Gly Ala Gly Glu Asp Ala Arg Ser Asp Asp Ser Ser 50 55 60Ser Arg Ile Ile Asn Gly Ser Asp Cys Asp Met His Thr Gln Pro Trp65 70 75 80Gln Ala Ala Leu Leu Leu Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val 85 90 95Leu Val His Pro Gln Trp Leu Leu Thr Ala Ala His Cys Arg Lys Lys 100 105 110Val Phe Arg Val Arg Leu Gly His Tyr Ser Leu Ser Pro Val Tyr Glu 115 120 125Ser Gly Gln Gln Met Phe Gln Gly Val Lys Ser Ile Pro His Pro Gly 130 135 140Tyr Ser His Pro Gly His Ser Asn Asp Leu Met Leu Ile Lys Leu Asn145 150 155 160Arg Arg Ile Arg Pro Thr Lys Asp Val Arg Pro Ile Asn Val Ser Ser 165 170 175His Cys Pro Ser Ala Gly Thr Lys Cys Leu Val Ser Gly Trp Gly Thr 180 185 190Thr Lys Ser Pro Gln Val His Phe Pro Lys Val Leu Gln Cys Leu Asn 195 200 205Ile Ser Val Leu Ser Gln Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln 210 215 220Ile Asp Asp Thr Met Phe Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser225 230 235 240Cys Gln Gly Asp Ser Gly Gly Pro Val Val Cys Asn Gly Ser Leu Gln 245 250 255Gly Leu Val Ser Trp Gly Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro 260 265 270Gly Val Tyr Thr Asn Leu Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr 275 280 285Ile Gln Ala Asn Ser 2902271PRTHomo sapiens 2Val Thr Glu His Val Leu Ala Asn Asn Asp Val Ser Cys Asp His Pro1 5 10 15Ser Asn Thr Val Pro Ser Gly Ser Asn Gln Asp Leu Gly Ala Gly Ala 20 25 30Gly Glu Asp Ala Arg Ser Asp Asp Ser Ser Ser Arg Ile Ile Asn Gly 35 40 45Ser Asp Cys Asp Met His Thr Gln Pro Trp Gln Ala Ala Leu Leu Leu 50 55 60Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val Leu Val His Pro Gln Trp65 70 75 80Leu Leu Thr Ala Ala His Cys Arg Lys Lys Val Phe Arg Val Arg Leu 85 90 95Gly His Tyr Ser Leu Ser Pro Val Tyr Glu Ser Gly Gln Gln Met Phe 100 105 110Gln Gly Val Lys Ser Ile Pro His Pro Gly Tyr Ser His Pro Gly His 115 120 125Ser Asn Asp Leu Met Leu Ile Lys Leu Asn Arg Arg Ile Arg Pro Thr 130 135 140Lys Asp Val Arg Pro Ile Asn Val Ser Ser His Cys Pro Ser Ala Gly145 150 155 160Thr Lys Cys Leu Val Ser Gly Trp Gly Thr Thr Lys Ser Pro Gln Val 165 170 175His Phe Pro Lys Val Leu Gln Cys Leu Asn Ile Ser Val Leu Ser Gln 180 185 190Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln Ile Asp Asp Thr Met Phe 195 200 205Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly 210 215 220Gly Pro Val Val Cys Asn Gly Ser Leu Gln Gly Leu Val Ser Trp Gly225 230 235 240Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro Gly Val Tyr Thr Asn Leu 245 250 255Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr Ile Gln Ala Asn Ser 260 265 2703293PRTHomo sapiens 3Met Ala Thr Ala Arg Pro Pro Trp Met Trp Val Leu Cys Ala Leu Ile1 5 10 15Thr Ala Leu Leu Leu Gly Val Thr Glu His Val Leu Ala Asn Asn Asp 20 25 30Val Ser Cys Asp His Pro Ser Asn Thr Val Pro Ser Gly Ser Asn Gln 35 40 45Asp Leu Gly Ala Gly Ala Gly Glu Asp Ala Arg Ser Asp Asp Ser Ser 50 55 60Ser Arg Ile Ile Asn Gly Ser Asp Cys Asp Met His Thr Gln Pro Trp65 70 75 80Gln Ala Ala Leu Leu Leu Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val 85 90 95Leu Val His Pro Gln Trp Leu Leu Thr Ala Ala His Cys Arg Lys Lys 100 105 110Val Phe Arg Val Arg Leu Gly His Tyr Ser Leu Ser Pro Val Tyr Glu 115 120 125Ser Gly Gln Gln Met Phe Gln Gly Val Lys Ser Ile Pro His Pro Gly 130 135 140Tyr Ser His Pro Gly His Ser Asn Asn Leu Met Leu Ile Lys Leu Asn145 150 155 160Arg Arg Ile Arg Pro Thr Lys Asp Val Arg Pro Ile Asn Val Ser Ser 165 170 175His Cys Pro Ser Ala Gly Thr Lys Cys Leu Val Ser Gly Trp Gly Thr 180 185 190Thr Lys Ser Pro Gln Val His Phe Pro Lys Val Leu Gln Cys Leu Asn 195 200 205Ile Ser Val Leu Ser Gln Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln 210 215 220Ile Asp Asp Thr Met Phe Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser225 230 235 240Cys Gln Gly Asp Ser Gly Gly Pro Val Val Cys Asn Gly Ser Leu Gln 245 250 255Gly Leu Val Ser Trp Gly Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro 260 265 270Gly Val Tyr Thr Asn Leu Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr 275 280 285Ile Gln Ala Asn Ser 2904271PRTHomo sapiens 4Val Thr Glu His Val Leu Ala Asn Asn Asp Val Ser Cys Asp His Pro1 5 10 15Ser Asn Thr Val Pro Ser Gly Ser Asn Gln Asp Leu Gly Ala Gly Ala 20 25 30Gly Glu Asp Ala Arg Ser Asp Asp Ser Ser Ser Arg Ile Ile Asn Gly 35 40 45Ser Asp Cys Asp Met His Thr Gln Pro Trp Gln Ala Ala Leu Leu Leu 50 55 60Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val Leu Val His Pro Gln Trp65 70 75 80Leu Leu Thr Ala Ala His Cys Arg Lys Lys Val Phe Arg Val Arg Leu 85 90 95Gly His Tyr Ser Leu Ser Pro Val Tyr Glu Ser Gly Gln Gln Met Phe 100 105 110Gln Gly Val Lys Ser Ile Pro His Pro Gly Tyr Ser His Pro Gly His 115 120 125Ser Asn Asn Leu Met Leu Ile Lys Leu Asn Arg Arg Ile Arg Pro Thr 130 135 140Lys Asp Val Arg Pro Ile Asn Val Ser Ser His Cys Pro Ser Ala Gly145 150 155 160Thr Lys Cys Leu Val Ser Gly Trp Gly Thr Thr Lys Ser Pro Gln Val 165 170 175His Phe Pro Lys Val Leu Gln Cys Leu Asn Ile Ser Val Leu Ser Gln 180 185 190Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln Ile Asp Asp Thr Met Phe 195 200 205Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly 210 215 220Gly Pro Val Val Cys Asn Gly Ser Leu Gln Gly Leu Val Ser Trp Gly225 230 235 240Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro Gly Val Tyr Thr Asn Leu 245 250 255Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr Ile Gln Ala Asn Ser 260 265 2705293PRTHomo sapiens 5Met Ala Thr Ala Arg Pro Pro Trp Met Trp Val Leu Cys Ala Leu Ile1 5 10 15Thr Ala Leu Leu Leu Gly Val Thr Glu His Val Leu Ala Asn Asn Asp 20 25 30Val Ser Cys Asp His Pro Ser Asn Thr Val Pro Ser Gly Ser Asn Gln 35 40 45Asp Leu Gly Ala Gly Ala Arg Glu Asp Ala Arg Ser Asp Asp Ser Ser 50 55 60Ser Arg Ile Ile Asn Gly Ser Asp Cys Asp Met His Thr Gln Pro Trp65 70 75 80Gln Ala Ala Leu Leu Leu Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val 85 90 95Leu Val His Pro Gln Trp Leu Leu Thr Ala Ala His Cys Arg Lys Lys 100 105 110Val Phe Arg Val Arg Leu Gly His Tyr Ser Leu Ser Pro Val Tyr Glu 115 120 125Ser Gly Gln Gln Met Phe Gln Gly Val Lys Ser Ile Pro His Pro Gly 130 135 140Tyr Ser His Pro Gly His Ser Asn Asn Leu Met Leu Ile Lys Leu Asn145 150 155 160Arg Arg Ile Arg Pro Thr Lys Asp Val Arg Pro Ile Asn Val Ser Ser 165 170 175His Cys Pro Ser Ala Gly Thr Lys Cys Leu Val Ser Gly Trp Gly Thr 180 185 190Thr Lys Ser Pro Gln Val His Phe Pro Lys Val Leu Gln Cys Leu Asn 195 200 205Ile Ser Val Leu Ser Gln Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln 210 215 220Ile Asp Asp Thr Met Phe Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser225 230 235 240Cys Gln Gly Asp Ser Gly Gly Pro Val Val Cys Asn Gly Ser Leu Gln 245 250 255Gly Leu Val Ser Trp Gly Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro 260 265 270Gly Val Tyr Thr Asn Leu Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr 275 280 285Ile Gln Ala Asn Ser 2906271PRTHomo sapiens 6Val Thr Glu His Val Leu Ala Asn Asn Asp Val Ser Cys Asp His Pro1 5 10 15Ser Asn Thr Val Pro Ser Gly Ser Asn Gln Asp Leu Gly Ala Gly Ala 20 25 30Arg Glu Asp Ala Arg Ser Asp Asp Ser Ser Ser Arg Ile Ile Asn Gly 35 40 45Ser Asp Cys Asp Met His Thr Gln Pro Trp Gln Ala Ala Leu Leu Leu 50 55 60Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val Leu Val His Pro Gln Trp65 70 75 80Leu Leu Thr Ala Ala His Cys Arg Lys Lys Val Phe Arg Val Arg Leu 85 90 95Gly His Tyr Ser Leu Ser Pro Val Tyr Glu Ser Gly Gln Gln Met Phe 100 105 110Gln Gly Val Lys Ser Ile Pro His Pro Gly Tyr Ser His Pro Gly His 115 120 125Ser Asn Asn Leu Met Leu Ile Lys Leu Asn Arg Arg Ile Arg Pro Thr 130 135 140Lys Asp Val Arg Pro Ile Asn Val Ser Ser His Cys Pro Ser Ala Gly145 150 155 160Thr Lys Cys Leu Val Ser Gly Trp Gly Thr Thr Lys Ser Pro Gln Val 165 170 175His Phe Pro Lys Val Leu Gln Cys Leu Asn Ile Ser Val Leu Ser Gln 180 185 190Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln Ile Asp Asp Thr Met Phe 195 200 205Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly 210 215 220Gly Pro Val Val Cys Asn Gly Ser Leu Gln Gly Leu Val Ser Trp Gly225 230 235 240Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro Gly Val Tyr Thr Asn Leu 245 250 255Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr Ile Gln Ala Asn Ser 260 265 2707293PRTHomo sapiens 7Met Ala Thr Ala Arg Pro Pro Trp Met Trp Val Leu Cys Ala Leu Ile1 5 10 15Thr Ala Leu Leu Leu Gly Val Thr Glu His Val Leu Ala Asn Asn Asp 20 25 30Val Ser Cys Asp His Pro Ser Asn Thr Val Pro Ser Gly Ser Asn Gln 35 40 45Asp Leu Gly Ala Gly Ala Arg Glu Asp Ala Arg Ser Asp Asp Ser Ser 50 55 60Ser Arg Ile Ile Asn Gly Ser Asp Cys Asp Met His Thr Gln Pro Trp65 70 75 80Gln Ala Ala Leu Leu Leu Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val 85 90 95Leu Val His Pro Gln Trp Leu Leu Thr Ala Ala His Cys Arg Lys Lys 100 105 110Val Phe Arg Val Arg Leu Gly His Tyr Ser Leu Ser Pro Val Tyr Glu 115 120 125Ser Gly Gln Gln Met Phe Gln Gly Val Lys Ser Ile Pro His Pro Gly 130 135 140Tyr Ser His Pro Gly His Ser Asn Asp Leu Met Leu Ile Lys Leu Asn145 150 155 160Arg Arg Ile Arg Pro Thr Lys Asp Val Arg Pro Ile Asn Val Ser Ser 165 170 175His Cys Pro Ser Ala Gly Thr Lys Cys Leu Val Ser Gly Trp Gly Thr 180 185 190Thr Lys Ser Pro Gln Val His Phe Pro Lys Val Leu Gln Cys Leu Asn 195 200 205Ile Ser Val Leu Ser Gln Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln 210 215 220Ile Asp Asp Thr Met Phe Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser225 230 235 240Cys Gln Gly Asp Ser Gly Gly Pro Val Val Cys Asn Gly Ser Leu Gln 245 250 255Gly Leu Val Ser Trp Gly Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro 260 265 270Gly Val Tyr Thr Asn Leu Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr 275 280 285Ile Gln Ala Asn Ser 2908271PRTHomo sapiens 8Val Thr Glu His Val Leu Ala Asn Asn Asp Val Ser Cys Asp His Pro1 5 10 15Ser Asn Thr Val Pro Ser Gly Ser Asn Gln Asp Leu Gly Ala Gly Ala 20 25 30Arg Glu Asp Ala Arg Ser Asp Asp Ser Ser Ser Arg Ile Ile Asn Gly 35 40 45Ser Asp Cys Asp Met His Thr Gln Pro Trp Gln Ala Ala Leu Leu Leu 50 55 60Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val Leu Val His Pro Gln Trp65 70 75 80Leu Leu Thr Ala Ala His Cys Arg Lys Lys Val Phe Arg Val Arg Leu 85 90 95Gly His Tyr Ser Leu Ser Pro Val Tyr Glu Ser Gly Gln Gln Met Phe 100 105 110Gln Gly Val Lys Ser Ile Pro His Pro Gly Tyr Ser His Pro Gly His 115 120 125Ser Asn Asp Leu Met Leu Ile Lys Leu Asn Arg Arg Ile Arg Pro Thr 130 135 140Lys Asp Val Arg Pro Ile Asn Val Ser Ser His Cys Pro Ser Ala Gly145 150 155 160Thr Lys Cys Leu Val Ser Gly Trp Gly Thr Thr Lys Ser Pro Gln Val 165 170 175His Phe Pro Lys Val Leu Gln Cys Leu Asn Ile Ser Val Leu Ser Gln 180 185 190Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln Ile Asp Asp Thr Met Phe 195 200 205Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly 210 215 220Gly Pro Val Val Cys Asn Gly Ser Leu Gln Gly Leu Val Ser Trp Gly225 230 235 240Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro Gly Val Tyr Thr Asn Leu 245 250 255Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr Ile Gln Ala Asn Ser 260 265 27091064PRTHomo sapiens 9Met Lys Ile Ala Thr Val Ser Val Leu Leu Pro Leu Ala Leu Cys Leu1 5 10 15Ile Gln Asp Ala Ala Ser Lys Asn Glu Asp Gln Glu Met Cys His Glu 20 25 30Phe Gln Ala Phe Met Lys Asn Gly Lys Leu Phe Cys Pro Gln Asp Lys 35 40 45Lys Phe Phe Gln Ser Leu Asp Gly Ile Met Phe Ile Asn Lys Cys Ala 50 55 60Thr Cys Lys Met Ile Leu Glu Lys Glu Ala Lys Ser Gln Lys Arg Ala65 70 75 80Arg His Leu Ala Arg Ala Pro Lys Ala Thr Ala Pro Thr Glu Leu Asn 85 90 95Cys Asp Asp Phe Lys Lys Gly Glu Arg Asp Gly Asp Phe Ile Cys Pro 100 105 110Asp Tyr Tyr Glu Ala Val Cys Gly Thr Asp Gly Lys Thr Tyr Asp Asn 115 120 125Arg Cys Ala Leu Cys Ala Glu Asn Ala Lys Thr Gly Ser Gln Ile Gly 130 135 140Val Lys Ser Glu Gly Glu Cys Lys Ser Ser Asn Pro Glu Gln Asp Val145 150 155 160Cys Ser Ala Phe Arg Pro Phe Val Arg Asp Gly Arg Leu Gly Cys Thr 165 170 175Arg Glu Asn Asp Pro Val Leu Gly Pro Asp Gly Lys Thr His Gly Asn 180 185 190Lys Cys Ala Met Cys Ala Glu Leu Phe Leu Lys

Glu Ala Glu Asn Ala 195 200 205Lys Arg Glu Gly Glu Thr Arg Ile Arg Arg Asn Ala Glu Lys Asp Phe 210 215 220Cys Lys Glu Tyr Glu Lys Gln Val Arg Asn Gly Arg Leu Phe Cys Thr225 230 235 240Arg Glu Ser Asp Pro Val Arg Gly Pro Asp Gly Arg Met His Gly Asn 245 250 255Lys Cys Ala Leu Cys Ala Glu Ile Phe Lys Gln Arg Phe Ser Glu Glu 260 265 270Asn Ser Lys Thr Asp Gln Asn Leu Gly Lys Ala Glu Glu Lys Thr Lys 275 280 285Val Lys Arg Glu Ile Val Lys Leu Cys Ser Gln Tyr Gln Asn Gln Ala 290 295 300Lys Asn Gly Ile Leu Phe Cys Thr Arg Glu Asn Asp Pro Ile Arg Gly305 310 315 320Pro Asp Gly Lys Met His Gly Asn Leu Cys Ser Met Cys Gln Ala Tyr 325 330 335Phe Gln Ala Glu Asn Glu Glu Lys Lys Lys Ala Glu Ala Arg Ala Arg 340 345 350Asn Lys Arg Glu Ser Gly Lys Ala Thr Ser Tyr Ala Glu Leu Cys Ser 355 360 365Glu Tyr Arg Lys Leu Val Arg Asn Gly Lys Leu Ala Cys Thr Arg Glu 370 375 380Asn Asp Pro Ile Gln Gly Pro Asp Gly Lys Val His Gly Asn Thr Cys385 390 395 400Ser Met Cys Glu Val Phe Phe Gln Ala Glu Glu Glu Glu Lys Lys Lys 405 410 415Lys Glu Gly Lys Ser Arg Asn Lys Arg Gln Ser Lys Ser Thr Ala Ser 420 425 430Phe Glu Glu Leu Cys Ser Glu Tyr Arg Lys Ser Arg Lys Asn Gly Arg 435 440 445Leu Phe Cys Thr Arg Glu Asn Asp Pro Ile Gln Gly Pro Asp Gly Lys 450 455 460Met His Gly Asn Thr Cys Ser Met Cys Glu Ala Phe Phe Gln Gln Glu465 470 475 480Glu Arg Ala Arg Ala Lys Ala Lys Arg Glu Ala Ala Lys Glu Ile Cys 485 490 495Ser Glu Phe Arg Asp Gln Val Arg Asn Gly Thr Leu Ile Cys Thr Arg 500 505 510Glu His Asn Pro Val Arg Gly Pro Asp Gly Lys Met His Gly Asn Lys 515 520 525Cys Ala Met Cys Ala Ser Val Phe Lys Leu Glu Glu Glu Glu Lys Lys 530 535 540Asn Asp Lys Glu Glu Lys Gly Lys Val Glu Ala Glu Lys Val Lys Arg545 550 555 560Glu Ala Val Gln Glu Leu Cys Ser Glu Tyr Arg His Tyr Val Arg Asn 565 570 575Gly Arg Leu Pro Cys Thr Arg Glu Asn Asp Pro Ile Glu Gly Leu Asp 580 585 590Gly Lys Ile His Gly Asn Thr Cys Ser Met Cys Glu Ala Phe Phe Gln 595 600 605Gln Glu Ala Lys Glu Lys Glu Arg Ala Glu Pro Arg Ala Lys Val Lys 610 615 620Arg Glu Ala Glu Lys Glu Thr Cys Asp Glu Phe Arg Arg Leu Leu Gln625 630 635 640Asn Gly Lys Leu Phe Cys Thr Arg Glu Asn Asp Pro Val Arg Gly Pro 645 650 655Asp Gly Lys Thr His Gly Asn Lys Cys Ala Met Cys Lys Ala Val Phe 660 665 670Gln Lys Glu Asn Glu Glu Arg Lys Arg Lys Glu Glu Glu Asp Gln Arg 675 680 685Asn Ala Ala Gly His Gly Ser Ser Gly Gly Gly Gly Gly Asn Thr Gln 690 695 700Asp Glu Cys Ala Glu Tyr Arg Glu Gln Met Lys Asn Gly Arg Leu Ser705 710 715 720Cys Thr Arg Glu Ser Asp Pro Val Arg Asp Ala Asp Gly Lys Ser Tyr 725 730 735Asn Asn Gln Cys Thr Met Cys Lys Ala Lys Leu Glu Arg Glu Ala Glu 740 745 750Arg Lys Asn Glu Tyr Ser Arg Ser Arg Ser Asn Gly Thr Gly Ser Glu 755 760 765Ser Gly Lys Asp Thr Cys Asp Glu Phe Arg Ser Gln Met Lys Asn Gly 770 775 780Lys Leu Ile Cys Thr Arg Glu Ser Asp Pro Val Arg Gly Pro Asp Gly785 790 795 800Lys Thr His Gly Asn Lys Cys Thr Met Cys Lys Glu Lys Leu Glu Arg 805 810 815Glu Ala Ala Glu Lys Lys Lys Lys Glu Asp Glu Asp Arg Ser Asn Thr 820 825 830Gly Glu Arg Ser Asn Thr Gly Glu Arg Ser Asn Asp Lys Glu Asp Leu 835 840 845Cys Arg Glu Phe Arg Ser Met Gln Arg Asn Gly Lys Leu Ile Cys Thr 850 855 860Arg Glu Asn Asn Pro Val Arg Gly Pro Tyr Gly Lys Met His Ile Asn865 870 875 880Lys Cys Ala Met Cys Gln Ser Ile Phe Asp Arg Glu Ala Asn Glu Arg 885 890 895Lys Lys Lys Asp Glu Glu Lys Ser Ser Ser Lys Pro Ser Asn Asn Ala 900 905 910Lys Asp Glu Cys Ser Glu Phe Arg Asn Tyr Ile Arg Asn Asn Glu Leu 915 920 925Ile Cys Pro Arg Glu Asn Asp Pro Val His Gly Ala Asp Gly Lys Phe 930 935 940Tyr Thr Asn Lys Cys Tyr Met Cys Arg Ala Val Phe Leu Thr Glu Ala945 950 955 960Leu Glu Arg Ala Lys Leu Gln Glu Lys Pro Ser His Val Arg Ala Ser 965 970 975Gln Glu Glu Asp Ser Pro Asp Ser Phe Ser Ser Leu Asp Ser Glu Met 980 985 990Cys Lys Asp Tyr Arg Val Leu Pro Arg Ile Gly Tyr Leu Cys Pro Lys 995 1000 1005Asp Leu Lys Pro Val Cys Gly Asp Asp Gly Gln Thr Tyr Asn Asn 1010 1015 1020Pro Cys Met Leu Cys His Glu Asn Leu Ile Arg Gln Thr Asn Thr 1025 1030 1035His Ile Arg Ser Thr Gly Lys Cys Glu Glu Ser Ser Thr Pro Gly 1040 1045 1050Thr Thr Ala Ala Ser Met Pro Pro Ser Asp Glu 1055 1060101042PRTHomo sapiens 10Lys Asn Glu Asp Gln Glu Met Cys His Glu Phe Gln Ala Phe Met Lys1 5 10 15Asn Gly Lys Leu Phe Cys Pro Gln Asp Lys Lys Phe Phe Gln Ser Leu 20 25 30Asp Gly Ile Met Phe Ile Asn Lys Cys Ala Thr Cys Lys Met Ile Leu 35 40 45Glu Lys Glu Ala Lys Ser Gln Lys Arg Ala Arg His Leu Ala Arg Ala 50 55 60Pro Lys Ala Thr Ala Pro Thr Glu Leu Asn Cys Asp Asp Phe Lys Lys65 70 75 80Gly Glu Arg Asp Gly Asp Phe Ile Cys Pro Asp Tyr Tyr Glu Ala Val 85 90 95Cys Gly Thr Asp Gly Lys Thr Tyr Asp Asn Arg Cys Ala Leu Cys Ala 100 105 110Glu Asn Ala Lys Thr Gly Ser Gln Ile Gly Val Lys Ser Glu Gly Glu 115 120 125Cys Lys Ser Ser Asn Pro Glu Gln Asp Val Cys Ser Ala Phe Arg Pro 130 135 140Phe Val Arg Asp Gly Arg Leu Gly Cys Thr Arg Glu Asn Asp Pro Val145 150 155 160Leu Gly Pro Asp Gly Lys Thr His Gly Asn Lys Cys Ala Met Cys Ala 165 170 175Glu Leu Phe Leu Lys Glu Ala Glu Asn Ala Lys Arg Glu Gly Glu Thr 180 185 190Arg Ile Arg Arg Asn Ala Glu Lys Asp Phe Cys Lys Glu Tyr Glu Lys 195 200 205Gln Val Arg Asn Gly Arg Leu Phe Cys Thr Arg Glu Ser Asp Pro Val 210 215 220Arg Gly Pro Asp Gly Arg Met His Gly Asn Lys Cys Ala Leu Cys Ala225 230 235 240Glu Ile Phe Lys Gln Arg Phe Ser Glu Glu Asn Ser Lys Thr Asp Gln 245 250 255Asn Leu Gly Lys Ala Glu Glu Lys Thr Lys Val Lys Arg Glu Ile Val 260 265 270Lys Leu Cys Ser Gln Tyr Gln Asn Gln Ala Lys Asn Gly Ile Leu Phe 275 280 285Cys Thr Arg Glu Asn Asp Pro Ile Arg Gly Pro Asp Gly Lys Met His 290 295 300Gly Asn Leu Cys Ser Met Cys Gln Ala Tyr Phe Gln Ala Glu Asn Glu305 310 315 320Glu Lys Lys Lys Ala Glu Ala Arg Ala Arg Asn Lys Arg Glu Ser Gly 325 330 335Lys Ala Thr Ser Tyr Ala Glu Leu Cys Ser Glu Tyr Arg Lys Leu Val 340 345 350Arg Asn Gly Lys Leu Ala Cys Thr Arg Glu Asn Asp Pro Ile Gln Gly 355 360 365Pro Asp Gly Lys Val His Gly Asn Thr Cys Ser Met Cys Glu Val Phe 370 375 380Phe Gln Ala Glu Glu Glu Glu Lys Lys Lys Lys Glu Gly Lys Ser Arg385 390 395 400Asn Lys Arg Gln Ser Lys Ser Thr Ala Ser Phe Glu Glu Leu Cys Ser 405 410 415Glu Tyr Arg Lys Ser Arg Lys Asn Gly Arg Leu Phe Cys Thr Arg Glu 420 425 430Asn Asp Pro Ile Gln Gly Pro Asp Gly Lys Met His Gly Asn Thr Cys 435 440 445Ser Met Cys Glu Ala Phe Phe Gln Gln Glu Glu Arg Ala Arg Ala Lys 450 455 460Ala Lys Arg Glu Ala Ala Lys Glu Ile Cys Ser Glu Phe Arg Asp Gln465 470 475 480Val Arg Asn Gly Thr Leu Ile Cys Thr Arg Glu His Asn Pro Val Arg 485 490 495Gly Pro Asp Gly Lys Met His Gly Asn Lys Cys Ala Met Cys Ala Ser 500 505 510Val Phe Lys Leu Glu Glu Glu Glu Lys Lys Asn Asp Lys Glu Glu Lys 515 520 525Gly Lys Val Glu Ala Glu Lys Val Lys Arg Glu Ala Val Gln Glu Leu 530 535 540Cys Ser Glu Tyr Arg His Tyr Val Arg Asn Gly Arg Leu Pro Cys Thr545 550 555 560Arg Glu Asn Asp Pro Ile Glu Gly Leu Asp Gly Lys Ile His Gly Asn 565 570 575Thr Cys Ser Met Cys Glu Ala Phe Phe Gln Gln Glu Ala Lys Glu Lys 580 585 590Glu Arg Ala Glu Pro Arg Ala Lys Val Lys Arg Glu Ala Glu Lys Glu 595 600 605Thr Cys Asp Glu Phe Arg Arg Leu Leu Gln Asn Gly Lys Leu Phe Cys 610 615 620Thr Arg Glu Asn Asp Pro Val Arg Gly Pro Asp Gly Lys Thr His Gly625 630 635 640Asn Lys Cys Ala Met Cys Lys Ala Val Phe Gln Lys Glu Asn Glu Glu 645 650 655Arg Lys Arg Lys Glu Glu Glu Asp Gln Arg Asn Ala Ala Gly His Gly 660 665 670Ser Ser Gly Gly Gly Gly Gly Asn Thr Gln Asp Glu Cys Ala Glu Tyr 675 680 685Arg Glu Gln Met Lys Asn Gly Arg Leu Ser Cys Thr Arg Glu Ser Asp 690 695 700Pro Val Arg Asp Ala Asp Gly Lys Ser Tyr Asn Asn Gln Cys Thr Met705 710 715 720Cys Lys Ala Lys Leu Glu Arg Glu Ala Glu Arg Lys Asn Glu Tyr Ser 725 730 735Arg Ser Arg Ser Asn Gly Thr Gly Ser Glu Ser Gly Lys Asp Thr Cys 740 745 750Asp Glu Phe Arg Ser Gln Met Lys Asn Gly Lys Leu Ile Cys Thr Arg 755 760 765Glu Ser Asp Pro Val Arg Gly Pro Asp Gly Lys Thr His Gly Asn Lys 770 775 780Cys Thr Met Cys Lys Glu Lys Leu Glu Arg Glu Ala Ala Glu Lys Lys785 790 795 800Lys Lys Glu Asp Glu Asp Arg Ser Asn Thr Gly Glu Arg Ser Asn Thr 805 810 815Gly Glu Arg Ser Asn Asp Lys Glu Asp Leu Cys Arg Glu Phe Arg Ser 820 825 830Met Gln Arg Asn Gly Lys Leu Ile Cys Thr Arg Glu Asn Asn Pro Val 835 840 845Arg Gly Pro Tyr Gly Lys Met His Ile Asn Lys Cys Ala Met Cys Gln 850 855 860Ser Ile Phe Asp Arg Glu Ala Asn Glu Arg Lys Lys Lys Asp Glu Glu865 870 875 880Lys Ser Ser Ser Lys Pro Ser Asn Asn Ala Lys Asp Glu Cys Ser Glu 885 890 895Phe Arg Asn Tyr Ile Arg Asn Asn Glu Leu Ile Cys Pro Arg Glu Asn 900 905 910Asp Pro Val His Gly Ala Asp Gly Lys Phe Tyr Thr Asn Lys Cys Tyr 915 920 925Met Cys Arg Ala Val Phe Leu Thr Glu Ala Leu Glu Arg Ala Lys Leu 930 935 940Gln Glu Lys Pro Ser His Val Arg Ala Ser Gln Glu Glu Asp Ser Pro945 950 955 960Asp Ser Phe Ser Ser Leu Asp Ser Glu Met Cys Lys Asp Tyr Arg Val 965 970 975Leu Pro Arg Ile Gly Tyr Leu Cys Pro Lys Asp Leu Lys Pro Val Cys 980 985 990Gly Asp Asp Gly Gln Thr Tyr Asn Asn Pro Cys Met Leu Cys His Glu 995 1000 1005Asn Leu Ile Arg Gln Thr Asn Thr His Ile Arg Ser Thr Gly Lys 1010 1015 1020Cys Glu Glu Ser Ser Thr Pro Gly Thr Thr Ala Ala Ser Met Pro 1025 1030 1035Pro Ser Asp Glu 1040115PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 11Asp Tyr Asn Met Ala1 5125PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 12Asp Tyr Tyr Met Ala1 5136PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 13Ser Ser Tyr Trp Ile Cys1 5146PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 14Thr Ser Tyr Trp Ile Cys1 5155PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 15Asn Tyr Gly Val Thr1 5165PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 16Asn Tyr Gly Val Ser1 5175PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 17Ser Tyr Gly Val Thr1 5185PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 18Asn Tyr Gly Val Ser1 5195PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 19Thr Phe Ala Ile Asn1 5205PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 20Gly Tyr Gly Val Ser1 5215PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 21Asn Tyr Gly Val Thr1 5225PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 22Ser Tyr Gly Val Ser1 5235PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 23Ser Tyr Pro Ile Ser1 5245PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 24Asp Tyr Gly Val Ser1 5259PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 25Asn Asn Tyr Val Asn Phe Val Met Cys1 5266PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 26Asp Asn Tyr Val Met Ser1 5275PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 27Gly Gly Gly Ile Tyr1 5285PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ser or AspMOD_RES(5)..(5)Thr or Ser 28Xaa Tyr Gly Val Xaa1 52917PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 29Thr Ile Ser Tyr Asp Ala Gly Arg Thr Tyr Tyr Arg Asp Ser Val Lys1 5 10 15Gly3017PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 30Ser Ile Ser Tyr Asp Gly Asp Thr Thr Tyr Tyr Arg Asp Ser Val Lys1 5 10 15Gly3116PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 31Cys Val Tyr Gly Leu Asp Val Asn Ile Tyr Tyr Ala Ser Trp Thr Lys1 5 10 153216PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 32Cys Val Tyr Gly Leu Asp Val Asn Ile Tyr Tyr Ala Ser Trp Thr Glu1 5 10 153316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 33Phe Ile Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser1 5 10 153416PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 34Phe Ile Gly Tyr Gly Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Ser1 5 10 153517PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 35Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala Lys1 5 10 15Ser3617PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 36Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Asn Ser Val Lys1 5 10 15Gly3717PRTArtificial SequenceDescription of Artificial Sequence

Synthetic peptide 37Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Phe Ala Lys1 5 10 15Ser3817PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(13)..(13)Ser or AsnMOD_RES(14)..(14)Trp, Ser or PheMOD_RES(15)..(15)Ala or ValMOD_RES(17)..(17)Ser or Gly 38Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Xaa Xaa Xaa Lys1 5 10 15Xaa3916PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 39Tyr Ile Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Thr Trp Ala Lys Ser1 5 10 154016PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 40Ala Ile Gly Arg Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser1 5 10 154116PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 41Phe Ile Gly Ser Ser Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser1 5 10 154216PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 42Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys Ser1 5 10 154316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 43Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Asp Ser Val Lys Gly1 5 10 154416PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 44Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Phe Ala Lys Ser1 5 10 154516PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(12)..(12)Ser or AspMOD_RES(13)..(13)Trp, Ser or PheMOD_RES(14)..(14)Ala or ValMOD_RES(16)..(16)Ser or Gly 45Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Xaa Xaa Xaa Lys Xaa1 5 10 154616PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 46Phe Ile Gly Ser Gly Gly Ser Pro Tyr Tyr Ala Ser Trp Ala Lys Ser1 5 10 154717PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 47Tyr Ile Thr Ser Glu Tyr Gly Val Ala Tyr Tyr Ala Thr Trp Ala Glu1 5 10 15Ser4816PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 48Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys Gly1 5 10 154916PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 49Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asn Trp Ala Lys Gly1 5 10 155016PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 50Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asp Ser Val Lys Gly1 5 10 155116PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 51Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asp Ser Val Lys Gly1 5 10 155216PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 52Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys Gly1 5 10 155316PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 53Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asn Phe Ala Lys Gly1 5 10 155416PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(9)..(9)Trp or PheMOD_RES(12)..(12)Asn or AspMOD_RES(13)..(13)Trp, Ser or PheMOD_RES(14)..(14)Ala or Val 54Ala Ile Gly Ser Ser Gly Val Ala Xaa Tyr Ala Xaa Xaa Xaa Lys Gly1 5 10 155516PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 55Ser Ile Asp Pro Gly Asp Asp Ser Thr Asp Tyr Ala Ser Trp Ala Thr1 5 10 155616PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 56Cys Ile Asp Pro Gly Asp Asp Ser Thr Tyr Tyr Ala Ser Trp Ala Thr1 5 10 155717PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 57Ser Ile Tyr Pro Asp His Gly Ser Val Asp Tyr Ala Asn Trp Val Asn1 5 10 15Gly5817PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 58Tyr Ile Tyr Pro Asp His Gly Ser Ala Asp Tyr Ala Thr Trp Val Asn1 5 10 15Gly5916PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Phe or AlaMOD_RES(5)..(5)Gly or SerMOD_RES(7)..(7)Phe or ValMOD_RES(9)..(9)Tyr, Trp or PheMOD_RES(12)..(12)Ser, Asp or AsnMOD_RES(13)..(13)Trp, Ser or PheMOD_RES(14)..(14)Ala or ValMOD_RES(16)..(16)Ser or Gly 59Xaa Ile Gly Ser Xaa Gly Xaa Ala Xaa Tyr Ala Xaa Xaa Xaa Lys Xaa1 5 10 156012PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 60Gly Ile Phe Asn Tyr Gly Thr Asp Tyr Phe Asp Tyr1 5 106112PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 61Asp Gly Thr Ile Pro Ala Gly Ser Trp Phe Ala Tyr1 5 106211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 62Gly Gly Gly Ser Ala Asp Phe Gly Phe Asp Leu1 5 106311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 63Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile1 5 106412PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 64Leu Cys Gly Val Asp Cys Ala Asp Ala Leu Asp Ser1 5 106511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 65Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala1 5 106613PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 66Ala Ala Tyr Ser Ala Gly Ser Ala Asp Ala Glu Asp Ile1 5 106712PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 67Glu Asn Ala Gly Ser Gly Trp Gly Glu Leu Asp Ile1 5 106811PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 68Asp Asn Val Gly Gly Asp Met Ser Leu Asp Ile1 5 106911PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 69Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile1 5 107011PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 70Asp Asp Val Gly Gly Gly Arg Ser Leu Asp Ile1 5 107111PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 71Glu Asn Pro Thr Tyr Gly Tyr Ala Tyr Asp Ala1 5 107217PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 72Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met Asp1 5 10 15Leu7311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 73Gly Asp Ala Gly Thr Ser Tyr Ser Phe Asn Phe1 5 107411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 74Gly Asp Ala Ala Ala Ser Tyr Ser Phe Asn Phe1 5 10759PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 75Glu Ser Gly Gly Ser Tyr Tyr Asp Leu1 5769PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 76Glu Thr Gly Gly Ser Trp Tyr Asp Leu1 57711PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 77Arg Ala Ser Glu Asp Ile Tyr Ser Gly Leu Ala1 5 107811PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 78Leu Ala Ser Lys Asn Ile Tyr Arg Asn Leu Ala1 5 107911PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 79Gln Ala Ser Glu Asn Ile Tyr Ser Leu Leu Ala1 5 108011PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 80Gln Ala Ser Gln Asn Ile Gly Asp Tyr Leu Ser1 5 108111PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 81Gln Ala Ser Glu Asp Ile Gly Ser Tyr Cys Ser1 5 108211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 82Gln Ala Ser Glu Ser Ile Ser Asn Glu Leu Ser1 5 108311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 83Gln Ala Ser Gln Ser Ile Ser Asn Tyr Val Ala1 5 108411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 84Gln Ala Ser Glu Ser Ile Ser Ser Asp Leu Ala1 5 108511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 85Gln Ala Ser Gln Asn Ile Asn Asn Tyr Leu Ser1 5 108611PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 86Gln Ala Ser Gln Ser Ile Gly Ser Tyr Leu Ser1 5 108711PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 87Gln Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ser1 5 108811PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 88Gln Ala Ser Gln Ser Ile Ser Asn Tyr Leu Ser1 5 108911PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 89Gln Ala Ser Gln Ser Ile Ser Thr Tyr Leu Ser1 5 109011PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 90Gln Ala Ser Glu Ser Ile Gly Asn Glu Leu Ser1 5 109111PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 91Gln Ala Ser Glu Ser Ile Gly Asn Ala Leu Ala1 5 109211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 92Gln Ala Ser Glu Ser Ile Ser Arg Tyr Leu Ser1 5 109311PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 93Gln Ala Ser Glu Ser Ile Ser Thr Tyr Leu Ser1 5 109411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 94Gln Ala Ser Gln Ser Ile Ser Thr Tyr Leu Ala1 5 109511PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 95Gln Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala1 5 109611PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(4)..(4)Glu or GlnMOD_RES(7)..(7)Ser or GlyMOD_RES(8)..(8)Asn or SerMOD_RES(9)..(9)Glu, Tyr or AlaMOD_RES(11)..(11)Ser or Ala 96Gln Ala Ser Xaa Ser Ile Xaa Xaa Xaa Leu Xaa1 5 10977PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 97Gly Ala Thr Thr Leu His Asp1 5987PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 98Asp Ala Ser Arg Leu Gln Asp1 5997PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 99Asp Ala Ser Asp Leu Ala Ser1 51007PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 100Ser Ala Ser Thr Leu Ala Ser1 51017PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 101Tyr Ala Ser Thr Leu Ala Ser1 51027PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 102Arg Ala Ser Thr Leu Ala Ser1 51037PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 103Ala Ala Ser Thr Leu Ala Ser1 51047PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 104Asp Ala Ser Asn Leu Ala Ser1 51057PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 105Ser Ala Ser Thr Leu Ala Ser1 51067PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 106Gln Ala Ser Thr Leu Ala Ser1 51077PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 107Lys Thr Ser Thr Leu Ala Ser1 51087PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 108Lys Ala Ser Thr Leu Ala Ser1 51097PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Tyr, Ser or AspMOD_RES(4)..(4)Thr or Asp 109Xaa Ala Ser Xaa Leu Ala Ser1 51109PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 110His Gln Gly Leu Ser Phe Pro Tyr Thr1 51119PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 111Gln Gln Tyr His Asp Tyr Pro Tyr Thr1 511211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 112Gln Ala Thr Ala Tyr Gly Ser Ser Gly Asn Ala1 5 1011312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 113His Gln Asp Tyr Thr Ser Asn Asp Val Glu Asn Thr1 5 1011412PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 114Gln Gln Asp Tyr Thr Gly Asn Asn Val Asp Asn Thr1 5 1011512PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 115Ala Gln Gly Phe Gly Ser Ser Gly Val Glu Asn Val1 5 1011612PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 116His Gln Gly Tyr Ser Ser Ser Asn Val Asp Asn Ile1 5 1011712PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 117Gln Gln Gly Tyr Thr Trp Asn Asn Val Asp Asn Val1 5 1011812PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 118His Gln Asp Tyr Thr Ser Asn Asn Val Asp Asn Thr1 5 1011912PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 119His Gln Asp Tyr Thr Ser Ser Asn Val Asp Asn Thr1 5 1012012PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 120His Gln Asp Tyr Thr Ser Asn Ser Val Asp Asn Thr1 5 1012112PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 121Ala Gln Gly Phe Ser Ser Ser Gly Val Glu Asn Val1 5 1012212PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 122Gln Gln Gly Asp Ser His Asn Asn Val Asp Asn Ile1 5 1012312PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 123Gln Gln Asp Tyr Ser Arg Ser Asn Ile Val Asn Ser1 5 1012412PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 124Gln Gln Asp Tyr Ser Ser Ser Asn Ile Val Asn Ser1 5 1012512PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 125Gln Gln Gly Tyr Ser Gly Ser Ser Val Glu Asn Thr1 5 1012612PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 126Gln Gln Gly Tyr Ser Gly Ser Asn Val Glu Asn Thr1 5 1012712PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(1)..(1)Ala, His or GlnMOD_RES(3)..(3)Gly or AspMOD_RES(4)..(4)Phe, Tyr or AspMOD_RES(5)..(5)Gly, Thr or SerMOD_RES(6)..(6)Ser or HisMOD_RES(7)..(7)Ser or AsnMOD_RES(8)..(8)Gly or AsnMOD_RES(10)..(10)Glu or AspMOD_RES(12)..(12)Val, Thr or Ile 127Xaa Gln Xaa Xaa Xaa Xaa Xaa Xaa Val Xaa Asn Xaa1 5 10128107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 128Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly1 5 10 15Glu Thr Val Thr Ile Gln Cys Arg Ala Ser Glu Asp Ile Tyr Ser Gly 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Gly Ala Thr Thr Leu His Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Ser Met His Ser65 70 75 80Glu Asp Glu Gly Ile Tyr Phe Cys His Gln Gly Leu Ser Phe Pro Tyr 85 90

95Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105129107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 129Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly1 5 10 15Glu Thr Val Thr Ile Glu Cys Leu Ala Ser Lys Asn Ile Tyr Arg Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Phe Leu Ile 35 40 45Ser Asp Ala Ser Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Thr Gly 50 55 60Ser Asp Ser Gly Ser Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr His Asp Tyr Pro Tyr 85 90 95Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105130109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 130Asp Val Val Met Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asn Ile Tyr Ser Leu 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Val Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ala Thr Ala Tyr Gly Ser Ser 85 90 95Gly Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105131109PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 131Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asn Ile Tyr Ser Leu 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Val Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ala Thr Ala Tyr Gly Ser Ser 85 90 95Gly Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105132110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 132Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Val Ile Lys Cys Gln Ala Ser Gln Asn Ile Gly Asp Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asp 85 90 95Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110133110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 133Ala Tyr Tyr Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Gly Ser Tyr 20 25 30Cys Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Val Gln Cys65 70 75 80Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Thr Gly Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Ser Glu Val Val Val Lys 100 105 110134110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 134Ala Tyr Asp Met Thr Gln Thr Pro Ala Ser Leu Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asp Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110135110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 135Ala Tyr Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110136110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 136Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110137110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 137Ala Tyr Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110138110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 138Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110139110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 139Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110140110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Tyr or IleMOD_RES(43)..(43)Pro or AlaMOD_RES(77)..(77)Cys or SerMOD_RES(80)..(80)Ser or ProMOD_RES(106)..(106)Glu or LysMOD_RES(108)..(108)Glu or ValMOD_RES(109)..(109)Ile or Val 140Ala Xaa Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Xaa Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Xaa Leu Gln Xaa65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Xaa Val Xaa Xaa Lys 100 105 110141110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 141Ala Tyr Tyr Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Gly Tyr Ser Ser Ser Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110142110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 142Ala Tyr Glu Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Gly Val Gln Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Trp Asn Asn 85 90 95Val Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110143110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 143Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Asn Asn Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110144110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 144Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Ser Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Ile Lys 100 105 110145110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 145Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Ser Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45Phe Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Thr Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Gln Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110146110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 146Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Arg Pro Lys Leu Leu Ile 35 40 45Phe Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110147110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 147Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110148110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 148Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Arg Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110149110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 149Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110150110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 150Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110151110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(43)..(43)Arg or AlaMOD_RES(49)..(49)Phe or TyrMOD_RES(106)..(106)Glu or LysMOD_RES(108)..(108)Glu or ValMOD_RES(109)..(109)Val or Ile 151Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Xaa Pro Lys Leu Leu Ile 35 40 45Xaa Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Xaa Val Xaa Xaa Lys 100 105 110152110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 152Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Leu Ser Trp Tyr His Gln Lys Ser Gly Gln Arg Pro Arg Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Ser 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110153110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 153Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Met Gly1 5 10 15Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Glu Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Gln Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110154110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 154Ala Tyr Asp Leu Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Gly Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Ser Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Ser Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110155110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 155Ala Tyr Asp Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110156110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 156Ala Tyr Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110157110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 157Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110158110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 158Ala Tyr Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110159110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 159Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110160110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 160Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110161110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 161Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110162110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Tyr or IleMOD_RES(43)..(43)Pro or AlaMOD_RES(77)..(77)Cys or SerMOD_RES(80)..(80)Ser or ProMOD_RES(106)..(106)Glu or LysMOD_RES(108)..(108)Glu or ValMOD_RES(109)..(109)Val or Ile 162Ala Xaa Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Xaa Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Xaa Leu Gln Xaa65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Xaa Val Xaa Xaa Lys 100 105 110163110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 163Ala Ile Glu Met Thr Gln Thr Pro Ser Ser Ala Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Arg Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Ile Ile Ser Asp Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Ser Arg Ser Asn 85 90 95Ile Val Asn Ser Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110164110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 164Ala Tyr Asp Met Thr Gln Thr Pro Ser Ser Ala Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Thr Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Ser Ser Ser Asn 85 90 95Ile Val Asn Ser Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110165110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 165Ala Tyr Asp Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Asn Leu Leu Ile 35 40 45Tyr Lys Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Arg Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Gly Ser Ser 85 90 95Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110166110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 166Ala Tyr Asp Met Thr Gln Thr Pro Val Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Gly Ser Asn 85 90 95Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110167121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 167Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Asn Met Ala Trp Val Arg Gln Ala Pro Lys Gly Gly Leu Glu Trp Val 35 40 45Thr Thr Ile Ser Tyr Asp Ala Gly Arg Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Thr Leu Ser65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Thr Gly Ile Phe Asn Tyr Gly Thr Asp Tyr Phe Asp Tyr Trp Gly 100 105 110Gln Gly

Val Met Val Thr Val Ser Ser 115 120168121PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 168Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ala Trp Val Arg Gln Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Tyr Asp Gly Asp Thr Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Ser Ser Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Asp Asp Thr Ala Asn Tyr Phe Cys 85 90 95Thr Thr Asp Gly Thr Ile Pro Ala Gly Ser Trp Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120169120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 169Gln Glu Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly1 5 10 15Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser 20 25 30Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Ala Cys Val Tyr Gly Leu Asp Val Asn Ile Tyr Tyr Ala Ser Trp 50 55 60Thr Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr65 70 75 80Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Gly Gly Gly Ser Ala Asp Phe Gly Phe Asp Leu Trp Gly Pro 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120170119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 170Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Thr Ser Tyr 20 25 30Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ala Cys Val Tyr Gly Leu Asp Val Asn Ile Tyr Tyr Ala Ser Trp Thr 50 55 60Glu Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu65 70 75 80Gln Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Gly Gly Gly Ser Ala Asp Phe Gly Phe Asp Leu Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115171118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 171Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30Val Thr Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115172119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 172Gln Ser Val Glu Glu Ser Arg Gly Gly Leu Ile Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Tyr Gly Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Gln65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Leu Cys Gly Val Asp Cys Ala Asp Ala Leu Asp Ser Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115173119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 173Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile Gly 35 40 45Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu65 70 75 80Lys Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Val 115174120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 174Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120175120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 175Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120176120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 176Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120177120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 177Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120178120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 178Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ser Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120179120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 179Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120180120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 180Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120181120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 181Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120182120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 182Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120183120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 183Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120184120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 184Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Asn Ser Val 50 55 60Lys Gly Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Phe Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120185120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 185Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Ser Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120186120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 186Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Ser Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Asn Ser Val 50 55 60Lys Gly Arg Phe Thr Ile

Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120187120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 187Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120188120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 188Glu Gln Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120189120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 189Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asn Leu Asn Thr Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120190120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 190Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Phe Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120191120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 191Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asn Thr Asn Leu Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120192120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 192Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120193120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 193Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Asn Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120194120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 194Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asn Asn Asn Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120195120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 195Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120196120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 196Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120197120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 197Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120198120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 198Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120199120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 199Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120200120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 200Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120201120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 201Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120202120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Val or GlnMOD_RES(24)..(24)Val or AlaMOD_RES(47)..(47)Trp or TyrMOD_RES(48)..(48)Ile or ValMOD_RES(49)..(49)Gly or SerMOD_RES(62)..(62)Ser or AsnMOD_RES(63)..(63)Trp, Ser or PheMOD_RES(64)..(64)Ala or ValMOD_RES(66)..(66)Ser or GlyMOD_RES(68)..(68)Ser or PheMOD_RES(73)..(73)Asp or AsnMOD_RES(74)..(74)Thr, Leu or AsnMOD_RES(75)..(75)Ser or AsnMOD_RES(76)..(76)Lys, Thr or LeuMOD_RES(79)..(79)Val or LeuMOD_RES(95)..(95)Phe or TyrMOD_RES(112)..(112)Pro or Gln 202Glu Xaa Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Xaa Xaa 35 40 45Xaa Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Xaa Xaa Xaa 50 55 60Lys Xaa Arg Xaa Thr Ile Ser Arg Xaa Xaa Xaa Xaa Asn Thr Xaa Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Xaa Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Xaa 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120203120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 203Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Asn Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Tyr Ile Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Thr Trp Ala Lys Ser 50 55 60Arg Ala Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Ala Ala Tyr Ser Ala Gly Ser Ala Asp Ala Glu Asp Ile Trp Gly Pro 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120204119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 204Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Ile Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Phe Ala 20 25 30Ile Asn Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Trp Ile Gly 35 40 45Ala Ile Gly Arg Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Lys

Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Arg Pro Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Glu Asn Ala Gly Ser Gly Trp Gly Glu Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115205118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 205Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Gly Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Arg Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asn Val Gly Gly Asp Met Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115206118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 206Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30Val Thr Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Ser Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115207118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 207Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Val Val Thr Val Ser Val 115208119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 208Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115209119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 209Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115210119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 210Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115211119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 211Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115212119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 212Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Ser Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115213119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 213Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115214119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 214Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115215119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 215Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115216119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 216Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115217119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 217Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115218119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 218Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Asp Ser Val Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115219119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 219Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115220119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 220Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Asp Ser Val Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115221119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 221Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115222119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 222Glu Gln Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115223119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 223Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50

55 60Ser Arg Phe Thr Ile Ser Arg Asn Thr Asn Leu Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115224119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 224Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Phe Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115225119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Val or GlnMOD_RES(24)..(24)Val or AlaMOD_RES(47)..(47)Tyr or TrpMOD_RES(48)..(48)Ile or ValMOD_RES(49)..(49)Gly or SerMOD_RES(61)..(61)Ser or AspMOD_RES(62)..(62)Trp, Ser or PheMOD_RES(63)..(63)Ala or ValMOD_RES(65)..(65)Ser or GlyMOD_RES(67)..(67)Ser or PheMOD_RES(72)..(72)Asp or AsnMOD_RES(73)..(73)Thr or AsnMOD_RES(74)..(74)Ser or AsnMOD_RES(75)..(75)Lys or LeuMOD_RES(78)..(78)Val or LeuMOD_RES(94)..(94)Phe or TyrMOD_RES(111)..(111)Pro or Gln 225Glu Xaa Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Xaa Xaa 35 40 45Xaa Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Xaa Xaa Xaa Lys 50 55 60Xaa Arg Xaa Thr Ile Ser Arg Xaa Xaa Xaa Xaa Asn Thr Xaa Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Xaa Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Xaa Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115226118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 226Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Ser Pro Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115227118PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 227Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Arg Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Val Val Thr Val Ser Ser 115228119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 228Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Pro 20 25 30Ile Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Trp Ile Gly 35 40 45Tyr Ile Thr Ser Glu Tyr Gly Val Ala Tyr Tyr Ala Thr Trp Ala Glu 50 55 60Ser Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu65 70 75 80Lys Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Val 85 90 95Arg Glu Asn Pro Thr Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115229124PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 229Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Asn Asp Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Trp Ile Gly 35 40 45Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys Gly 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Ala Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met Asp 100 105 110Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120230125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 230Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125231125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 231Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125232125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 232Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125233125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 233Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ser Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125234125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 234Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125235125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 235Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Asn Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125236125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 236Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125237125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 237Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125238125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 238Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125239125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 239Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125240125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 240Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asp Ser Val Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg His Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 125241125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 241Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10

15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125242125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 242Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asp Ser Val Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125243125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 243Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125244125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 244Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125245125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 245Glu Gln Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125246125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 246Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asn Thr Asn Leu Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125247125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 247Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125248125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 248Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125249125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 249Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125250125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 250Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125251125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 251Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125252125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 252Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125253125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 253Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125254125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 254Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125255125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 255Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125256125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 256Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Phe Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125257125PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Val or GlnMOD_RES(5)..(5)Val or LeuMOD_RES(24)..(24)Val or AlaMOD_RES(48)..(48)Ile or ValMOD_RES(49)..(49)Gly or SerMOD_RES(58)..(58)Trp or PheMOD_RES(61)..(61)Asp or AsnMOD_RES(62)..(62)Trp, Ser or PheMOD_RES(63)..(63)Ala or ValMOD_RES(67)..(67)Ser or PheMOD_RES(72)..(72)His, Asn or AspMOD_RES(73)..(73)Thr or AsnMOD_RES(74)..(74)Ser or AsnMOD_RES(75)..(75)Lys or LeuMOD_RES(78)..(78)Val or LeuMOD_RES(94)..(94)Phe or TyrMOD_RES(117)..(117)Pro or Arg 257Glu Xaa Gln Leu Xaa Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Xaa 35 40 45Xaa Ala Ile Gly Ser Ser Gly Val Ala Xaa Tyr Ala Xaa Xaa Xaa Lys 50 55 60Gly Arg Xaa Thr Ile Ser Arg Xaa Xaa Xaa Xaa Asn Thr Xaa Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Xaa Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Xaa Gly Thr Leu Val Thr Val Ser Ser 115 120 125258122PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 258Gln Glu Gln Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala1 5 10 15Ser Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Asn 20 25 30Tyr Val Asn Phe Val Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly 35 40 45Leu Glu Trp Ile Ala Ser Ile Asp Pro Gly Asp Asp Ser Thr Asp Tyr 50 55 60Ala Ser

Trp Ala Thr Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr65 70 75 80Thr Val Thr Leu Gln Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr 85 90 95Tyr Phe Cys Ala Arg Gly Asp Ala Gly Thr Ser Tyr Ser Phe Asn Phe 100 105 110Trp Gly Pro Gly Thr Leu Val Thr Val Ser 115 120259120PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 259Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala1 5 10 15Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Asn 20 25 30Tyr Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Ala Cys Ile Asp Pro Gly Asp Asp Ser Thr Tyr Tyr Ala Ser Trp 50 55 60Ala Thr Gly Arg Phe Thr Ile Ser Arg Ala Ser Ser Thr Thr Val Thr65 70 75 80Leu Gln Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Gly Asp Ala Ala Ala Ser Tyr Ser Phe Asn Phe Trp Gly Pro 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120260117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 260Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr1 5 10 15Leu Thr Leu Thr Cys Lys Ala Ser Gly Ile Asp Phe Asn Gly Gly Gly 20 25 30Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala 35 40 45Ser Ile Tyr Pro Asp His Gly Ser Val Asp Tyr Ala Asn Trp Val Asn 50 55 60Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Gln Asn Thr Val Phe Leu65 70 75 80Gln Leu Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Glu Ser Gly Gly Ser Tyr Tyr Asp Leu Trp Gly Pro Gly Thr Leu 100 105 110Val Thr Val Ser Ser 115261117PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 261Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Phe Asn Gly Gly Gly 20 25 30Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala 35 40 45Tyr Ile Tyr Pro Asp His Gly Ser Ala Asp Tyr Ala Thr Trp Val Asn 50 55 60Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Gln Asn Thr Val Phe Leu65 70 75 80Gln Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Glu Thr Gly Gly Ser Trp Tyr Asp Leu Trp Gly Pro Gly Thr Leu 100 105 110Val Thr Val Ser Ser 115262214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 262Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly1 5 10 15Glu Thr Val Thr Ile Gln Cys Arg Ala Ser Glu Asp Ile Tyr Ser Gly 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Gly Ala Thr Thr Leu His Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Ser Met His Ser65 70 75 80Glu Asp Glu Gly Ile Tyr Phe Cys His Gln Gly Leu Ser Phe Pro Tyr 85 90 95Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala 100 105 110Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu145 150 155 160Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205Phe Asn Arg Asn Glu Cys 210263214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 263Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly1 5 10 15Glu Thr Val Thr Ile Glu Cys Leu Ala Ser Lys Asn Ile Tyr Arg Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Phe Leu Ile 35 40 45Ser Asp Ala Ser Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Thr Gly 50 55 60Ser Asp Ser Gly Ser Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser65 70 75 80Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr His Asp Tyr Pro Tyr 85 90 95Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala 100 105 110Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu145 150 155 160Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205Phe Asn Arg Asn Glu Cys 210264216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 264Asp Val Val Met Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asn Ile Tyr Ser Leu 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Val Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ala Thr Ala Tyr Gly Ser Ser 85 90 95Gly Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala Asp 100 105 110Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr 115 120 125Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys 130 135 140Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly145 150 155 160Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn 180 185 190Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val 195 200 205Lys Ser Phe Asn Arg Asn Glu Cys 210 215265216PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 265Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asn Ile Tyr Ser Leu 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Val Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ala Thr Ala Tyr Gly Ser Ser 85 90 95Gly Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala Asp 100 105 110Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr 115 120 125Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys 130 135 140Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly145 150 155 160Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn 180 185 190Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val 195 200 205Lys Ser Phe Asn Arg Asn Glu Cys 210 215266217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 266Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Val Ile Lys Cys Gln Ala Ser Gln Asn Ile Gly Asp Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asp 85 90 95Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215267217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 267Ala Tyr Tyr Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Gly Ser Tyr 20 25 30Cys Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Val Gln Cys65 70 75 80Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Thr Gly Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Ser Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215268217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 268Ala Tyr Asp Met Thr Gln Thr Pro Ala Ser Leu Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asp Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215269217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 269Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215270217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 270Ala Tyr Tyr Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Gly Tyr Ser Ser Ser Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys

Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215271217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 271Ala Tyr Glu Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Asp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Gly Val Gln Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Trp Asn Asn 85 90 95Val Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215272217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 272Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Asn Asn Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215273217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 273Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Ser Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Ile Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215274217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 274Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Ser Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45Phe Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Thr Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Gln Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215275217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 275Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215276217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 276Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30Leu Ser Trp Tyr His Gln Lys Ser Gly Gln Arg Pro Arg Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Ser 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215277217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 277Asn Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Met Gly1 5 10 15Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Glu Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Gln Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Asn Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215278217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 278Ala Tyr Asp Leu Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Gly Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Ser Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Ser Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215279217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 279Ala Tyr Asp Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215280217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 280Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215281217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 281Ala Ile Glu Met Thr Gln Thr Pro Ser Ser Ala Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Arg Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Ile Ile Ser Asp Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Ser Arg Ser Asn 85 90 95Ile Val Asn Ser Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170

175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215282217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 282Ala Tyr Asp Met Thr Gln Thr Pro Ser Ser Ala Ser Glu Pro Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Thr Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Ser Ser Ser Asn 85 90 95Ile Val Asn Ser Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215283217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 283Ala Tyr Asp Met Thr Gln Thr Pro Ala Ser Val Glu Val Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Asn Leu Leu Ile 35 40 45Tyr Lys Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Arg Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Gly Ser Ser 85 90 95Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215284217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 284Ala Tyr Asp Met Thr Gln Thr Pro Val Ser Val Glu Ala Ala Val Gly1 5 10 15Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys65 70 75 80Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Gly Ser Asn 85 90 95Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Ala 100 105 110Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu 115 120 125Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro 130 135 140Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn145 150 155 160Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 180 185 190Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 195 200 205Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215285451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 285Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Asn Met Ala Trp Val Arg Gln Ala Pro Lys Gly Gly Leu Glu Trp Val 35 40 45Thr Thr Ile Ser Tyr Asp Ala Gly Arg Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Thr Leu Ser65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Thr Gly Ile Phe Asn Tyr Gly Thr Asp Tyr Phe Asp Tyr Trp Gly 100 105 110Gln Gly Val Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val 130 135 140Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu145 150 155 160Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 180 185 190Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro 195 200 205Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr 210 215 220Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 245 250 255Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu 260 265 270Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 275 280 285His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 290 295 300Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly305 310 315 320Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 325 330 335Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 340 345 350Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 355 360 365Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 370 375 380Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 405 410 415Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 420 425 430His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 435 440 445Pro Gly Lys 450286451PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 286Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Tyr Met Ala Trp Val Arg Gln Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Ser Tyr Asp Gly Asp Thr Thr Tyr Tyr Arg Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Ser Ser Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ser Asp Asp Thr Ala Asn Tyr Phe Cys 85 90 95Thr Thr Asp Gly Thr Ile Pro Ala Gly Ser Trp Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val 130 135 140Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu145 150 155 160Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 180 185 190Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro 195 200 205Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr 210 215 220Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 245 250 255Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu 260 265 270Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 275 280 285His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 290 295 300Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly305 310 315 320Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 325 330 335Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 340 345 350Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 355 360 365Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 370 375 380Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 405 410 415Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 420 425 430His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 435 440 445Pro Gly Lys 450287450PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 287Gln Glu Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly1 5 10 15Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser 20 25 30Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Ala Cys Val Tyr Gly Leu Asp Val Asn Ile Tyr Tyr Ala Ser Trp 50 55 60Thr Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr65 70 75 80Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Gly Gly Gly Ser Ala Asp Phe Gly Phe Asp Leu Trp Gly Pro 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr 130 135 140Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr145 150 155 160Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser 180 185 190Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala 195 200 205Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile 210 215 220Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly225 230 235 240Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 245 250 255Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 260 265 270Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His 275 280 285Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 290 295 300Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys305 310 315 320Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 325 330 335Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr 340 345 350Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu 355 360 365Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 370 375 380Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val385 390 395 400Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 405 410 415Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 420 425 430Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 435 440 445Gly Lys 450288449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 288Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Thr Ser Tyr 20 25 30Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ala Cys Val Tyr Gly Leu Asp Val Asn Ile Tyr Tyr Ala Ser Trp Thr 50 55 60Glu Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu65 70 75 80Gln Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Gly Gly Gly Ser Ala Asp Phe Gly Phe Asp Leu Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr 115 120 125Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu 130 135 140Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp145 150 155 160Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser 180 185 190Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys 210 215 220Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser 245 250 255Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp 260 265 270Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr 275 280 285Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val 290 295 300Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu305 310 315 320Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg 325 330 335Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val 340 345

350Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr 355 360 365Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr 370 375 380Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys 405 410 415Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu 420 425 430Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly 435 440 445Lys289448PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 289Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30Val Thr Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro 115 120 125Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 130 135 140Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn145 150 155 160Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 180 185 190Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 195 200 205Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 210 215 220Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 245 250 255Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 260 265 270Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 275 280 285Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 290 295 300Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe305 310 315 320Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 325 330 335Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 340 345 350Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 355 360 365Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 370 375 380Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 405 410 415Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 420 425 430Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445290449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 290Gln Ser Val Glu Glu Ser Arg Gly Gly Leu Ile Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Tyr Gly Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Gln65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Leu Cys Gly Val Asp Cys Ala Asp Ala Leu Asp Ser Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr 115 120 125Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu 130 135 140Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp145 150 155 160Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser 180 185 190Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys 210 215 220Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser 245 250 255Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp 260 265 270Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr 275 280 285Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val 290 295 300Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu305 310 315 320Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg 325 330 335Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val 340 345 350Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr 355 360 365Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr 370 375 380Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys 405 410 415Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu 420 425 430Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly 435 440 445Lys291449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 291Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile Gly 35 40 45Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu65 70 75 80Lys Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr 115 120 125Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu 130 135 140Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp145 150 155 160Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser 180 185 190Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys 210 215 220Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser 245 250 255Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp 260 265 270Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr 275 280 285Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val 290 295 300Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu305 310 315 320Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg 325 330 335Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val 340 345 350Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr 355 360 365Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr 370 375 380Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys 405 410 415Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu 420 425 430Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly 435 440 445Lys292450PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 292Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser145 150 155 160Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly225 230 235 240Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 290 295 300Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys305 310 315 320Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val385 390 395 400Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445Gly Lys 450293447PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 293Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser145 150 155 160Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val225 230 235 240Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys305 310 315 320Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser385 390 395 400Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445294450PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 294Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Asn Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Tyr Ile Gly

Ser Ala Gly Ser Thr Tyr Tyr Ala Thr Trp Ala Lys Ser 50 55 60Arg Ala Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Ala Ala Tyr Ser Ala Gly Ser Ala Asp Ala Glu Asp Ile Trp Gly Pro 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr 130 135 140Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr145 150 155 160Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser 180 185 190Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala 195 200 205Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile 210 215 220Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly225 230 235 240Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 245 250 255Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 260 265 270Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His 275 280 285Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 290 295 300Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys305 310 315 320Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 325 330 335Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr 340 345 350Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu 355 360 365Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 370 375 380Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val385 390 395 400Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 405 410 415Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 420 425 430Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 435 440 445Gly Lys 450295449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 295Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Ile Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Phe Ala 20 25 30Ile Asn Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Trp Ile Gly 35 40 45Ala Ile Gly Arg Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Lys Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Arg Pro Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Glu Asn Ala Gly Ser Gly Trp Gly Glu Leu Asp Ile Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr 115 120 125Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu 130 135 140Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp145 150 155 160Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser 180 185 190Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys 210 215 220Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser 245 250 255Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp 260 265 270Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr 275 280 285Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val 290 295 300Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu305 310 315 320Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg 325 330 335Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val 340 345 350Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr 355 360 365Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr 370 375 380Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys 405 410 415Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu 420 425 430Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly 435 440 445Lys296448PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 296Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Gly Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Arg Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asn Val Gly Gly Asp Met Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro 115 120 125Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 130 135 140Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn145 150 155 160Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 180 185 190Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 195 200 205Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 210 215 220Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 245 250 255Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 260 265 270Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 275 280 285Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 290 295 300Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe305 310 315 320Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 325 330 335Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 340 345 350Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 355 360 365Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 370 375 380Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 405 410 415Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 420 425 430Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445297448PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 297Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30Val Thr Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Ser Gly Ser Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro 115 120 125Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 130 135 140Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn145 150 155 160Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 180 185 190Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 195 200 205Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 210 215 220Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 245 250 255Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 260 265 270Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 275 280 285Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 290 295 300Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe305 310 315 320Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 325 330 335Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 340 345 350Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 355 360 365Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 370 375 380Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 405 410 415Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 420 425 430Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445298448PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 298Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Val Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro 115 120 125Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 130 135 140Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn145 150 155 160Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 180 185 190Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 195 200 205Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 210 215 220Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 245 250 255Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 260 265 270Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 275 280 285Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 290 295 300Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe305 310 315 320Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 325 330 335Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 340 345 350Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 355 360 365Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 370 375 380Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 405 410 415Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 420 425 430Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445299449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 299Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys300446PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 300Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445301448PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 301Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Ser Pro Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro 115 120 125Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 130 135 140Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn145 150 155 160Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 180 185 190Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 195 200 205Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 210 215 220Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 245 250 255Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 260 265 270Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 275 280 285Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 290 295 300Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe305 310 315 320Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 325 330 335Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 340 345 350Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 355 360 365Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 370 375 380Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 405 410 415Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 420 425 430Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445302448PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 302Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Asn1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Tyr Ile Gly 35 40 45Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys Ser 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Asp Val Gly Gly Gly Arg Ser Leu Asp Ile Trp Gly Pro Gly Thr 100 105 110Val Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro 115 120 125Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 130 135 140Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn145 150 155 160Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr 180 185 190Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser 195 200 205Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro 210 215 220Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 245 250 255Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 260 265 270Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 275 280 285Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 290 295 300Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe305 310 315 320Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 325 330 335Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 340 345 350Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 355 360 365Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 370 375 380Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 405 410 415Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 420 425 430Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445303449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 303Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Pro 20 25 30Ile Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Trp Ile Gly 35 40 45Tyr Ile Thr Ser Glu Tyr Gly Val Ala Tyr Tyr Ala Thr Trp Ala Glu 50 55 60Ser Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu65 70 75 80Lys Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Val 85 90 95Arg Glu Asn Pro Thr Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Pro Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr 115 120 125Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu 130 135 140Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp145 150 155 160Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser 180 185 190Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys 210 215 220Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro225 230 235 240Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser 245 250 255Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp 260 265 270Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr 275 280 285Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val 290 295 300Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu305 310 315 320Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg 325 330 335Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val 340 345 350Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr 355 360 365Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr 370 375 380Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys 405 410 415Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu 420 425 430Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly 435 440 445Lys304454PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 304Gln Ser Val Lys Glu Ser Glu Gly Gly Leu Phe Lys Pro Thr Asp Thr1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Asn Asp Tyr Gly 20 25 30Val Ser Trp Val Arg Gln Ala Pro Gly Asn Gly Leu Glu Trp Ile Gly 35 40 45Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Trp Ala Lys Gly 50 55 60Arg Ser Thr Ile Thr Arg Asn Thr Asn Leu Asn Thr Val Thr Leu Lys65 70 75 80Met Ala Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met Asp 100 105 110Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125Gly Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly 130 135 140Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro145 150 155 160Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 165 170 175Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 180 185 190Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val 195 200 205Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg 210 215 220Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn225 230 235 240Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp 245 250 255Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp 260 265 270Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn 275 280 285Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn 290 295 300Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp305 310 315 320Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro 325 330 335Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala 340 345 350Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys 355 360 365Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile 370 375

380Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn385 390 395 400Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys 405 410 415Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys 420 425 430Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe 435 440 445Ser Arg Thr Pro Gly Lys 450305455PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 305Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu145 150 155 160Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro225 230 235 240Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 290 295 300Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp305 310 315 320Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 340 345 350Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 355 360 365Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys385 390 395 400Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 420 425 430Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 435 440 445Leu Ser Leu Ser Pro Gly Lys 450 455306452PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 306Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu145 150 155 160Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu225 230 235 240Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Leu Gly Lys 450307453PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 307Gln Glu Gln Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala1 5 10 15Ser Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Asn 20 25 30Tyr Val Asn Phe Val Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly 35 40 45Leu Glu Trp Ile Ala Ser Ile Asp Pro Gly Asp Asp Ser Thr Asp Tyr 50 55 60Ala Ser Trp Ala Thr Gly Arg Phe Thr Ile Ser Lys Ala Ser Ser Thr65 70 75 80Thr Val Thr Leu Gln Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr 85 90 95Tyr Phe Cys Ala Arg Gly Asp Ala Gly Thr Ser Tyr Ser Phe Asn Phe 100 105 110Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser 130 135 140Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val145 150 155 160Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 180 185 190Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala 195 200 205His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly 210 215 220Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu225 230 235 240Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val 245 250 255Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val 260 265 270Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val 275 280 285Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser 290 295 300Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met305 310 315 320Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala 325 330 335Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro 340 345 350Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln 355 360 365Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr 370 375 380Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr385 390 395 400Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu 405 410 415Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser 420 425 430Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser 435 440 445Arg Thr Pro Gly Lys 450308450PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 308Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ala1 5 10 15Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Asn 20 25 30Tyr Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Ala Cys Ile Asp Pro Gly Asp Asp Ser Thr Tyr Tyr Ala Ser Trp 50 55 60Ala Thr Gly Arg Phe Thr Ile Ser Arg Ala Ser Ser Thr Thr Val Thr65 70 75 80Leu Gln Val Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Gly Asp Ala Ala Ala Ser Tyr Ser Phe Asn Phe Trp Gly Pro 100 105 110Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr 130 135 140Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr145 150 155 160Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser 180 185 190Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala 195 200 205Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile 210 215 220Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly225 230 235 240Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 245 250 255Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 260 265 270Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His 275 280 285Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 290 295 300Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys305 310 315 320Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 325 330 335Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr 340 345 350Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu 355 360 365Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 370 375 380Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val385 390 395 400Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 405 410 415Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 420 425 430Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 435 440 445Gly Lys 450309447PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 309Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr1 5 10 15Leu Thr Leu Thr Cys Lys Ala Ser Gly Ile Asp Phe Asn Gly Gly Gly 20 25 30Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala 35 40 45Ser Ile Tyr Pro Asp His Gly Ser Val Asp Tyr Ala Asn Trp Val Asn 50 55 60Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Gln Asn Thr Val Phe Leu65 70 75 80Gln Leu Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Glu Ser Gly Gly Ser Tyr Tyr Asp Leu Trp Gly Pro Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro Leu 115 120 125Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser145 150 155 160Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val225 230 235 240Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 260 265 270Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 290 295 300Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys305 310 315 320Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser385 390 395 400Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445310447PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 310Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Phe Asn Gly Gly Gly 20 25 30Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala 35 40 45Tyr Ile Tyr Pro Asp His Gly Ser Ala Asp Tyr Ala Thr Trp Val Asn 50 55 60Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Gln Asn Thr Val Phe Leu65

70 75 80Gln Met Thr Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95Arg Glu Thr Gly Gly Ser Trp Tyr Asp Leu Trp Gly Pro Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro Leu 115 120 125Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser145 150 155 160Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val225 230 235 240Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 260 265 270Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 290 295 300Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys305 310 315 320Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser385 390 395 400Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445311107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 311Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu1 5 10 15Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu65 70 75 80Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105312330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 312Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330313330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 313Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330314327PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 314Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg1 5 10 15Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65 70 75 80Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro 100 105 110Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp145 150 155 160Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys225 230 235 240Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser305 310 315 320Leu Ser Leu Ser Leu Gly Lys 325315327PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 315Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg1 5 10 15Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65 70 75 80Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp145 150 155 160Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys225 230 235 240Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser305 310 315 320Leu Ser Leu Ser Leu Gly Lys 3253166PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 316Leu Arg Pro Asn Gln Leu1 53176PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 317Gln Gly Val Lys Ser Ile1 531814PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 318Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln Ile Asp Asp Thr1 5 1031913PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 319Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro Gly Val Tyr1 5 10320299PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 320Ile Glu Ser Ala Lys Gln Thr Lys Gln Met Val Asp Cys Ser His Tyr1 5 10 15Lys Lys Leu Pro Pro Gly Gln Gln Arg Phe Cys His Arg Glu Tyr Asp 20 25 30Pro Ile Cys Gly Ser Asp Gly Lys Thr Tyr Lys Asn Asp Cys Phe Phe 35 40 45Cys Ser Lys Val Lys Lys Thr Asp Gly Thr Leu Lys Phe Val His Phe 50 55 60Gly Lys Cys Gly Asn Ser Val Thr Asp Lys Thr His Thr Cys Pro Pro65 70 75 80Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 85 90 95Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 100 105 110Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 115 120 125Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 130 135 140Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val145 150 155 160Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 165 170 175Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 180 185 190Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 195 200 205Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 210 215 220Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu225 230 235 240Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 245 250 255Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 260 265 270Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 275 280 285Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 290 295321110PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 321Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110322224PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 322Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Thr Ser Asn Tyr Gly Val Ser Tyr Tyr Ala Ser Trp Ala 50 55 60Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr65 70 75

80Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Pro Asp Tyr Gly Tyr Ala Tyr Asp Ala Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser145 150 155 160Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220323217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 323Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Asn Glu 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Gly Phe Gly Ser Ser Gly 85 90 95Val Glu Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215324223PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 324Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Gly Phe Ile Gly Ser Gly Gly Phe Ala Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Asp Val Gly Gly Gly Lys Ser Leu Asp Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220325217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 325Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Tyr Thr Ser Ser Asn 85 90 95Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215326229PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 326Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Asn Asp Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Ala Ile Gly Ser Ser Gly Val Ala Trp Tyr Ala Asn Phe Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Arg Asp Tyr Gly Tyr Arg Ala Asp Asp Ala Thr Ser Gly Met 100 105 110Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu145 150 155 160Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 195 200 205Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220Pro Lys Ser Cys Asp225327217PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 327Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Gly Asn Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Ser His Asn Asn 85 90 95Val Asp Asn Ile Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215328227PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 328Ile Ile Asn Gly Ser Asp Cys Asp Met His Thr Gln Pro Trp Gln Ala1 5 10 15Ala Leu Leu Leu Arg Pro Asn Gln Leu Tyr Cys Gly Ala Val Leu Val 20 25 30His Pro Gln Trp Leu Leu Thr Ala Ala His Cys Arg Lys Lys Val Phe 35 40 45Arg Val Arg Leu Gly His Tyr Ser Leu Ser Pro Val Tyr Glu Ser Gly 50 55 60Gln Gln Met Phe Gln Gly Val Lys Ser Ile Pro His Pro Gly Tyr Ser65 70 75 80His Pro Gly His Ser Asn Asp Leu Met Leu Ile Lys Leu Asn Arg Arg 85 90 95Ile Arg Pro Thr Lys Asp Val Arg Pro Ile Asn Val Ser Ser His Cys 100 105 110Pro Ser Ala Gly Thr Lys Cys Leu Val Ser Gly Trp Gly Thr Thr Lys 115 120 125Ser Pro Gln Val His Phe Pro Lys Val Leu Gln Cys Leu Asn Ile Ser 130 135 140Val Leu Ser Gln Lys Arg Cys Glu Asp Ala Tyr Pro Arg Gln Ile Asp145 150 155 160Asp Thr Met Phe Cys Ala Gly Asp Lys Ala Gly Arg Asp Ser Cys Gln 165 170 175Gly Asp Ser Gly Gly Pro Val Val Cys Asn Gly Ser Leu Gln Gly Leu 180 185 190Val Ser Trp Gly Asp Tyr Pro Cys Ala Arg Pro Asn Arg Pro Gly Val 195 200 205Tyr Thr Asn Leu Cys Lys Phe Thr Lys Trp Ile Gln Glu Thr Ile Gln 210 215 220Ala Asn Ser22532923PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(2)..(2)Tyr or Ile 329Ala Xaa Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys 2033015PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(9)..(9)Pro or Ala 330Trp Tyr Gln Gln Lys Pro Gly Lys Xaa Pro Lys Leu Leu Ile Tyr1 5 10 1533132PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(21)..(21)Cys or SerMOD_RES(24)..(24)Ser or Pro 331Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Xaa Leu Gln Xaa Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 3033210PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(6)..(6)Glu or LysMOD_RES(8)..(8)Glu or ValMOD_RES(9)..(9)Ile or Val 332Phe Gly Gly Gly Thr Xaa Val Xaa Xaa Lys1 5 1033330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Val or GlnMOD_RES(24)..(24)Val or Ala 333Glu Xaa Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Ser 20 25 3033414PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(12)..(12)Trp or TyrMOD_RES(13)..(13)Ile or ValMOD_RES(14)..(14)Gly or Ser 334Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Xaa Xaa Xaa1 5 1033532PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Ser or PheMOD_RES(7)..(7)Asp or AsnMOD_RES(8)..(8)Thr, Leu or AsnMOD_RES(9)..(9)Ser or AsnMOD_RES(10)..(10)Lys, Thr or LeuMOD_RES(13)..(13)Val or LeuMOD_RES(29)..(29)Phe or Tyr 335Arg Xaa Thr Ile Ser Arg Xaa Xaa Xaa Xaa Asn Thr Xaa Tyr Leu Gln1 5 10 15Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Xaa Cys Ala Arg 20 25 3033611PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(3)..(3)Pro or Gln 336Trp Gly Xaa Gly Thr Thr Val Thr Val Ser Ser1 5 1033723PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 337Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys 2033815PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(9)..(9)Arg or AlaMOD_RES(15)..(15)Phe or Tyr 338Trp Tyr Gln Gln Lys Pro Gly Lys Xaa Pro Lys Leu Leu Ile Xaa1 5 10 1533932PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 339Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 3034010PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(6)..(6)Glu or LysMOD_RES(8)..(8)Glu or ValMOD_RES(9)..(9)Val or Ile 340Phe Gly Gly Gly Thr Xaa Val Xaa Xaa Lys1 5 1034130PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Val or GlnMOD_RES(24)..(24)Val or Ala 341Glu Xaa Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Ser 20 25 3034214PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(12)..(12)Tyr or TrpMOD_RES(13)..(13)Ile or ValMOD_RES(14)..(14)Gly or Ser 342Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Xaa Xaa Xaa1 5 1034332PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Ser or PheMOD_RES(7)..(7)Asp or AsnMOD_RES(8)..(8)Thr or AsnMOD_RES(9)..(9)Ser or AsnMOD_RES(10)..(10)Lys or LeuMOD_RES(13)..(13)Val or LeuMOD_RES(29)..(29)Phe or Tyr 343Arg Xaa Thr Ile Ser Arg Xaa Xaa Xaa Xaa Asn Thr Xaa Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Xaa Cys Ala Arg 20 25 3034411PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(3)..(3)Pro or Gln 344Trp Gly Xaa Gly Thr Leu Val Thr Val Ser Ser1 5 1034523PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(2)..(2)Tyr or Ile 345Ala Xaa Arg Met Thr Gln Ser Pro Ser Ser Phe Ser Ala Ser Thr Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys 2034615PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(9)..(9)Pro or Ala 346Trp Tyr Gln Gln Lys Pro Gly Lys Xaa Pro Lys Leu Leu Ile Tyr1 5 10 1534732PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(21)..(21)Cys or SerMOD_RES(24)..(24)Ser or Pro 347Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Xaa Leu Gln Xaa Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 3034810PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(6)..(6)Glu or LysMOD_RES(8)..(8)Glu or ValMOD_RES(9)..(9)Val or Ile 348Phe Gly Gly Gly Thr Xaa Val Xaa Xaa Lys1 5 1034930PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Val or GlnMOD_RES(5)..(5)Val or LeuMOD_RES(24)..(24)Val or Ala 349Glu Xaa Gln Leu Xaa Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Asn 20 25 3035014PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(13)..(13)Ile or ValMOD_RES(14)..(14)Gly or Ser 350Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Xaa Xaa1 5

1035132PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptideMOD_RES(2)..(2)Ser or PheMOD_RES(7)..(7)His, Asn or AspMOD_RES(8)..(8)Thr or AsnMOD_RES(9)..(9)Ser or AsnMOD_RES(10)..(10)Lys or LeuMOD_RES(13)..(13)Val or LeuMOD_RES(29)..(29)Phe or Tyr 351Arg Xaa Thr Ile Ser Arg Xaa Xaa Xaa Xaa Asn Thr Xaa Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Xaa Cys Ala Arg 20 25 3035211PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(3)..(3)Pro or Arg 352Trp Gly Xaa Gly Thr Leu Val Thr Val Ser Ser1 5 10353275PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 353Asn Asn Asp Val Ser Cys Asp His Pro Ser Asn Thr Val Pro Ser Gly1 5 10 15Ser Asn Gln Asp Leu Gly Ala Gly Ala Gly Glu Asp Ala Arg Ser Asp 20 25 30Asp Ser Ser Ser Arg Ile Ile Asn Gly Ser Asp Cys Asp Met His Thr 35 40 45Gln Pro Trp Gln Ala Ala Leu Leu Leu Arg Pro Asn Gln Leu Tyr Cys 50 55 60Gly Ala Val Leu Val His Pro Gln Trp Leu Leu Thr Ala Ala His Cys65 70 75 80Arg Lys Lys Val Phe Arg Val Arg Leu Gly His Tyr Ser Leu Ser Pro 85 90 95Val Tyr Glu Ser Gly Gln Gln Met Phe Gln Gly Val Lys Ser Ile Pro 100 105 110His Pro Gly Tyr Ser His Pro Gly His Ser Asn Asp Leu Met Leu Ile 115 120 125Lys Leu Asn Arg Arg Ile Arg Pro Thr Lys Asp Val Arg Pro Ile Asn 130 135 140Val Ser Ser His Cys Pro Ser Ala Gly Thr Lys Cys Leu Val Ser Gly145 150 155 160Trp Gly Thr Thr Lys Ser Pro Gln Val His Phe Pro Lys Val Leu Gln 165 170 175Cys Leu Asn Ile Ser Val Leu Ser Gln Lys Arg Cys Glu Asp Ala Tyr 180 185 190Pro Arg Gln Ile Asp Asp Thr Met Phe Cys Ala Gly Asp Lys Ala Gly 195 200 205Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Val Val Cys Asn Gly 210 215 220Ser Leu Gln Gly Leu Val Ser Trp Gly Asp Tyr Pro Cys Ala Arg Pro225 230 235 240Asn Arg Pro Gly Val Tyr Thr Asn Leu Cys Lys Phe Thr Lys Trp Ile 245 250 255Gln Glu Thr Ile Gln Ala Asn Ser Gly Asn Ser Asp Tyr Lys Asp Asp 260 265 270Asp Asp Lys 2753544PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 354Leu Leu Val Tyr13557PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 355Glu Glu Ala Gln Gly Asp Lys1 535610PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptideMOD_RES(7)..(7)NorValMOD_RES(10)..(10)Lys(Dnp) 356Arg Pro Lys Pro Val Glu Xaa Trp Arg Lys1 5 10

Claims

1. An isolated antibody that binds to KLK5, wherein the antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:28; (b) HVR-H2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:38, SEQ ID NO:45, and SEQ ID NO:54; (c) HVR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:65, SEQ ID NO:69, and SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:96; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:109; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:127.

2. The antibody of claim 1, wherein the antibody comprises: (a) HVR-H1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:22, and SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53; (c) HVR-H3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:65, SEQ ID NO:69, and SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:82, SEQ ID NO:87, and SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:101, and SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO:115, SEQ ID NO:119, and SEQ ID NO:122.

3. The antibody of claim 1, wherein the antibody comprises: (i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:17; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:35; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:115; (ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:87; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:119; or (iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:24; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:52; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:72; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:91; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:122.

4. The antibody of claim 1, wherein the antibody comprises a) a VH sequence of SEQ ID NO:202 and a VL sequence of SEQ ID NO:140; b) a VH sequence of SEQ ID NO:225 and a VL sequence of SEQ ID NO:151; or c) a VH sequence of SEQ ID NO:257 and a VL sequence of SEQ ID NO:162.

5. The antibody of claim 1, wherein the antibody comprises a) a VH sequence of SEQ ID NO:201 and a VL sequence of SEQ ID NO:139; b) a VH sequence of SEQ ID NO:221 and a VL sequence of SEQ ID NO:149; or c) a VH sequence of SEQ ID NO:248 or SEQ ID NO:254, and a VL sequence of SEQ ID NO:160.

6. An isolated antibody that binds to KLK5, wherein the antibody comprises a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:201 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:139; b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:221 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:149; or c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:248 or SEQ ID NO:254, and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:160.

7. An isolated antibody that binds to KLK5, wherein the antibody comprises: (i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:79; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:112; (ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:80; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:100; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:113; (iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:34; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:64; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:81; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:99; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:114; (iv) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:18; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:66; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:102; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:116; (v) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:19; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:40; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:67; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:84; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:117; (vi) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:85; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:103; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118; (vii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:41; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:86; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:104; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118; (viii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:46; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:120; (ix) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:42; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:70; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:89; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:105; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:118; or (x) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:47; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:71; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:90; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:106; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:121.

8. The antibody of claim 7, wherein the antibody comprises a VH sequence selected from the group consisting of SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:226, SEQ ID NO:227, and SEQ ID NO:228, and a VL sequence selected from the group consisting of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:152, SEQ ID NO:153, and SEQ ID NO:154.

9. The antibody of claim 7, wherein the antibody comprises (a) a VH sequence of SEQ ID NO:170 and a VL sequence of SEQ ID NO:131; (b) a VH sequence of SEQ ID NO:171 and a VL sequence of SEQ ID NO:132; (c) a VH sequence of SEQ ID NO:172 and a VL sequence of SEQ ID NO:133; (d) a VH sequence of SEQ ID NO:203 and a VL sequence of SEQ ID NO:141; (e) a VH sequence of SEQ ID NO:204 and a VL sequence of SEQ ID NO:142; (f) a VH sequence of SEQ ID NO:205 and a VL sequence of SEQ ID NO:143; (g) a VH sequence of SEQ ID NO:206 and a VL sequence of SEQ ID NO:144; (h) a VH sequence of SEQ ID NO:226 and a VL sequence of SEQ ID NO:152; (i) a VH sequence of SEQ ID NO:227 and a VL sequence of SEQ ID NO:153; or (j) a VH sequence of SEQ ID NO:228 and a VL sequence of SEQ ID NO:154.

10. An isolated antibody that binds to KLK5, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:170 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:131; (b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:171 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:132; (c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:172 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:133; (d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:203 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:141; (e) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:204 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:142; (f) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:205 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:143; (g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:206 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:144; (h) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:226 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:152; (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:227 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:153; or (j) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:228 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:154.

11. The antibody of claim 1, wherein the antibody is an IgG1 or IgG4.

12. The antibody of claim 1, wherein the antibody inhibits the biological activity of KLK5 by at least 50% as measured by one or more methods selected from the group consisting of a recombinant KLK5 direct activity assay, coupled pro-KLK1 fluorescent peptide assay, a coupled pro-KLK7 fluorescent peptide assay, a pro-KLK1 LC/MS assay, a pro-KLK7 LC/MS assay, and a K.sub.i(app) assay.

13. The antibody of claim 1, wherein the biological activity is the serine protease activity of KLK5.

14. The antibody of claim 1, wherein the antibody is a monoclonal antibody.

15. The antibody of claim 1, wherein the antibody is a human, humanized, or chimeric antibody.

16. The antibody of claim 1, wherein the antibody is an antibody fragment that binds KLK5.

17. An antibody that forms a thermodynamic epitope when bound to KLK5 comprising one or more of the sequences selected from the group consisting of SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:318, and SEQ ID NO:319 as measured by hydrogen exchange mass spectrometry.

18. An antibody that competes for binding with the antibody of claim 1.

19. An antibody that binds to the same epitope as the antibody of claim 1.

20. An isolated nucleic acid encoding the antibody of claim 1.

21. A host cell comprising the nucleic acid of claim 20.

22. A method of producing an antibody comprising culturing the host cell of claim 21 so that the antibody is produced.

23. An immunoconjugate comprising the antibody of claim 1.

24. A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

25-34. (canceled)

35. A method of treating an individual having a disease, wherein the disease is selected from the group consisting of Netherton Syndrome, asthma, atopic dermatitis, psoriasis, eosinophilic esophagitis and rosacea comprising administering to the individual an effective amount of the antibody of claim 1.

36. The method of claim 35, wherein the asthma is selected from the group consisting of atopic asthma, allergic asthma, non-allergic asthma, exercise-induced asthma, aspirin sensitive/exacerbated asthma, mild asthma, moderate to severe asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, newly diagnosed and untreated asthma, asthma due to smoking, asthma uncontrolled on corticosteroids, T helper lymphocyte type 2 (Th2) or type 2 (Th2) high, or Type 2 (T2)-driven asthma, eosinophilic asthma, periostin-high asthma, eosinophil-high asthma, Th2-low asthma or nonTh2-driven asthma, periostin-low asthma, and eosinophil-low asthma.

37. The method of claim 36, wherein the asthma is Th2-low asthma.

38. A method of inhibiting the biological activity of KLK5 in an individual comprising administering to the individual an effective amount of the antibody of claim 1 to inhibit the biological activity of KLK5.

39. An antibody that specifically binds to human KLK5, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, Pro225, and Lys233 according to standard protease numbering.

40. The antibody of claim 39, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, Asp178, Arg224, and Lys233 according to standard protease numbering.

41. The antibody of claim 39, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Pro130, Ser131, Ala132, Gly133, Val162, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Tyr172, Pro173, Arg174, Gln174A, Ile176, Asp177, and Lys233 according to standard protease numbering.

42. The antibody of claim 39, wherein the antibody binds to an epitope on human KLK5 comprising one or more amino acid residues selected from the group consisting of Ser131, Ala132, Gly133, Leu163, Ser164, Gln165, Lys166, Arg167, Glu169, Asp170, Ala171, Pro173, Arg174, Gly184, Asp185, Lys186, Ala186A, Arg188, Asn223, Arg224, and Pro225 according to standard protease numbering.

43. An antibody when bound to human KLK5 results in a conformational change of human KLK5, wherein the conformational change allosterically results in the disruption of the substrate binding site and/or the active site of human KLK5.