Antigen Binding Proteins Capable of Binding Thymic Stromal Lymphopoietin

Abstract

The present disclosure provides compositions and methods relating to antigen binding proteins which bind to human thymic stromal lymphopoietin (TSLP), including antibodies. In particular embodiments, the disclosure provides fully human, humanized and chimeric anti-TSLP antibodies and derivatives of such antibodies. The disclosure further provides nucleic acids encoding such antibodies and antibody fragments and derivatives, and methods of making and using such antibodies including methods of treating and preventing TSLP-related inflammatory and fibrotic disorders.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a Continuation of U.S. patent application Ser. No. 15/014,828, filed Feb. 3, 2016, which is a Divisional Application of U.S. patent application Ser. No. 13/438,739, filed Apr. 3, 2012, now U.S. Pat. No. 9,284,372, issued Mar. 15, 2016, which is a Divisional of U.S. patent application Ser. No. 13/185,021, filed Jul. 18, 2011, now U.S. Pat. No. 8,163,284, issued Apr. 24, 2012, which is a Divisional of U.S. patent application Ser. No. 12/231,944, filed Sep. 8, 2008, now U.S. Pat. No. 7,982,016, issued Jul. 19, 2011, which is hereby incorporated by reference, which claims the benefit under 35 U.S.C. .sctn. 119 of U.S. Provisional Application No. 61/091,676, filed Aug. 25, 2008 and U.S. Provisional Application No. 60/971,178 filed Sep. 10, 2007.

REFERENCE TO THE SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled A-1276-US-DIV2_List_ST25.txt, created Apr. 3, 2012, which is 155 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0003] The field of this invention relates to compositions of antigen binding proteins including antibodies capable of binding human thymic stromal lymphopoietin, as well as related methods.

BACKGROUND OF THE INVENTION

[0004] The prevalence of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergies appears to be increasing in recent years, particularly in developed countries, affecting an increasing percentage of the population (Kay, N Engl. J. Med. 344:30-37(2001)). Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine produced in response to pro-inflammatory stimuli. TSLP has been discovered to promote allergic inflammatory responses primarily through its activity on dendritic and mast cells (Soumelis et al., Nat Immun 3(7): 673-680 (2002), Allakhverdi et al., J. Exp. Med. 204(2):253-258 (2007)). Human TSLP expression has been reported to be increased in asthmatic airways correlating to disease severity (Ying et al., J. Immunol. 174: 8183-8190 (2005)). In addition, TSLP protein levels are detectable in the concentrated bronchoalveoloar lavage (BAL) fluid of asthma patients, and other patients suffering from allergic disorders. Also, increased levels of TSLP protein and mRNA are found in the lesional skin of atopic dermatitis (AD) patients. Therefore, TSLP antagonists would be useful in treating inflammatory disorders.

[0005] In addition, TSLP has also been found to promote fibrosis, as reported in U.S. application Ser. No. 11/344,379. Fibrotic disease results during the tissue repair process if the fibrosis phase continues unchecked, leading to extensive tissue remodeling and the formation of permanent scar tissue (Wynn, Nature Rev. Immunol. 4, 583 (2004)). It has been estimated that up to 45% of deaths in the United States can be attributed to fibroproliferative diseases, which can affect many tissues and organ systems (Wynn, supra, at 595 (2004)).

[0006] Currently, anti-inflammatory treatments are used to treat fibrotic disorders, since fibrosis is common to many persistent inflammatory diseases such as idopathic pulmonary fibrosis, progressive kidney disease, and liver cirrhosis. However, the mechanisms involved in regulation of fibrosis appear to be distinctive from those of inflammation, and anti-inflammatory therapies are not always effective in reducing or preventing fibrosis (Wynn, supra). Therefore, a need remains for developing treatments to reduce and prevent fibrosis.

[0007] Therefore, antagonists to TSLP would be expected to be useful for treating these inflammatory and fibrotic disorders. The present disclosure provides such treatments and methods of treating.

SUMMARY OF THE INVENTION

[0008] In one aspect, the present disclosure provides an isolated antigen binding protein comprising a. a light chain CDR3 sequence selected from i. a light chain CDR3 sequence that differs by no more than a total of two amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences of A1 to A27; ii. QQAX.sub.8SFPLT (SEQ ID NO: 251); and b. a heavy chain CDR3 sequence selected from i. a heavy chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences of A1 to A27; ii.GGGIX.sub.12VADYYX.sub.13YGMDV (SEQ ID NO: 255); iii. DX.sub.21GX.sub.22SGWPLFX.sub.23Y (SEQ ID NO: 259); wherein X.sub.8 is an N residue or a D residue;X.sub.12is a P residue or an A residue; X.sub.13 is a Y residue or an F residue; X.sub.21 is a G residue or an R residue;X.sub.22 is an S residue or a T residue; X.sub.23 is an A residue or a D residue, and wherein said antigen binding protein specifically binds to TSLP.

[0009] In another aspect, the isolated antigen binding protein of the present disclosure further comprises at least one of the following: a. a light chain CDR1 sequence selected from i. a light chain CDR1 sequence that differs by no more than three amino acids additions, substitutions, and/or deletions from a light chain CDR1 sequence of A1-A27; ii. RSSQSLX.sub.1YSDGX.sub.2TYLN (SEQ ID NO: 246); iii. RASQX.sub.4X.sub.5SSWLA (SEQ ID NO: 249); b. a light chain CDR2 sequence selected from i. a light chain CDR2 sequence that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDR2 sequence of A1-A27; ii. KVSX.sub.3 (residues 1-4 of SEQ ID NO: 247); iii. X.sub.6X.sub.7SSLQS (SEQ ID NO: 250); or iv. QDX.sub.9KRPS (SEQ ID NO: 252); and c. a heavy chain CDR1 sequence selected from i. a heavy chain CDR1 sequence that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDR1 sequence of A1-A27; ii. X.sub.10YGMH (SEQ ID NO: 253); and iii. X.sub.15X.sub.16YMX.sub.17 (SEQ ID NO: 257); and d. a heavy chain CDR2 sequence selected from i. a heavy chain CDR2 sequence that differs by no more than three amino acid additions, substitutions, and/or deletions from a CDR2 sequence of A1-A27; VIWX.sub.11DGSNKYYADSVKG (SEQ ID NO: 254); iii. VISYDGSX.sub.14KYYADSVKG (SEQ ID NO: 256); and iv. WINPNSGGTNX.sub.18X.sub.19X.sub.20KFQG (SEQ ID NO: 258); wherein Xi is a V residue or an I residue; X.sub.2 is an N residue or a D residue; X.sub.3 is a Y residue or an N residue; X.sub.4 is a G residue or a S residue; X s is a L residue or an I residue; X.sub.6 is an N residue or a T residue; X.sub.7 is a T residue or an A residue; X.sub.9 is a K residue or an N residue; X.sub.10 is an S residue or an N residue; X.sub.11 is a Y residue or an F residue; X.sub.14 is a Y residue or a N residue; X.sub.15 is a D residue or G residue; X.sub.16 is a Y residue or a D residue; X.sub.17 is a Y residue or an H residue; X.sub.18 is a Y residue or an H residue; X.sub.19 is a V residue or an A residue; X.sub.20 is a Q residue or an R residue,and wherein said antigen binding protein specifically binds to TSLP.

[0010] In another aspect of the present disclosure, the isolated antigen binding protein of claim 1 comprises either: a. a light chain variable domain comprising: i. a light chain CDR1 sequence selected from A1-A27; ii a light chain CDR2 sequence selected from A1-A27; iii. a light chain CDR3 sequence selected from A1-A27; or b. a heavy chain variable domain comprising i. a heavy chain CDR1 sequence selected from A1-A27; ii. a heavy chain CDR2 sequence selected from A1-A27, and iii. a heavy chain CDR3 sequence selected from A1-A27; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0011] In a further aspect, the isolated antigen binding protein comprises either a. a light chain variable domain sequence selected from i amino acids having a sequence at least 80% identical to a light chain variable domain sequence selected from L1-L27; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the light chain variable domain sequence of L1-L27; iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a light chain variable domain sequence of L1-L27; b. a heavy chain variable domain sequence selected from i. a sequence of amino acids that is at least 80% identical to a heavy chain variable domain sequence of H1-H27; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the heavy chain variable domain sequence of H1-H27; iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a heavy chain variable domain sequence of H1-H27; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein said antigen binding protein specifically binds to TSLP.

[0012] In a further aspect, an isolated antigen binding protein of the present disclosure comprises either: a. a light chain variable domain sequence selected from : L1-L27; b. a heavy chain variable domain sequence selected from H1-H27; or, c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antigen binding protein specifically binds to TSLP.

[0013] In a futher aspect, the isolated binding protein comprises a light chain variable domain sequence and a heavy chain variable domain sequence selected from L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13.1H13, L13.2H13, L14.1H14, L14.2H14, L15.1H15, L15.2H15, L16.1H16, L16.2H16, L17H17, L18.1H18, L18.2H18, L19.1H19, L19.2H19, L20.1H20, L20.2H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, and L27H27.

[0014] In a further aspect, the isolated antigen binding protein comprises a binding protein that binds to TSLP with substantially the same Kd as a reference antibody selected from A2, A3, A4, and A5. In another aspect, the isolated antigen binding protein comprises a binding protein that inhibits TSLP activity according to the primary cell OPG assay with the same IC50 as a reference antibody selected from A2, A3, A4 or A5.

[0015] In a still further aspect, the isolated antigen binding protein cross-competes for binding of TSLP with a reference antibody. In another aspect, the isolated antigen binding protein binds the same epitope as a reference antibody, e.g., A2, A4, A5, A6, A7, A10, A21, A23, or A26.

[0016] In one aspect, the isolated antigen binding protein is selected from a human antibody, a humanized antibody, chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an F(fa')x fragment, a domain antibody, an IgD antibody, an IgE antibody, and IgM antibody, and IgG1 antibody, and IgG2 antibody, and IgG3 antibody, and IgG4 antibody, and IgG4 antibody having at least one mutation in the hinge region that alleviates a tendency to for intra H-chain disulfide bonds. In one aspect, the isolated antigen binding protein is a human antibody.

[0017] Also provided is an isolated nucleic acid molecule comprising a polynucleotide sequence encoding the light chain variable domain, the heavy chain variable domain, or both, of the antigen binding agent of the present disclosure. In one embodiment, the polynucleotide comprises a light chain variable sequence L1-L27, and/or a heavy chain variable sequence H1-H27, or both.

[0018] Also provided are vectors comprising the polynucleotides of the present disclosure. In one embodiment the vector is an expression vector. Also provided is a host cell comprising the vector. Also provided is a hybridoma capable of producing the antigen binding protein of the present invention. Also provided is a method of making the antigen binding protein comprising culturing the host cell under conditions that allow it to express the antigen binding protein.

[0019] Also provided is a pharmaceutical composition comprising the antigen binding proteins of the present invention. In one embodiment the pharmaceutical composition comprises a human antibody. Also provided is a method of treating a TSLP-related inflammatory condition in a subject in need of such treatment comprising administering a therapeutically effective amount of the composition to the subject. In one embodiment, the inflammatory condition is allergic asthma, allergic rhinosinusitis, allergic conjunctivitis, or atopic dermatitis. Also provided is a method of treating a TSLP-related fibrotic disorder in a subject in need of such treatment comprising administering a therapeutically effective amount of the composition to the subject. In one embodiment, the fibrotic disorder is scleroderma, interstitial lung disease, idiopathic pulmonary fibrosis, fibrosis arising from chronic hepatitis B or C, radiation-induced fibrosis, and fibrosis arising from wound healing.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1A-1F provide the amino acid sequence of the light chain CDR1, CDR2, and CDR3 regions of A1-A27. Further provided is an exemplary nucleotide sequence encoding each CDR.

[0021] FIG. 2A-2F provide the amino acid sequence of the heavy chain CDR1, CDR2, and CDR3 regions of A1-A27. Further provided is an exemplary nucleotide sequence encoding each CDR.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention relates to antigen binding agents, including antigen binding proteins, that specifically bind to the cytokine human thymic stromal lymphopoietin (TSLP), including antigen binding proteins that inhibit TSLP binding and signaling such as antagonistic TSLP antibodies, antibody fragments, and antibody derivatives. The antigen binding agents are useful for inhibiting or blocking binding of TSLP to its receptor, and for treating inflammatory diseases, fibrotic diseases, and other related conditions.

[0023] The present invention further provides compositions, kits, and methods relating to antigen binding proteins that bind to TSLP. Also provided are nucleic acid molecules, and derivatives and fragments thereof, comprising a sequence of polynucleotides that encode all or a portion of a polypeptide that binds to TSLP, such as a nucleic acid encoding all or part of an anti-TSLP antibody, antibody fragment, or antibody derivative. The present invention further provides vectors and plasmids comprising such nucleic acids, and cells or cell lines comprising such nucleic acids and/or vectors and plasmids. The provided methods include, for example, methods of making, identifying, or isolating antigen binding proteins that bind to human TSLP such as anti-TSLP antibodies, methods of determining whether an antigen binding protein binds to TSLP, methods of making compositions, such as pharmaceutical compositions, comprising an antigen binding protein that binds to TSLP, and methods for administering an antigen binding protein that binds to TSLP in a subject, for example, methods for treating a condition mediated by TSLP, and for modulating a biological activity associated with TSLP signalling in vivo or in vitro.

TSLP

[0024] Thymic stromal lymphopoietin (TSLP) refers to a four a-helical bundle type I cytokine which is a member of the IL-2 family but most closely related to IL-7. Cytokines are low molecular weight regulatory proteins secreted in response to certain stimuli, which act on receptors on the membrane of target cells. Cytokines regulate a variety of cellular responses. Cytokines are generally described in references such as Cytokines, A. Mire-Sluis and R. Thorne, ed., Academic Press, New York, (1998).

[0025] TSLP was originally cloned from a murine thymic stromal cell line (Sims et al J. Exp. Med 192 (5), 671-680 (2000)), and found to support early B and T cell development. Human TSLP was later cloned and found to have a 43 percent identity in amino acid sequence to the murine homolog (Quentmeier et al. Leukemia 15, 1286-1292 (2001), and U.S. Pat. No: 6,555,520, which is herein incorporated by reference). The polynucleotide and amino acid sequence of human TSLP are presented in SEQ ID NO: 1 and 2 respectively. TSLP was found to bind with low affinity to a receptor chain from the hematopoietin receptor family called TSLP receptor (TSLPR), which is described in U.S. patent application Ser. No: 09/895,945 (publication No: 2002/0068323) (SEQ ID NO: 3 and 4). The polynucleotide sequence encoding human TSLPR is presented as SEQ ID NO: 3 of the present application, and the amino acid sequence is presented as SEQ ID NO: 4 of the present application respectively. The soluble domain of the TSLPR is approximately amino acids 25 through 231 of SEQ ID NO: 4. TSLP binds with high affinity to a heterodimeric complex of TSLPR and the interleukin 7 receptor alpha IL-7Ra (Park et al., J. Exp. Med 192:5 (2000), U.S. patent application Ser. No. 09/895,945, publication number U.S. 2002/0068323). The sequence of IL-7 receptor a is shown in FIG. 2 of U.S. Pat. No. 5,264,416, which is herein incorporated by reference. The sequence of the soluble domain of the IL-7 receptor a is amino acid 1 to 219 of FIG. 2 in U.S. Pat. No. 5,264,416.

[0026] As used herein the term "TSLP polypeptides" refers to various forms of TSLP useful as immunogens. These include TSLP expressed in modified form, in which a furin cleavage site has been removed through modification of the amino acid sequence, as described in PCT patent application publication WO 03/032898. Modified TSLP retains activity but the full length sequence is more easily expressed in mammalian cells such as CHO cells. Examples of TSLP polypeptides include SEQ ID NO: 2, SEQ ID NO: 373, and SEQ ID NO: 375.

[0027] In addition, cynomolgus TSLP has been identified and is shown in Example 1 below and is set forth in SEQ ID NO: 380, for example.

[0028] TSLP is produced in human epithelial cells including skin, bronchial, tracheal, and airway epithelial cells, keratinocytes, stromal and mast cells, smooth muscle cells, and lung and dermal fibroblasts, as determined by quantitative mRNA analysis (Soumelis et al, Nature Immunol. 3 (7) 673-680 (2002)). Both murine and human TSLP are involved in promoting allergic inflammation.

TABLE-US-00001 TABLE 1 Protein Database(s) (or Accession Name Species Synonyms Patent Application) No. TSLP Homo sapiens Thymic stromal GENBANK/ AAK67490 lymphopoietin protein SEQ ID NO: 2 of US Patent No.6555520 Modified Homo sapiens Thymic stromal SEQ ID NOS: 10, TSLP lymphopoietin 12, 14, 16, 17, 18 of WO 03/032898 TSLP Mus musculus Thymic stroma derived GENBANK AAF81677 lymphopoietin; Thymic stromal derived lymphopoietin TSLPR Homo sapiens Cytokine receptor-like 2 SEQ ID NO: 5 of (CRL2); IL-XR; Thymic US 2002/0068323 stromal lymphopoietin protein receptor TSLPR Mus Cytokine receptor-like GENBANK, Q8CII9 factor 2; Type I cytokine SWISSPROT receptor delta 1; Cytokine receptor-like molecule 2 (CRLM-2); Thymic stromal lymphopoietin protein receptor IL-7R Homo sapiens Interleukin-7 receptor GENBANK/ NM_002185 US Patent No. 5264416

TSLP Activity

[0029] TSLP activities include the proliferation of BAF cells expressing human TSLPR (BAF/HTR), as described in PCT patent application publication WO 03/032898. The BAF/HTR bioassay utilizes a murine pro B lymphocyte cell line, which has been transfected with the human TSLP receptor. The BAF/HTR cells are dependent upon huTSLP for growth, and proliferate in response to active huTSLP added in test samples. Following an incubation period, cell proliferation is measured by the addition of ALAMAR BLUE dye I or tritiated thymidine. Proliferation may also be measured using a commercially available kit such as the CYQUANT cell proliferation assay kit (Invitrogen).

[0030] Additional assays for huTSLP activity include, for example, an assay measuring induction of T cell growth from human bone marrow by TSLP as described in U.S. Pat. No. 6,555,520. Another TSLP activity is the ability to activate STATS as described in the reference to Levin et al., J. Immunol. 162:677-683 (1999) and PCT patent application WO 03/032898. Additional assays include TSLP induced CCL17/TARC production from primary human monocytes and dendritic cells as described in US application publication no. 2006/0039910 (Ser. No. 11/205,909).

[0031] Cell based assays useful for measuring TSLP activity are described in the examples below. These include the BAF cell proliferation assay described above, as well as the primary cell assay described below measuring TSLP induced osteoprotegerin (OPG) production from primary human dendritic cells, as well cynomolgus peripheral blood mononuclear cell assay, also described below.

[0032] TSLP activities further include in vivo activities. These can be measured in mouse models, for example, such as those described in Zhou et al., Nat Immunol 6(10), 1047-1053 (2005), and Yoo et al., J Exp Med. 202 (4), 541-549 (2005). For example, an anti-murine TSLP antibody was shown to decrease BALF cellularity and BALF levels of IL-5 and 11-13 in an Ova-asthma model (Zhou et al).

Definitions

[0033] Polynucleotide and polypeptide sequences are indicated using standard one- or three-letter abbreviations. Unless otherwise indicated, polypeptide sequences have their amino termini at the left and their carboxy termini at the right, and single-stranded nucleic acid sequences, and the top strand of double-stranded nucleic acid sequences, have their 5' termini at the left and their 3' termini at the right. A particular polypeptide or polynucleotide sequence also can be described by explaining how it differs from a reference sequence.

[0034] Polynucleotide and polypeptide sequences of particular light and heavy chain variable domains., L1 ("light chain variable domain 1"), H1 ("heavy chain variable domain 1"), etc. Antibodies comprising a light chain and heavy chain are indicated by combining the name of the light chain and the name of the heavy chain variable domains. For example, "L4H7," indicates an antibody comprising the light chain variable domain of L4 and the heavy chain variable domain of H7.

[0035] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well known and commonly used in the art. The methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990), which are incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The terminology used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0036] The following terms, unless otherwise indicated, shall be understood to have the following meanings: The term "isolated molecule" (where the molecule is, for example, a polypeptide, a polynucleotide, or an antibody) is a molecule that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is substantially free of other molecules from the same species (3) is expressed by a cell from a different species, or (4) does not occur in nature. Thus, a molecule that is chemically synthesized, or expressed in a cellular system different from the cell from which it naturally originates, will be "isolated" from its naturally associated components. A molecule also may be rendered substantially free of naturally associated components by isolation, using purification techniques well known in the art. Molecule purity or homogeneity may be assayed by a number of means well known in the art. For example, the purity of a polypeptide sample may be assayed using polyacrylamide gel electrophoresis and staining of the gel to visualize the polypeptide using techniques well known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well known in the art for purification.

[0037] The terms "TSLP inhibitor" and "TSLP antagonist" are used interchangeably. Each is a molecule that detectably inhibits TSLP signalling. The inhibition caused by a TSLP inhibitor need not be complete so long as it is detectable using an assay. For example, the cell-based assay described in Example 4 below, demonstrates an assay useful for determining TSLP signaling inhibition.

[0038] The terms "peptide" "polypeptide" and "protein" each refers to a molecule comprising two or more amino acid residues joined to each other by peptide bonds. These terms encompass, e.g., native and artificial proteins, protein fragments and polypeptide analogs (such as muteins, variants, and fusion proteins) of a protein sequence as well as post-translationally, or otherwise covalently or non-covalently, modified proteins. A peptide, polypeptide, or protein may be monomeric or polymeric.

[0039] The term "polypeptide fragment" as used herein refers to a polypeptide that has an amino-terminal and/or carboxy-terminal deletion as compared to a corresponding full-length protein. Fragments can be, for example, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 50, 70, 80, 90, 100, 150 or 200 amino acids in length. Fragments can also be, for example, at most 1,000, 750, 500, 250, 200, 175, 150, 125, 100, 90, 80, 70, 60, 50, 40, 30, 20, 15, 14, 13, 12, 11, or 10 amino acids in length. A fragment can further comprise, at either or both of its ends, one or more additional amino acids, for example, a sequence of amino acids from a different naturally-occurring protein (e.g., an Fc or leucine zipper domain) or an artificial amino acid sequence (e.g., an artificial linker sequence).

[0040] Polypeptides of the invention include polypeptides that have been modified in any way and for any reason, for example, to: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties. Analogs include muteins of a polypeptide. For example, single or multiple amino acid substitutions (e.g., conservative amino acid substitutions) may be made in the naturally occurring sequence (e.g., in the portion of the polypeptide outside the domain(s) forming intermolecular contacts). A "conservative amino acid substitution" is one that does not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterize the parent sequence or are necessary for its functionality). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991), which are each incorporated herein by reference.

[0041] A "variant" of a polypeptide comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted from and/or substituted into the amino acid sequence relative to another polypeptide sequence. Variants of the invention include fusion proteins. Variants of antibodies described herein also include those that result from processing. Such variants include those having one, two, three, four, five, six, seven, eight, nine ten or more additional amino acids at the N-terminus of a light or heavy chain, e.g., as a result of inefficient signal sequence cleavage. Such variants also include those missing one or more amino acids from the N- or C-termini of a light or heavy chain.

[0042] A "derivative" of a polypeptide is a polypeptide (e.g., an antibody) that has been chemically modified, e.g., via conjugation to another chemical moiety such as, for example, polyethylene glycol, albumin (e.g., human serum albumin), phosphorylation, and glycosylation. Unless otherwise indicated, the term "antibody" includes, in addition to antibodies comprising two full-length heavy chains and two full-length light chains, derivatives, variants, fragments, and muteins thereof, examples of which are described below.

[0043] An "antigen binding protein" according to the present disclosure is a protein capable of binding to an antigen and, optionally, a scaffold or framework portion that allows the antigen binding portion to adopt a conformation that promotes binding of the antigen binding protein to the antigen. In one embodiment an antigen binding protein of the present invention comprises at least one CDR. Examples of antigen binding proteins include antibodies, antibody fragments (e.g., an antigen binding portion of an antibody), antibody derivatives, and antibody analogs. The antigen binding protein can comprise, for example, an alternative protein scaffold or artificial scaffold with grafted CDRs or CDR derivatives. Such scaffolds include, but are not limited to, antibody-derived scaffolds comprising mutations introduced to, for example, stabilize the three-dimensional structure of the antigen binding protein as well as wholly synthetic scaffolds comprising, for example, a biocompatible polymer. See, for example, Korndorfer et al., 2003, Proteins: Structure, Function, and Bioinformatics, Volume 53, Issue 1:121-129; Roque et al., 2004, Biotechnol. Prog. 20:639-654. In addition, peptide antibody mimetics ("PAMs") can be used, as well as scaffolds based on antibody mimetics utilizing fibronection components as a scaffold.

[0044] An antigen binding protein can have, for example, the structure of a naturally occurring immunoglobulin. An "immunoglobulin" is a tetrameric molecule. In a naturally occurring immunoglobulin, each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2' ed. Raven Press, N.Y. (1989)) (incorporated by reference in its entirety for all purposes). The variable regions of each light/heavy chain pair form the antibody binding site such that an intact immunoglobulin has two binding sites.

[0045] Naturally occurring immunoglobulin chains exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. From N-terminus to C-terminus, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat et al. in Sequences of Proteins of Immunological Interest, 5.sup.th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991. Intact antibodies include polyclonal, monoclonal, chimeric, humanized or fully human having full length heavy and light chains.

[0046] An "antibody" refers to an intact immunoglobulin or to an antigen binding portion thereof that competes with the intact antibody for specific binding, unless otherwise specified. Antigen binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Antigen binding portions include Fab, Fab', F(ab').sub.2, Fd, Fv, and domain antibodies (dAbs), and complementarity determining region (CDR) fragments, single-chain antibodies (scFv), diabodies, triabodies, tetrabodies, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide.

[0047] A Fab fragment is a monovalent fragment having the V.sub.L, V.sub.H, C.sub.L and C.sub.H1 domains; a F(ab').sub.2 fragment is a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment has the V.sub.H and C.sub.H1 domains; an Fv fragment has the V.sub.L and V.sub.H domains of a single arm of an antibody; and a dAb fragment has a V.sub.H domain, a V.sub.L domain, or an antigen-binding fragment of a V.sub.H or V.sub.L domain (U.S. Pat. Nos. 6,846,634, 6,696,245, US App. Pub. No. 05/0202512, 04/0202995, 04/0038291, 04/0009507, 03/0039958, Ward et al., Nature 341:544-546, 1989).

[0048] A single-chain antibody (scFv) is an antibody in which a V.sub.L and a V.sub.H region are joined via a linker (e.g., a synthetic sequence of amino acid residues) to form a continuous protein chain wherein the linker is long enough to allow the protein chain to fold back on itself and form a monovalent antigen binding site (see, e.g., Bird et al., 1988, Science 242:423-26 and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-83). Diabodies are bivalent antibodies comprising two polypeptide chains, wherein each polypeptide chain comprises V.sub.H and V.sub.L domains joined by a linker that is too short to allow for pairing between two domains on the same chain, thus allowing each domain to pair with a complementary domain on another polypeptide chain (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-48, and Poljak et al., 1994, Structure 2:1121-23). If the two polypeptide chains of a diabody are identical, then a diabody resulting from their pairing will have two identical antigen binding sites. Polypeptide chains having different sequences can be used to make a diabody with two different antigen binding sites. Similarly, tribodies and tetrabodies are antibodies comprising three and four polypeptide chains, respectively, and forming three and four antigen binding sites, respectively, which can be the same or different.

[0049] Complementarity determining regions (CDRs) and framework regions (FR) of a given antibody may be identified using the system described by Kabat et al. in Sequences of Proteins of Immunological Interest, 5.sup.th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991. One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an antigen binding protein. An antigen binding protein may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently. The CDRs permit the antigen binding protein to specifically bind to a particular antigen of interest.

[0050] An antigen binding protein may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For example, a naturally occurring human immunoglobulin typically has two identical binding sites, while a "bispecific" or "bifunctional" antibody has two different binding sites.

[0051] The term "human antibody" includes all antibodies that have one or more variable and constant regions derived from human immunoglobulin sequences. In one embodiment, all of the variable and constant domains are derived from human immunoglobulin sequences (a fully human antibody). These antibodies may be prepared in a variety of ways, examples of which are described below, including through the immunization with an antigen of interest of a mouse that is genetically modified to express antibodies derived from human heavy and/or light chain-encoding genes.

[0052] A humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and/or light chains of the non-human species antibody are mutated to produce the humanized antibody. In another embodiment, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the antigen is not significantly worse than the binding of the non-human antibody to the antigen. Examples of how to make humanized antibodies may be found in U.S. Pat. Nos. 6,054,297, 5,886,152 and 5,877,293.

[0053] The term "chimeric antibody" refers to an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies. In one embodiment, one or more of the CDRs are derived from a human anti-TSLP antibody. In another embodiment, all of the CDRs are derived from a human anti-TSLP antibody. In another embodiment, the CDRs from more than one human anti-TSLP antibodies are mixed and matched in a chimeric antibody. For instance, a chimeric antibody may comprise a CDR1 from the light chain of a first human anti-TSLP antibody, a CDR2 and a CDR3 from the light chain of a second human anti-TSLP antibody, and the CDRs from the heavy chain from a third anti-TSLP antibody. Further, the framework regions may be derived from one of the same anti-TSLP antibodies, from one or more different antibodies, such as a human antibody, or from a humanized antibody. In one example of a chimeric antibody, a portion of the heavy and/or light chain is identical with, homologous to, or derived from an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is/are identical with, homologous to, or derived from an antibody (-ies) from another species or belonging to another antibody class or subclass. Also included are fragments of such antibodies that exhibit the desired biological activity (i.e., the ability to specifically bind the human TSLP receptor).

[0054] Fragments or analogs of antibodies can be readily prepared by those of ordinary skill in the art following the teachings of this specification and using techniques well-known in the art. Preferred amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases. Computerized comparison methods can be used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. See, e.g., Bowie et al., 1991, Science 253:164.

[0055] A "CDR grafted antibody" is an antibody comprising one or more CDRs derived from an antibody of a particular species or isotype and the framework of another antibody of the same or different species or isotype.

[0056] A "multi-specific antibody" is an antibody that recognizes more than one epitope on one or more antigens. A subclass of this type of antibody is a "bi-specific antibody" which recognizes two distinct epitopes on the same or different antigens.

[0057] An antigen binding protein including an antibody "specifically binds" to an antigen, such as TSLP if it binds to the antigen with a high binding affinity as determined by a Kd (or corresponding Kb, as defined below) value of 10 M or less.

[0058] An "antigen binding domain," "antigen binding region," or "antigen binding site" is a portion of an antigen binding protein that contains amino acid residues (or other moieties) that interact with an antigen and contribute to the antigen binding protein's specificity and affinity for the antigen. For an antibody that specifically binds to its antigen, this will include at least part of at least one of its CDR domains.

[0059] The "percent identity" of two polynucleotide or two polypeptide sequences is determined by comparing the sequences using the GAP computer program (a part of the GCG Wisconsin Package, version 10.3 (Accelrys, San Diego, Calif.)) using its default parameters.

[0060] The terms "polynucleotide," "oligonucleotide" and "nucleic acid" are used interchangeably throughout and include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs (e.g., peptide nucleic acids and non-naturally occurring nucleotide analogs), and hybrids thereof. The nucleic acid molecule can be single-stranded or double-stranded. In one embodiment, the nucleic acid molecules of the invention comprise a contiguous open reading frame encoding an antibody, or a fragment, derivative, mutein, or variant thereof, of the invention.

[0061] Two single-stranded polynucleotides are "the complement" of each other if their sequences can be aligned in an anti-parallel orientation such that every nucleotide in one polynucleotide is opposite its complementary nucleotide in the other polynucleotide, without the introduction of gaps, and without unpaired nucleotides at the 5' or the 3' end of either sequence. A polynucleotide is "complementary" to another polynucleotide if the two polynucleotides can hybridize to one another under moderately stringent conditions. Thus, a polynucleotide can be complementary to another polynucleotide without being its complement.

[0062] A "vector" is a nucleic acid that can be used to introduce another nucleic acid linked to it into a cell. One type of vector is a "plasmid," which refers to a linear or circular double stranded DNA molecule into which additional nucleic acid segments can be ligated. Another type of vector is a viral vector (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), wherein additional DNA segments can be introduced into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors comprising a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. An "expression vector" is a type of vector that can direct the expression of a chosen polynucleotide.

[0063] A nucleotide sequence is "operably linked" to a regulatory sequence if the regulatory sequence affects the expression (e.g., the level, timing, or location of expression) of the nucleotide sequence. A "regulatory sequence" is a nucleic acid that affects the expression (e.g., the level, timing, or location of expression) of a nucleic acid to which it is operably linked. The regulatory sequence can, for example, exert its effects directly on the regulated nucleic acid, or through the action of one or more other molecules (e.g., polypeptides that bind to the regulatory sequence and/or the nucleic acid). Examples of regulatory sequences include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Further examples of regulatory sequences are described in, for example, Goeddel, 1990, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. and Baron et al., 1995, Nucleic Acids Res. 23:3605-06.

[0064] A "host cell" is a cell that can be used to express a nucleic acid, e.g., a nucleic acid of the invention. A host cell can be a prokaryote, for example, E. coli, or it can be a eukaryote, for example, a single-celled eukaryote (e.g., a yeast or other fungus), a plant cell (e.g., a tobacco or tomato plant cell), an animal cell (e.g., a human cell, a monkey cell, a hamster cell, a rat cell, a mouse cell, or an insect cell) or a hybridoma. Exemplary host cells include Chinese hamster ovary (CHO) cell lines or their derivatives including CHO strain DXB-11, which is deficient in DHFR (see Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77:4216-20), CHO cell lines which grow in serum-free media (see Rasmussen et al., 1998, Cytotechnology 28:31), CS-9 cells, a derivative of DXB-11 CHO cells, and AM-1/D cells (described in U.S. patent No. 6,210,924). Other CHO cells lines include CHO-K1 (ATCC #CCL-61), EM9 (ATCC #CRL-1861), and UV20(ATCC #CRL-1862). Examples of other host cells include COS-7 line of monkey kidney cells (ATCC CRL 1651) (see Gluzman et al., 1981, Cell 23:175), L cells, C127 cells, 3T3 cells (ATCC CCL 163), HeLa cells, BHK (ATCC CRL 10) cell lines, the CV1/EBNA cell line derived from the African green monkey kidney cell line CV1 (ATCC CCL 70) (see McMahan et al., 1991, EMBO J. 10:2821), human embryonic kidney cells such as 293, 293 EBNA or MSR 293, human epidermal A431 cells, human Colo205 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HL-60, U937, HaK or Jurkat cells. Typically, a host cell is a cultured cell that can be transformed or transfected with a polypeptide-encoding nucleic acid, which can then be expressed in the host cell. The phrase "recombinant host cell" can be used to denote a host cell that has been transformed or transfected with a nucleic acid to be expressed. A host cell also can be a cell that comprises the nucleic acid but does not express it at a desired level unless a regulatory sequence is introduced into the host cell such that it becomes operably linked with the nucleic acid. It is understood that the term host cell refers not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to, e.g., mutation or environmental influence, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

Antigen Binding Proteins

[0065] In one aspect, the present disclosure provides antigen binding proteins such as antibodies, antibody fragments, antibody derivatives, antibody muteins, and antibody variants that bind to human TSLP. Antigen binding proteins in accordance with the present disclosure includes antigen binding proteins that bind to human TSLP, and thereby reduce TSLP activity. For example, antigen binding proteins may interfere with the binding of TSLP to its receptor, and thus reduce TSLP activity. In one embodiment, the present invention provides an antigen binding protein that comprises one or more CDR sequences that differ from a CDR sequence shown in FIG. 1A-1F or FIG. 2A-2F by no more than 5, 4, 3, 2, 1, or 0 amino acid residues.

[0066] In another embodiment, at least one of the antigen binding protein CDR3 sequence is a sequence from FIG. 1A-1F or FIG. 2A-2F. In another embodiment, the antigen binding protein's light chain CDR3 sequence is a light chain sequence from A1 through A27, and the antigen binding protein heavy chain CDR3 sequence is a heavy chain CDR3 sequence from A1 through A27.

[0067] In another embodiment, the antigen binding protein further comprises 1, 2, 3, 4, or 5 CDR sequences that each independently differs by 5, 4, 3, 2, 1, or 0 single amino acid additions, substitutions, and/or deletions from a CDR sequence of A1-A27. The light chain CDR's of exemplary antigen binding proteins A1-A27 and the heavy chain CDR's of exemplary binding proteins A1-A27 are shown in FIG. 1A-1F and FIG. 2A-2F, respectively. Also shown are polynucleotide sequences which encode the amino acid sequences of the CDRs. In addition, consensus sequences of the CDR sequences are provided below.

TABLE-US-00002 CDR CONSENSUS SEQUENCES VARIABLE LIGHT CHAIN CDRs Group 1a LC CDR1 Consensus X.sub.1 X.sub.2 A16.1 R S S Q S L V Y S D G N T Y L N A18.1 V N A13.1 V D A19.1 V D A20.1 V D A14.1 V N A15.1 I N RSSQSLX.sub.1YSDGX.sub.2TYLN (SEQ ID NO: 246) X.sub.1 is a V (valine) residue or an I (isoleucine) residue, X.sub.2 is an N (asparagine) residue or a D (aspartic) acid residue; LC CDR2 Consensus X.sub.3 A16.1 K V S Y W D S A18.1 Y A13.1 N A19.1 N A20.1 N A14.1 N A15.1 N KVSX.sub.3WDS (SEQ ID NO: 247) X.sub.3 is a Y (tyrosine) residue or an N (asparagine) residue; LC CDR3 consensus A16.1 M Q G T H W P P A A18.1 A13.1 A19.1 A20.1 A14.1 A15.1 MQGTHQPPA (SEQ ID NO: 248) Group Ib LC CDR1 consensus X.sub.4 X.sub.5 A13.2 R A S Q G L S S W L A A14.2 G L A19.2 G L A20.2 G L A16.2 S L A18.2 S L A15.2 G I RASQX.sub.4X.sub.5SSWLA (SEQ ID NO: 249) X.sub.4 is a G (glycine) residue or an S (serine) residue; X.sub.5 is a L (leucine) residue or an I (isoleucine) residue; LC CDR2 consensus X.sub.6 X.sub.7 A13.2 N T S S L Q S A14.2 N T A19.2 N T A20.2 N T A16.2 N A A18.2 N A A15.2 T T X.sub.6X.sub.7SSLQS (SEQ ID NO: 250) X.sub.6 is an N (asparagine) residue or a T (threonine) residue; X.sub.7 is a T(theonine) residue or an A (alanine) residue; LC CDR3 consensus X.sub.8 A13.2 Q Q A N S F P L T A14.2 N A19.2 N A20.2 N A16.2 N A18.2 N A15.2 D QQAX.sub.8SFPLT (SEQ ID NO: 251) X.sub.8 is a N (asparagine) residue or a D (aspartic acid) residue; Group 2 LC CDR1 consensus A6 S G D K L G D K Y A C A8 SGDKLGDKYAC (SEQ ID NO: 15) LC CDR2 consensus X A6 Q D K K R P S A8 N QDX.sub.9KRPS (SEQ ID NO: 252) X.sub.9 is a K (lysine) residue or an N (asparagine) residue; LC CDR3 consensus A6 Q A W D S S T V V A8 QAWDSSTVV (SEQ ID NO: 107) Group 3 LC CDR1 consensus A3 T G S S S N I G A G F D V H A4 TGSSSNIGAGFDVH (SEQ ID NO: 10) LC CDR2 consensus A3 D N N N R P S A4 DNNNRPS (SEQ ID NO: 57) LC CDR3 consensus A3 Q S Y D S N L S G S I V V A4 QSYDSNLSGSIVV (SEQ ID NO: 102) VARIABLE HEAVY CHAIN CDRS Group 1 HC CDR1 consensus X.sub.10 A13 S Y G M H A14 S A19 S A20 S A16 N A18 N A15 N X.sub.10YGMH (SEQ ID NO: 253) X.sub.10 is a S (serine) or an N (asparagine) residue; HC CDR2 consensus X.sub.11 A13 V I W Y D G S N K Y Y A D S V K G A14 Y A19 Y A20 Y A16 Y A18 Y A15 F VIWX.sub.11DGSNKYYADSVKG (SEQ ID NO: 254) X.sub.11 is a Y (tyrosine) residue or a F (phenylalanine) residue. HC CDR3 consensus X.sub.12 X.sub.13 A13 G G G I P V A D Y Y Y Y G M D V A14 P Y A19 P Y A20 P Y A16 A Y A18 A Y A15 A F GGGIX.sub.12VADYYX.sub.13YGMDV (SEQ ID NO: 255) X.sub.12 is a P (proline) residue or an A (alanine) residue; X.sub.13 is a Y (tyrosine) residue or a F (phenylalanine) residue. Group 2 HC CDR1 consensus A6 S Y G I H A8 SYGIH (SEQ ID NO: 147) HC CDR2 consensus X.sub.14 A6 V I S Y D G S Y K Y Y A D S V K G A8 N VISYDGSX.sub.14KYYADSVKG (SEQ ID NO: 256) X.sub.14 is a Y (tyrosine) or an N (asparagine) residue. HC CDR3 consensus A6 G D S W N D R L N Y Y F Y D M D V A8 GDSWNDRLNYYFYDMDV (SEQ ID NO: 214) Group 3 HC CDR1 consensus X.sub.15 X.sub.16 X.sub.17 A3 D Y Y M Y A4 G D H X.sub.15X.sub.16YMX17 (SEQ ID NO: 257) X.sub.15 is a D (aspartic acid) or G (glycine) residue; X.sub.16 is a Y (tyrosine) or D (aspartic acid) residue; X.sub.17 is a Y (tyrosine) or an H (histidine) residue. HC CDR2 consensus X.sub.18 X.sub.19 X.sub.20 A3 W I N P N S G G T N Y V Q K F Q G A4 H A R WINPNSGGTNX.sub.18X.sub.19X.sub.20KFQG (SEQ ID NO: 258) X.sub.18 is a Y (tyrosine) or H (histidine) residue; X.sub.19 is a V (valine) or A (alanine) residue; X.sub.20 is a Q (glutamine) or R (arginine) residue. HC CDR3 consensus X.sub.21 X.sub.22 X.sub.23 A3 D G G S S G W P L F A Y A4 R T D (SEQ ID NO: 259) X.sub.21 is a G (glycine) or R (arginine) residue; X.sub.22 is a S (serine) or T (threonine) residue; X.sub.23 is an A (alanine) or D (aspartic acid) residue.

[0068] Table 2 below provides nucleic acid (DNA) sequences encoding the variable heavy domains (H#) and variable light domains (L#), and the amino acid sequences of the variable heavy and variable light domains for exemplary TSLP antigen binding proteins A1-A27, respectively. CDRs 1, 2 & 3 for each variable domain are sequential from the beginning to the end of each sequence. Framework (Fr) regions are underlined. Frameworks 1, 2, 3 & 4 for each variable domain are sequential from the beginning to the end of each sequence (e.g., the first underlined portion of the sequence is Fr1, the second is Fr2, the third is Fr3 & the last is Fr4 in each sequence).

TABLE-US-00003 TABLE 2 H1 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGTCT AGTGGGAGCTACCAACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCG TCTCCTCA (SEQ ID NO: 260) H1 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVIWYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASLVGATNYYGMDVWGQGTTVTV SS (SEQ ID NO: 261) L1 DNA TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATC ACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGG ACAGGCCCCTGTACTTGTCATCTCTGGTAAAAACTACCGGCCCTCAGGGATCCCAGACCG ATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGA AGATGAGGCTGACTACTACTGTAACTCCCGGGACAGAAGTGGTAACCATCTGGTGTTTTC GGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 262) L1 Protein SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVISGKNYRPSGIPDRFSG SSSGNTASLTITGAQAEDEADYYCNSRDRSGNHLVFGGGTKLTVL (SEQ ID NO: 263) H2 DNA GAAGTGCAGCTGGTGGAGTCTGGGGGAGTCGTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTTTACCATGCACTGGGTCCGTCAAGCT CCGGGGAAGGGTCTGGAGTGGGTCTCTCTTATTAGTTGGGATGGTGGTAGCACATACTAT GCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACAGCAAAAACTCCCTGTA TATGCAAATGAACAGTCTGAGAACTGAGGACAGCGCCTTGTATTACTGTGCAAGAGGTC CTTACTACTACTTCTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCT CA (SEQ ID NO: 264) H2 Protein EVQLVESGGVVVQPGGSLRLSCAASGFTFDDFTMHWVRQAPGKGLEWVSLISWDGGSTYY ADSVKGRFTISRDNSKNSLYMQMNSLRTEDSALYYCARGPYYYFYGMDVWGQGTTVTVSS (SEQ ID NO: 265) L2 DNA TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATC ACATGCCAAGGAGACAGCCTCAGAACCTATTATGCAAGCTGGTACCAGCAGAAGCCAGG ACAGGCCCCTATACTTGTCATCTCTGATAAAAACAACCGGCCCTCAGGGATCCCAGACCG ATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGA AGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGATAACCATCTAGTGGTATT TCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 266) L2 Protein SSELTQDPAVSVALGQTVRITCQGDSLRTYYASWYQQKPGQAPILVISDKNNRPSGIPDRFSG SSSGNTASLTITGAQAEDEADYYCNSRDSSDNHLVVFGGGTKLTVL (SEQ ID NO: 267) H3 DNA CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGATACACCTTCACCGACTACTATATGTACTGGGTGCGACAGGC CCCTGGACAAGGGCCTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACT ATGTACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCC TACATGGAGCTGAGCAGGATGAGATCCGACGACACGGCCGTGTATTACTGTGCGAGAGA TGGGGGTAGCAGTGGCTGGCCCCTCTTTGCCTACTGGGGCCTGGGAACCCTGGTCACCGT CTCCTCA (SEQ ID NO: 268) H3 Protein QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMYWVRQAPGQGPEWMGWINPNSGGTN YVQKFQGRVTMTRDTSISTAYMELSRMRSDDTAVYYCARDGGSSGWPLFAYWGLGTLVTV SS (SEQ ID NO: 269) L3 DNA CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCAT CTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTTTGATGTACACTGGTACCAGCA GCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGATAACAACAATCGGCCCTCAGGGGT CCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCT CCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAACCTGAGTGGTTC GATTGTGGTTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 270) L3 Protein QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGFDVHWYQQLPGTAPKLLIYDNNNRPSGVPDR FSGSKSGTSASLAITGLQAEDEADYYCQSYDSNLSGSIVVFGGGTKLTVL (SEQ ID NO: 271) H4 DNA CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGATACATCTTCACCGGCGACTATATGCACTGGGTGCGACAGGC CCCTGGACAAGGGCTGGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACC ATGCACGGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCC TACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGTGAGAGA TAGGGGTACCAGTGGCTGGCCACTCTTTGACTATTGGGGCCAGGGAACACTGGTCACCGT CTCCTCA (SEQ ID NO: 272) H4 Protein QVQLVQSGAEVKKPGASVKVSCKASGYIFTGDYMHWVRQAPGQGLEWMGWINPNSGGTN HARKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCVRDRGTSGWPLFDYWGQGTLVTV SS (SEQ ID NO: 273) L4 DNA CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCAT CTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTTTGATGTGCACTGGTACCAGCT GCTTCCAGGAACAGCCCCCAAACTCCTCATCTTTGATAACAACAATCGCCCCTCAGGGGT CCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCT CCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAACCTGAGTGGTTC GATTGTGGTATTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 274) L4 Protein QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGFDVHWYQLLPGTAPKLLIFDNNNRPSGVPDR FSGSKSGTSASLAITGLQAEDEADYYCQSYDSNLSGSIVVFGGGTKLTVL (SEQ ID NO: 275) H5 DNA CAGATGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGAACCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGACTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAACACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCACCAGAGACAATTCCAAGAACACTCTG AATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGC CCCTCAGTGGGAGCTAGTTCATGAAGCTTTTGATATCTGGGGCCAAGGGACAATGGTCAC CGTCTCTTCA (SEQ ID NO: 360) H5 Protein QMQLVESGGGVVQPGRSLRLSCAASGFTFRTYGMHWVRQAPGKGLEWVAVIWYDGSNKH YADSVKGRFTITRDNSKNTLNLQMNSLRAEDTAVYYCARAPQWELVHEAFDIWGQGTMVT VSS (SEQ ID NO: 361) L5 DNA TCCTATGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATT ACCTGTGGGGGAAACAACCTTGGAAGTAAAAGTGTGCACTGGTACCAGCAGAAGCCAGG CCAGGCCCCTGTGCTGGTCGTCTATGATGATAGCGACCGGCCCTCATGGATCCCTGAGCG ATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGGCGAAGCCG GGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGTGATCATGTGGTATTTC GGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 362) L5 Protein SYVLTQPPSVSVAPGQTARITCGGNNLGSKSVHWYQQKPGQAPVLVVYDDSDRPSWIPERFS GSNSGNTATLTISRGEAGDEADYYCQVWDSSSDHVVFGGGTKLTVL (SEQ ID NO: 363) H6 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCATTTTCAGTAGCTATGGCATTCACTGGGTCCGCCAGGCT CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTTATAAATACTA TGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGGG GACTCCTGGAACGACAGATTAAACTACTACTTCTACGATATGGACGTCTGGGGCCAAGG GACCACGGTCACCGTCTCCTCA (SEQ ID NO: 276) H6 Protein QVQLVESGGGVVQPGRSLRLSCAASGFIFSSYGIHWVRQAPGKGLEWVAVISYDGSYKYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDSWNDRLNYYFYDMDVWGQGT TVTVSS (SEQ ID NO: 277) L6 DNA TCCTATGAGCTGACTCAGGCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATC ACCTGCTCTGGAGATAAATTGGGGGATAAATATGCTTGCTGGTATCAGCAGAAGCCAGG CCAGTCCCCTGTGCTGGTCATCTATCAAGATAAGAAGCGGCCCTCAGGGATCCCTGAGCG ATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTAT GGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCACTGTGGTATTTCGGCGGA GGGACCAAGCTGACCGTCCTA (SEQ ID NO: 278) L6 Protein SYELTQAPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDKKRPSGIPERFSG SNSGNTATLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVL (SEQ ID NO: 279) H7 DNA CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCG CCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTTCATCCATTACAGTGGGACCACCT ACTACAACCCGTCCCTCAAGAGTCGACTTACCCTATCAGTAGACACGTCTAAGAGCCAGT TCTCCCTGAAGCTGAACTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAG AAGTTGGCAGCTCGTCGGGTAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACC GTCTCCTCA (SEQ ID NO: 280) H7 Protein QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGFIHYSGTTYYNP SLKSRLTLSVDTSKSQFSLKLNSVTAADTAVYYCAREVGSSSGNWFDPWGQGTLVTVSS (SEQ ID NO: 281) L7 DNA TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATC ACCTGCTCTGGAGATAAATTGGGGGATAAATATGCTTGCTGGTATCAGCAGAAGCCAGG CCAGTCCCCTGTGGTGGTCATCTATCAAGATAACAAGCGGCCCTCAGGGATCCCTGAGCG ATTCTCTGGCTCCAACTCTGGGAACACAGCCACTTTGACCATCAGCGGGACCCAGGCTAT GGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCACCACTGCGATATTTCGGCGGA GGGACCAAGCTGACCGTCCTA (SEQ ID NO: 282) L7 Protein SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVVVIYQDNKRPSGIPERFSG SNSGNTATLTISGTQAMDEADYYCQAWDSTTAIFGGGTKLTVL (SEQ ID NO: 283) H8 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCATTCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGACTCCTGGAACGACAGATTAAACTACTACTTCTACGATATGGACGTCTGGGGCCAAG GGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 284) H8 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVISYDGSNKYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDSWNDRLNYYFYDMDVWGQGT TVTVSS (SEQ ID NO: 285) L8 DNA TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATC ACCTGCTCTGGAGATAAATTGGGGGATAAATATGCTTGCTGGTATCAGCAGAAGCCAGG CCAGTCCCCTGTACTGGTCATCTATCAAGATAACAAGCGGCCCTCAGGGATCCCTGAGCG ATTCTCTGGCTCCAACTCTGGGAACACAGCCACTTTGACCATCAGCGGGACCCAGGCTAT GGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCACTGTGGTATTTCGGCGGA GGGACCAAGCTGACCGTCCTA (SEQ ID NO: 286) L8 Protein SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDNKRPSGIPERFSG SNSGNTATLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVL (SEQ ID NO: 287) H9 DNA CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATATACCTTCAATAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATACATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACTCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGAG GTCCGGGCGTATAGCAGTGGCTGGTACGCCGCCTTTGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA (SEQ ID NO: 288) H9 Protein QVQLVESGGGVVQPGRSLRLSCAASGYTFNSYGMHWVRQAPGKGLEWVAVIWYDGSNTY YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAREVRAYSSGWYAAFDYWGQGTL VTVSS (SEQ ID NO: 289) L9 DNA TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATC ACATGCCAAGGAGACAGCCTCAGAATCTTTTATGCAAACTGGTACCAGCAGAAGCCAGG ACAGGCCCCTGTAGTTGTCTTCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCG ATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGCGGCTCAGGCGGA AGATGAGGCTGACTATTATTGTAACTCCCGGGACAGCAGTGGTAACCATGTGGTATTTCG GCGGAGGGACCACGCTGACCGTCCTA (SEQ ID NO: 290) L9 Protein

SSELTQDPAVSVALGQTVRITCQGDSLRIFYANWYQQKPGQAPVVVFYGKNNRPSGIPDRFS GSSSGNTASLTITAAQAEDEADYYCNSRDSSGNHVVFGGGTTLTVL (SEQ ID NO: 291) H10 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAACGTCTGGATTCACCTTCAGTAGTTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAGTAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGT AAGAAGTGGGAGCTACTACGAACAGTATTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCGCCGTCTCCTCA (SEQ ID NO: 292) H10 Protein QVQLVESGGGVVQPGRSLRLSCATSGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSSKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVRSGSYYEQYYYGMDVWGQGTT VAVSS (SEQ ID NO: 293) L10 DNA GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGCCGGGCAAATCAGTACATTAGCACCTATTTAAATTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAGGTCCTGATTTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCA AGGTTCAGTGGCAGTGGATTTGAGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCAACTTACTACTGTCAGCAGAGCTACACTACCCCGATCACCTTTCGGCCA AGGGACACGACTGGAGATTAAA (SEQ ID NO: 294) L10 Protein DIQMTQSPSSLSASVGDRVTITCRANQYISTYLNWYQQKPGKAPKVLIYAASSLQSGVPSRFS GSGFETDFTLTISSLQPEDFATYYCQQSYTTPITFGQGTRLEIK (SEQ ID NO: 295) H11 DNA GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGTTATAGCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTGGTCGTACTAGTAGCGTATACTA CGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGT ATCTGCACATGAACAGCCTGAGAGACGAGGACACGGCTGTGTATTACTGTGCGAGAAGT GGGATCTACTACGACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA (SEQ ID NO: 296) H11 Protein EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISGRTSSVYYA DSVKGRFTISRDNAKNSLYLHMNSLRDEDTAVYYCARSGIYYDYYGMDVWGQGTTVTVSS (SEQ ID NO: 297) L11 DNA GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCCCC ATCAACTGCAAGTCCAGCCAGAGTGTTTTAAACAGCTCCAACAATAAGAACTACTTAGCT TGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGACATCCACCCGG GAAGGCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCAC CATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTATTTTACTAC TCCGTGGACGTTTCGGCCAAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 298) L11 Protein DIVMTQSPDSLAVSLGERAPINCKSSQSVLNSSNNKNYLAWYQQKPGQPPKLLIYWTSTREG GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYFTTPWTFGQGTKVEIK (SEQ ID NO: 299) H12 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGCAGCCACTGCTATAGATTACTACTACTCCTACGGTATGGACGTCTGGGGCCTAGGGAC CACGGTCACCGTCTCCTCA (SEQ ID NO: 300) H12 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGAATAIDYYYSYGMDVWGLGTT VTVSS (SEQ ID NO: 301) L12 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTGGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGGGTATTAGTAGCTGGTTAGCCTGGTATCAGCGGAAACCA GGAAAAGCCCCTAAGTTCCTGATCTATACTGCATCCAGTTTGCAAAGTGGGGTCCCATCA CGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTCTGCAACTTACTATTGTCAACAGGCTGACAGTTTCCCGCTCACTTTTCGGCGG AGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 302) L12 Protein DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQRKPGKAPKFLIYTASSLQSGVPSRFS GSGSGTDFTLTISSLQPEDSATYYCQQADSFPLTFGGGTKVEIK (SEQ ID NO: 303) H13 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATACCAGTAGCTGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 304) H13 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGGIPVADYYYYGMDVWGQGTT VTVSS (SEQ ID NO: 305) L13.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCGTCTACAGTGATGGAGACACCTACTTGAATTGG TTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACTGGGAC TCTGGGGTCCCATACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGCAAATC AGCAGGGTGGAGGCTGAGGATGTTGGGATTTACTACTGCATGCAAGGTACACACTGGCC TCCGGCCTTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 306) L13.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGDTYLNWFQQRPGQSPRRLIYKVSNWDSG VPYRFSGSGSGTDFTLQISRVEAEDVGIYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 307) L13.2 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGGGTCTTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCCAAGCTCCTGATGTATAACACATCCAGTTTGCAAAGTGGGGTCCCATC AAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAGTCTCACCATCAGCAGCCTGCAGC CTGAAGATTTTGCAAGTTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTTCGGCG GAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 308) L13.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQGLSSWLAWYQQKPGKAPKLLMYNTSSLQSGVPSRF SGSGSGTDFSLTISSLQPEDFASYYCQQANSFPLTFGGGTKVEIK (SEQ ID NO: 309) H14 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATACCAGTAGCTGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 304) H14 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGGIPVADYYYYGMDVWGQGTT VTVSS (SEQ ID NO: 305) L14.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCGTCTACAGTGATGGAAACACCTACTTGAATTGG TTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACTGGGAC TCTGGGGTCCCAGACAGATTCAGCGGCATTGGGTCAGGCACTGACTTCACACTGAAAATC AGCAGGGTGGAGGCTGAGGATGTTGGGGTTTACTACTGCATGCAAGGTACACACTGGCC TCCGGCCTTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 310) L14.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNWDSG VPDRFSGIGSGTDFTLKISRVEAEDVGVYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 311) L14.2 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGGGTCTTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCCAAGCTCCTGATGTATAACACATCCAGTTTGCAAAGTGGGGTCCCATC AAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAGTCTCACCATCAGCAGCCTGCAGC CTGAAGATTTTGCAAGTTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTTCGGCG GAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 312) L14.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQGLSSWLAWYQQKPGKAPKLLMYNTSSLQSGVPSRF SGSGSGTDFSLTISSLQPEDFASYYCQQANSFPLTFGGGTKVEIK (SEQ ID NO: 309) H15 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCCCCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGACTGGAATGGGTGGCAGTTATATGGTTTGATGGAAGTAATAAATACT ATGCGGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATCCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATAGCAGTGGCTGACTACTACTTCTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 313) H15 Protein QVQLVESGGGVVQPGKSLRLSCAASGFPFSNYGMHWVRQAPGKGLEWVAVIWFDGSNKYY ADSVKGRFTISRDNPKNTLYLQMNSLRAEDTAVYYCARGGGIAVADYYFYGMDVWGQGTT VTVSS (SEQ ID NO: 314) L15.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCATATACAGTGATGGAAACACTTACTTGAATTGG TTTCAACAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACTGGGAC TCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAAT CAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCAAGGTACACACTGGC CTCCGGCCTTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 315) L15.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLIYSDGNTYLNWFQQRPGQSPRRLIYKVSNWDSGV PDRFSGSGSGTDFTLKISRVEAEDVGIYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 316) L15.2 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATTACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAGGTCCTGACCTATACTACATCCAGTTTGCAAAGTGGGGTCCCATCA AGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCTACTTACTTTTGTCAACAGGCTGACAGTTTCCCTCTCACTTTTCGGCGGG GGGACCAAGGTGGAGATCAAA (SEQ ID NO: 317) L15.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLTYTTSSLQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYFCQQADSFPLTFGGGTKVEIK (SEQ ID NO: 318) H16 DNA CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATAGCAGTGGCTGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 319) H16 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVIWYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGGIAVADYYYYGMDVWGQG TTVTVSS (SEQ ID NO: 320) L16.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGG TTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTTACTGGGAC TCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAAGCACTGATTTCACACTGAAAAT CAGTAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGC CTCCGGCCTTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 321) L16.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSYWDSG VPDRFSGSGSSTDFTLKISRVEAEDVGVYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 322) L16.2 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGAGTCTTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAACTCCTGCTCCATAATGCATCCAGTTTGCAAAGTGGGGTCCCATCA AGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGTAAATTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTTCGGCGGA GGGACCAGGGTGGAGATCAAA (SEQ ID NO: 323) L16.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQSLSSWLAWYQQKPGKAPKLLLHNASSLQSGVPSRFS GSGSGTDFTLTISSLQPEDFVNYYCQQANSFPLTFGGGTRVEIK (SEQ ID NO: 324)

H17 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTAAGACT CTCCTGTGCAGCGTCTGGATTCACCTTAAGTAGTTATGGCATGCTCTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTTTATGGTTTGATGGAAGTTATAAAAACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGA TAGTACAACTATGGCCCACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTC A (SEQ ID NO: 325) H17 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTLSSYGMLWVRQAPGKGLEWVAVLWFDGSYKNY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSTTMAHFDYWGQGTLVTVSS (SEQ ID NO: 326) L17 DNA CAGACTGTGGTGACCCAGGAGCCATCGTTCTCAGTGTCCCCTGGAGGGACAGTCACACTC ACTTGTGGCTTGAACTCTGGCTCAGTCTCTACTAGTTACTTCCCCAGCTGGTACCAGCAG ACCCCAGGCCAGGCTCCACGCACGCTCATCTACAGCACAAACAGTCGCTCTTCTGGGGTC CCTGATCGCTTCTCTGGCTCCATCCTTGGGAACAAAGCTGCCCTCACCATCACGGGGGCC CAGGCAGATGATGAATCTGATTATTACTGTGTGCTGTATATGGGTAGAGGCATTTGGGTG TTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 327) L17 Protein QTVVTQEPSFSVSPGGTVTLTCGLNSGSVSTSYFPSWYQQTPGQAPRTLIYSTNSRSSGVPDRF SGSILGNKAALTITGAQADDESDYYCVLYMGRGIWVFGGGTKLTVL (SEQ ID NO: 328) H18 DNA CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATAGCAGTGGCTGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 319) H18 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVIWYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGGIAVADYYYYGMDVWGQG TTVTVSS (SEQ ID NO: 320) L18.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGG TTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTTACTGGGAC TCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAAT CAGTAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGC CTCCGGCCTTTCGGCCAAGGGACACGACTGGAGATCAAA (SEQ ID NO: 329) L18.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSYWDSG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 330) L18.2 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGAGTCTTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAACTCCTGCTCTATAATGCATCCAGTTTGCAAAGTGGGGCCCCATCA AGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGTAACTTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTTCGGCGGA GGGACCAGGGTGGAGATCAAA (SEQ ID NO: 331) L18.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQSLSSWLAWYQQKPGKAPKLLLYNASSLQSGAPSRFS GSGSGTDFTLTISSLQPEDFVTYYCQQANSFPLTFGGGTRVEIK (SEQ ID NO: 332) H19 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATACCAGTAGCTGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 304) H19 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGGIPVADYYYYGMDVWGQGTT VTVSS (SEQ ID NO: 305) L19.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCGTCTACAGTGATGGAGACACCTACTTGAATTGG TTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACTGGGAC TCTGGGGTCCCATACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGCAAATC AGCAGGGTGGAGGCTGAGGATGTTGGGATTTACTACTGCATGCAAGGTACACACTGGCC TCCGGCCTTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 306) L19.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGDTYLNWFQQRPGQSPRRLIYKVSNWDSG VPYRFSGSGSGTDFTLQISRVEAEDVGIYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 307) L19.2 DNA GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGGGTCTTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCCAAGCTCCTGATGTATAACACATCCAGTTTGCAAAGTGGGGTCCCATC AAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAGTCTCACCATCAGCAGCCTGCAGC CTGAAGATTTTGCAAGTTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTTCGGCG GAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 308) L19.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQGLSSWLAWYQQKPGKAPKLLMYNTSSLQSGVPSRF SGSGSGTDFSLTISSLQPEDFASYYCQQANSFPLTFGGGTKVEIK (SEQ ID NO: 309) H20 DNA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGG GGGGGGTATACCAGTAGCTGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 304) H20 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGGIPVADYYYYGMDVWGQGTT VTVSS (SEQ ID NO: 305) L20.1 DNA GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAAAGCCTCGTCTACAGTGATGGAGACACCTACTTGAATTGG TTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACTGGGAC TCTGGGGTCCCATACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGCAAATC AGCAGGGTGGAGGCTGAGGATGTTGGGATTTACTACTGCATGCAAGGTACACACTGGCC TCCGGCCTTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 306) L20.1 Protein DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGDTYLNWFQQRPGQSPRRLIYKVSNWDSG VPYRFSGSGSGTDFTLQISRVEAEDVGIYYCMQGTHWPPAFGQGTRLEIK (SEQ ID NO: 307) L20.2 DNA GACATCCAGATGACCCAGTCCCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAGGGTCTTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCCAAGCTCCTGATGTATAACACATCCAGTTTGCAAAGTGGGGTCCCATC AAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAGTCTCACCATCAGCAGCCTGCAGC CTGAAGATTTTGCAAGTTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTTCGGCG GAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 333) L20.2 Protein DIQMTQSPSSVSASVGDRVTITCRASQGLSSWLAWYQQKPGKAPKLLMYNTSSLQSGVPSRF SGSGSGTDFSLTISSLQPEDFASYYCQQANSFPLTFGGGTKVEIK (SEQ ID NO: 309) H21 DNA GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCAGCAATTAGTGGTAGTGGTGGAAGTACACACT ACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGA TCTCAACTGGGGAGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 334) H21 Protein EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTHYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDLNWGAFDIWGQGTMVTVSS (SEQ ID NO: 335) L21 DNA CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCAT CTCCTGCACTGGGAGCAGCTCCAACATTGGGGCGGGTTATGTTGTACATTGGTACCAGCA GCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGT CCCTGACCAATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGACT CCAGTCTGAGGATGAGGCTGATTATTACTGCAAAGCATGGGATAACAGCCTGAATGCTC AAGGGGTATTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 336) L21 Protein QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYVVHWYQQLPGTAPKLLIYGNSNRPSGVPDQ FSGSKSGTSASLAITGLQSEDEADYYCKAWDNSLNAQGVFGGGTKLTVL (SEQ ID NO: 337) H22 DNA GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCGGGGGGGTCCCTGAGACT CTCCTGTGCAGGCTCTGGATTCTCCTTTAGAGGCTATGTCATGACTTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTCTCAGGAATTAGTGGTAGTGGTGGTAGCACATACTA CGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT GTCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGA GACAGCTCGAACTACTACTCCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCATCGT CTCCTCA (SEQ ID NO: 338) H22 Protein EVQLLESGGGLAQPGGSLRLSCAGSGFSFRGYVMTWVRQAPGKGLEWVSGISGSGGSTYYA DSVKGRFTISRDNSKNTLCLQMNSLRAEDTAVYYCAKGDSSNYYSGMDVWGQGTTVIVSS (SEQ ID NO: 339) L22 DNA GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACC ATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAACTCCAACAATAAGAACTACTTAGCT TGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCTTCTACCCGG GAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACC ATCAGCAGCCTGCAGGCTGAGGATGTGGCAATTTATTACTGTCAGCAATTTTATGGTCCT CCTCTCACTTTTCGGCGGAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 340) L22 Protein DIVMTQSPDSLAVSLGERATINCKSSQSVLYNSNNKNYLAWYQQKPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAIYYCQQFYGPPLTFGGGTKVEIK (SEQ ID NO: 341) H23 DNA CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAATGGTGGCACAAACT ATGGACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCC TACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGG GAACTGGAACGACGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTC A (SEQ ID NO: 342) H23 Protein QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNNGGTN YGQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGNWNDDAFDIWGQGTMVTVSS (SEQ ID NO: 343) L23 DNA TCCTATGAGCTGACTCAGTCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATC ACCTGTTCTGGTGATAAATTGGGGGATAAATTTGCTTTCTGGTATCAGCAGAAGCCAGGC CAGTCCCCTGTGCTGGTCATCTATCAAGATAGCAAGCGGCCCTCAGGGATCCCTGAGCGA TTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATG GATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCGCCGGGGGGGTATTTCGGCG GAGGGACCAAGTTGACCGTCCTA (SEQ ID NO: 344) L23 Protein SYELTQSPSVSVSPGQTASITCSGDKLGDKFAFWYQQKPGQSPVLVIYQDSKRPSGIPERFSGS NSGNTATLTISGTQAMDEADYYCQAWDSSAGGVFGGGTKLTVL (SEQ ID NO: 345) H24 DNA CAGGTGCAACTGGAGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACT ATGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAT GGGGTTTACTATGGTTCGGGGAGCCCTCTACTACGGTATGGACGTCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCA (SEQ ID NO: 346) H24 Protein QVQLEESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY VDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARMGFTMVRGALYYGMDVWGQGT TVTVSS (SEQ ID NO: 347) L24 DNA TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATC ACATGCCAAGGAGACAGCCTCAGAAGCTATCATGCAAGCTGGTACCAGCAGAAGCCAGG ACAGGCCCCTGTACTTGTCATCTATGGTGAAAACAACCGGCCCTCAGGGATCCCAGACCG ATTCTCTGACTCCAGTTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGA AGATGAGGCTGACTATTATTGTAATTATCGGGACAACAGTGGTAACCATCTGGTGTTTCG

GCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 348) L24 Protein SSELTQDPAVSVALGQTVRITCQGDSLRSYHASWYQQKPGQAPVLVIYGENNRPSGIPDRFSD SSSGNTASLTITGAQAEDEADYYCNYRDNSGNHLVFGGGTKLTVL (SEQ ID NO: 349) H25 DNA GAGGTGCAGCTGTTGGAATCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTCGTAGTGGTAGTACCACATACT ACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGTGGAACC GAGATATTTTGACTGGTTATTAGGCGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTC A (SEQ ID NO: 350) H25 Protein EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISRSGSTTYYAD SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVEPRYFDWLLGDWGQGTLVTVSS (SEQ ID NO: 351) L25 DNA GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACC ATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAACTCCAACAATAAGAACTACTTAGCT TGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCTTCTACCCGG GAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACC ATCAGCAGCCTGCAGGCTGAGGATGTGGCAATTTATTACTGTCAGCAATTTTATGGTCCT CCTCTCACTTTTCGGCGGAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 340) L25 Protein DIVMTQSPDSLAVSLGERATINCKSSQSVLYNSNNKNYLAWYQQKPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAIYYCQQFYGPPLTFGGGTKVEIK (SEQ ID NO: 341) H26 DNA CAGGTGCAGCTGGTGGAGTCGGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTAAATGGTATGAAGGAAGTAATAAATACT ATGGAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATTTGCAAATGAACAGTCTGAGAGGCGAGGATACGGCTGTGTATTACTGTGCGAGAGG CGCCCACGACTACGGTGACTTCTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGG TCACCGTCTCCTCA (SEQ ID NO: 352) H26 Protein QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVKWYEGSNKY YGDSVKGRFTISRDNSKNTLYLQMNSLRGEDTAVYYCARGAHDYGDFYYGMDVWGQGTT VTVSS (SEQ ID NO: 353) L26 DNA TCCTATGAACTGACTCAGCCAGCCTCAGTGTCCGTGTCCCCAGGACAGATAGCCAGCATC ACCTGCTCTGGAGATAATTTGGGGGATAAATATATTTGCTGGTATCAGCAGAAGCCAGGC CAGTCCCCTGTGCGGGTCATCTATCAAGATAACAAGCGGCCCTCAGGGATCCCTGAGCGT TTCTCTGGCTCCAATTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATG GATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCACTGTGGTATTTCGGCGGAG GGACCAAGCTGACCGTCCTA (SEQ ID NO: 354) L26 Protein SYELTQPASVSVSPGQIASITCSGDNLGDKYICWYQQKPGQSPVRVIYQDNKRPSGIPERFSGS NSGNTATLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVL (SEQ ID NO: 355) H27 DNA GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTTATAGTGGCGGTAGCACATACT ACGCAGGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGA TCGGGAGGGAGCGACTTGGTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCA CCGTCTCCTCA (SEQ ID NO: 356) H27 Protein EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISYSGGSTYYA GSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDREGATWYYGMDVWGQGTTVTV SS (SEQ ID NO: 357) L27 DNA TCCTATGAACTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATC ACCTGCTCTGGAGATAAATTGGGGGAAAGCTATGCTTGCTGGTATCAGCAGAAGCCAGG CCAGTCCCCTGTACTGGTCATCTATCAAGATTACAAGCGGCCCTCAGGGATCCCTGAGCG CTTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTAT GGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGAAGTACTGTACTATTTCGGCGGA GGGACCAAGCTGACCGTCCTA (SEQ ID NO: 358) L27 Protein SYELTQPPSVSVSPGQTASITCSGDKLGESYACWYQQKPGQSPVLVIYQDYKRPSGIPERFSGS NSGNTATLTISGTQAMDEADYYCQAWDRSTVLFGGGTKLTVL (SEQ ID NO: 359)

[0069] Particular embodiments of antigen binding proteins of the present invention comprise one or more amino acid sequences that are identical to the amino acid sequences of one or more of the CDRs and may further comprise one or more FRs illustrated above. In one embodiment, the antigen binding protein comprises a light chain CDR1 sequence illustrated above. In another embodiment, the antigen binding protein comprises a light chain CDR2 sequence illustrated above. In another embodiment, the antigen binding protein comprises a light chain CDR3 sequence illustrated above. In another embodiment, the antigen binding protein comprises a heavy chain CDR1 sequence illustrated in above. In another embodiment, the antigen binding protein comprises a heavy chain CDR2 sequence illustrated above. In another embodiment, the antigen binding protein comprises a heavy chain CDR3 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a light chain FR1 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a light chain FR2 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a light chain FR3 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a light chain FR4 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a heavy chain FR1 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a heavy chain FR2 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a heavy chain FR3 sequence illustrated above. In another embodiment, the antigen binding protein further comprises a heavy chain FR4 sequence illustrated above.

[0070] In one embodiment, the present disclosure provides an antigen binding protein comprising a light chain variable domain comprising a sequence of amino acids that differs from the sequence of a light chain variable domain selected from the group consisting of L1 through L27only at 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 residues, wherein each such sequence difference is independently either a deletion, insertion, or substitution of one amino acid residue. In another embodiment, the light-chain variable domain comprises a sequence of amino acids that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to the sequence of a light chain variable domain selected from the group consisting of L1-L27. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to a nucleotide sequence that encodes a light chain variable domain selected from the group consisting of L1-L27. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide that encodes a light chain variable domain selected from the group consisting of L1-L27. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under highly stringent conditions to a complement of a light chain polynucleotide of L1-L27.

[0071] In another embodiment, the present invention provides an antigen binding protein comprising a heavy chain variable domain comprising a sequence of amino acids that differs from the sequence of a heavy chain variable domain selected from the group consisting of Hl-H27 only at 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 residue(s), wherein each such sequence difference is independently either a deletion, insertion, or substitution of one amino acid residue. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to the sequence of a heavy chain variable domain selected from the group consisting of H1-H27. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to a nucleotide sequence that encodes a heavy chain variable domain selected from the group consisting of H1-H27. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide that encodes a heavy chain variable domain selected from the group consisting of H1-H27. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under highly stringent conditions to the complement of a polynucleotide that encodes a heavy chain variable domain selected from the group consisting of H1-H27.

[0072] In some of the embodiments provided in Table 2 above, two light chains are associated with a single heavy chain, identified, for example as L-12.1, L-12.2, etc. These alternative light chains are each paired with a single heavy chain. In these embodiments, light chain and heavy chain combination may be assayed as described below and the combination of light chain and heavy chain that provides the greater TSLP neutralizing activity may be selected.

[0073] Additional embodiments include antigen binding proteins comprising the combinations L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, and L27H27.

[0074] Antigen binding proteins (e.g., antibodies, antibody fragments, and antibody derivatives) of the invention can further comprise any constant region known in the art. The light chain constant region can be, for example, a kappa- or lambda-type light chain constant region, e.g., a human kappa- or lambda-type light chain constant region. The heavy chain constant region can be, for example, an alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant regions, e.g., a human alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant region. In one embodiment, the light or heavy chain constant region is a fragment, derivative, variant, or mutein of a naturally occurring constant region.

[0075] In one embodiment, the antigen binding proteins comprise an IgG, such as IgG1, IgG2, IgG3, or IgG4.

[0076] Techniques are known for deriving an antibody of a different subclass or isotype from an antibody of interest, i.e., subclass switching. Thus, IgG antibodies may be derived from an IgM antibody, for example, and vice versa. Such techniques allow the preparation of new antibodies that possess the antigen-binding properties of a given antibody (the parent antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody. Recombinant DNA techniques may be employed. Cloned DNA encoding particular antibody polypeptides may be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype. See also Lantto et al., 2002, Methods Mol. Biol. 178:303-16.

[0077] In one embodiment, an antigen binding protein of the invention comprises the IgG1 heavy chain constant domain or a fragment of the IgG1 heavy chain domain In one embodiment, an antigen binding protein of the invention further comprises the constant light chain kappa or lambda domains or a fragment of these. Light chain constant regions and polynucleotides encoding them are provided in Table 3 below. In another embodiment, an antigen binding protein of the invention further comprises a heavy chain constant domain, or a fragment thereof, such as the IgG2 heavy chain constant region shown below in Table 3.

[0078] The nucleic acid (DNA) encoding constant heavy and constant light chain domains, and the amino acids sequences of heavy and light chain domains are provided below. Lambda variable domains can be fused to lambda constant domains and kappa variable domains can be fused to kappa constant domains.

TABLE-US-00004 TABLE 3 IgG2 Heavy Constant domain DNA (SEQ ID NO: 364) gctagcaccaagggcccatcggtcttccccctggcgccctgctccaggag cacctccgagagcacagcggccctgggctgcctggtcaaggactacttcc ccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcggcgtg cacaccttcccagctgtcctacagtcctcaggactctactccctcagcag cgtggtgaccgtgccctccagcaacttcggcacccagacctacacctgca acgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgc aaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggacc gtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctccc ggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaagacccc gaggtccagttcaactggtacgtggacggcgtggaggtgcataatgccaa gacaaagccacgggaggagcagttcaacagcacgttccgtgtggtcagcg tcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgc aaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctccaa aaccaaagggcagccccgagaaccacaggtgtacaccctgcccccatccc gggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggc ttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccgga gaacaactacaagaccacacctcccatgctggactccgacggctccttct tcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaac gtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgca gaagagcctctccctgtctccgggtaaatga IgG2 Heavy Constant domain Protein (SEQ ID NO: 365) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKC KVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK* Kappa Light Constant domain DNA (SEQ ID NO: 366) cgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagca gttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatc ccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggt aactcccaggagagtgtcacagagcaggacagcaaggacagcacctacag cctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaag agcttcaacaggggagagtgttag Kappa Light Constant domain Protein (SEQ ID NO: 367) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC* Lambda Light Constant domain DNA (SEQ ID NO: 368) ggccaaccgaaagcggcgccctcggtcactctgttcccgccctcctctga ggagcttcaagccaacaaggccacactggtgtgtctcataagtgacttct acccgggagccgtgacagtggcctggaaggcagatagcagccccgtcaag gcgggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgc ggccagcagctatctgagcctgacgcctgagcagtggaagtcccacagaa gctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtg gcccctacagaatgttcatag Lambda Light Constant domain Protein (SEQ ID NO: 369) GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS*

[0079] The antigen binding proteins of the present invention include those comprising, for example, the variable domain combinations L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13.1H13, L13.2H13, L14.1H14, L14.2H14, L15.1H15, L15.2H15, L16.1H16, L16.2H16, L17H17, L18.1H18, L18.2H18, L19.1H19, L19.2H19, L20.1H20, L20.2H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, and L27H27. having a desired isotype (for example, IgA, IgG1, IgG2, IgG3, IgG4, IgM, IgE, and IgD) as well as Fab or F(ab').sub.2 fragments thereof. Moreover, if an IgG4 is desired, it may also be desired to introduce a point mutation in the hinge region as described in Bloom et al., 1997, Protein Science 6:407 (incorporated by reference herein) to alleviate a tendency to form intra-H chain disulfide bonds that can lead to heterogeneity in the IgG4 antibodies.

Antibodies and Antibody Fragments

[0080] As used herein, the term "antibody" refers to an intact antibody, or an antigen binding fragment thereof, as described in the definition section herein. An antibody may comprise a complete antibody molecule (including polyclonal, monoclonal, chimeric, humanized, or human versions having full length heavy and/or light chains), or comprise an antigen binding fragment thereof. Antibody fragments include F(ab').sub.2, Fab, Fab', Fv, Fc, and Fd fragments, and can be incorporated into single domain antibodies, monovalent antibodies, single-chain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (See e.g., Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136). Antibody polypeptides are also disclosed in U.S. Pat. No. 6,703,199, including fibronectin polypeptide monobodies. Other antibody polypeptides are disclosed in U.S. Patent Publication 2005/0238646, which are single-chain polypeptides. Monovalent antibody fragments are disclosed in US Patent Publication 20050227324.

[0081] Antigen binding fragments derived from an antibody can be obtained, for example, by proteolytic hydrolysis of the antibody, for example, pepsin or papain digestion of whole antibodies according to conventional methods. By way of example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment termed F(ab').sub.2. This fragment can be further cleaved using a thiol reducing agent to produce 3.5S Fab' monovalent fragments. Optionally, the cleavage reaction can be performed using a blocking group for the sulfhydryl groups that result from cleavage of disulfide linkages. As an alternative, an enzymatic cleavage using papain produces two monovalent Fab fragments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. Pat. No. 4,331,647, Nisonoff et al., Arch. Biochem. Biophys. 89:230, 1960; Porter, Biochem. J. 73:119, 1959; Edelman et al., in Methods in Enzymology 1:422 (Academic Press 1967); and by Andrews, S. M. and Titus, J. A. in Current Protocols in Immunology (Coligan J. E., et al., eds), John Wiley & Sons, New York (2003), pages 2.8.1-2.8.10 and 2.10A.1-2.10A.5. Other methods for cleaving antibodies, such as separating heavy chains to form monovalent light-heavy chain fragments (Fd), further cleaving of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody.

[0082] An antibody fragment may also be any synthetic or genetically engineered protein. For example, antibody fragments include isolated fragments consisting of the light chain variable region, "Fv" fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (scFv proteins).

[0083] Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed "minimal recognition units", or "hypervariable region") can be obtained by constructing polynucleotides that encode the CDR of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology 2:106, 1991; Courtenay-Luck, "Genetic Manipulation of Monoclonal Antibodies," in Monoclonal Antibodies: Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166 (Cambridge University Press 1995); and Ward et al., "Genetic Manipulation and Expression of Antibodies," in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137 (Wiley-Liss, Inc. 1995)).

[0084] Thus, in one embodiment, the binding agent comprises at least one CDR as described herein. The binding agent may comprise at least two, three, four, five or six CDR's as described herein. The binding agent further may comprise at least one variable region domain of an antibody described herein. The variable region domain may be of any size or amino acid composition and will generally comprise at least one CDR sequence responsible for binding to TSLP, for example heavy chain CDR1, CDR2, CDR3 and/or the light chain CDRs specifically described herein and which is adjacent to or in frame with one or more framework sequences. In general terms, the variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (V.sub.H) and/or light (V.sub.L) chain variable domains. Thus, for example, the V region domain may be monomeric and be a V.sub.H or V.sub.L domain, which is capable of independently binding human TSLP with an affinity at least equal to 1.times.10.sup.7M or less as described below. Alternatively, the V region domain may be dimeric and contain V.sub.H-V.sub.H, V.sub.H-V.sub.L, or V.sub.L-V.sub.L, dimers. The V region dimer comprises at least one V.sub.H and at least one V.sub.L chain that may be non-covalently associated (hereinafter referred to as Fv). If desired, the chains may be covalently coupled either directly, for example via a disulfide bond between the two variable domains, or through a linker, for example a peptide linker, to form a single chain Fv (scFv). The variable region domain may be any naturally occurring variable domain or an engineered version thereof. By engineered version is meant a variable region domain that has been created using recombinant DNA engineering techniques. Such engineered versions include those created, for example, from a specific antibody variable region by insertions, deletions, or changes in or to the amino acid sequences of the specific antibody. Particular examples include engineered variable region domains containing at least one CDR and optionally one or more framework amino acids from a first antibody and the remainder of the variable region domain from a second antibody.

[0085] The variable region domain may be covalently attached at a C-terminal amino acid to at least one other antibody domain or a fragment thereof. Thus, for example, a VH domain that is present in the variable region domain may be linked to an immunoglobulin CH1 domain, or a fragment thereof. Similarly a V.sub.L domain may be linked to a C.sub.K domain or a fragment thereof. In this way, for example, the antibody may be a Fab fragment wherein the antigen binding domain contains associated V.sub.H and V.sub.L domains covalently linked at their C-termini to a CH1 and C.sub.K domain, respectively. The CH1 domain may be extended with further amino acids, for example to provide a hinge region or a portion of a hinge region domain as found in a Fab' fragment, or to provide further domains, such as antibody CH2 and CH3 domains.

Derivatives of Antigen Binding Proteins

[0086] The nucleotide sequences shown in FIG. 1A-1F, FIG. 2A-2F, and Table 2 above can be altered, for example, by random mutagenesis or by site-directed mutagenesis (e.g., oligonucleotide-directed site-specific mutagenesis) to create an altered polynucleotide comprising one or more particular nucleotide substitutions, deletions, or insertions as compared to the non-mutated polynucleotide. Examples of techniques for making such alterations are described in Walder et al., 1986, Gene 42:133; Bauer et al. 1985, Gene 37:73; Craik, BioTechniques, Jan. 1985, 12-19; Smith et al., 1981, Genetic Engineering: Principles and Methods, Plenum Press; and U.S. Pat. Nos. 4,518,584 and 4,737,462. These and other methods can be used to make, for example, derivatives of TSLP antigen binding proteins that have a desired property, for example, increased affinity, avidity, or specificity for TSLP, increased activity or stability in vivo or in vitro, or reduced in vivo side-effects as compared to the underivatized antigen binding proteins.

[0087] Other derivatives of anti-TSLP antigen binding proteins including antibodies within the scope of this invention include covalent or aggregative conjugates of anti-TSLP antibodies, or fragments thereof, with other proteins or polypeptides, such as by expression of recombinant fusion proteins comprising heterologous polypeptides fused to the N-terminus or C-terminus of an anti-TSLP antibody polypeptide. For example, the conjugated peptide may be a heterologous signal (or leader) polypeptide, e.g., the yeast alpha-factor leader, or a peptide such as an epitope tag. Antigen binding protein-containing fusion proteins can comprise peptides added to facilitate purification or identification of antigen binding protein (e.g., poly-His). An antigen binding protein also can be linked to the FLAG peptide as described in Hopp et al., Bio/Technology 6:1204, 1988, and U.S. Pat. No. 5,011,912. The FLAG peptide is highly antigenic and provides an epitope reversibly bound by a specific monoclonal antibody (mAb), enabling rapid assay and facile purification of expressed recombinant protein. Reagents useful for preparing fusion proteins in which the FLAG peptide is fused to a given polypeptide are commercially available (Sigma, St. Louis, Mo.).

[0088] Oligomers that contain one or more antigen binding proteins may be employed as TSLP antagonists. Oligomers may be in the form of covalently-linked or non-covalently-linked dimers, trimers, or higher oligomers. Oligomers comprising two or more antigen binding proteins are contemplated for use, with one example being a homodimer. Other oligomers include heterodimers, homotrimers, heterotrimers, homotetramers, heterotetramers, etc.

[0089] One embodiment is directed to oligomers comprising multiple antigen binding proteins joined via covalent or non-covalent interactions between peptide moieties fused to the antigen binding proteins. Such peptides may be peptide linkers (spacers), or peptides that have the property of promoting oligomerization. Leucine zippers and certain polypeptides derived from antibodies are among the peptides that can promote oligomerization of antigen binding proteins attached thereto, as described in more detail below.

[0090] In particular embodiments, the oligomers comprise from two to four antigen binding proteins capable of binding to TSLP. The antigen binding proteins of the oligomer may be in any form, such as any of the forms described above, e.g., variants or fragments.

[0091] In one embodiment, an oligomer is prepared using polypeptides derived from immunoglobulins. Preparation of fusion proteins comprising certain heterologous polypeptides fused to various portions of antibody-derived polypeptides (including the Fc domain) has been described, e.g., by Ashkenazi et al., 1991, PNAS USA 88:10535; Byrn et al., 1990, Nature 344:677; and Hollenbaugh et al., 1992 "Construction of Immunoglobulin Fusion Proteins", in Current Protocols in Immunology, Suppl. 4, pages 10.19.1-10.19.11.

[0092] One embodiment of the present invention is directed to a dimer comprising two fusion proteins created by fusing a fragment of an anti-TSLP antibody to the Fc region of an antibody. The dimer can be made by, for example, inserting a gene fusion encoding the fusion protein into an appropriate expression vector, expressing the gene fusion in host cells transformed with the recombinant expression vector, and allowing the expressed fusion protein to assemble much like antibody molecules, whereupon interchain disulfide bonds form between the Fc moieties to yield the dimer. The term "Fc polypeptide" as used herein includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing the hinge region that promotes dimerization also are included. Fusion proteins comprising Fc moieties (and oligomers formed therefrom) offer the advantage of facile purification by affinity chromatography over Protein A or Protein G columns.

[0093] One suitable Fc polypeptide, described in PCT application WO 93/10151 (hereby incorporated by reference), is a single chain polypeptide extending from the N-terminal hinge region to the native C-terminus of the Fc region of a human IgG1 antibody. Another useful Fc polypeptide is the Fc mutein described in U.S. Pat. No. 5,457,035 and in Baum et al., 1994, EMBO J. 13:3992-4001. The amino acid sequence of this mutein is identical to that of the native Fc sequence presented in WO 93/10151, except that amino acid 19 has been changed from Leu to Ala, amino acid 20 has been changed from Leu to Glu, and amino acid 22 has been changed from Gly to Ala. The mutein exhibits reduced affinity for Fc receptors.

[0094] In other embodiments, the variable portion of the heavy and/or light chains of an anti-TSLP antibody may be substituted for the variable portion of an antibody heavy and/or light chain.

[0095] Alternatively, the oligomer is a fusion protein comprising multiple antigen binding proteins, with or without peptide linkers (spacer peptides). Among the suitable peptide linkers are those described in U.S. Pat. Nos. 4,751,180 and 4,935,233.

[0096] Another method for preparing oligomeric antigen binding proteins involves use of a leucine zipper. Leucine zipper domains are peptides that promote oligomerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., 1988, Science 240:1759), and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble oligomeric proteins are described in PCT application WO 94/10308, and the leucine zipper derived from lung surfactant protein D (SPD) described in Hoppe et al., 1994, FEBS Letters 344:191, hereby incorporated by reference. The use of a modified leucine zipper that allows for stable trimerization of a heterologous protein fused thereto is described in Fanslow et al., 1994, Semin. Immunol. 6:267-78. In one approach, recombinant fusion proteins comprising an anti-TSLP antibody fragment or derivative fused to a leucine zipper peptide are expressed in suitable host cells, and the soluble oligomeric anti-TSLP antibody fragments or derivatives that form are recovered from the culture supernatant.

[0097] As described herein, antibodies comprise at least one CDR. For example, one or more CDR may be incorporated into known antibody framework regions (IgG1, IgG2, etc.), or conjugated to a suitable vehicle to enhance the half-life thereof. Suitable vehicles include, but are not limited to Fc, polyethylene glycol (PEG), albumin, transferrin, and the like. These and other suitable vehicles are known in the art. Such conjugated CDR peptides may be in monomeric, dimeric, tetrameric, or other form. In one embodiment, one or more water-soluble polymer is bonded at one or more specific position, for example at the amino terminus, of a binding agent.

[0098] In certain preferred embodiments, an antibody comprises one or more water soluble polymer attachments, including, but not limited to, polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. See, e.g., U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. In certain embodiments, a derivative binding agent comprises one or more of monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers. In certain embodiments, one or more water-soluble polymer is randomly attached to one or more side chains. In certain embodiments, PEG can act to improve the therapeutic capacity for a binding agent, such as an antibody. Certain such methods are discussed, for example, in U.S. Pat. No. 6,133,426, which is hereby incorporated by reference for any purpose.

[0099] It will be appreciated that an antibody of the present invention may have at least one amino acid substitution, deletion, or addition, providing that the antibody retains binding specificity.

[0100] Therefore, modifications to the antibody structures are encompassed within the scope of the invention. These may include amino acid substitutions, which may be conservative or non-conservative, that do not destroy the human TSLP binding capability of an antibody. Conservative amino acid substitutions may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid moieties. A conservative amino acid substitution may also involve a substitution of a native amino acid residue with a normative residue such that there is little or no effect on the polarity or charge of the amino acid residue at that position.

[0101] Non-conservative substitutions may involve the exchange of a member of one class of amino acids or amino acid mimetics for a member from another class with different physical properties (e.g. size, polarity, hydrophobicity, charge). Such substituted residues may be introduced into regions of the human antibody that are homologous with non-human antibodies, or into the non-homologous regions of the molecule.

[0102] Moreover, one skilled in the art may generate test variants containing a single amino acid substitution at each desired amino acid residue. The variants can then be screened using activity assays known to those skilled in the art. Such variants could be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants with such a change may be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations.

[0103] A skilled artisan will be able to determine suitable variants of the polypeptide as set forth herein using well-known techniques. In certain embodiments, one skilled in the art may identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to be important for activity. In certain embodiments, one can identify residues and portions of the molecules that are conserved among similar polypeptides. In certain embodiments, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

[0104] Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues which are important for activity or structure in similar proteins. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues.

[0105] One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of an antibody with respect to its three dimensional structure. In certain embodiments, one skilled in the art may choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues may be involved in important interactions with other molecules.

[0106] A number of scientific publications have been devoted to the prediction of secondary structure. See Moult J., Curr. Op. in Biotech., 7(4):422-427 (1996), Chou et al., Biochemistry, 13(2):222-245 (1974); Chou et al., Biochemistry, 113(2):211-222 (1974); Chou et al., Adv. Enzymol. Relat. Areas Mol. Biol., 47:45-148 (1978); Chou et al., Ann. Rev. Biochem., 47:251-276 and Chou et al., Biophys. J., 26:367-384 (1979). Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or proteins which have a sequence identity of greater than 30%, or similarity greater than 40% often have similar structural topologies. The recent growth of the protein structural database (PDB) has provided enhanced predictability of secondary structure, including the potential number of folds within a polypeptide's or protein's structure. See Holm et al., Nucl. Acid. Res., 27(1):244-247 (1999). It has been suggested (Brenner et al., Curr. Op. Struct. Biol., 7(3):369-376 (1997)) that there are a limited number of folds in a given polypeptide or protein and that once a critical number of structures have been resolved, structural prediction will become dramatically more accurate.

[0107] Additional methods of predicting secondary structure include "threading" (Jones, D., Curr. Opin. Struct. Biol., 7(3):377-87 (1997); Sippl et al., Structure, 4(1):15-19 (1996)), "profile analysis" (Bowie et al., Science, 253:164-170 (1991); Gribskov et al., Meth. Enzym., 183:146-159 (1990); Gribskov et al., Proc. Nat. Acad. Sci., 84(13):4355-4358 (1987)), and "evolutionary linkage" (See Holm, supra (1999), and Brenner, supra (1997)).

[0108] It will be understood by one skilled in the art that some proteins, such as antibodies, may undergo a variety of posttranslational modifications. The type and extent of these modifications often depends on the host cell line used to express the protein as well as the culture conditions. Such modifications may include variations in glycosylation, methionine oxidation, diketopiperizine formation, aspartate isomerization and asparagine deamidation. A frequent modification is the loss of a carboxy-terminal basic residue (such as lysine or arginine) due to the action of carboxypeptidases (as described in Harris, R. J. Journal of Chromatography 705:129-134, 1995).

[0109] In certain embodiments, variants of antibodies include glycosylation variants wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a parent polypeptide. In certain embodiments, variants comprise a greater or a lesser number of N-linked glycosylation sites than the native protein. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional preferred antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the parent amino acid sequence. Cysteine variants may be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines.

[0110] Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art at the time such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify important residues of antibodies to human TSLP, or to increase or decrease the affinity of the antibodies to human TSLP described herein.

[0111] According to certain embodiments, preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and/or (4) confer or modify other physiochemical or functional properties on such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made in the naturally-occurring sequence (in certain embodiments, in the portion of the polypeptide outside the domain(s) forming intermolecular contacts). In certain embodiments, a conservative amino acid substitution typically may not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991), which are each incorporated herein by reference.

[0112] In certain embodiments, antibodies of the invention may be chemically bonded with polymers, lipids, or other moieties.

[0113] In addition, the antigen binding proteins may comprise at least one of the CDRs described herein incorporated into a biocompatible framework structure. In one example, the biocompatible framework structure comprises a polypeptide or portion thereof that is sufficient to form a conformationally stable structural support, or framework, or scaffold, which is able to display one or more sequences of amino acids that bind to an antigen (e.g., CDRs, a variable region, etc.) in a localized surface region. Such structures can be a naturally occurring polypeptide or polypeptide "fold" (a structural motif), or can have one or more modifications, such as additions, deletions or substitutions of amino acids, relative to a naturally occurring polypeptide or fold. These scaffolds can be derived from a polypeptide of any species (or of more than one species), such as a human, other mammal, other vertebrate, invertebrate, plant, bacteria or virus.

[0114] Typically the biocompatible framework structures are based on protein scaffolds or skeletons other than immunoglobulin domains. For example, those based on fibronectin, ankyrin, lipocalin, neocarzinostain, cytochrome b, CP1 zinc finger, PST1, coiled coil, LACI-D1, Z domain and tendamistat domains may be used (See e.g., Nygren and Uhlen, 1997, Current Opinion in Structural Biology, 7, 463-469).

[0115] Additionally, in another embodiment, one skilled in the art will recognize that the antigen binding proteins can include one or more of heavy chain CDR1, CDR2, CDR3, and/or light chain CDR1, CDR2 and CDR3 having one amino acid substitution, provided that the antibody retains the binding specificity of the non-substituted CDR. The non-CDR portion of the antibody may be a non-protein molecule, wherein the binding agent cross-blocks the binding of an antibody disclosed herein to human TSLP and/or inhibits TSLP activity. The non-CDR portion of the antibody may be a non-protein molecule in which the antibody exhibits a similar binding pattern to human TSLP proteins in a competition binding assay as that exhibited by at least one of antibodies A1-A27, and/or neutralizes the activity of TSLP. The non-CDR portion of the antibody may be composed of amino acids, wherein the antibody is a recombinant binding protein or a synthetic peptide, and the recombinant binding protein cross-blocks the binding of an antibody disclosed herein to human TSLP and/or neutralizes TSLP in vitro or in vivo. The non-CDR portion of the antibody may be composed of amino acids, wherein the antibody is a recombinant antibody, and the recombinant antibody exhibits a similar binding pattern to human TSLP polypeptides in a competition binding assay as exhibited by at least one of the antibodies A1-A27, and/or neutralizes TSLP activity.

Methods of Making Antigen Binding Proteins, specifically Antibodies.

[0116] An antigen binding protein such as an antibody comprising one or more of heavy chain CDR1, CDR2, CDR3, and/or light chain CDR1, CDR2 and CDR3 as described above, may be obtained by expression from a host cell containing DNA coding for these sequences. A DNA coding for each CDR sequence may be determined on the basis of the amino acid sequence of the CDR and synthesized together with any desired antibody variable region framework and constant region DNA sequences using oligonucleotide synthesis techniques, site-directed mutagenesis and polymerase chain reaction (PCR) techniques as appropriate. DNA coding for variable region frameworks and constant regions is widely available to those skilled in the art from genetic sequences databases such as GenBank.RTM..

[0117] Additional embodiments include chimeric antibodies, e.g., humanized versions of non-human (e.g., murine) monoclonal antibodies. Such humanized antibodies may be prepared by known techniques, and offer the advantage of reduced immunogenicity when the antibodies are administered to humans. In one embodiment, a humanized monoclonal antibody comprises the variable domain of a murine antibody (or all or part of the antigen binding site thereof) and a constant domain derived from a human antibody. Alternatively, a humanized antibody fragment may comprise the antigen binding site of a murine monoclonal antibody and a variable domain fragment (lacking the antigen-binding site) derived from a human antibody. Procedures for the production of chimeric and further engineered monoclonal antibodies include those described in Riechmann et al., 1988, Nature 332:323, Liu et al., 1987, Proc. Nat. Acad. Sci. USA 84:3439, Larrick et al., 1989, Bio/Technology 7:934, and Winter et al., 1993, TIPS 14:139. In one embodiment, the chimeric antibody is a CDR grafted antibody. Techniques for humanizing antibodies are discussed in, e.g., U.S. Pat. Nos. 5,869,619, 5,225,539, 5,821,337, 5,859,205, 6,881,557, Padlan et al., 1995, FASEB J. 9:133-39, and Tamura et al., 2000, J. Immunol. 164:1432-41. Addition techniques for producing humanized antibodies such as those are described in Zhang, W., et al., Molecular Immunology. 42(12):1445-1451, 2005; Hwang W. et al., Methods. 36(1):35-42, 2005; Dall'Acqua WF, et al., Methods 36(1):43-60, 2005; and Clark, M., Immunology Today. 21(8):397-402, 2000).

[0118] Procedures have been developed for generating human or partially human antibodies in non-human animals. For example, mice in which one or more endogenous immunoglobulin genes have been inactivated by various means have been prepared. Human immunoglobulin genes have been introduced into the mice to replace the inactivated mouse genes. Antibodies produced in the animal incorporate human immunoglobulin polypeptide chains encoded by the human genetic material introduced into the animal In one embodiment, a non-human animal, such as a transgenic mouse, is immunized with TSLP protein, for example, such that antibodies directed against various TSLP polypeptides are generated in the animal. Examples of suitable immunogens are provided in the Examples below.

[0119] Examples of techniques for production and use of transgenic animals for the production of human or partially human antibodies are described in U.S. Pat. Nos. 5,814,318, 5,569,825, and 5,545,806, Davis et al., 2003, Production of human antibodies from transgenic mice in Lo, ed. Antibody Engineering: Methods and Protocols, Humana Press, NJ:191-200, Kellermann et al., 2002, Curr Opin Biotechnol. 13:593-97, Russel et al., 2000, Infect Immun 68:1820-26, Gallo et al., 2000, Eur J Immun 30:534-40, Davis et al., 1999, Cancer Metastasis Rev. 18:421-25, Green, 1999, J Immunol Methods. 231:11-23, Jakobovits, 1998, Advanced Drug Delivery Reviews 31:33-42, Green et al., 1998, J Exp Med. 188:483-95, Jakobovits A, 1998, Exp. Opin. Invest. Drugs. 7:607-14, Tsuda et al., 1997, Genomics. 42:413-21, Mendez et al., 1997, Nat Genet. 15:146-56, Jakobovits, 1994, Curr Biol. 4:761-63, Arbones et al., 1994, Immunity. 1:247-60, Green et al., 1994, Nat Genet. 7:13-21, Jakobovits et al., 1993, Nature. 362:255-58, Jakobovits et al., 1993, Proc Natl Acad Sci U S A. 90:2551-55. Chen, J., M. Trounstine, F. W. Alt, F. Young, C. Kurahara, J. Loring, D. Huszar. "Immunoglobulin gene rearrangement in B-cell deficient mice generated by targeted deletion of the JH locus." International Immunology 5 (1993): 647-656, Choi et al., 1993, Nature Genetics 4: 117-23, Fishwild et al., 1996, Nature Biotechnology 14: 845-51, Harding et al., 1995, Annals of the New York Academy of Sciences, Lonberg et al., 1994, Nature 368: 856-59, Lonberg, 1994, Transgenic Approaches to Human Monoclonal Antibodies in Handbook of Experimental Pharmacology 113: 49-101, Lonberg et al., 1995, Internal Review of Immunology 13: 65-93, Neuberger, 1996, Nature Biotechnology 14: 826, Taylor et al., 1992, Nucleic Acids Research 20: 6287-95, Taylor et al., 1994, International Immunology 6: 579-91, Tomizuka et al., 1997, Nature Genetics 16: 133-43, Tomizuka et al., 2000, Proceedings of the National Academy of Sciences USA 97: 722-27, Tuaillon et al., 1993, Proceedings of the National Academy of Sciences USA 90: 3720-24, and Tuaillon et al., 1994, Journal of Immunology 152: 2912-20.

[0120] In another aspect, the present invention provides monoclonal antibodies that bind to human TSLP. Monoclonal antibodies may be produced using any technique known in the art, e.g., by immortalizing spleen cells harvested from the transgenic animal after completion of the immunization schedule. The spleen cells can be immortalized using any technique known in the art, e.g., by fusing them with myeloma cells to produce hybridomas. Myeloma cells for use in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas). Examples of suitable cell lines for use in mouse fusions include Sp-20, P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 4 1, Sp210-Ag14, FO, NSO/U, MPC-11, MPC11-X.sub.45-GTG 1.7 and S194/5XXO Bul; examples of cell lines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210. Other cell lines useful for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2 and UC729-6.

[0121] In one embodiment, a hybridoma cell line is produced by immunizing an animal (e.g., a transgenic animal having human immunoglobulin sequences) with a TSLP immunogen; harvesting spleen cells from the immunized animal; fusing the harvested spleen cells to a myeloma cell line, thereby generating hybridoma cells; establishing hybridoma cell lines from the hybridoma cells, and identifying a hybridoma cell line that produces an antibody that binds a TSLP polypeptide. Such hybridoma cell lines, and TSLP monoclonal antibodies produced by them, are encompassed by the present invention.

[0122] Monoclonal antibodies secreted by a hybridoma cell line can be purified using any technique known in the art. Hybridomas or mAbs may be further screened to identify mAbs with particular properties, such as blocking a TSLP activity such as osteoprotegerin (OPG) production from primary human dendritic cells. Examples of such assays are provided in the examples below. Molecular evolution of the complementarity determining regions (CDRs) in the center of the antibody binding site also has been used to isolate antibodies with increased affinity, for example, as described by Schier et al., 1996, J. Mol. Biol. 263:551. Accordingly, such techniques are useful in preparing antibodies to human TSLP.

[0123] Antigen binding proteins directed against human TSLP can be used, for example, in assays to detect the presence of TSLP either in vitro or in vivo.

[0124] Although human, partially human, or humanized antibodies will be suitable for many applications, particularly those involving administration of the antibody to a human subject, other types of antigen binding proteins will be suitable for certain applications. The non-human antibodies of the invention can be, for example, derived from any antibody-producing animal, such as mouse, rat, rabbit, goat, donkey, or non-human primate (such as monkey (e.g., cynomologus or rhesus monkey) or ape (e.g., chimpanzee)). Non-human antibodies of the invention can be used, for example, in in vitro and cell-culture based applications, or any other application where an immune response to the antibody of the invention does not occur, is insignificant, can be prevented, is not a concern, or is desired. In one embodiment, a non-human antibody of the invention is administered to a non-human subject. In another embodiment, the non-human antibody does not elicit an immune response in the non-human subject. In another embodiment, the non-human antibody is from the same species as the non-human subject, e.g., a mouse antibody of the invention is administered to a mouse. An antibody from a particular species can be made by, for example, immunizing an animal of that species with the desired immunogen or using an artificial system for generating antibodies of that species (e.g., a bacterial or phage display-based system for generating antibodies of a particular species), or by converting an antibody from one species into an antibody from another species by replacing, e.g., the constant region of the antibody with a constant region from the other species, or by replacing one or more amino acid residues of the antibody so that it more closely resembles the sequence of an antibody from the other species. In one embodiment, the antibody is a chimeric antibody comprising amino acid sequences derived from antibodies from two or more different species.

[0125] Antigen binding proteins may be prepared by any of a number of conventional techniques.

[0126] For example, they may be purified from cells that naturally express them (e.g., an antibody can be purified from a hybridoma that produces it), or produced in recombinant expression systems, using any technique known in the art. See, for example, Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds.), Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Land (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1988).

[0127] Any expression system known in the art can be used to make the recombinant polypeptides of the invention. In general, host cells are transformed with a recombinant expression vector that comprises DNA encoding a desired polypeptide. Among the host cells that may be employed are prokaryotes, yeast or higher eukaryotic cells. Prokaryotes include gram negative or gram positive organisms, for example E. coli or bacilli. Higher eukaryotic cells include insect cells and established cell lines of mammalian origin. Examples of suitable mammalian host cell lines include the COS-7 line of monkey kidney cells (ATCC CRL 1651) (Gluzman et al., 1981, Cell 23:175), L cells, 293 cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells, HeLa cells, BHK (ATCC CRL 10) cell lines, and the CVI/EBNA cell line derived from the African green monkey kidney cell line CVI (ATCC CCL 70) as described by McMahan et al., 1991, EMBO J. 10: 2821. Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are described by Pouwels et al. (Cloning Vectors: A Laboratory Manual, Elsevier, New York, 1985).

[0128] The transformed cells can be cultured under conditions that promote expression of the polypeptide, and the polypeptide recovered by conventional protein purification procedures. One such purification procedure is described in the Examples below. Polypeptides contemplated for use herein include substantially homogeneous recombinant mammalian anti-TSLP antibody polypeptides substantially free of contaminating endogenous materials.

[0129] Antigen binding proteins may be prepared, and screened for desired properties, by any of a number of known techniques. Certain of the techniques involve isolating a nucleic acid encoding a polypeptide chain (or portion thereof) of an antigen binding protein of interest (e.g., an TSLP antibody), and manipulating the nucleic acid through recombinant DNA technology. The nucleic acid may be fused to another nucleic acid of interest, or altered (e.g., by mutagenesis or other conventional techniques) to add, delete, or substitute one or more amino acid residues, for example

[0130] Single chain antibodies may be formed by linking heavy and light chain variable domain (Fv region) fragments via an amino acid bridge (short peptide linker), resulting in a single polypeptide chain. Such single-chain Fvs (scFvs) have been prepared by fusing DNA encoding a peptide linker between DNAs encoding the two variable domain polypeptides (V.sub.L and V.sub.H). The resulting polypeptides can fold back on themselves to form antigen-binding monomers, or they can form multimers (e.g., dimers, trimers, or tetramers), depending on the length of a flexible linker between the two variable domains (Kortt et al., 1997, Prot. Eng. 10:423; Kortt et al., 2001, Biomol. Eng. 18:95-108). By combining different V.sub.L and V.sub.H-comprising polypeptides, one can form multimeric scFvs that bind to different epitopes (Kriangkum et al., 2001, Biomol. Eng. 18:31-40). Techniques developed for the production of single chain antibodies include those described in U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879; Ward et al., 1989, Nature 334:544, de Graaf et al., 2002, Methods Mol Biol. 178:379-87. Single chain antibodies derived from antibodies provided herein include, but are not limited to, scFvs comprising the variable domain combinations L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, and L27H27 are encompassed by the present invention.

[0131] Once synthesized, the DNA encoding an antibody of the invention or fragment thereof may be propagated and expressed according to any of a variety of well-known procedures for nucleic acid excision, ligation, transformation, and transfection using any number of known expression vectors. Thus, in certain embodiments expression of an antibody fragment may be preferred in a prokaryotic host, such as Escherichia coli (see, e.g., Pluckthun et al., 1989 Methods Enzymol. 178:497-515). In certain other embodiments, expression of the antibody or a fragment thereof may be preferred in a eukaryotic host cell, including yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris), animal cells (including mammalian cells) or plant cells. Examples of suitable animal cells include, but are not limited to, myeloma (such as a mouse NSO line), COS, CHO, or hybridoma cells. Examples of plant cells include tobacco, corn, soybean, and rice cells.

[0132] One or more replicable expression vectors containing DNA encoding an antibody variable and/or constant region may be prepared and used to transform an appropriate cell line, for example, a non-producing myeloma cell line, such as a mouse NSO line or a bacteria, such as E. coli, in which production of the antibody will occur. In order to obtain efficient transcription and translation, the DNA sequence in each vector should include appropriate regulatory sequences, particularly a promoter and leader sequence operatively linked to the variable domain sequence. Particular methods for producing antibodies in this way are generally well-known and routinely used. For example, basic molecular biology procedures are described by Maniatis et al. (Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, New York, 1989; see also Maniatis et al, 3rd ed., Cold Spring Harbor Laboratory, New York, (2001)). DNA sequencing can be performed as described in Sanger et al. (PNAS 74:5463, (1977)) and the Amersham International plc sequencing handbook, and site directed mutagenesis can be carried out according to methods known in the art (Kramer et al., Nucleic Acids Res. 12:9441, (1984); Kunkel Proc. Natl. Acad. Sci. USA 82:488-92 (1985); Kunkel et al., Methods in Enzymol. 154:367-82 (1987); the Anglian Biotechnology Ltd. handbook). Additionally, numerous publications describe techniques suitable for the preparation of antibodies by manipulation of DNA, creation of expression vectors, and transformation and culture of appropriate cells (Mountain A and Adair, J R in Biotechnology and Genetic Engineering Reviews (ed. Tombs, M P, 10, Chapter 1, 1992, Intercept, Andover, UK); "Current Protocols in Molecular Biology", 1999, F. M. Ausubel (ed.), Wiley Interscience, New York).

[0133] Where it is desired to improve the affinity of antibodies according to the invention containing one or more of the above-mentioned CDRs can be obtained by a number of affinity maturation protocols including maintaining the CDRs (Yang et al., J. Mol. Biol., 254, 392-403, 1995), chain shuffling (Marks et al., Bio/Technology, 10, 779-783, 1992), use of mutation strains of E. coli. (Low et al., J. Mol. Biol., 250, 350-368, 1996), DNA shuffling (Patten et al., Curr. Opin. Biotechnol., 8, 724-733, 1997), phage display (Thompson et al., J. Mol. Biol., 256, 7-88, 1996) and PCR (Crameri, et al., Nature, 391, 288-291, 1998). All of these methods of affinity maturation are discussed by Vaughan et al. (Nature Biotechnology, 16, 535-539, 1998).

[0134] Other antibodies according to the invention may be obtained by conventional immunization and cell fusion procedures as described herein and known in the art. Monoclonal antibodies of the invention may be generated using a variety of known techniques. In general, monoclonal antibodies that bind to specific antigens may be obtained by methods known to those skilled in the art (see, for example, Kohler et al., Nature 256:495, 1975; Coligan et al. (eds.), Current Protocols in Immunology, 1:2.5.12.6.7 (John Wiley & Sons 1991); U.S. Patent Nos. RE 32,011, 4,902,614, 4,543,439, and 4,411,993; Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Plenum Press, Kennett, McKearn, and Bechtol (eds.) (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press (1988); Picksley et al., "Production of monoclonal antibodies against proteins expressed in E. coli," in DNA Cloning 2: Expression Systems, 2nd Edition, Glover et al. (eds.), page 93 (Oxford University Press 1995)). Antibody fragments may be derived therefrom using any suitable standard technique such as proteolytic digestion, or optionally, by proteolytic digestion (for example, using papain or pepsin) followed by mild reduction of disulfide bonds and alkylation. Alternatively, such fragments may also be generated by recombinant genetic engineering techniques as described herein.

[0135] Monoclonal antibodies can be obtained by injecting an animal, for example, a rat, hamster, a rabbit, or preferably a mouse, including for example a transgenic or a knock-out, as known in the art, with an immunogen comprising human TSLP of SEQ ID NO: 2, other TSLP polypeptide sequences as described herein, or a fragment thereof, according to methods known in the art and described herein. The presence of specific antibody production may be monitored after the initial injection and/or after a booster injection by obtaining a serum sample and detecting the presence of an antibody that binds to human TSLP or fragment thereof using any one of several immunodetection methods known in the art and described herein. From animals producing the desired antibodies, lymphoid cells, most commonly cells from the spleen or lymph node, are removed to obtain B-lymphocytes. The B lymphocytes are then fused with a drug-sensitized myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal and that optionally has other desirable properties (e.g., inability to express endogenous Ig gene products, e.g., P3X63-Ag 8.653 (ATCC No. CRL 1580); NSO, SP20) to produce hybridomas, which are immortal eukaryotic cell lines.

[0136] The lymphoid (e.g., spleen) cells and the myeloma cells may be combined for a few minutes with a membrane fusion-promoting agent, such as polyethylene glycol or a nonionic detergent, and then plated at low density on a selective medium that supports the growth of hybridoma cells but not unfused myeloma cells. A preferred selection media is HAT (hypoxanthine, aminopterin, thymidine). After a sufficient time, usually about one to two weeks, colonies of cells are observed. Single colonies are isolated, and antibodies produced by the cells may be tested for binding activity to human TSLP using any one of a variety of immunoassays known in the art and described herein. The hybridomas are cloned (e.g., by limited dilution cloning or by soft agar plaque isolation) and positive clones that produce an antibody specific to human TSLP are selected and cultured. The monoclonal antibodies from the hybridoma cultures may be isolated from the supernatants of hybridoma cultures.

[0137] An alternative method for production of a murine monoclonal antibody is to inject the hybridoma cells into the peritoneal cavity of a syngeneic mouse, for example, a mouse that has been treated (e.g., pristane-primed) to promote formation of ascites fluid containing the monoclonal antibody. Monoclonal antibodies can be isolated and purified by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein-A Sepharose, size-exclusion chromatography, and ion-exchange chromatography (see, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3; Baines et al., "Purification of Immunoglobulin G (IgG)," in Methods in Molecular Biology, Vol. 10, pages 79-104 (The Humana Press, Inc. 1992)). Monoclonal antibodies may be purified by affinity chromatography using an appropriate ligand selected based on particular properties of the antibody (e.g., heavy or light chain isotype, binding specificity, etc.). Examples of a suitable ligand, immobilized on a solid support, include Protein A, Protein G, an anticonstant region (light chain or heavy chain) antibody, an anti-idiotype antibody, and TSLP, or fragment or variant thereof.

[0138] An antibody of the present invention may also be a fully human monoclonal antibody. Fully human monoclonal antibodies may be generated by any number of techniques as those previsously described above. Such methods further include, but are not limited to, Epstein Barr Virus (EBV) transformation of human peripheral blood cells (e.g., containing B lymphocytes), in vitro immunization of human B-cells, fusion of spleen cells from immunized transgenic mice carrying inserted human immunoglobulin genes, isolation from human immunoglobulin V region phage libraries, or other procedures as known in the art and based on the disclosure herein. For example, fully human monoclonal antibodies may be obtained from transgenic mice that have been engineered to produce specific human antibodies in response to antigenic challenge. Methods for obtaining fully human antibodies from transgenic mice are described, for example, by Green et al., Nature Genet. 7:13, 1994; Lonberg et al., Nature 368:856, 1994; Taylor et al., Int. Immun 6:579, 1994; U.S. Pat. No. 5,877,397; Bruggemann et al., 1997 Curr. Opin. Biotechnol. 8:455-58; Jakobovits et al., 1995 Ann. N. Y. Acad. Sci. 764:525-35. In this technique, elements of the human heavy and light chain locus are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci (see also Bruggemann et al., Curr. Opin. Biotechnol. 8:455-58 (1997)). For example, human immunoglobulin transgenes may be mini-gene constructs, or transloci on yeast artificial chromosomes, which undergo B-cell-specific DNA rearrangement and hypermutation in the mouse lymphoid tissue. Fully human monoclonal antibodies may be obtained by immunizing the transgenic mice, which may then produce human antibodies specific for human TSLP. Lymphoid cells of the immunized transgenic mice can be used to produce human antibody-secreting hybridomas according to the methods described herein. Polyclonal sera containing fully human antibodies may also be obtained from the blood of the immunized animals.

[0139] One exemplary method for generating human antibodies of the invention includes immortalizing human peripheral blood cells by EBV transformation, as described, for example, in U.S. Pat. No. 4,464,456. Such an immortalized B-cell line (or lymphoblastoid cell line) producing a monoclonal antibody that specifically binds to human TSLP can be identified by immunodetection methods as provided herein, for example, an ELISA, and then isolated by standard cloning techniques. The stability of the lymphoblastoid cell line producing an anti-TSLP antibody may be improved by fusing the transformed cell line with a murine myeloma to produce a mouse-human hybrid cell line according to methods known in the art (see, e.g., Glasky et al., Hybridoma 8:377-89 (1989)). Still another method to generate human monoclonal antibodies is in vitro immunization, which includes priming human splenic B-cells with human TSLP followed by fusion of primed B-cells with a heterohybrid fusion partner. See, e.g., Boerner et al., 1991 J. Immunol. 147:86-95.

[0140] In certain embodiments, a B-cell that is producing an anti-human TSLP antibody is selected and the light chain and heavy chain variable regions are cloned from the B-cell according to molecular biology techniques known in the art (WO 92/02551; U.S. Pat. No. 5,627,052; Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48 (1996)) and described herein. B-cells from an immunized animal may be isolated from the spleen, lymph node, or peripheral blood sample by selecting a cell that is producing an antibody that specifically binds to TSLP. B-cells may also be isolated from humans, for example, from a peripheral blood sample. Methods for detecting single B-cells that are producing an antibody with the desired specificity are well known in the art, for example, by plaque formation, fluorescence-activated cell sorting, in vitro stimulation followed by detection of specific antibody, and the like. Methods for selection of specific antibody-producing B-cells include, for example, preparing a single cell suspension of B-cells in soft agar that contains human TSLP. Binding of the specific antibody produced by the B-cell to the antigen results in the formation of a complex, which may be visible as an immunoprecipitate. After the B-cells producing the desired antibody are selected, the specific antibody genes may be cloned by isolating and amplifying DNA or mRNA according to methods known in the art and described herein.

[0141] An additional method for obtaining antibodies of the invention is by phage display. See, e.g., Winter et al., 1994 Annu. Rev. Immunol. 12:433-55; Burton et al., 1994 Adv. Immunol. 57:191-280. Human or murine immunoglobulin variable region gene combinatorial libraries may be created in phage vectors that can be screened to select Ig fragments (Fab, Fv, sFv, or multimers thereof) that bind specifically to TSLP or variant or fragment thereof. See, e.g., U.S. Pat. No. 5,223,409; Huse et al., 1989 Science 246:1275-81; Sastry et al., Proc. Natl. Acad. Sci. USA 86:5728-32 (1989); Alting-Mees et al., Strategies in Molecular Biology 3:1-9 (1990); Kang et al., 1991 Proc. Natl. Acad. Sci. USA 88:4363-66; Hoogenboom et al., 1992 J. Molec. Biol. 227:381-388; Schlebusch et al., 1997 Hybridoma 16:47-52 and references cited therein. For example, a library containing a plurality of polynucleotide sequences encoding Ig variable region fragments may be inserted into the genome of a filamentous bacteriophage, such as M13 or a variant thereof, in frame with the sequence encoding a phage coat protein. A fusion protein may be a fusion of the coat protein with the light chain variable region domain and/or with the heavy chain variable region domain According to certain embodiments, immunoglobulin Fab fragments may also be displayed on a phage particle (see, e.g., U.S. Pat. No. 5,698,426).

[0142] Heavy and light chain immunoglobulin cDNA expression libraries may also be prepared in lambda phage, for example, using .lamda.ImmunoZap.TM. (H) and .lamda.ImmunoZap.TM. (L) vectors (Stratagene, La Jolla, Calif.). Briefly, mRNA is isolated from a B-cell population, and used to create heavy and light chain immunoglobulin cDNA expression libraries in the .lamda.ImmunoZap(H) and .lamda.ImmunoZap(L) vectors. These vectors may be screened individually or co-expressed to form Fab fragments or antibodies (see Huse et al., supra; see also Sastry et al., supra). Positive plaques may subsequently be converted to a non-lytic plasmid that allows high level expression of monoclonal antibody fragments from E. coli.

[0143] In one embodiment, in a hybridoma the variable regions of a gene expressing a monoclonal antibody of interest are amplified using nucleotide primers. These primers may be synthesized by one of ordinary skill in the art, or may be purchased from commercially available sources. (See, e.g., Stratagene (La Jolla, Calif.), which sells primers for mouse and human variable regions including, among others, primers for V.sub.Ha, V.sub.Hb, V.sub.Hc, V.sub.Hd, C.sub.H1, V.sub.L and C.sub.L regions.) These primers may be used to amplify heavy or light chain variable regions, which may then be inserted into vectors such as ImmunoZAP.TM. H or ImmunoZAP.TM. L (Stratagene), respectively. These vectors may then be introduced into E. coli, yeast, or mammalian-based systems for expression. Large amounts of a single-chain protein containing a fusion of the V.sub.H and V.sub.L domains may be produced using these methods (see Bird et al., Science 242:423-426, 1988).

[0144] Once cells producing antibodies according to the invention have been obtained using any of the above-described immunization and other techniques, the specific antibody genes may be cloned by isolating and amplifying DNA or mRNA therefrom according to standard procedures as described herein. The antibodies produced therefrom may be sequenced and the CDRs identified and the DNA coding for the CDRs may be manipulated as described previously to generate other antibodies according to the invention.

[0145] Antigen binding proteins of the present invention preferably modulate TSLP activity in one of the cell-based assay described herein and/or the in vivo assay described herein and/or cross-block the binding of one of the antibodies described in this application and/or are cross-blocked from binding TSLP by one of the antibodies described in this application. Particularly useful are antigen binding proteins that cross-compete with an exemplary antibody described herein, i.e., cross-block the binding of one of the exemplary antibodies described in this application and are cross-blocked from binding TSLP by one of the exemplary antibodies. Accordingly such binding agents can be identified using the assays described herein.

[0146] In certain embodiments, antibodies are generated by first identifying antibodies that bind to TSLP and/or neutralize in the cell-based assays described herein and/or cross-block the antibodies described in this application and/or are cross-blocked from binding TSLP by one of the antibodies described in this application. The CDR regions from these antibodies are then used to insert into appropriate biocompatible frameworks to generate antigen binding proteins. The non-CDR portion of the binding agent may be composed of amino acids, or may be a non-protein molecule. The assays described herein allow the characterization of binding agents. Preferably the binding agents of the present invention are antibodies as defined herein.

[0147] Antigen binding proteins of the present invention include those that bind to the same epitope as an exemplary antibody described herein. As discussed in Example 9, epitopes may be structural or functional. Structural epitopes may be thought of as the patch of the target which is covered by the antibody. Functional epitopes are a subset of the structural epitopes and comprise those residues which directly contribute to the affinity of the interaction (e.g. hydrogen bonds, ionic interactions). One method of determining the epitope of an antibody is by using scanning mutations in the target molecule and measuring the effect of the mutation on binding. Given the three-dimensional structure of the antibody binding region, mutations in the epitope can decrease or increase the binding affinity of the antibody for the mutated target.

[0148] Antigen binding proteins may be defined by their epitopes. As seen in Table 6, although the antibodies may all bind to TSLP, they are affected differently by the mutation of certain residues in TSLP an indication that their respective epitopes do not completely overlap. Preferred antigen binding proteins include those that share at least a portion of the structural epitope of a reference antibody described herein.

[0149] For example, a preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A2. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K67E, K97E, K98E, R100E, K101E, or K103E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation K21E, T25R, S28R, S64R, or K73E. Although the antigen binding protein and A2 may be affected similarly by some mutations and not others, the more identity there is between the antigen binding protein and A2 on the effect of mutations in certain residues of TSLP, the more the antigen binding protein and reference antibody share a structural epitope.

[0150] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A4. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K97E, K98E, R100E, K101E, or K103E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation K10E, A14R, K21E, D22R, K73E, K75E, or A76R.

[0151] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A5. This is evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation K12E, D22R, S4OR, R122E, N124E, R125E, or K129E.

[0152] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A6. This is evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation S40R, S42R, H46R, R122E, or K129E.

[0153] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A7. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K101E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation D2R, T4R, D7R, S42R, H46R, T49R, E5OR, Q112R, R122E, R125E, or K129E.

[0154] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A10. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K97E, K98E, R100E, K101E, or K103E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation N5R, S17R, T18R, K21E, D22R, T25R, T33R, H46R, A63R, S64R, A66R, E68R, K73E, K75E, A76R, A92R, T93R, Q94R, or A95R.

[0155] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A21. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K97E, K98E, R100E, K101E, or K103E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation K21E, K21R, D22R, T25R, T33R, S64R, K73E, K75E, E111R, or S114R.

[0156] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A23. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K67E, K97E, K98E, R100E, K101E, or K103E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation E9R, K10E, K12E, A13R, S17R, S20R, K21E, K21R, K73E, K75E, N124E, or R125E.

[0157] Another preferred antigen binding protein is one that shares at least a portion of the same structural epitope as A26. This is evidenced by an increase in binding affinity as compared to for wild-type TSLP when TSLP has mutation K97E, K98E, R100E, K101E, or K103E. This may also be evidenced by a decrease in binding affinity as compared to for wild-type TSLP when TSLP has mutation A14R, K21E, D22R, A63R, S64R, K67E, K73E, A76R, A92R, or A95R.

[0158] Comparing the mutations that affect binding amongst the antibody, it suggests that certain residues of TSLP tend to be part of the antibodies ability to bind TSLP and block TSLP activity.

[0159] Such residues include K21, D22, K73, and K129. Thus, preferred antigen binding protein include those that have a higher affinity for wild-type TSLP than for a TSLP comprising mutation K21E, those that have a higher affinity for wild-type TSLP than for a TSLP comprising mutation D21R, those that have a higher affinity for wild-type TSLP than for a TSLP comprising mutation K73E, and those that have a higher affinity for wild-type TSLP than for a TSLP comprising mutation K129E.

[0160] Furthermore, many of the exemplary antigen binding proteins described herein share the attribute that the affinity for TSLP increases when the basic patch of amino acids at positions 97-103 are changed to acidic amino acids..

Nucleic Acids

[0161] In one aspect, the present invention provides isolated nucleic acid molecules. The nucleic acids comprise, for example, polynucleotides that encode all or part of an antigen binding protein, for example, one or both chains of an antibody of the invention, or a fragment, derivative, mutein, or variant thereof, polynucleotides sufficient for use as hybridization probes, PCR primers or sequencing primers for identifying, analyzing, mutating or amplifying a polynucleotide encoding a polypeptide, anti-sense nucleic acids for inhibiting expression of a polynucleotide, and complementary sequences of the foregoing. The nucleic acids can be any length. They can be, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 750, 1,000, 1,500, 3,000, 5,000 or more nucleotides in length, and/or can comprise one or more additional sequences, for example, regulatory sequences, and/or be part of a larger nucleic acid, for example, a vector. The nucleic acids can be single-stranded or double-stranded and can comprise RNA and/or DNA nucleotides, and artificial variants thereof (e.g., peptide nucleic acids).

[0162] Nucleic acids encoding antibody polypeptides (e.g., heavy or light chain, variable domain only, or full length) may be isolated from B-cells of mice that have been immunized with a TSLP antigen. The nucleic acid may be isolated by conventional procedures such as polymerase chain reaction (PCR).

[0163] Nucleic acid sequences encoding the variable regions of the heavy and light chain variable regions are shown above. The skilled artisan will appreciate that, due to the degeneracy of the genetic code, each of the polypeptide sequences disclosed herein is encoded by a large number of other nucleic acid sequences. The present invention provides each degenerate nucleotide sequence encoding each antigen binding protein of the invention.

[0164] The invention further provides nucleic acids that hybridize to other nucleic acids (e.g., nucleic acids comprising a nucleotide sequence of any of A1-A27) under particular hybridization conditions. Methods for hybridizing nucleic acids are well-known in the art. See, e.g., Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. As defined herein, a moderately stringent hybridization condition uses a prewashing solution containing 5.times. sodium chloride/sodium citrate (SSC), 0.5% SDS, 1.0 mM EDTA (pH 8.0), hybridization buffer of about 50% formamide, 6.times.SSC, and a hybridization temperature of 55.degree. C. (or other similar hybridization solutions, such as one containing about 50% formamide, with a hybridization temperature of 42.degree. C.), and washing conditions of 60.degree. C., in 0.5.times.SSC, 0.1% SDS. A stringent hybridization condition hybridizes in 6.times.SSC at 45.degree. C., followed by one or more washes in 0.1.times.SSC, 0.2% SDS at 68.degree. C. Furthermore, one of skill in the art can manipulate the hybridization and/or washing conditions to increase or decrease the stringency of hybridization such that nucleic acids comprising nucleotide sequences that are at least 65, 70, 75, 80, 85, 90, 95, 98 or 99% identical to each other typically remain hybridized to each other. The basic parameters affecting the choice of hybridization conditions and guidance for devising suitable conditions are set forth by, for example, Sambrook, Fritsch, and Maniatis (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters 9 and 11; and Current Protocols in Molecular Biology, 1995, Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4), and can be readily determined by those having ordinary skill in the art based on, for example, the length and/or base composition of the DNA.

[0165] Changes can be introduced by mutation into a nucleic acid, thereby leading to changes in the amino acid sequence of a polypeptide (e.g., an antigen binding protein) that it encodes. Mutations can be introduced using any technique known in the art. In one embodiment, one or more particular amino acid residues are changed using, for example, a site-directed mutagenesis protocol. In another embodiment, one or more randomly selected residues is changed using, for example, a random mutagenesis protocol. However it is made, a mutant polypeptide can be expressed and screened for a desired property.

[0166] Mutations can be introduced into a nucleic acid without significantly altering the biological activity of a polypeptide that it encodes. For example, one can make nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues. In one embodiment, a nucleotide sequence provided herein for A1-A27, or a desired fragment, variant, or derivative thereof, is mutated such that it encodes an amino acid sequence comprising one or more deletions or substitutions of amino acid residues that are shown herein for A1-A27 to be residues where two or more sequences differ. In another embodiment, the mutagenesis inserts an amino acid adjacent to one or more amino acid residues shown herein for A1-A27 to be residues where two or more sequences differ. Alternatively, one or more mutations can be introduced into a nucleic acid that selectively change the biological activity. (e.g., binding to TSLP) of a polypeptide that it encodes. For example, the mutation can quantitatively or qualitatively change the biological activity. Examples of quantitative changes include increasing, reducing or eliminating the activity. Examples of qualitative changes include changing the antigen specificity of an antigen binding protein.

[0167] In another aspect, the present invention provides nucleic acid molecules that are suitable for use as primers or hybridization probes for the detection of nucleic acid sequences of the invention. A nucleic acid molecule of the invention can comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide of the invention, for example, a fragment that can be used as a probe or primer or a fragment encoding an active portion (e.g., a TSLP binding portion) of a polypeptide of the invention.

[0168] Probes based on the sequence of a nucleic acid of the invention can be used to detect the nucleic acid or similar nucleic acids, for example, transcripts encoding a polypeptide of the invention. The probe can comprise a label group, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used to identify a cell that expresses the polypeptide.

[0169] In another aspect, the present invention provides vectors comprising a nucleic acid encoding a polypeptide of the invention or a portion thereof. Examples of vectors include, but are not limited to, plasmids, viral vectors, non-episomal mammalian vectors and expression vectors, for example, recombinant expression vectors.

[0170] The recombinant expression vectors of the invention can comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell. The recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid sequence to be expressed. Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cells (e.g., SV40 early gene enhancer, Rous sarcoma virus promoter and cytomegalovirus promoter), those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences, see Voss et al., 1986, Trends Biochem. Sci. 11:287, Maniatis et al., 1987, Science 236:1237, incorporated by reference herein in their entireties), and those that direct inducible expression of a nucleotide sequence in response to particular treatment or condition (e.g., the metallothionin promoter in mammalian cells and the tet-responsive and/or streptomycin responsive promoter in both prokaryotic and eukaryotic systems (see id.). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.

[0171] In another aspect, the present invention provides host cells into which a recombinant expression vector of the invention has been introduced. A host cell can be any prokaryotic cell (for example, E. coli) or eukaryotic cell (for example, yeast, insect, or mammalian cells (e.g., CHO cells)). Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die), among other methods.

Indications

[0172] TSLP is involved in promoting various inflammatory disorders, in particular allergic inflammatory disorders. As used herein the term "allergic inflammation" refers to the manifestations of immunoglobulin E (IgE)-related immunological responses. (Manual of Allergy and Immunology, Chapter 2, Alvin M. Sanico, Bruce S. Bochner, and Sarbjit S. Saini, Adelman et al, ed., Lippincott, Williams, Wilkins, Philadelphia, Pa., (2002)). Allergic inflammation as used herein is generally characterized by the infiltration into the affected tissue of type 2 helper T cells (T.sub.H2 cells) (Kay, supra). Allergic inflammation includes pulmonary inflammatory diseases such as allergic rhinosinusitis, asthma, allergic conjunctivitis, in addition to inflammatory skin conditions such as atopic dermatis (Manual of Allergy and Immunology, supra). As used herein the term "TSLP-related allergic inflammation" refers to allergic inflammation conditions in which TSLP is upregulated, or is demonstrated to be otherwise involved.

[0173] Allergic asthma is a chronic inflammatory disorder of the airways characterized by airway eosinophilia, high levels of serum IgE and mast cell activation, which contribute to airway hyperresponsiveness, epithelial damage and mucus hypersecretion (Wills-Karp, M, Ann. Rev. Immunol. 17:255-281 (1999), Manual of Allergy and Immunology, supra). Studies have demonstrated that varying degrees of chronic inflammation are present in the airways of all asthmatics, even during symptom-free periods. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. (Manual of Allergy and Immunology, supra).

[0174] Atopic dermatitis is a chronic pruritic inflammatory skin disease characterized by skin lesions, featuring an elevated serum total IgE, eosinophilia, and increased release of histamine from basophils and mast cells. Persons suffering from atopic dermatitis exhibit exaggerated T.sub.H2 responses and initiation of atopic dermatitis lesions is thought to be mediated by means of early skin infiltration of T.sub.H2 lymphocytes releasing high levels of IL-4, IL-5 and IL-13 (Leung, J. Allergy Clin Immunol 105:860-76 (2000)). The relationship between TSLP and other inflammatory cytokines is described in U.S. application Ser. No. 11/205,904, publication 2006/0039910, which is herein incorporated by reference.

[0175] Human TSLP expression as detected by in situ hybridization was reported to be increased in asthmatic airways correlating with disease severity (Ying et al., J. Immunology 174:8183-8190 (2005)). Analysis of TSLP mRNA levels in asthmatic patient lung samples showed increased expression of TSLP compared to controls. In addition, TSLP protein levels are detectable in the concentrated bronchoalveolar lavage (B AL) fluid of asthma patients, lung transplant patients, and cystic fibrosis patients. TSLP has recently been found to be released in response to microbes and trauma as well as inflammation, and to activate mast cells (Allakhverdi et al., J Exp. Med 20492: 253-258 (2007).

[0176] Human TSLP protein was shown to correlate with disease in bronchial mucosa and BAL fluid of subjects with moderate/severe asthma and COPD. (Ying et al., J Immunol 181(4):2790-8 (2008).

[0177] Over-expression of TSLP in the lungs of transgenic mice leads to asthma-like airway inflammation (Zhou et al., Nat. Immunol 10:1047-1053 (2005). In addition, it has been reported that TSLPR deficient mice failed to develop asthma in OVA-asthma models, demonstrating that TSLP is required for development of asthma in airway inflammation models (Zhou et al, supra, Carpino et al., Mol. Cell Biol. 24:2584-2592 (2004).

[0178] In addition to asthma, increased levels of TSLP protein and mRNA are found in the lesional skin of atopic dermatitis (AD) patients and in inflamed tonsilar epithelial cells (Soumelis et al., Nature

[0179] Immunol: 3 (7): 673-680 (2002). Over-expression of TSLP in the skin of transgenic mice leads to an AD-like phenotype. (Yoo et al., J Exp Med 202:541-549 (2005)).

[0180] Therefore, TSLP antagonists, specifically the TSLP antigen binding proteins and antibodies of the instant application, are useful as therapeutic treatment for allergic inflammation, in particular, asthma and atopic dermatitis.

[0181] In addition, TSLP antagonists, particularly the TSLP antigen binding proteins and antibodies of the present disclosure are also useful for treating fibrotic disorders. TSLP has been demonstrated to be involved in promoting fibrotic disorders, as described in application Ser. No. 11/344,379. TSLP has been found to induce fibroblast accumulation and collagen deposition in animals. Injection of murine TSLP, for example, intradermally into mice resulted in fibrosis within the subcutis of the mice, characterized by fibroblast proliferation and collagen deposition. Antagonizing TSLP activity would result in preventing or decreasing fibroblast proliferation and collagen deposition in a tissue.

[0182] As used herein the term "fibroproliferative disease" or "fibrotic disease or disorder" refers to conditions involving fibrosis in one or more tissues. As used herein the term "fibrosis" refers to the formation of fibrous tissue as a reparative or reactive process, rather than as a normal constituent of an organ or tissue. Fibrosis is characterized by fibroblast accumulation and collagen deposition in excess of normal deposition in any particular tissue. As used herein the term "fibrosis" is used synonymously with "fibroblast accumulation and collagen deposition". Fibroblasts are connective tissue cells, which are dispersed in connective tissue throughout the body. Fibroblasts secrete a nonrigid extracellular matrix containing type I and/or type III collagen. In response to an injury to a tissue, nearby fibroblasts migrate into the wound, proliferate, and produce large amounts of collagenous extracellular matrix. Collagen is a fibrous protein rich in glycine and proline that is a major component of the extracellular matrix and connective tissue, cartilage, and bone. Collagen molecules are triple-stranded helical structures called a-chains, which are wound around each other in a ropelike helix. Collagen exists in several forms or types; of these, type I, the most common, is found in skin, tendon, and bone; and type III is found in skin, blood vessels, and internal organs.

[0183] Fibrotic disorders include, but are not limited to, systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, restenosis, pulmonary inflammation and fibrosis, idiopathic pulmonary fibrosis, liver cirrhosis, fibrosis as a result of chronic hepatitis B or C infection, kidney disease, heart disease resulting from scar tissue, and eye diseases such as macular degeneration, and retinal and vitreal retinopathy. Additional fibrotic diseases include fibrosis resulting from chemotherapeutic drugs, radiation-induced fibrosis, and injuries and burns.

[0184] Scleroderma is a fibrotic disorder characterized by a thickening and induration of the skin caused by the overproduction of new collagen by fibroblasts in skin and other organs. Scleroderma may occur as a local or systemic disease. Systemic scleroderma may affect a number of organs. Systemic sclerosis is characterized by formation of hyalinized and thickened collagenous fibrous tissue, with thickening of the skin and adhesion to underlying tissues, especially of the hands and face. The disease may also be characterized by dysphagia due to loss of peristalsis and submucosal fibrosis of the esophagus, dyspnea due to pulmonary fibrosis, myocardial fibrosis, and renal vascular changes. (Stedman's Medical Dictionary, 26.sup.th Edition, Williams & Wilkins, 1995)). Pulmonary fibrosis affects 30 to 70% of scleroderma patients, often resulting in restrictive lung disease (Atamas et al. Cytokine and Growth Factor Rev 14: 537-550 (2003)). Idiopathic pulmonary fibrosis is a chronic, progressive and usually lethal lung disorder, thought to be a consequence of a chronic inflammatory process (Kelly et al., Curr Pharma Design 9: 39-49 (2003)).

[0185] Therefore, TSLP antagonists, specifically the TSLP antigen binding proteins and antibodies of the instant application, are useful as therapeutic treatment for fibrotic diseases, including but not limited to scleroderma, interstitial lung disease, idiopathic pulmonary fibrosis, fibrosis arising from chronic hepatitis B or C, radiation-induced fibrosis, and fibrosis arising from wound healing.

[0186] Although the above indications are preferred, other disease, disorder, or condition may be amenable to treatment with or may be prevented by administration of an antigen binding to a subject. Such diseases, disorders, and conditions include, but are not limited to, inflammation, autoimmune disease, cartilage inflammation, fibrotic disease and/or bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEA Syndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, SEA Syndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome), dermatomyositis, psoriatic arthritis, scleroderma, systemic lupus erythematosus, vasculitis, myolitis, polymyolitis, dermatomyolitis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, ploymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis, primary biliary sclerosis, sclerosing cholangitis, Sjogren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, dermatitis, atopic dermatitis, atherosclerosis, lupus, Still's disease, Systemic Lupus Erythematosus (SLE), myasthenia gravis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, celiac disease, multiple schlerosis (MS), asthma, COPD, Guillain-Barre disease, Type I diabetes mellitus, Graves' disease, Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, GVHD, and the like. In specific embodiments, pharmaceutical compositions comprising a therapeutically effective amount of TSLP antigen binding proteins are provided.

[0187] The term "treatment" encompasses alleviation or prevention of at least one symptom or other aspect of a disorder, or reduction of disease severity, and the like. An antigen binding protein need not effect a complete cure, or eradicate every symptom or manifestation of a disease, to constitute a viable therapeutic agent. As is recognized in the pertinent field, drugs employed as therapeutic agents may reduce the severity of a given disease state, but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents. Similarly, a prophylactically administered treatment need not be completely effective in preventing the onset of a condition in order to constitute a viable prophylactic agent. Simply reducing the impact of a disease (for example, by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reducing the likelihood that the disease will occur or worsen in a subject, is sufficient. One embodiment of the invention is directed to a method comprising administering to a patient an antigen binding protein in an amount and for a time sufficient to induce a sustained improvement over baseline of an indicator that reflects the severity of the particular disorder.

Pharmaceutical Compositions

[0188] In some embodiments, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or a plurality of the antigen binding proteins of the invention together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant. In addition, the invention provides methods of treating a patient by administering such pharmaceutical composition. The term "patient" includes human and animal subjects.

[0189] Pharmaceutical compositions comprising one or more antigen binding proteins may be used to reduce TSLP activity. Pharmaceutical compositions comprising one or more antigen binding proteins may be used in treating the consequences, symptoms, and/or the pathology associated with TSLP activity. Pharmaceutical compositions comprising one or more antigen binding proteins may be used in methods of inhibiting binding and/or signaling of TSLP to TSLPR comprising providing the antigen binding protein of the invention to TSLP.

[0190] In certain embodiments, acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HC1, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, sucrose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and/or pharmaceutical adjuvants. See, REMINGTON'S PHARMACEUTICAL SCIENCES, 18'' Edition, (A. R. Genrmo, ed.), 1990, Mack Publishing Company.

[0191] In certain embodiments, the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format and desired dosage. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, supra. In certain embodiments, such compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antigen binding proteins of the invention. In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In specific embodiments, pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, and may further include sorbitol or a suitable substitute therefor. In certain embodiments of the invention, TSLP antigen binding protein compositions may be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES, supra) in the form of a lyophilized cake or an aqueous solution. Further, in certain embodiments, the TSLP antigen binding protein product may be formulated as a lyophilizate using appropriate excipients such as sucrose.

[0192] The pharmaceutical compositions of the invention can be selected for parenteral delivery. Alternatively, the compositions may be selected for inhalation or for delivery through the digestive tract, such as orally. The formulation components are present preferably in concentrations that are acceptable to the site of administration. In certain embodiments, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8. Including about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, and about 8.0.

[0193] When parenteral administration is contemplated, the therapeutic compositions for use in this invention may be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired TSLP antigen binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which the TSLP antigen binding protein is formulated as a sterile, isotonic solution, properly preserved. In certain embodiments, the preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that may provide controlled or sustained release of the product which can be delivered via depot injection. In certain embodiments, hyaluronic acid may also be used, having the effect of promoting sustained duration in the circulation. In certain embodiments, implantable drug delivery devices may be used to introduce the desired antigen binding protein.

[0194] Pharmaceutical compositions of the invention can be formulated for inhalation. In these embodiments, TSLP antigen binding proteins are advantageously formulated as a dry, inhalable powder. In specific embodiments, TSLP antigen binding protein inhalation solutions may also be formulated with a propellant for aerosol delivery. In certain embodiments, solutions may be nebulized. Pulmonary administration and formulation methods therefore are further described in International Patent Application No. PCTUS94/001875, which is incorporated by reference and describes pulmonary delivery of chemically modified proteins.

[0195] It is also contemplated that formulations can be administered orally. TSLP antigen binding proteins that are administered in this fashion can be formulated with or without carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. In certain embodiments, a capsule maybe designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized Additional agents can be included to facilitate absorption of the TSLP antigen binding protein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.

[0196] A pharmaceutical composition of the invention is preferably provided to comprise an effective quantity of one or a plurality of TSLP antigen binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions may be prepared in unit-dose form.

[0197] Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[0198] Additional pharmaceutical compositions will be evident to those skilled in the art, including formulations involving TSLP antigen binding proteins in sustained- or controlled- delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See, for example, International Patent Application No. PCT/US93/00829, which is incorporated by reference and describes controlled release of porous polymeric microparticles for delivery of pharmaceutical compositions.

[0199] Sustained-release preparations may include semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides (as disclosed in U.S. Pat. No. 3,773,919 and European Patent Application Publication No. EP 058481, each of which is incorporated by reference), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al, 1983, Biopolymers 2:547-556), poly (2-hydroxyethyl-inethacrylate) (Langer et al, 1981, J. Biomed. Mater. Res. 15:167-277 and Langer, 1982, Chem. Tech. 12:98-105), ethylene vinyl acetate (Langer et al, 1981, supra) or poly-D(-)-3-hydroxybutyric acid (European Patent Application Publication No. EP 133,988).

[0200] Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art. See, e.g., Eppstein et al, 1985, Proc. Natl Acad. Sci U.S.A. 82.3688-3692; European Patent Application Publication Nos. EP 036,676; EP 088,046 and EP 143,949, incorporated by reference.

[0201] Pharmaceutical compositions used for in vivo administration are typically provided as sterile preparations. Sterilization can be accomplished by filtration through sterile filtration membranes. When the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. Compositions for parenteral administration can be stored in lyophilized form or in a solution. Parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0202] Aspects of the invention includes self-buffering TSLP antigen binding protein formulations, which can be used as pharmaceutical compositions, as described in international patent application WO 0613818 1A2 (PCT/US2006/022599), which is incorporated by referencein its entirety herein. One embodiment provides self-buffering TSLP antigen binding protein formulations comprising an TSLP antigen binding protein in which the total salt concentration is less than 150 mM.

[0203] The therapeutically effective amount of TSLP antigen binding protein-containing pharmaceutical composition to be employed will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will vary depending, in part, upon the molecule delivered, the indication for which the TSLP antigen binding protein is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient.

[0204] In certain embodiments, the clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect. A typical dosage may range from about 0.1 .mu.g/kg to up to about 30 mg/kg or more, depending on the factors mentioned above. In specific embodiments, the dosage may range from 0.1 .mu.g/kg up to about 30 mg/kg, optionally from 1 .mu.g/kg up to about 30 mg/kg or from 10 .mu.g/kg up to about 5 mg/kg.

[0205] Dosing frequency will depend upon the pharmacokinetic parameters of the particular TSLP antigen binding protein in the formulation used. Typically, a clinician administers the composition until a dosage is reached that achieves the desired effect. The composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them.

[0206] Appropriate dosages may be ascertained through use of appropriate dose-response data. In certain embodiments, the antigen binding proteins of the invention can be administered to patients throughout an extended time period. Chronic administration of an antigen binding protein of the invention minimizes the adverse immune or allergic response commonly associated with antigen binding proteins that are not fully human, for example an antibody raised against a human antigen in a non-human animal, for example, a non-fully human antibody or non-human antibody produced in a non-human species.

[0207] The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices. In certain embodiments, the compositions may be administered by bolus injection or continuously by infusion, or by implantation device.

[0208] The composition also may be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. In certain embodiments, where an implantation device is used, the device may be implanted into any suitable tissue or organ, and delivery of the desired molecule may be via diffusion, timed-release bolus, or continuous administration.

[0209] Combination Therapies

[0210] In further embodiments, antigen binding protein are administered in combination with other agents useful for treating the condition with which the patient is afflicted. Examples of such agents include both proteinaceous and non-proteinaceous drugs. When multiple therapeutics are co-administered, dosages may be adjusted accordingly, as is recognized in the pertinent art. "Co-administration" and combination therapy are not limited to simultaneous administration, but also include treatment regimens in which an antigen binding protein is administered at least once during a course of treatment that involves administering at least one other therapeutic agent to the patient.

[0211] The invention having been described, the following examples are offered by way of illustration, and not limitation.

EXAMPLE 1

Preparation of Antigen

[0212] Several forms of recombinant TSLP were used as immunogens. Human TSLP was expressed both in E.coli and in mammalian cells. The E. coli produced human TSLP was an untagged full-length protein. TSLP protein was produced in COS PKB cells having a deleted furin cleavage site produced by deleting nucleotides 382-396 (AGAAAAAGGAAAGTC, SEQ ID NO: 370) corresponding to amino acids 128-132 (RKRKV, SEQ ID NO: 371). This protein contained a C terminal polyHIS-Flag tag (Nucleotide sequence=ATGTTCCCTTTTGCCTTACTATATGTTCTGTCAGTTTCTTTCAGGAAAATCTTCATCTTACA ACTTGTAGGGCTGGTGTTAACTTACGACTTCACTAACTGTGACTTTGAGAAGATTAAAGC AGCCTATCTCAGTACTATTTCTAAAGACCTGATTACATATATGAGTGGGACCAAAAGTAC CGAGTTCAACAACACCGTCTCTTGTAGCAATCGGCCACATTGCCTTACTGAAATCCAGAG CCTAACCTTCAATCCCACCGCCGGCTGCGCGTCGCTCGCCAAAGAAATGTTCGCCATGAA AACTAAGGCTGCCTTAGCTATCTGGTGCCCAGGCTATTCGGAAACTCAGATAAATGCTAC TCAGGCAATGAAGAAGAGGACAACCAATAAATGTCTGGAACAAGTGTCACAATTACAAG GATTGTGGCGTCGCTTCAATCGACCTTTACTGAAACAACAGCATCACCATCACCATCACG ACTACAAAGACGATGACGACAAA (SEQ ID NO: 372);

[0213] Protein sequence=MFPFALLYVLSVSFRKIFILQLVGLVLTYDFTNCDFEKIKAAYLSTISKDLITYMSGTKSTEFN- N TVSCSNRPHCLTEIQSLTFNPTAGCASLAKEMFAMKTKAALAIWCPGYSETQINATQAMKKR TTNKCLEQVSQLQGLWRRFNRPLLKQQHHHHHHDYKDDDDK (SEQ ID NO: 373).

[0214] In another campaign, a full length TSLP C terminal polyHIS-Flag tagged protein was produced in COS PKB cells (Nucleotide sequence=ATGTTCCCTTTTGCCTTACTATATGTTCTGTCAGTTTCTTTCAGGAAAATCTTCATCTTACA ACTTGTAGGGCTGGTGTTAACTTACGACTTCACTAACTGTGACTTTGAGAAGATTAAAGC AGCCTATCTCAGTACTATTTCTAAAGACCTGATTACATATATGAGTGGGACCAAAAGTAC CGAGTTCAACAACACCGTCTCTTGTAGCAATCGGCCACATTGCCTTACTGAAATCCAGAG CCTAACCTTCAATCCCACCGCCGGCTGCGCGTCGCTCGCCAAAGAAATGTTCGCCATGAA AACTAAGGCTGCCTTAGCTATCTGGTGCCCAGGCTATTCGGAAACTCAGATAAATGCTAC TCAGGCAATGAAGAAGAGGAGAAAAAGGAAAGTCACAACCAATAAATGTCTGGAACAA GTGTCACAATTACAAGGATTGTGGCGTCGCTTCAATCGACCTTTACTGAAACAACAGCAT CACCATCACCATCACGACTACAAAGACGATGACGACAAA (SEQ ID NO: 374); Protein sequence=MFPFALLYVLSVSFRKIFILQLVGLVLTYDFTNCDFEKIKAAYLSTISKDLITYMSGTKSTEFN- N TVSCSNRPHCLTEIQSLTFNPTAGCASLAKEMFAMKTKAALAIWCPGYSETQINATQAMKKR RKRKVTTNKCLEQVSQLQGLWRRFNRPLLKQQHHHHHHDYKDDDDK (SEQ ID NO: 375). Note that the amino acid sequence 1-28 (MFPFALLYVLSVSFRKIFILQLVGLVLT, SEQ ID NO: 376) is a signal peptide cleaved from the mature product of both these proteins.

[0215] In addition, cynomolgus TSLP was cloned and subcloned/expressed similarly with either the furin cleavage site (nucleotide 358-372 (AGAAAAAGGAAAGTC, SEQ ID NO: 370) corresponding to amino acids 120-124 (RKRKV, SEQ ID NO: 371)) deleted (DNA=ATGGAGACAGACACACTCCTGCTATGGGTACTGCTGCTCTGGGTTCCAGGTTCCACCGG TTACGACTTCACTAACTGTGACTTTCAGAAGATTGAAGCAGACTATCTCCGTACTATTTCT AAAGACCTGATTACATATATGAGTGGGACTAAAAGTACCGACTTCAACAACACCGTCTC CTGTAGCAATCGGCCACACTGCCTTACTGAAATCCAGAGCCTAACCTTCAATCCCACCCC CCGCTGCGCGTCGCTCGCCAAGGAAATGTTCGCCAGGAAAACTAAGGCTACCCTCGCTCT CTGGTGCCCAGGCTATTCGGAAACTCAGATAAATGCTACTCAGGCAATGAAGAAGAGGA CAACCAATAAATGTCTGGAACAAGTGTCACAATTACTAGGATTGTGGCGTCGCTTCATTC GAACTTTACTGAAACAACAGCACCACCACCACCACCATGACTATAAAGACGATGACGAC AAAT (SEQ ID NO: 377); Protein=METDTLLLWVLLLWVPGSTGYDFTNCDFQKIEADYLRTISKDLITYMSGTKSTDF- NNTVSCS NRPHCLTEIQSLTFNPTPRCASLAKEMFARKTKATLALWCPGYSETQINATQAMKKRTTNKC LEQVSQLLGLWRRFIRTLLKQQHHHHHHDYKDDDDK (SEQ ID NO: 378) or as a full-length/native product (nucleotide sequence=ATGGAGACAGACACACTCCTGCTATGGGTACTGCTGCTCTGGGTTCCAGGTTCCACCGGT TACGACTTCACTAACTGTGACTTTCAGAAGATTGAAGCAGACTATCTCCGTACTATTTCT AAAGACCTGATTACATATATGAGTGGGACTAAAAGTACCGACTTCAACAACACCGTCTC CTGTAGCAATCGGCCACACTGCCTTACTGAAATCCAGAGCCTAACCTTCAATCCCACCCC CCGCTGCGCGTCGCTCGCCAAGGAAATGTTCGCCAGGAAAACTAAGGCTACCCTCGCTCT CTGGTGCCCAGGCTATTCGGAAACTCAGATAAATGCTACTCAGGCAATGAAGAAGAGGA GAAAAAGGAAAGTCACAACCAATAAATGTCTGGAACAAGTGTCACAATTACTAGGATTG TGGCGTCGCTTCATTCGAACTTTACTGAAACAACAGCACCACCACCACCACCATGACTAT AAAGACGATGACGACAAA (SEQ ID NO: 379); Protein=METDTLLLWVLLLWVPGSTGYDFTNCDFQKIEADYLRTISKDLITYMSGTKSTDFNNTVSCS NRPHCLTEIQSLTFNPTPRCASLAKEMFARKTKATLALWCPGYSETQINATQAMKKRRKRKV TTNKCLEQVSQLLGLWRRFIRTLLKQQHHHHHHDYKDDDDK (SEQ ID NO: 380) fused to the same C terminal polyHIS-Flag in COS PKB cells.. Note that the amino acid sequence 1-20 (METDTLLLWVLLLWVPGSTG, SEQ ID NO: 381) is a signal peptide cleaved from the mature product of both these cynomolgus proteins.

EXAMPLE 2

Mouse Anti-Human TSLP Antibodies

[0216] hTSLP-Fc was used for immunization of Balb/c mice (Jackson Laboratories, Bar Harbor,

[0217] Maine). After several rounds of immunization, lymphocytes were released from the spleen and were fused with mouse myeloma cells, NS1 (ATCC) by chemical fusion with 50% PEG/DMSO (Sigma). The fused cells were seeded in 96-well plates at the density of 2.times.10.sup.4 cells/well in 200 ul of DMEM HAT (0.1 mM hypoxanthine, 0.16 mM thymidine, 4 mM aminopterin, Sigma) media supplemented with 10% FBS, 5% Origen Cloning Factor (BioVeris.TM.), 1.times. Penicillin-Streptomycin-Glutamine, Sodium Pyruvate (Invitrogen). Medium was replaced 7 days post-fusion with DMEM HT (0.1 mM hypoxanthine, 0.16 mM thymidine) media supplemented with 10% FBS, 5% Origen Cloning Factor (BioVeris.TM.), 1.times. Penicillin-Streptomycin-Glutamine, Sodium Pyruvate (Invitrogen). Conditioned media was collected two days after medium change and preceded for primary screening.

EXAMPLE 3

Fully Human Antibody Generation

[0218] Fully human monoclonal antibodies specific for TSLP were generated using the XenoMouse.RTM. technology according to protocols described, for example, in U.S. 2005/0118643, U.S. Pat. Nos: 6,114,598, 6,162,963, 7,049,426, 7,064,244, Green et al., Nature Genetics 7:13-21 (1994), Medez et al. Nature Genetics 15:146-156 (1997), Green and Jakobovitis J. Ex. Med. 188:483-495 (1998) (all of which are incorporated by reference herein), and as described below.

[0219] Two campaigns were conducted. In campaign 1, IgG2 and IgG4 cohorts of XenoMouse.RTM. were utilized. 50% of the mice received E. coli produced human TSLP and 50% received mammalian produced human TSLP (described above). Serum titers were monitored by ELISA (described below) and mice with the best titers were fused to generate hybridomas using the following protocols.

[0220] Selected mice were sacrificed and the draining lymph nodes harvested and pooled from each cohort. The lymphoid cells were enriched for B cells and the B cells fused with myeloma cells to create hybridomas. The fused hybridoma lines were then plated in hybridoma media and cultured for 10-14 days at 37.degree. C. The hybridoma supernatants were screened for IgG antibodies binding to TSLP by ELISA as described below.

[0221] A second campaign was initiated in which two cohorts of IgG2 XenoMouse.RTM. were immunized with mammalian produced human TSLP, and one cohort was boosted with cynomolgus TSLP. After several rounds of immunization, lymphocytes from lymph nodes were fused and cultured as described above. After culturing, hybridoma supernatants were screened for binding to TSLP by ELISA, as described below.

[0222] The polyclonal supernatants from both campaigns were selected for further subcloning on the basis of the assays set out below. The hybridomas containing antibodies that are potent inhibitors of TSLP activity were identified, and cross-reactivity with cyno TSLP was further determined. The results are shown in Example 5 below. Promising hybridoma supernatants were selected on the basis of their performance in the primary DC assay described below. Those hybridomas were single cell cloned and expanded for further testing. The antibodies were then purified as described below.

[0223] Antibodies were purified from conditioned media of the hybridomas using MAB SELECT (GE Healthcare) resin. 100 ul of a 1:2 slurry of MAB SELECT resin equilibrated in PBS was added to between 7 and 10 ml of conditioned media (CM). The tubes were placed on rotators at 4-8.degree. C. overnight. The tubes were centrifuged at 1,000.times.g for 5 minutes and the non-bound fraction was decanted. The resin was washed with 5ml of PBS, and centrifuged and decanted as above. The resin was then transferred to a SPIN-X, 0.45 um, 2 ml tube. The resin was washed an additional two times with 0.5 ml of PBS and centrifuged. The Mabs were eluted with 0.2 ml of 0.1M acetic acid by incubating at room temperature with occasional mixing for 10 minutes. The tubes were centrifuged, and 30 ul of 1M Tris buffer Ph 8.0 is added to the eluate. Purified Mab's were stored 4-8.degree. C.

EXAMPLE 4

Antibody Assays

[0224] A. ELISA to Detect Presence of Anti-TSLP Antibody

[0225] ELISAs were performed by coating COSTAR 3368 medium binding 96 well plates with recombinantly produced wtHuTSLP or pHisFlag at 2 ug/ml 50 ul/well in 1.times. PBS/0.05% azide, and incubated overnight at 4.degree. C. The plates were washed and blocked with 250 ul of 1.times. PBS/1% milk (the assay diluent), and incubated at least 30 minutes at room temperature.

[0226] Approximately 50 ul/well hybridoma supernatants, positive control mouse antibody M385, or negative control were added, and incubated at room temperature for 2 hours. The plates were washed, and a secondary antibody, goat anti-human IgG Fc HPR (Pierce), or alternatively a goat anti-mouse IgG HPR (Jackson Labs), was applied at 400 ng/ml in assay diluent. The plates were incubated 1 hr at RT, washed, and the OD at 450 nm read.

[0227] B Screening of Anti-TSLP Hybridoma Supernatants was Performed using one of the Following Functional Assays

[0228] 1. 96 well plates were coated with soluble hulL-7Ra-huTSLPR-Fc protein, with an 8 aa acid linker (SGGAPMLS, SEQ ID NO: 382) between the receptor and a human Fc, and incubated overnight at 4.degree. C.

[0229] 2. The plates were washed and blocked for 1 hour at RT with PBS+1% BSA+5% sucrose.

[0230] 3. The plates were incubated with biotinylated huTSLPHFdel (HF stands for polyHis Flag, where the TSLP has the furin cleavage site deleted) (del). The plates were then incubated (+/-) hybridoma supernatants or mouse anti-human TSLP (M385) as a positive control for 2h at RT.

[0231] 4. SA-HRP detection (streptavidin-horseradish peroxidase). SA binds strongly to the biotin portion of biotinylated huTSLPHFdel and HRP catalyzes the oxidation of the chromogen, TMB (which turns blue), by hydrogen peroxide.

[0232] B. Cell Based Assays

[0233] 1) The inhibition of TSLP-induced proliferation of stable BAF cell line expressing the human TSLPR-IL7R complex by hybridoma supernatants or purified antibodies was determined according to the following protocol.

[0234] 1. BAF: Hu TSLPR stable cell lines in growth media, RPMI 1640+10% FBS+1% L-Glutamine+0.1% Pen/Strep+0.1% 2-ME were washed to remove TSLP used in maintenance media, that is the same as the growth media but with the addition of 10 ng/mL of huTSLPHFwt.

[0235] 2. HuTSLPwtpHF (+/-) or cynomolgus TSLPwtpHF (+/-) were incubated with hybridoma supernatants/purified antibody/or mouse anti-human TSLP (M385) for 30 minutes at room temperature in wells.

[0236] 3. 5.times.10.sup.4 BAF cells/well were added and incubated for 3 days.

[0237] 4. The cells were pulsed with tritiated thymidine (1 uCi/well) overnight. Cell proliferation of the BAF cells, or the inhibition thereof, was assessed by the amount of tritiated thymidine incorporation (CPM) by the cells.

[0238] 2) Primary cell assay. Inhibition of TSLP induced osteoprotegerin (OPG) (described in U.S. Pat. No. 6,284,728) production from primary human dendritic cells (DC) by hybridomas or purified antibodies was determined according to the following protocol.

[0239] 1. Peripheral blood CD11c+myeloid DCs were enriched from normal inhouse donor leukapheresis packs using CD1c(BDCA-1) DC isolation kit (Miltenyi Biotec) .

[0240] 2. huTSLPwtpHF (+/-) or cynomolgus TSLPwtpHF were incubated with supernatants or purified antibody or mouse anti-human TSLP for 30 minutes at room temperature.

[0241] 3. 1.times.105 cells/well were added and incubated for 48 hours. Supernatants were harvested and assayed for human OPG production by ELISA, and the inhibition of OPG production by the hybridoma supernatants or purified antibodies was determined. The OPG ELISA was performed using an R&D systems DuoSet.RTM. development kit. Anti-TSLP antibodies inhibited OPG production from cells in a dose-dependent manner

[0242] 3) Cynomolgus Peripheral Blood Mononuclear Cell Assay. Inhibition of CynoTSLP induced CCL22/MDC production by hybridoma supernatants or purified antibodies was determined according to the following protocol.

[0243] 1. Peripheral blood mononuclear cells (PBMC) from peripheral blood obtained from cynomolgus monkeys (SNBL) were obtained by overlaying 1:1 blood:PBS mixture over isolymph.

[0244] 2. Cynomolgus TSLPwtpHF(+/-) supernatants/purified antibody or soluble hulL-7Ra-huTSLPR-Fc were incubated for 30 minutes at room temperature.

[0245] 3. 4.times.10.sup.5 cells/well were added and incubated for 5 days. The supernatants were harvested and assayed for cynomolgus CCL22/MDC production by ELISA .

EXAMPLE 5

K.sub.D Determinations

[0246] The surface plasmon resonance experiments described in this patent application were conducted at 25.degree. C. using a BIACORE 3000 instrument (Biacore International AB, Uppsala, Sweden) equipped with a CM4 sensor chip. Anti-Fey specific capture antibodies were covalently immobilized to two flow cells on the CM4 chip using standard amine-coupling chemistry with HBS-EP as the running buffer. Briefly, each flow cell was activated with a 1:1 (v/v) mixture of 0.1 M NHS and 0.4 M EDC. AffiniPure Goat Anti-Human IgG, Fcy Fragment Specific antibody (Jackson ImmunoResearch Inc. West Grove, Pa.) at 30 ug/ml in 10 mM sodium acetate, pH 5.0 was immobilized with a target level of 3,000 RUs on two flow cells. Residual reactive surfaces were deactivated with an injection of 1 M ethanolamine The running buffer was then switched to HBS-EP+0.1 mg/ml BSA for all remaining steps.

[0247] The following antibodies were tested. A5 IgG2 was a purified clonal antibody, A2 IgG1 and IgG2 were recombinant purified antibodies, and A3 IgG4 and A4 IgG4 were clonal supernatants. The antibodies were diluted appropriately in running buffer so that a 2 minute injection at 10 .mu.l/min over the test flow cell resulted in approximately 110-175 response units of antibody captured on the test flow cell surface. No antibody was captured on the control flow cell surface. Human, cyno, or murine TSLP at various concentrations, along with buffer blanks were then flown over the two flow cells. The concentration ranges for human and cyno TSLP were from 0.44-100 nM while the concentration range for murine TSLP was from 8.2-6000 nM. A flow rate of 50 ul/min was used and a 2 minute association phase followed by a 10-30 minute dissociation phase. After each cycle the surfaces were regenerated with a 30 second injection of 10 mM glycine pH 1.5. Fresh antibody was then captured on the test flow cell to prepare for the next cycle.

[0248] Data was double referenced by subtracting the control surface responses to remove bulk refractive index changes, and then subtracting the averaged buffer blank response to remove systematic artifacts from the experimental flow cells. The TSLP data were processed and globally fit to a 1:1 interaction model with a local Rmax in BIA evaluation Software v 4.1. (Biacore International AB, Uppsala, Sweden). Association (k.sub.a) and dissociation (k.sub.d) rate constants were determined and used to calculate the dissociation equilibrium constant (K.sub.D). The dissociation rate constants and dissociation equilibrium constants are summarized in the table found in Example 6.

EXAMPLE 6

In Vitro Activity of Antibodies

[0249] The following antibodies were characterized using the BIACORE assay described above for kd and KD. The primary dendritic cell assay was used for determining IC50 (pM). The data for A5 was generated with purified clonal antibody, for A2 was generated with recombinant purified antibody, and data for A3 and A4 was generated using clonal supernatant. All versions of TSLP were generated from mammalian cells.

TABLE-US-00005 Antibody TSLP kd (1/x) off-rate KD (pM) IC50 (pM) A5 IgG2 Hu TSLP 7.36 .times. 10.sup.-5 29.2 100-220 Cyno TSLP 8.64 .times. 10.sup.-5 51.2 680-970 Mu TSLP 8.81 .times. 10.sup.-4 377,000 Nd A2 IgG1 Hu TSLP 3.49 .times. 10.sup.-4 203 600-1700 Cyno TSLP 1.04 .times. 10.sup.-4 46.8 250-860 Mu TSLP -- -- -- A2 IgG2 Hu TSLP 2.85 .times. 10.sup.-4 157 6-24 Cyno TSLP 9.42 .times. 10.sup.-5 37.6 Nd Mu TSLP no binding no binding n/a A3 IgG4 Hu TSLP 2.7 .times. 10.sup.-4 170 6-24 Cyno TSLP Nd nd Nd Mu TSLP Nd nd Nd A4 IgG4 Hu TSLP 3.30 .times. 10.sup.-4 340 30-59 Cyno TSLP Nd nd Nd Mu TSLP Nd nd Nd

EXAMPLE 7

Recombinant Expression and Purification of Antibodies

Development of Stable Cell Line Expressing Antibodies

[0250] Overlapping oligonucleotides were synthesized corresponding to the primary sequence of the light chain or heavy chain variable domain for both the sense and anti-sense strand. This oligonucleotide pool was employed in a standard PCR. Product from this first reaction was used as template in a second PCR amplification. Amplified variable heavy chain and variable light chain fragments were sub-cloned into an intermediate vector and sequenced to identify error-free products. The variable heavy chain fragment was cloned into a transient expression vector containing a signal peptide and human IgG2 constant region. The variable light chain fragment was cloned into a transient expression vector containing a signal peptide and human lambda constant region. The complete heavy chain gene was transferred into the vector pDC324. The complete light chain gene was transferred into the expression vector, pDC323.

[0251] The CS-9 host cells used for transfection of the anti-TSLP expression plasmids are a CHO cell line derived from DXB-11 cells through adaptation to serum-free media (Rasmussen et al, Cytotechnology 28:31-42, 1998). The anti-TSLP cell lines were created by transfecting CS-9 host cells with the expression plasmids pDC323-anti-TSLP-lambda and pDC324-anti-TSLP-IgG2 using a standard electroporation or lipofection procedure. After transfection of the host cell line with the expression plasmids, the cells were grown in selection medium for 2-3 weeks to allow for selection of the plasmids and recovery of the cells. In some cases, the medium was supplemented with 3% dialyzed fetal bovine serum (ds or dFBS). If serum was used, it was removed from the medium after the selection period. The cells were grown in selective medium until they achieved >85% viability. This pool of transfected cells was then cultured in culture medium.

Cell Line Cloning

[0252] A cell bank was made of selected clones according to the following procedure. The cloning step ensures that clonal populations and cell banks were generated enabling a reproducible performance in commercial manufacturing. An amplified pool of antibody-expressing cells was seeded under limiting dilution in 96-well plates, and candidate clones were evaluated for growth and productivity performance in small-scale studies

EXAMPLE 8

Antibody Cross-Competition

[0253] A common way to define epitopes is through competition experiments. Antibodies that compete with each other can be thought of as binding the same site on the target. This example describes a method of determining competition for binding to TSLP and the results of the method when applied to a number of antibodies described herein.

[0254] Binning experiments can be conducted in a number of ways, and the method employed may have an effect on the assay results. Common to these methods is that TSLP is typically bound by one reference antibody and probed by another. If the reference antibody prevents the binding of the probe antibody then the antibodies are said to be in the same bin. The order in which the antibodies are employed is important. If antibody A is employed as the reference antibody and blocks the binding of antibody B the converse is not always true: antibody B used as the reference antibody will not necessarily block antibody A. There are a number of factors in play here: the binding of an antibody can cause conformational changes in the target which prevent the binding of the second antibody, or epitopes which overlap but do not completely occlude each other may allow for the second antibody to still have enough high-affinity interactions with the target to allow binding. Antibodies with a much higher affinity may have a greater ability to bump a blocking antibody out of the way. In general, if competition is observed in either order the antibodies are said to bin together, and if both antibodies can block each other then it is likely that the epitopes overlap more completely.

[0255] For this Example, a modification of the Multiplexed Binning method described by Jia, et al (J. Immunological Methods, 288 (2004) 91-98) was used. Because the presence of a furin cleavage site within TSLP can lead to heterogeneity of TSLP protein preps, a TSLP having the arginine within the furin cleavage site mutated to alanine was used. See U.S. Pat. No. 7,288,633. Each Bead Code of streptavidin-coated LUMINEX beads (Luminex, #L100-L1XX-01, XX specifies the bead code) was incubated in 100 ul of 6 pg/bead biotinylated monovalent mouse-anti-human IgG capture antibody (BD Pharmingen, #555785) for 1 hour at room temperature in the dark, then washed 3.times. with PBSA, phosphate buffered saline (PBS) plus 1% bovine serum albumin (BSA). Each bead code was separately incubated with 100 ul of a 1:10 dilution anti-TSLP antibody (Coating Antibody) for 1 hour then washed. The beads were pooled then dispensed to a 96-well filter plate (Millipore, #MSBVN1250). 100ul of 2ug/ml parental TSLP was added to half the wells and buffer to the other half and incubated for 1 hour then washed. 100 ul of a 1:10 dilution anti-TSLP antibody (Detection Ab) was added to one well with TSLP and one well without TSLP, incubated for 1 hour then washed. An irrelevant human-IgG (Jackson, #009-000-003) as well as a no antibody condition (blank) were run as negative controls. 20 ul PE-conjugated monovalent mouse-anti-human IgG (BD Pharmingen, #555787) was added to each well and incubated for 1 hour then washed. Beads were resuspended in 75 ul PBSA and at least 100 events/bead code were collected on the BIOPLEX instrument (BioRad).

[0256] Median Fluorescent Intensity (MFI) of the antibody pair without TSLP was subtracted from signal of the corresponding reaction containing TSLP. For the antibody pair to be considered bound simultaneously, and therefore in different bins, the value of the reaction had to meet two criteria: 1) the values had to be 2 times greater than the coating antibody paired with itself, the irrelevant or the blank, whichever was highest, and 2) the values had to be greater than the signal of the detection antibody present with the irrelevant or the blank coated bead.

[0257] Analysis of competition between the antibodies was complicated by the fact that there was an incongruity between the performance of antibodies as probes versus their performance as blockers. However, if one considers only those bins of antibodies that are unambiguous (i.e. each antibody will block the others when used as a reference) a minimum of eight bins were found as shown in Table 4 below.

TABLE-US-00006 TABLE 4 Bin 1 2 3 4 5 6 7 8 A5 A6 A27 A24 A10 A4 A2 A23 A17 A7 A11 A12 A26 A23 A21 A6 A6 A11 A24 A10 A4 A23 A26

[0258] It is notable that some antibodies, such as A23 and A6, are found in multiple bins. It is possible to determine other binning relationships, and the inclusion or exclusion of antibodies from these bins was biased towards exclusion.

[0259] The results of the assay determined which of the other antibodies cross-compete for binding with the reference antibody. By "cross-competes for binding" it is meant that the reference antibody when used as the blocking antibody is able to block binding of the other antibody when used as a probe and vice versa. In other words, if the reference antibody was able to block the other antibody but the other antibody was not able to block the reference antibody, the antibodies were not said to cross-compete. A list of cross-competing antibodies is provided in Table 5.

TABLE-US-00007 TABLE 5 Reference Exemplary Cross- Antibody Competing Antibodies A2 A21, A23 A4 A10, A23, A26 A5 A6, A8, A11, A17 A6 A5, A7, A8, A11, A17, A23 A7 A6, A8, A11, A17 A8 A5, A6, A7, A17, A23 A10 A4, A12, A24, A26 A11 A5, A6, A7, A17, A24, A27 A12 A10, A24, A26 A17 A5, A6, A7, A8, A11 A21 A2, A23, A27 A23 A2, A4, A6, A8, A21 A24 A10, A11, A12, A26, A27 A26 A4, A10, A12, A24 A27 A11, A21, A24

EXAMPLE 9

Epitope Mapping

[0260] While epitopes are often thought of as linear sequences, it is more often the case that an antibody recognizes a face of the target which is composed of discontinuous amino acids. These amino acids may be far apart on the linear sequence but brought close together through the folding of the target, and antibodies which recognize such an epitope are known as conformation-sensitive or just conformational antibodies. This kind of binding may be defined through the use of denatured Western blots, wherein prior to running on a gel the target is heated in the presence of detergent and reducing agent to unfold it. The blot from this gel may then be probed by antibodies, and an antibody which is able to recognize the target after this treatment probably recognizes a linear epitope. Although the epitopes of antibodies which bind linear sequences may be defined through binding to peptides (e.g. PepSpot), conformational antibodies would not be expected to bind standard peptides with high affinity.

[0261] Reduced, heat-denatured, purified parental TSLP protein was loaded on 10% Bis-Tris NUPAGE gel in MES SDS Running Buffer. Protein was transferred to PVDF Membrane, blocked with 5% Non-fat Dry Milk (NFDM) in PBS+0.05% Tween (PBST), and incubated with TSLP antibodies for 1 hour at RT. The blots were washed 3.times. in PBST then incubated with a goat anti-huIgG secondary antibody for 1 hour at RT. The blots were washed again and incubated with an anti-goat IgG:Alexa 680. After washing 3.times. in PBST, the blots were scanned on the LiCor to visualize bands.

[0262] Antibodies A2, A4, A5, A6, A7, A10, A21, A23, and A26 were characterized using this method. Antibodies A2, A4, and A5 bound to the linear epitope as evidenced by a strong band on the Western Blot. All other antibodies were conformational as due to no or extremely weak bands on the Western Blot.

[0263] Epitopes may be further defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and consist of those residues which directly contribute to the affinity of the interaction (e.g. hydrogen bonds, ionic interactions). Structural epitopes may be thought of as the patch of the target which is covered by the antibody.

[0264] Scanning mutagenesis was employed to further define the epitopes bound by the antibodies. Alanine scanning mutagenesis is used frequently to define functional epitopes; the substitution of alanine (methyl sidechain) is essentially an amputation of the wild-type amino acid sidechain and is fairly subtle. Interactions with the protein backbone, such as hydrogen bonding to the amide linkages, would likely not be revealed with alanine scanning Instead, arginine and glutamic acid scanning mutagenesis was used. These two sidechains were chosen due to their large steric bulk and their charge, which allows mutations which occur in the structural epitope to have a greater effect on antibody binding. Arginine was generally employed except when the WT reside was arginine or lysine, and in these cases the residue was mutated to glutamic acid to switch the charge. In a few cases, the WT residue was mutated to both arginine and glutamic acid.

[0265] Ninety-five amino acids, distributed throughout TSLP, were selected for mutation to arginine or glutamic acid. As hydrophobic residues are generally found inside the folded core of a protein, the selection was biased towards charged or polar amino acids to reduce the likelihood of the mutation resulting in misfolded protein. As there was no crystal structure, these residues were chosen essentially at random and distributed throughout TSLP. As described in Example 8, a TSLP containing a mutated furin cleavage site was used.

[0266] BIOPLEX.TM. binding assay was used to measure binding anti-TSLP antibodies to mutant TSLP. A biotinylated Penta-His Ab (Qiagen, Lot#: 130163339) was bound onto 100 bead codes of streptavidin-coated beads (Luminex, #L100-L1XX-01, XX specifies the bead code). These were used to capture the his-tagged protein. The 100 bead codes allowed the multiplexing of all 85 mutants, 3 parental controls, an irrelevant protein and 12 blanks. Antibody binding to mutant protein was compared to antibody binding to the parental.

[0267] 100 ul of a 1:5 dilution of the TSLP mutants and parental in supernatant and 1 ug/mL purified TSLP WT, 1 ug/mL irrelevant protein or no protein were bound to the coated beads for 1 hour at RT with vigorous shaking. The beads were washed and aliquoted into a 96-well filter plate (Millipore). 100 ul anti-TSLP antibodies in 4-fold dilutions were added to triplicate wells, incubated for 0.5 hours at RT and washed. 100 ul of 1:250 dilution of PE-conjugated anti-human IgG Fc (Jackson, #109-116-170) was added to each well, incubated for 0.5 hours and washed. Beads were resuspended in 75 uL, shaken for at least 3 mins, and read on the BIOPLEX.TM..

[0268] A residue was considered part of the structural epitope (a "hit") when mutating it to arginine or glutamic acid disrupted antibody binding. This was seen as a shift in the EC50 or a reduction of maximum signal compared to antibody binding to parental TSLP.

[0269] Statistical analyses of antibody binding curves to parental and mutants were used to identify statistically significant EC50 shifts. The analysis took into consideration variation in the assay and curve fitting.

[0270] The EC50s of the mutant binding curves and parental binding curves were compared. Statistically significant differences were identified as hits for further consideration. The curves with "nofit" or "badfit" flags were excluded from this analysis.

[0271] Two sources of variations were considered in the comparison of EC50 estimates, variation from the curve fit and the bead-bead variation. Parental and mutants were linked to different beads, hence their difference were confounded with the bead-bead difference. The curve fit variation was estimated by the standard error of the log EC50 estimates. Bead-bead variation was experimentally determined using an experiment where parental controls were linked to each one of the beads. The bead variation in EC50 estimates of parental binding curve were used to estimate the bead-bead variation.

[0272] The comparisons of two EC50s (in log scale) were conducted using Student's t-test. A t-statistics is calculated as the ratio between delta (the absolute differences between EC50 estimates) and the standard deviation of delta. The variance of delta is estimated by the sum of the three components, variance estimate of EC50 for mutant and parental curves in the nonlinear regression and two times the bead-bead variance estimated from a separate experiment. The multiple of two for the bead-bead variance is due to the assumption that both mutant and parental beads have the same variance.

[0273] The degree of freedom of the standard deviation of delta was calculated using the Satterthwaite's (1946) approximation. Individual p-values and confidence intervals (95% and 99%) were derived based on Student's t distribution for each comparison. In the case of multiple parental controls, a conservative approach was implemented by picking the parental control that was most similar to the mutant, i.e., picking the ones with the largest p-values.

[0274] Multiplicity adjustments were important to control the false positives while conducting a large number of tests simultaneously. Two forms of multiplicity adjustment were implemented for this analysis: family wise error (FWE) control and false discovery rate (FDR) control. The FWE approach controls the probability that one or more hits are not real; FDR approach controls the expected proportion of false positive among the selected hits. The former approach is more conservative and less powerful than the latter one. There are many methods available for both approaches, for this analysis, Hochberg's (1988) method was chosen for FWE analysis and Benjamini-Hochberg's (1995) FDR method for FDR analysis. Adjusted p-values for both approaches were calculated either for each antibody or the whole assay.

[0275] Mutations whose EC50 was significantly different from parental, i.e. having an FWE adjusted p-value for each antibody of less than 0.01, or a maximal signal below 50% of parental were considered part of the structural epitope (Table 6). Mutations that were significant by either EC50 shirt or max signal reduction for all antibodies were considered misfolded. These mutations were; Y15R, T55R, T74R and A77R.

TABLE-US-00008 TABLE 6 Summary of mutations that affect antibody binding in the BIOPLEX and are part of the structural epitope. Antibody Linear Increased Binding Affinity Decreased Binding Afinity A2 Yes K67E, K97E, K98E, K21E, T25R, S28R, S64R, K73E R100E, K101E, K103E A4 Yes K97E, K98E, R100E, K10E, A14R, K21E, D22R, K101E, K103E K73E, K75E, A76R A5 Yes K12E, D22R, S40R, R122E, N124E, R125E, K129E A6 No S40R, S42R, H46R, R122E, K129E A7 No K101E D2R, T4R, D7R, S42R, H46R, T49R, E50R, Q112R, R122E, R125E, K129E A10 No K97E, K98E, R100E, N5R, S17R, T18R, K21E, K101E, K103E D22R, T25R, T33R, H46R, A63R, S64R, A66R, E68R, K73E, K75E, A76R, A92R, T93R, Q94R, A95R A21 No K97E, K98E, R100E, K21E, K21R, D22R, T25R, T33R, K101E, K103E S64R, K73E, K75E, E111R, S114R A23 No K67E, K97E, K98E, E9R, K10E, K12E, A13R, S17R, R100E, K101E, K103E S20R, K21E, K21R, K73E, K75E, N124E,R125E A26 No K97E, K98E, R100E, A14R, K21E, D22R, A63R, S64R, K101E, K103E K67E, K73E, A76R, A92R, A95R

[0276] There were several mutations that disrupted the binding of multiple antibodies, notably K73E, K21E, and D22R. The mutagenesis serves to verify the data generated by binning and to further narrow in on the epitope space. The mutations in TSLP appear to affect clusters of antibodies that bin together.

EXAMPLE 10

Toxicology

[0277] Antibodies that bind human TSLP yet also cross-react with TSLP of other species allow for toxicology testing in those species. In this example, an antibody that cross-reacts with cynomolgus monkey TSLP was administered to cynomolgus monkeys. The monkeys were then observed for toxic effects.

[0278] A single-dose safety pharmacology study in cynomolgus monkeys indicated that a single 300 mg/kg intravenous dose of the antibody had no cardiovascular, respiratory, body temperature, or neurobehavioral effects.

[0279] Cynomolgus monkeys (5/sex/group) were given 30, 100, or 300 mg/kg doses once weekly for 4 weeks, subcutaneously. No adverse toxicology was observed at any dose. The antibody did not affect clinical observations, body weight, ophthalmology, ECGs, clinical pathology or anatomic pathology.

[0280] In a separate study, four male telemeterized cynomolgus monkeys were given a single intravenous dose of vehicle (day 1) and 300 mg/kg antibody (day 3). Over a four day observation period no effects on cardiovascular, respiratory, or neurological function was observed.

[0281] The antibody was further tested to determine cross-reactivity with normal human and cynomolgus monkey tissue as recommended in the FDA guideline "Points to Consider in the Manufacture and Testing of Monoclonal Anitbody Prducts for Human Use" (FDA Center for Biologics Evaluation and Research, 28 Feb. 1997). No staining of normal tissue at 1 or 50 ug/mL was observed.

[0282] The above results suggest that the antibody is not expected to produce toxic effects in humans.

Sequence CWU 1

1

3821743DNAHomo sapiensCDS(200)..(676) 1gcagccagaa agctctggag catcagggag actccaactt aaggcaacag catgggtgaa 60taagggcttc ctgtggactg gcaatgagag gcaaaacctg gtgcttgagc actggcccct 120aaggcaggcc ttacagatct cttacactcg tggtgggaag agtttagtgt gaaactgggg 180tggaattggg tgtccacgt atg ttc cct ttt gcc tta cta tat gtt ctg tca 232 Met Phe Pro Phe Ala Leu Leu Tyr Val Leu Ser 1 5 10gtt tct ttc agg aaa atc ttc atc tta caa ctt gta ggg ctg gtg tta 280Val Ser Phe Arg Lys Ile Phe Ile Leu Gln Leu Val Gly Leu Val Leu 15 20 25act tac gac ttc act aac tgt gac ttt gag aag att aaa gca gcc tat 328Thr Tyr Asp Phe Thr Asn Cys Asp Phe Glu Lys Ile Lys Ala Ala Tyr 30 35 40ctc agt act att tct aaa gac ctg att aca tat atg agt ggg acc aaa 376Leu Ser Thr Ile Ser Lys Asp Leu Ile Thr Tyr Met Ser Gly Thr Lys 45 50 55agt acc gag ttc aac aac acc gtc tct tgt agc aat cgg cca cat tgc 424Ser Thr Glu Phe Asn Asn Thr Val Ser Cys Ser Asn Arg Pro His Cys60 65 70 75ctt act gaa atc cag agc cta acc ttc aat ccc acc gcc ggc tgc gcg 472Leu Thr Glu Ile Gln Ser Leu Thr Phe Asn Pro Thr Ala Gly Cys Ala 80 85 90tcg ctc gcc aaa gaa atg ttc gcc atg aaa act aag gct gcc tta gct 520Ser Leu Ala Lys Glu Met Phe Ala Met Lys Thr Lys Ala Ala Leu Ala 95 100 105atc tgg tgc cca ggc tat tcg gaa act cag ata aat gct act cag gca 568Ile Trp Cys Pro Gly Tyr Ser Glu Thr Gln Ile Asn Ala Thr Gln Ala 110 115 120atg aag aag agg aga aaa agg aaa gtc aca acc aat aaa tgt ctg gaa 616Met Lys Lys Arg Arg Lys Arg Lys Val Thr Thr Asn Lys Cys Leu Glu 125 130 135caa gtg tca caa tta caa gga ttg tgg cgt cgc ttc aat cga cct tta 664Gln Val Ser Gln Leu Gln Gly Leu Trp Arg Arg Phe Asn Arg Pro Leu140 145 150 155ctg aaa caa cag taaaccatct ttattatggt catatttcac agcccaaaat 716Leu Lys Gln Glnaaatcatctt tattaagtaa aaaaaaa 7432159PRTHomo sapiens 2Met Phe Pro Phe Ala Leu Leu Tyr Val Leu Ser Val Ser Phe Arg Lys1 5 10 15Ile Phe Ile Leu Gln Leu Val Gly Leu Val Leu Thr Tyr Asp Phe Thr 20 25 30Asn Cys Asp Phe Glu Lys Ile Lys Ala Ala Tyr Leu Ser Thr Ile Ser 35 40 45Lys Asp Leu Ile Thr Tyr Met Ser Gly Thr Lys Ser Thr Glu Phe Asn 50 55 60Asn Thr Val Ser Cys Ser Asn Arg Pro His Cys Leu Thr Glu Ile Gln65 70 75 80Ser Leu Thr Phe Asn Pro Thr Ala Gly Cys Ala Ser Leu Ala Lys Glu 85 90 95Met Phe Ala Met Lys Thr Lys Ala Ala Leu Ala Ile Trp Cys Pro Gly 100 105 110Tyr Ser Glu Thr Gln Ile Asn Ala Thr Gln Ala Met Lys Lys Arg Arg 115 120 125Lys Arg Lys Val Thr Thr Asn Lys Cys Leu Glu Gln Val Ser Gln Leu 130 135 140Gln Gly Leu Trp Arg Arg Phe Asn Arg Pro Leu Leu Lys Gln Gln145 150 15531116DNAHomo sapiensCDS(1)..(1116) 3atg ggg cgg ctg gtt ctg ctg tgg gga gct gcc gtc ttt ctg ctg gga 48Met Gly Arg Leu Val Leu Leu Trp Gly Ala Ala Val Phe Leu Leu Gly1 5 10 15ggc tgg atg gct ttg ggg caa gga gga gca gca gaa gga gta cag att 96Gly Trp Met Ala Leu Gly Gln Gly Gly Ala Ala Glu Gly Val Gln Ile 20 25 30cag atc atc tac ttc aat tta gaa acc gtg cag gtg aca tgg aat gcc 144Gln Ile Ile Tyr Phe Asn Leu Glu Thr Val Gln Val Thr Trp Asn Ala 35 40 45agc aaa tac tcc agg acc aac ctg act ttc cac tac aga ttc aac ggt 192Ser Lys Tyr Ser Arg Thr Asn Leu Thr Phe His Tyr Arg Phe Asn Gly 50 55 60gat gag gcc tat gac cag tgc acc aac tac ctt ctc cag gaa ggt cac 240Asp Glu Ala Tyr Asp Gln Cys Thr Asn Tyr Leu Leu Gln Glu Gly His65 70 75 80act tca ggg tgc ctc cta gac gca gag cag cga gac gac att ctc tat 288Thr Ser Gly Cys Leu Leu Asp Ala Glu Gln Arg Asp Asp Ile Leu Tyr 85 90 95ttc tcc atc agg aat ggg acg cac ccc gtt ttc acc gca agt cgc tgg 336Phe Ser Ile Arg Asn Gly Thr His Pro Val Phe Thr Ala Ser Arg Trp 100 105 110atg gtt tat tac ctg aaa ccc agt tcc ccg aag cac gtg aga ttt tcg 384Met Val Tyr Tyr Leu Lys Pro Ser Ser Pro Lys His Val Arg Phe Ser 115 120 125tgg cat cag gat gca gtg acg gtg acg tgt tct gac ctg tcc tac ggg 432Trp His Gln Asp Ala Val Thr Val Thr Cys Ser Asp Leu Ser Tyr Gly 130 135 140gat ctc ctc tat gag gtt cag tac cgg agc ccc ttc gac acc gag tgg 480Asp Leu Leu Tyr Glu Val Gln Tyr Arg Ser Pro Phe Asp Thr Glu Trp145 150 155 160cag tcc aaa cag gaa aat acc tgc aac gtc acc ata gaa ggc ttg gat 528Gln Ser Lys Gln Glu Asn Thr Cys Asn Val Thr Ile Glu Gly Leu Asp 165 170 175gcc gag aag tgt tac tct ttc tgg gtc agg gtg aag gct atg gag gat 576Ala Glu Lys Cys Tyr Ser Phe Trp Val Arg Val Lys Ala Met Glu Asp 180 185 190gta tat ggg cca gac aca tac cca agc gac tgg tca gag gtg aca tgc 624Val Tyr Gly Pro Asp Thr Tyr Pro Ser Asp Trp Ser Glu Val Thr Cys 195 200 205tgg cag aga ggc gag att cgg gat gcc tgt gca gag aca cca acg cct 672Trp Gln Arg Gly Glu Ile Arg Asp Ala Cys Ala Glu Thr Pro Thr Pro 210 215 220ccc aaa cca aag ctg tcc aaa ttt att tta att tcc agc ctg gcc atc 720Pro Lys Pro Lys Leu Ser Lys Phe Ile Leu Ile Ser Ser Leu Ala Ile225 230 235 240ctt ctg atg gtg tct ctc ctc ctt ctg tct tta tgg aaa tta tgg aga 768Leu Leu Met Val Ser Leu Leu Leu Leu Ser Leu Trp Lys Leu Trp Arg 245 250 255gtg aag aag ttt ctc att ccc agc gtg cca gac ccg aaa tcc atc ttc 816Val Lys Lys Phe Leu Ile Pro Ser Val Pro Asp Pro Lys Ser Ile Phe 260 265 270ccc ggg ctc ttt gag ata cac caa ggg aac ttc cag gag tgg atc aca 864Pro Gly Leu Phe Glu Ile His Gln Gly Asn Phe Gln Glu Trp Ile Thr 275 280 285gac acc cag aac gtg gcc cac ctc cac aag atg gca ggt gca gag caa 912Asp Thr Gln Asn Val Ala His Leu His Lys Met Ala Gly Ala Glu Gln 290 295 300gaa agt ggc ccc gag gag ccc ctg gta gtc cag ttg gcc aag act gaa 960Glu Ser Gly Pro Glu Glu Pro Leu Val Val Gln Leu Ala Lys Thr Glu305 310 315 320gcc gag tct ccc agg atg ctg gac cca cag acc gag gag aaa gag gcc 1008Ala Glu Ser Pro Arg Met Leu Asp Pro Gln Thr Glu Glu Lys Glu Ala 325 330 335tct ggg gga tcc ctc cag ctt ccc cac cag ccc ctc caa ggc ggt gat 1056Ser Gly Gly Ser Leu Gln Leu Pro His Gln Pro Leu Gln Gly Gly Asp 340 345 350gtg gtc aca atc ggg ggc ttc acc ttt gtg atg aat gac cgc tcc tac 1104Val Val Thr Ile Gly Gly Phe Thr Phe Val Met Asn Asp Arg Ser Tyr 355 360 365gtg gcg ttg tga 1116Val Ala Leu 3704371PRTHomo sapiens 4Met Gly Arg Leu Val Leu Leu Trp Gly Ala Ala Val Phe Leu Leu Gly1 5 10 15Gly Trp Met Ala Leu Gly Gln Gly Gly Ala Ala Glu Gly Val Gln Ile 20 25 30Gln Ile Ile Tyr Phe Asn Leu Glu Thr Val Gln Val Thr Trp Asn Ala 35 40 45Ser Lys Tyr Ser Arg Thr Asn Leu Thr Phe His Tyr Arg Phe Asn Gly 50 55 60Asp Glu Ala Tyr Asp Gln Cys Thr Asn Tyr Leu Leu Gln Glu Gly His65 70 75 80Thr Ser Gly Cys Leu Leu Asp Ala Glu Gln Arg Asp Asp Ile Leu Tyr 85 90 95Phe Ser Ile Arg Asn Gly Thr His Pro Val Phe Thr Ala Ser Arg Trp 100 105 110Met Val Tyr Tyr Leu Lys Pro Ser Ser Pro Lys His Val Arg Phe Ser 115 120 125Trp His Gln Asp Ala Val Thr Val Thr Cys Ser Asp Leu Ser Tyr Gly 130 135 140Asp Leu Leu Tyr Glu Val Gln Tyr Arg Ser Pro Phe Asp Thr Glu Trp145 150 155 160Gln Ser Lys Gln Glu Asn Thr Cys Asn Val Thr Ile Glu Gly Leu Asp 165 170 175Ala Glu Lys Cys Tyr Ser Phe Trp Val Arg Val Lys Ala Met Glu Asp 180 185 190Val Tyr Gly Pro Asp Thr Tyr Pro Ser Asp Trp Ser Glu Val Thr Cys 195 200 205Trp Gln Arg Gly Glu Ile Arg Asp Ala Cys Ala Glu Thr Pro Thr Pro 210 215 220Pro Lys Pro Lys Leu Ser Lys Phe Ile Leu Ile Ser Ser Leu Ala Ile225 230 235 240Leu Leu Met Val Ser Leu Leu Leu Leu Ser Leu Trp Lys Leu Trp Arg 245 250 255Val Lys Lys Phe Leu Ile Pro Ser Val Pro Asp Pro Lys Ser Ile Phe 260 265 270Pro Gly Leu Phe Glu Ile His Gln Gly Asn Phe Gln Glu Trp Ile Thr 275 280 285Asp Thr Gln Asn Val Ala His Leu His Lys Met Ala Gly Ala Glu Gln 290 295 300Glu Ser Gly Pro Glu Glu Pro Leu Val Val Gln Leu Ala Lys Thr Glu305 310 315 320Ala Glu Ser Pro Arg Met Leu Asp Pro Gln Thr Glu Glu Lys Glu Ala 325 330 335Ser Gly Gly Ser Leu Gln Leu Pro His Gln Pro Leu Gln Gly Gly Asp 340 345 350Val Val Thr Ile Gly Gly Phe Thr Phe Val Met Asn Asp Arg Ser Tyr 355 360 365Val Ala Leu 370533DNAHomo sapiens 5caaggagaca gcctcagaag ctattatgca agc 33611PRTHomo sapiens 6Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser1 5 10733DNAHomo sapiens 7caaggagaca gcctcagaac ctattatgca agc 33811PRTHomo sapiens 8Gln Gly Asp Ser Leu Arg Thr Tyr Tyr Ala Ser1 5 10942DNAHomo sapiens 9actgggagca gctccaacat cggggcaggt tttgatgtac ac 421014PRTHomo sapiens 10Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Phe Asp Val His1 5 101142DNAHomo sapiens 11actgggagca gctccaacat cggggcaggt tttgatgtgc ac 421233DNAHomo sapiens 12gggggaaaca accttggaag taaaagtgtg cac 331311PRTHomo sapiens 13Gly Gly Asn Asn Leu Gly Ser Lys Ser Val His1 5 101433DNAHomo sapiens 14tctggagata aattggggga taaatatgct tgc 331511PRTHomo sapiens 15Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Cys1 5 101633DNAHomo sapiens 16caaggagaca gcctcagaat cttttatgca aac 331711PRTHomo sapiens 17Gln Gly Asp Ser Leu Arg Ile Phe Tyr Ala Asn1 5 101833DNAHomo sapiens 18cgggcaaatc agtacattag cacctattta aat 331911PRTHomo sapiens 19Arg Ala Asn Gln Tyr Ile Ser Thr Tyr Leu Asn1 5 102051DNAHomo sapiens 20aagtccagcc agagtgtttt aaacagctcc aacaataaga actacttagc t 512117PRTHomo sapiens 21Lys Ser Ser Gln Ser Val Leu Asn Ser Ser Asn Asn Lys Asn Tyr Leu1 5 10 15Ala2233DNAHomo sapiens 22cgggcgagtc agggtattag tagctggtta gcc 332311PRTHomo sapiens 23Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala1 5 102448DNAHomo sapiens 24aggtctagtc aaagcctcgt ctacagtgat ggagacacct acttgaat 482516PRTHomo sapiens 25Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asp Thr Tyr Leu Asn1 5 10 152633DNAHomo sapiens 26cgggcgagtc agggtcttag cagctggtta gcc 332711PRTHomo sapiens 27Arg Ala Ser Gln Gly Leu Ser Ser Trp Leu Ala1 5 102848DNAHomo sapiens 28aggtctagtc aaagcctcgt ctacagtgat ggaaacacct acttgaat 482916PRTHomo sapiens 29Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn1 5 10 153048DNAHomo sapiens 30aggtctagtc aaagcctcat atacagtgat ggaaacactt acttgaat 483116PRTHomo sapiens 31Arg Ser Ser Gln Ser Leu Ile Tyr Ser Asp Gly Asn Thr Tyr Leu Asn1 5 10 153248DNAHomo sapiens 32aggtctagtc aaagcctcgt atacagtgat ggaaacacct acttgaat 483316PRTHomo sapiens 33Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn1 5 10 153433DNAHomo sapiens 34cgggcgagtc agagtcttag cagctggtta gcc 333511PRTHomo sapiens 35Arg Ala Ser Gln Ser Leu Ser Ser Trp Leu Ala1 5 103642DNAHomo sapiens 36ggcttgaact ctggctcagt ctctactagt tacttcccca gc 423714PRTHomo sapiens 37Gly Leu Asn Ser Gly Ser Val Ser Thr Ser Tyr Phe Pro Ser1 5 103848DNAHomo sapiens 38aggtctagtc aaagcctcgt ctacagtgat ggagacacct acttgaat 483916PRTHomo sapiens 39Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asp Thr Tyr Leu Asn1 5 10 154042DNAHomo sapiens 40actgggagca gctccaacat tggggcgggt tatgttgtac at 424114PRTHomo sapiens 41Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Val Val His1 5 104251DNAHomo sapiens 42aagtccagcc agagtgtttt atacaactcc aacaataaga actacttagc t 514317PRTHomo sapiens 43Lys Ser Ser Gln Ser Val Leu Tyr Asn Ser Asn Asn Lys Asn Tyr Leu1 5 10 15Ala4433DNAHomo sapiens 44tctggtgata aattggggga taaatttgct ttc 334511PRTHomo sapiens 45Ser Gly Asp Lys Leu Gly Asp Lys Phe Ala Phe1 5 104633DNAHomo sapiens 46caaggagaca gcctcagaag ctatcatgca agc 334711PRTHomo sapiens 47Gln Gly Asp Ser Leu Arg Ser Tyr His Ala Ser1 5 104833DNAHomo sapiens 48tctggagata atttggggga taaatatatt tgc 334911PRTHomo sapiens 49Ser Gly Asp Asn Leu Gly Asp Lys Tyr Ile Cys1 5 105033DNAHomo sapiens 50tctggagata aattggggga aagctatgct tgc 335111PRTHomo sapiens 51Ser Gly Asp Lys Leu Gly Glu Ser Tyr Ala Cys1 5 105221DNAHomo sapiens 52ggtaaaaact accggccctc a 21537PRTHomo sapiens 53Gly Lys Asn Tyr Arg Pro Ser1 55421DNAHomo sapiens 54gataaaaaca accggccctc a 21557PRTHomo sapiens 55Asp Lys Asn Asn Arg Pro Ser1 55621DNAHomo sapiens 56gataacaaca atcggccctc a 21577PRTHomo sapiens 57Asp Asn Asn Asn Arg Pro Ser1 55821DNAHomo sapiens 58gataacaaca atcgcccctc a 215921DNAHomo sapiens 59gatgatagcg accggccctc a 21607PRTHomo sapiens 60Asp Asp Ser Asp Arg Pro Ser1 56121DNAHomo sapiens 61caagataaga agcggccctc a 21627PRTHomo sapiens 62Gln Asp Lys Lys Arg Pro Ser1 56321DNAHomo sapiens 63caagataaca agcggccctc a 21648PRTHomo sapiens 64Gln Lys Asn Lys Pro Arg Pro Ser1 5657PRTHomo sapiens 65Gln Asp Asn Lys Arg Pro Ser1 56621DNAHomo sapiens 66ggtaaaaaca accggccctc a 21677PRTHomo sapiens 67Gly Lys Asn Asn Arg Pro Ser1 56821DNAHomo sapiens 68gctgcatcca gtttgcaaag t 21697PRTHomo sapiens 69Ala Ala Ser Ser Leu Gln Ser1 57021DNAHomo sapiens 70tggacatcca cccgggaagg c 21717PRTHomo sapiens 71Trp Thr Ser Thr Arg Glu Gly1 57221DNAHomo sapiens 72actgcatcca gtttgcaaag t 21737PRTHomo sapiens 73Thr Ala Ser Ser Leu Gln Ser1 57421DNAHomo sapiens 74aaggtttcta actgggactc t 21757PRTHomo sapiens 75Lys Val Ser Asn Trp Asp Ser1 57621DNAHomo sapiens 76aacacatcca gtttgcaaag t 21777PRTHomo sapiens 77Asn Thr Ser Ser Leu Gln Ser1 57821DNAHomo sapiens 78actacatcca gtttgcaaag t 21797PRTHomo sapiens 79Thr Thr Ser Ser Leu Gln Ser1 58021DNAHomo sapiens 80aaggtttctt actgggactc t 21817PRTHomo sapiens 81Lys Val Ser Tyr Trp Asp Ser1 58221DNAHomo sapiens 82aatgcatcca gtttgcaaag t 21837PRTHomo sapiens 83Asn Ala Ser Ser Leu

Gln Ser1 58421DNAHomo sapiens 84agcacaaaca gtcgctcttc t 21857PRTHomo sapiens 85Ser Thr Asn Ser Pro Ser Ser1 5867PRTHomo sapiens 86Asn Thr Ser Ser Lys Gln Ser1 58721DNAHomo sapiens 87ggtaacagca atcggccctc a 21887PRTHomo sapiens 88Gly Asn Ser Asn Arg Pro Ser1 58921DNAHomo sapiens 89tgggcttcta cccgggaatc c 21907PRTHomo sapiens 90Trp Ala Ser Thr Arg Glu Ser1 59121DNAHomo sapiens 91caagatagca agcggccctc a 21927PRTHomo sapiens 92Gln Asp Ser Lys Arg Pro Ser1 59321DNAHomo sapiens 93ggtgaaaaca accggccctc a 21947PRTHomo sapiens 94Gly Glu Asn Asn Arg Pro Ser1 59521DNAHomo sapiens 95caagattaca agcggccctc a 21967PRTHomo sapiens 96Gln Asp Tyr Lys Arg Pro Ser1 59735DNAHomo sapiens 97aactcccggg acagaagtgg taaccatctg gtgtt 359811PRTHomo sapiens 98Asn Ser Arg Asp Arg Ser Gly Asn His Leu Val1 5 109937DNAHomo sapiens 99aactcccggg acagcagtga taaccatcta gtggtat 3710012PRTHomo sapiens 100Asn Ser Arg Asp Ser Ser Asp Asn His Leu Val Val1 5 1010140DNAHomo sapiens 101cagtcctatg acagcaacct gagtggttcg attgtggttt 4010213PRTHomo sapiens 102Gln Ser Tyr Asp Ser Asn Leu Ser Gly Ser Ile Val Val1 5 1010340DNAHomo sapiens 103cagtcctatg acagcaacct gagtggttcg attgtggtat 4010434DNAHomo sapiens 104caggtgtggg atagtagtag tgatcatgtg gtat 3410511PRTHomo sapiens 105Gln Val Trp Asp Ser Ser Ser Asp His Val Val1 5 1010628DNAHomo sapiens 106caggcgtggg acagcagcac tgtggtat 281079PRTHomo sapiens 107Gln Ala Trp Asp Ser Ser Thr Val Val1 510828DNAHomo sapiens 108caggcgtggg acagcaccac tgcgatat 281099PRTHomo sapiens 109Gln Ala Trp Asp Ser Thr Thr Ala Ile1 511034DNAHomo sapiens 110aactcccggg acagcagtgg taaccatgtg gtat 3411111PRTHomo sapiens 111Asn Ser Arg Asp Ser Ser Gly Asn His Val Val1 5 1011228DNAHomo sapiens 112cagcagagct acactacccc gatcacct 281139PRTHomo sapiens 113Gln Gln Ser Tyr Thr Thr Pro Ile Thr1 511428DNAHomo sapiens 114cagcagtatt ttactactcc gtggacgt 281159PRTHomo sapiens 115Gln Gln Tyr Phe Thr Thr Pro Trp Thr1 511628DNAHomo sapiens 116caacaggctg acagtttccc gctcactt 281179PRTHomo sapiens 117Gln Gln Ala Asp Ser Phe Pro Leu Thr1 511828DNAHomo sapiens 118atgcaaggta cacactggcc tccggcct 281199PRTHomo sapiens 119Met Gln Gly Thr His Trp Pro Pro Ala1 512028DNAHomo sapiens 120caacaggcta acagtttccc tctcactt 281219PRTHomo sapiens 121Gln Gln Ala Asn Ser Phe Pro Leu Thr1 512227DNAHomo sapiens 122atgcaaggta cacactggcc tccggcc 2712328DNAHomo sapiens 123caacaggctg acagtttccc tctcactt 2812431DNAHomo sapiens 124gtgctgtata tgggtagagg catttgggtg t 3112510PRTHomo sapiens 125Val Leu Tyr Met Gly Arg Gly Ile Trp Val1 5 1012637DNAHomo sapiens 126aaagcatggg ataacagcct gaatgctcaa ggggtat 3712712PRTHomo sapiens 127Lys Ala Trp Asp Asn Ser Leu Asn Ala Gln Gly Val1 5 1012828DNAHomo sapiens 128cagcaatttt atggtcctcc tctcactt 281299PRTHomo sapiens 129Gln Gln Phe Tyr Gly Pro Pro Leu Thr1 513030DNAHomo sapiens 130caggcgtggg acagcagcgc cgggggggta 3013110PRTHomo sapiens 131Gln Ala Trp Asp Ser Ser Ala Gly Gly Val1 5 1013234DNAHomo sapiens 132aattatcggg acaacagtgg taaccatctg gtgt 3413311PRTHomo sapiens 133Asn Tyr Arg Asp Asn Ser Gly Asn His Leu Val1 5 1013428DNAHomo sapiens 134caggcgtggg acagaagtac tgtactat 281359PRTHomo sapiens 135Gln Ala Trp Asp Arg Ser Thr Val Leu1 513615DNAHomo sapiens 136aactatggca tgcac 151375PRTHomo sapiens 137Asn Tyr Gly Met His1 513815DNAHomo sapiens 138gattttacca tgcac 151395PRTHomo sapiens 139Asp Phe Thr Met His1 514015DNAHomo sapiens 140gactactata tgtac 151415PRTHomo sapiens 141Asp Tyr Tyr Met Tyr1 514215DNAHomo sapiens 142ggcgactata tgcac 151435PRTHomo sapiens 143Gly Asp Tyr Met His1 514415DNAHomo sapiens 144acctatggca tgcac 151455PRTHomo sapiens 145Thr Tyr Gly Met His1 514615DNAHomo sapiens 146agctatggca ttcac 151475PRTHomo sapiens 147Ser Tyr Gly Ile His1 514821DNAHomo sapiens 148agtggtggtt actactggag c 211497PRTHomo sapiens 149Ser Gly Gly Tyr Tyr Trp Ser1 515015DNAHomo sapiens 150agctatggca tgcac 151515PRTHomo sapiens 151Ser Tyr Gly Met His1 515215DNAHomo sapiens 152agttatggca tgcac 1515315DNAHomo sapiens 153agttatagca tgaac 151545PRTHomo sapiens 154Ser Tyr Ser Met Asn1 515515DNAHomo sapiens 155agttatggca tgctc 151565PRTHomo sapiens 156Ser Tyr Gly Met Leu1 515715DNAHomo sapiens 157agctatgcca tgagc 151585PRTHomo sapiens 158Ser Tyr Ala Met Ser1 515915DNAHomo sapiens 159ggctatgtca tgact 151605PRTHomo sapiens 160Gly Tyr Val Met Thr1 516115DNAHomo sapiens 161ggctactata tgcac 151625PRTHomo sapiens 162Gly Tyr Tyr Met His1 51635PRTHomo sapiens 163Asp Phe Thr Met His1 516451DNAHomo sapiens 164gttatatggt atgatggaag taataaatac tatgcagact ccgtgaaggg c 5116517PRTHomo sapiens 165Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly16651DNAHomo sapiens 166cttattagtt gggatggtgg tagcacatac tatgcagact ctgtgaaggg c 5116717PRTHomo sapiens 167Leu Ile Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly16851DNAHomo sapiens 168tggatcaacc ctaacagtgg tggcacaaac tatgtacaga agtttcaggg c 5116917PRTHomo sapiens 169Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Val Gln Lys Phe Gln1 5 10 15Gly17051DNAHomo sapiens 170tggatcaacc ctaacagtgg tggcacaaac catgcacgga agtttcaggg c 5117117PRTHomo sapiens 171Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn His Ala Arg Lys Phe Gln1 5 10 15Gly17251DNAHomo sapiens 172gttatatggt atgatggaag taataaacac tatgcagact ccgtgaaggg c 5117317PRTHomo sapiens 173Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala Asp Ser Val Lys1 5 10 15Gly17451DNAHomo sapiens 174gttatatcat atgatggaag ttataaatac tatgcagact ccgtgaaggg c 5117517PRTHomo sapiens 175Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly17648DNAHomo sapiens 176ttcatccatt acagtgggac cacctactac aacccgtccc tcaagagt 4817716PRTHomo sapiens 177Phe Ile His Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 1517851DNAHomo sapiens 178gttatatcat atgatggaag taataaatac tatgcagact ccgtgaaggg c 5117917PRTHomo sapiens 179Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly18051DNAHomo sapiens 180gttatatggt atgatggaag taatacatac tatgcagact ccgtgaaggg c 5118117PRTHomo sapiens 181Val Ile Trp Tyr Asp Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly18251DNAHomo sapiens 182gttatatggt atgatggaag tagtaaatac tatgcagact ccgtgaaggg c 5118317PRTHomo sapiens 183Val Ile Trp Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly18451DNAHomo sapiens 184tacattagtg gtcgtactag tagcgtatac tacgcagact ctgtgaaggg c 5118517PRTHomo sapiens 185Tyr Ile Ser Gly Arg Thr Ser Ser Val Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly18651DNAHomo sapiens 186gttatatggt ttgatggaag taataaatac tatgcggact ccgtgaaggg c 5118717PRTHomo sapiens 187Val Ile Trp Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly18851DNAHomo sapiens 188gttttatggt ttgatggaag ttataaaaac tatgcagact ccgtgaaggg c 5118917PRTHomo sapiens 189Val Leu Trp Phe Asp Gly Ser Tyr Lys Asn Tyr Ala Asp Ser Val Lys1 5 10 15Gly19051DNAHomo sapiens 190gcaattagtg gtagtggtgg aagtacacac tacgcagact ccgtgaaggg c 5119117PRTHomo sapiens 191Ala Ile Ser Gly Ser Gly Gly Ser Thr His Tyr Ala Asp Ser Val Lys1 5 10 15Gly19251DNAHomo sapiens 192ggaattagtg gtagtggtgg tagcacatac tacgcagact ccgtgaaggg c 5119317PRTHomo sapiens 193Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly19451DNAHomo sapiens 194tggatcaacc ctaacaatgg tggcacaaac tatggacaga agtttcaggg c 5119517PRTHomo sapiens 195Trp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Gly Gln Lys Phe Gln1 5 10 15Gly19651DNAHomo sapiens 196gttatatggt atgatggaag taataaatac tatgtagact ccgtgaaggg c 5119717PRTHomo sapiens 197Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val Lys1 5 10 15Gly19851DNAHomo sapiens 198gctattagtc gtagtggtag taccacatac tacgcagact ccgtgaaggg c 5119917PRTHomo sapiens 199Ala Ile Ser Arg Ser Gly Ser Thr Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly20051DNAHomo sapiens 200gttaaatggt atgaaggaag taataaatac tatggagact ccgtgaaggg c 5120151DNAHomo sapiens 201gctattagtt atagtggcgg tagcacatac tacgcaggct ccgtgaaggg c 5120217PRTHomo sapiens 202Ala Ile Ser Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Gly Ser Val Lys1 5 10 15Gly20336DNAHomo sapiens 203ctagtgggag ctaccaacta ctacggtatg gacgtc 3620412PRTHomo sapiens 204Leu Val Gly Ala Thr Asn Tyr Tyr Gly Met Asp Val1 5 1020530DNAHomo sapiens 205ccttactact acttctacgg tatggacgtc 3020610PRTHomo sapiens 206Pro Tyr Tyr Tyr Phe Tyr Gly Met Asp Val1 5 1020736DNAHomo sapiens 207gatgggggta gcagtggctg gcccctcttt gcctac 3620812PRTHomo sapiens 208Asp Gly Gly Ser Ser Gly Trp Pro Leu Phe Ala Tyr1 5 1020936DNAHomo sapiens 209gataggggta ccagtggctg gccactcttt gactat 3621012PRTHomo sapiens 210Asp Arg Gly Thr Ser Gly Trp Pro Leu Phe Asp Tyr1 5 1021139DNAHomo sapiens 211gcccctcagt gggagctagt tcatgaagct tttgatatc 3921213PRTHomo sapiens 212Ala Pro Gln Trp Glu Leu Val His Glu Ala Phe Asp Ile1 5 1021351DNAHomo sapiens 213ggggactcct ggaacgacag attaaactac tacttctacg atatggacgt c 5121417PRTHomo sapiens 214Gly Asp Ser Trp Asn Asp Arg Leu Asn Tyr Tyr Phe Tyr Asp Met Asp1 5 10 15Val21536DNAHomo sapiens 215gaagttggca gctcgtcggg taactggttc gacccc 3621612PRTHomo sapiens 216Glu Val Gly Ser Ser Ser Gly Asn Trp Phe Asp Pro1 5 1021745DNAHomo sapiens 217gaggtccggg cgtatagcag tggctggtac gccgcctttg actac 4521815PRTHomo sapiens 218Glu Val Arg Ala Tyr Ser Ser Gly Trp Tyr Ala Ala Phe Asp Tyr1 5 10 1521948DNAHomo sapiens 219gtaagaagtg ggagctacta cgaacagtat tactacggta tggacgtc 4822016PRTHomo sapiens 220Val Arg Ser Gly Ser Tyr Tyr Glu Gln Tyr Tyr Tyr Gly Met Asp Val1 5 10 1522136DNAHomo sapiens 221agtgggatct actacgacta ctacggtatg gacgtc 3622212PRTHomo sapiens 222Ser Gly Ile Tyr Tyr Asp Tyr Tyr Gly Met Asp Val1 5 1022348DNAHomo sapiens 223ggggcagcca ctgctataga ttactactac tcctacggta tggacgtc 4822416PRTHomo sapiens 224Gly Ala Ala Thr Ala Ile Asp Tyr Tyr Tyr Ser Tyr Gly Met Asp Val1 5 10 1522548DNAHomo sapiens 225ggggggggta taccagtagc tgactactac tactacggta tggacgtc 4822616PRTHomo sapiens 226Gly Gly Gly Ile Pro Val Ala Asp Tyr Tyr Tyr Tyr Gly Met Asp Val1 5 10 1522748DNAHomo sapiens 227ggggggggta tagcagtggc tgactactac ttctacggta tggacgtc 4822816PRTHomo sapiens 228Gly Gly Gly Ile Ala Val Ala Asp Tyr Tyr Phe Tyr Gly Met Asp Val1 5 10 1522948DNAHomo sapiens 229ggggggggta tagcagtggc tgactactac tactacggta tggacgtc 4823016PRTHomo sapiens 230Gly Gly Gly Ile Ala Val Ala Asp Tyr Tyr Tyr Tyr Gly Met Asp Val1 5 10 1523130DNAHomo sapiens 231gatagtacaa ctatggccca ctttgactac 3023210PRTHomo sapiens 232Asp Ser Thr Thr Met Ala His Phe Asp Tyr1 5 1023327DNAHomo sapiens 233gatctcaact ggggagcttt tgatatc 272349PRTHomo sapiens 234Asp Leu Asn Trp Gly Ala Phe Asp Ile1 523536DNAHomo sapiens 235ggagacagct cgaactacta ctccggtatg gacgtc 3623612PRTHomo sapiens 236Gly Asp Ser Ser Asn Tyr Tyr Ser Gly Met Asp Val1 5 1023730DNAHomo sapiens 237gggaactgga acgacgatgc ttttgatatc 3023810PRTHomo sapiens 238Gly Asn Trp Asn Asp Asp Ala Phe Asp Ile1 5 1023948DNAHomo sapiens 239atggggttta ctatggttcg gggagccctc tactacggta tggacgtc 4824016PRTHomo sapiens 240Met Gly Phe Thr Met Val Arg Gly Ala Leu Tyr Tyr Gly Met Asp Val1 5 10 1524130DNAHomo sapiens 241ccgagatatt ttgactggtt attaggcgac 3024210PRTHomo sapiens 242Arg Pro Tyr Phe Asp Trp Leu Leu Gly Asp1 5 1024342DNAHomo sapiens 243ggcgcccacg actacggtga cttctactac ggtatggacg tc 4224439DNAHomo sapiens 244gatcgggagg gagcgacttg gtactacggt atggacgtc 3924513PRTHomo sapiens 245Asp Arg Glu Gly Ala Thr Trp Tyr Tyr Gly Met Asp Val1 5 1024616PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(7)..(7)Val or IleMOD_RES(12)..(12)Asn or Asp 246Arg Ser Ser Gln Ser Leu Xaa Tyr Ser Asp Gly Xaa Thr Tyr Leu Asn1 5 10 152477PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(4)..(4)Tyr or Asn 247Lys Val Ser Xaa Trp Asp Ser1 52489PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequence 248Met Gln Gly Thr His Gln Pro Pro Ala1 524911PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(5)..(5)Gly or SerMOD_RES(6)..(6)Leu or Ile 249Arg Ala Ser Gln Xaa Xaa Ser Ser Trp Leu Ala1 5 102507PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(1)..(1)Asn or ThrMOD_RES(2)..(2)Thr or Ala 250Xaa Xaa Ser Ser Leu Gln Ser1 52519PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(4)..(4)Asn or Asp 251Gln Gln Ala Xaa Ser Phe Pro Leu Thr1 52527PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(3)..(3)Lys or Asn 252Gln Asp Xaa Lys Arg Pro Ser1 52535PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(1)..(1)Ser or Asn 253Xaa Tyr Gly Met His1 525417PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(4)..(4)Tyr or Phe 254Val Ile Trp Xaa Asp Gly Ser Asn Lys

Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly25516PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(5)..(5)Pro or AlaMOD_RES(11)..(11)Tyr or Phe 255Gly Gly Gly Ile Xaa Val Ala Asp Tyr Tyr Xaa Tyr Gly Met Asp Val1 5 10 1525617PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(8)..(8)Tyr or Asn 256Val Ile Ser Tyr Asp Gly Ser Xaa Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly2575PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(1)..(1)Asp or GlyMOD_RES(2)..(2)Tyr or AspMOD_RES(5)..(5)Tyr or His 257Xaa Xaa Tyr Met Xaa1 525817PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(11)..(11)Tyr or HisMOD_RES(12)..(12)Val or AlaMOD_RES(13)..(13)Gln or Arg 258Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Xaa Xaa Xaa Lys Phe Gln1 5 10 15Gly25912PRTArtificial SequenceDescription of Artificial Sequence Synthetic consensus sequenceMOD_RES(2)..(2)Gly or ArgMOD_RES(4)..(4)Ser or ThrMOD_RES(11)..(11)Ala or Asp 259Asp Xaa Gly Xaa Ser Gly Trp Pro Leu Phe Xaa Tyr1 5 10260363DNAHomo sapiens 260caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtat attactgtgc gagtctagtg 300ggagctacca actactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360tca 363261121PRTHomo sapiens 261Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Leu Val Gly Ala Thr Asn Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser 115 120262326DNAHomo sapiens 262tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120caggcccctg tacttgtcat ctctggtaaa aactaccggc cctcagggat cccagaccga 180ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240gatgaggctg actactactg taactcccgg gacagaagtg gtaaccatct ggtgttttcg 300gcggagggac caagctgacc gtccta 326263108PRTHomo sapiens 263Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln1 5 10 15Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Ser 35 40 45Gly Lys Asn Tyr Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Arg Ser Gly Asn His 85 90 95Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105264360DNAHomo sapiens 264gaagtgcagc tggtggagtc tgggggagtc gtggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattttacca tgcactgggt ccgtcaagct 120ccggggaagg gtctggagtg ggtctctctt attagttggg atggtggtag cacatactat 180gcagactctg tgaagggccg attcaccatc tccagagaca acagcaaaaa ctccctgtat 240atgcaaatga acagtctgag aactgaggac agcgccttgt attactgtgc aagaggtcct 300tactactact tctacggtat ggacgtctgg ggccaaggga ccacggtcac cgtctcctca 360265120PRTHomo sapiens 265Glu Val Gln Leu Val Glu Ser Gly Gly Val Val Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Phe 20 25 30Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr65 70 75 80Met Gln Met Asn Ser Leu Arg Thr Glu Asp Ser Ala Leu Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Tyr Tyr Tyr Phe Tyr Gly Met Asp Val Trp Gly Gln 100 105 110Gly Thr Thr Val Thr Val Ser Ser 115 120266328DNAHomo sapiens 266tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60acatgccaag gagacagcct cagaacctat tatgcaagct ggtaccagca gaagccagga 120caggccccta tacttgtcat ctctgataaa aacaaccggc cctcagggat cccagaccga 180ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240gatgaggctg actattactg taactcccgg gacagcagtg ataaccatct agtggtattt 300cggcggaggg accaagctga ccgtccta 328267109PRTHomo sapiens 267Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln1 5 10 15Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Thr Tyr Tyr Ala 20 25 30Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Ser 35 40 45Asp Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Asp Asn His 85 90 95Leu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105268363DNAHomo sapiens 268caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc gactactata tgtactgggt gcgacaggcc 120cctggacaag ggcctgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gtacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggatgag atccgacgac acggccgtgt attactgtgc gagagatggg 300ggtagcagtg gctggcccct ctttgcctac tggggcctgg gaaccctggt caccgtctcc 360tca 363269121PRTHomo sapiens 269Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Val Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Met Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Gly Ser Ser Gly Trp Pro Leu Phe Ala Tyr Trp Gly 100 105 110Leu Gly Thr Leu Val Thr Val Ser Ser 115 120270340DNAHomo sapiens 270cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60tcctgcactg ggagcagctc caacatcggg gcaggttttg atgtacactg gtaccagcag 120cttccaggaa cagcccccaa actcctcatc tatgataaca acaatcggcc ctcaggggtc 180cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240caggctgagg atgaggctga ttattactgc cagtcctatg acagcaacct gagtggttcg 300attgtggttt ttcggcggag ggaccaagct gaccgtccta 340271113PRTHomo sapiens 271Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln1 5 10 15Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30Phe Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45Leu Ile Tyr Asp Asn Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Asn 85 90 95Leu Ser Gly Ser Ile Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 100 105 110Leu272363DNAHomo sapiens 272caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata catcttcacc ggcgactata tgcactgggt gcgacaggcc 120cctggacaag ggctggagtg gatgggatgg atcaacccta acagtggtgg cacaaaccat 180gcacggaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgt gagagatagg 300ggtaccagtg gctggccact ctttgactat tggggccagg gaacactggt caccgtctcc 360tca 363273121PRTHomo sapiens 273Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Gly Asp 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn His Ala Arg Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Arg Asp Arg Gly Thr Ser Gly Trp Pro Leu Phe Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120274340DNAHomo sapiens 274cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60tcctgcactg ggagcagctc caacatcggg gcaggttttg atgtgcactg gtaccagctg 120cttccaggaa cagcccccaa actcctcatc tttgataaca acaatcgccc ctcaggggtc 180cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240caggctgagg atgaggctga ttattactgc cagtcctatg acagcaacct gagtggttcg 300attgtggtat ttcggcggag ggaccaagct gaccgtccta 340275113PRTHomo sapiens 275Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln1 5 10 15Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30Phe Asp Val His Trp Tyr Gln Leu Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45Leu Ile Phe Asp Asn Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Asn 85 90 95Leu Ser Gly Ser Ile Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val 100 105 110Leu276378DNAHomo sapiens 276caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt cattttcagt agctatggca ttcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtta taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaggggac 300tcctggaacg acagattaaa ctactacttc tacgatatgg acgtctgggg ccaagggacc 360acggtcaccg tctcctca 378277126PRTHomo sapiens 277Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Ser Tyr 20 25 30Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Asp Ser Trp Asn Asp Arg Leu Asn Tyr Tyr Phe Tyr Asp 100 105 110Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125278319DNAHomo sapiens 278tcctatgagc tgactcaggc accctcagtg tccgtgtccc caggacagac agccagcatc 60acctgctctg gagataaatt gggggataaa tatgcttgct ggtatcagca gaagccaggc 120cagtcccctg tgctggtcat ctatcaagat aagaagcggc cctcagggat ccctgagcga 180ttctctggct ccaactctgg gaacacagcc actctgacca tcagcgggac ccaggctatg 240gatgaggctg actattactg tcaggcgtgg gacagcagca ctgtggtatt tcggcggagg 300gaccaagctg accgtccta 319279106PRTHomo sapiens 279Ser Tyr Glu Leu Thr Gln Ala Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala 20 25 30Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45Gln Asp Lys Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Thr Val Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105280366DNAHomo sapiens 280caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggttcatcc attacagtgg gaccacctac 180tacaacccgt ccctcaagag tcgacttacc ctatcagtag acacgtctaa gagccagttc 240tccctgaagc tgaactctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300gttggcagct cgtcgggtaa ctggttcgac ccctggggcc agggaaccct ggtcaccgtc 360tcctca 366281122PRTHomo sapiens 281Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Phe Ile His Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Leu Ser Val Asp Thr Ser Lys Ser Gln Phe65 70 75 80Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Glu Val Gly Ser Ser Ser Gly Asn Trp Phe Asp Pro Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120282319DNAHomo sapiens 282tcctatgagc tgactcagcc accctcagtg tccgtgtccc caggacagac agccagcatc 60acctgctctg gagataaatt gggggataaa tatgcttgct ggtatcagca gaagccaggc 120cagtcccctg tggtggtcat ctatcaagat aacaagcggc cctcagggat ccctgagcga 180ttctctggct ccaactctgg gaacacagcc actttgacca tcagcgggac ccaggctatg 240gatgaggctg actattactg tcaggcgtgg gacagcacca ctgcgatatt tcggcggagg 300gaccaagctg accgtccta 319283106PRTHomo sapiens 283Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala 20 25 30Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Val Val Ile Tyr 35 40 45Gln Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Thr Thr Ala Ile 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105284378DNAHomo sapiens 284caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca ttcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaggggac 300tcctggaacg acagattaaa

ctactacttc tacgatatgg acgtctgggg ccaagggacc 360acggtcaccg tctcctca 378285126PRTHomo sapiens 285Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Asp Ser Trp Asn Asp Arg Leu Asn Tyr Tyr Phe Tyr Asp 100 105 110Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125286319DNAHomo sapiens 286tcctatgagc tgactcagcc accctcagtg tccgtgtccc caggacagac agccagcatc 60acctgctctg gagataaatt gggggataaa tatgcttgct ggtatcagca gaagccaggc 120cagtcccctg tactggtcat ctatcaagat aacaagcggc cctcagggat ccctgagcga 180ttctctggct ccaactctgg gaacacagcc actttgacca tcagcgggac ccaggctatg 240gatgaggctg actattactg tcaggcgtgg gacagcagca ctgtggtatt tcggcggagg 300gaccaagctg accgtccta 319287106PRTHomo sapiens 287Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala 20 25 30Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45Gln Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Thr Val Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105288372DNAHomo sapiens 288caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggata taccttcaat agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa tacatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca tttccaagaa cactctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagaggtc 300cgggcgtata gcagtggctg gtacgccgcc tttgactact ggggccaggg aaccctggtc 360accgtctcct ca 372289124PRTHomo sapiens 289Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Asn Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Val Arg Ala Tyr Ser Ser Gly Trp Tyr Ala Ala Phe Asp 100 105 110Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120290325DNAHomo sapiens 290tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60acatgccaag gagacagcct cagaatcttt tatgcaaact ggtaccagca gaagccagga 120caggcccctg tagttgtctt ctatggtaaa aacaaccggc cctcagggat cccagaccga 180ttctctggct ccagctcagg aaacacagct tccttgacca tcactgcggc tcaggcggaa 240gatgaggctg actattattg taactcccgg gacagcagtg gtaaccatgt ggtatttcgg 300cggagggacc acgctgaccg tccta 325291108PRTHomo sapiens 291Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln1 5 10 15Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ile Phe Tyr Ala 20 25 30Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Phe Tyr 35 40 45Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Ala Ala Gln Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His 85 90 95Val Val Phe Gly Gly Gly Thr Thr Leu Thr Val Leu 100 105292375DNAHomo sapiens 292caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcaa cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtag taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagagtaaga 300agtgggagct actacgaaca gtattactac ggtatggacg tctggggcca agggaccacg 360gtcgccgtct cctca 375293125PRTHomo sapiens 293Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Val Arg Ser Gly Ser Tyr Tyr Glu Gln Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Ala Val Ser Ser 115 120 125294322DNAHomo sapiens 294gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaaatca gtacattagc acctatttaa attggtatca gcagaaacca 120gggaaagccc ctaaggtcct gatttatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatt tgagacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcagcag agctacacta ccccgatcac ctttcggcca 300agggacacga ctggagatta aa 322295107PRTHomo sapiens 295Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Asn Gln Tyr Ile Ser Thr Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Phe Glu Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105296363DNAHomo sapiens 296gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agttatagca tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtttcatac attagtggtc gtactagtag cgtatactac 180gcagactctg tgaagggccg attcaccatc tccagagaca atgccaagaa ctcactgtat 240ctgcacatga acagcctgag agacgaggac acggctgtgt attactgtgc gagaagtggg 300atctactacg actactacgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 360tca 363297121PRTHomo sapiens 297Glu 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 Thr Phe Ser Ser Tyr 20 25 30Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Gly Arg Thr Ser Ser Val Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu His Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ser Gly Ile Tyr Tyr Asp Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val Ser Ser 115 120298340DNAHomo sapiens 298gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccccc 60atcaactgca agtccagcca gagtgtttta aacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca tttactggac atccacccgg 180gaaggcgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcagta ttttactact 300ccgtggacgt ttcggccaag ggaccaaggt ggagatcaaa 340299113PRTHomo sapiens 299Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Pro Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Gly Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Phe Thr Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110Lys300375DNAHomo sapiens 300caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggggca 300gccactgcta tagattacta ctactcctac ggtatggacg tctggggcct agggaccacg 360gtcaccgtct cctca 375301125PRTHomo sapiens 301Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ala Ala Thr Ala Ile Asp Tyr Tyr Tyr Ser Tyr Gly Met 100 105 110Asp Val Trp Gly Leu Gly Thr Thr Val Thr Val Ser Ser 115 120 125302322DNAHomo sapiens 302gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtgggaga cagagtcacc 60atcacttgtc gggcgagtca gggtattagt agctggttag cctggtatca gcggaaacca 120ggaaaagccc ctaagttcct gatctatact gcatccagtt tgcaaagtgg ggtcccatca 180cggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattctg caacttacta ttgtcaacag gctgacagtt tcccgctcac ttttcggcgg 300agggaccaag gtggagatca aa 322303107PRTHomo sapiens 303Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Arg Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Thr Ala Ser Ser Leu Gln 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 Ser Ala Thr Tyr Tyr Cys Gln Gln Ala Asp Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105304375DNAHomo sapiens 304caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagggggg 300ggtataccag tagctgacta ctactactac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctca 375305125PRTHomo sapiens 305Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Gly Ile Pro Val Ala Asp Tyr Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125306337DNAHomo sapiens 306gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtc tacagtgatg gagacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc catacagatt cagcggcagt gggtcaggca ctgatttcac actgcaaatc 240agcagggtgg aggctgagga tgttgggatt tactactgca tgcaaggtac acactggcct 300ccggcctttc ggccaaggga cacgactgga gattaaa 337307112PRTHomo sapiens 307Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Gln Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Ala Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110308322DNAHomo sapiens 308gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtcttagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ccaagctcct gatgtataac acatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcagtctca ccatcagcag cctgcagcct 240gaagattttg caagttacta ttgtcaacag gctaacagtt tccctctcac ttttcggcgg 300agggaccaag gtggagatca aa 322309107PRTHomo sapiens 309Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Leu Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Met 35 40 45Tyr Asn Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105310337DNAHomo sapiens 310gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtc tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcatt gggtcaggca ctgacttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tactactgca tgcaaggtac acactggcct 300ccggcctttc ggccaaggga cacgactgga gattaaa 337311112PRTHomo sapiens 311Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln

Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ile Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Ala Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110312322DNAHomo sapiens 312gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtcttagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ccaagctcct gatgtataac acatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcagtctca ccatcagcag cctgcagcct 240gaagattttg caagttacta ttgtcaacag gctaacagtt tccctctcac ttttcggcgg 300agggaccaag gtggagatca aa 322313375DNAHomo sapiens 313caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaagtc cctgagactc 60tcctgtgcag cgtctggatt ccccttcagt aactatggca tgcactgggt ccgccaggct 120ccaggcaagg gactggaatg ggtggcagtt atatggtttg atggaagtaa taaatactat 180gcggactccg tgaagggccg attcaccatc tccagagaca atcccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagggggg 300ggtatagcag tggctgacta ctacttctac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctca 375314125PRTHomo sapiens 314Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Lys1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Ser Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Gly Ile Ala Val Ala Asp Tyr Tyr Phe Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125315337DNAHomo sapiens 315gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcata tacagtgatg gaaacactta cttgaattgg 120tttcaacaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttgggatt tattactgca tgcaaggtac acactggcct 300ccggcctttc ggccaaggga cacgactgga gattaaa 337316112PRTHomo sapiens 316Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ile Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Ala Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110317322DNAHomo sapiens 317gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60attacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaaggtcct gacctatact acatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg ctacttactt ttgtcaacag gctgacagtt tccctctcac ttttcggcgg 300ggggaccaag gtggagatca aa 322318107PRTHomo sapiens 318Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Thr 35 40 45Tyr Thr Thr Ser Ser Leu Gln 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 Phe Cys Gln Gln Ala Asp Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105319375DNAHomo sapiens 319caggtgcaac tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagggggg 300ggtatagcag tggctgacta ctactactac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctca 375320125PRTHomo sapiens 320Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Gly Ile Ala Val Ala Asp Tyr Tyr Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125321337DNAHomo sapiens 321gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc ttactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaagca ctgatttcac actgaaaatc 240agtagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccggcctttc ggccaaggga cacgactgga gattaaa 337322112PRTHomo sapiens 322Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Tyr Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Ser Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Ala Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110323322DNAHomo sapiens 323gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gagtcttagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gctccataat gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg taaattacta ttgtcaacag gctaacagtt tccctctcac ttttcggcgg 300agggaccagg gtggagatca aa 322324107PRTHomo sapiens 324Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Leu Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu 35 40 45His Asn Ala Ser Ser Leu Gln 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 Val Asn Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Arg Val Glu Ile Lys 100 105325357DNAHomo sapiens 325caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctaagactc 60tcctgtgcag cgtctggatt caccttaagt agttatggca tgctctgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt ttatggtttg atggaagtta taaaaactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg agccgaggac acggctgtgt attactgtgc gagagatagt 300acaactatgg cccactttga ctactggggc cagggaaccc tggtcaccgt ctcctca 357326119PRTHomo sapiens 326Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr 20 25 30Gly Met Leu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Leu Trp Phe Asp Gly Ser Tyr Lys Asn Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Ser Thr Thr Met Ala His Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115327331DNAHomo sapiens 327cagactgtgg tgacccagga gccatcgttc tcagtgtccc ctggagggac agtcacactc 60acttgtggct tgaactctgg ctcagtctct actagttact tccccagctg gtaccagcag 120accccaggcc aggctccacg cacgctcatc tacagcacaa acagtcgctc ttctggggtc 180cctgatcgct tctctggctc catccttggg aacaaagctg ccctcaccat cacgggggcc 240caggcagatg atgaatctga ttattactgt gtgctgtata tgggtagagg catttgggtg 300tttcggcgga gggaccaagc tgaccgtcct a 331328110PRTHomo sapiens 328Gln Thr Val Val Thr Gln Glu Pro Ser Phe Ser Val Ser Pro Gly Gly1 5 10 15Thr Val Thr Leu Thr Cys Gly Leu Asn Ser Gly Ser Val Ser Thr Ser 20 25 30Tyr Phe Pro Ser Trp Tyr Gln Gln Thr Pro Gly Gln Ala Pro Arg Thr 35 40 45Leu Ile Tyr Ser Thr Asn Ser Arg Ser Ser Gly Val Pro Asp Arg Phe 50 55 60Ser Gly Ser Ile Leu Gly Asn Lys Ala Ala Leu Thr Ile Thr Gly Ala65 70 75 80Gln Ala Asp Asp Glu Ser Asp Tyr Tyr Cys Val Leu Tyr Met Gly Arg 85 90 95Gly Ile Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110329337DNAHomo sapiens 329gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc ttactgggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agtagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggcct 300ccggcctttc ggccaaggga cacgactgga gatcaaa 337330112PRTHomo sapiens 330Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Lys Val Ser Tyr Trp Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr His Trp Pro Pro Ala Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110331322DNAHomo sapiens 331gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gagtcttagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gctctataat gcatccagtt tgcaaagtgg ggccccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg taacttacta ttgtcaacag gctaacagtt tccctctcac ttttcggcgg 300agggaccagg gtggagatca aa 322332107PRTHomo sapiens 332Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Leu Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu 35 40 45Tyr Asn Ala Ser Ser Leu Gln Ser Gly Ala 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 Val Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Arg Val Glu Ile Lys 100 105333322DNAHomo sapiens 333gacatccaga tgacccagtc cccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggtcttagc agctggttag cctggtatca gcagaaacca 120gggaaagccc ccaagctcct gatgtataac acatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcagtctca ccatcagcag cctgcagcct 240gaagattttg caagttacta ttgtcaacag gctaacagtt tccctctcac ttttcggcgg 300agggaccaag gtggagatca aa 322334354DNAHomo sapiens 334gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagca attagtggta gtggtggaag tacacactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatctc 300aactggggag cttttgatat ctggggccaa gggacaatgg tcaccgtctc ttca 354335118PRTHomo sapiens 335Glu 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 Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr His Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Leu Asn Trp Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr 100 105 110Met Val Thr Val Ser Ser 115336337DNAHomo sapiens 336cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60tcctgcactg ggagcagctc caacattggg gcgggttatg ttgtacattg gtaccagcag 120cttccaggaa cagcccccaa actcctcatc tatggtaaca gcaatcggcc ctcaggggtc 180cctgaccaat tctctggctc caagtctggc acctcagcct ccctggccat cactggactc 240cagtctgagg atgaggctga ttattactgc aaagcatggg ataacagcct gaatgctcaa 300ggggtatttc ggcggaggga ccaagctgac cgtccta 337337112PRTHomo sapiens 337Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln1 5 10 15Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30Tyr Val Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Gln Phe 50 55 60Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu65 70 75 80Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Lys Ala Trp Asp Asn Ser 85 90 95Leu Asn Ala Gln Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110338363DNAHomo sapiens 338gaggtgcagc tgttggagtc tgggggaggc ttggcacagc cgggggggtc cctgagactc 60tcctgtgcag gctctggatt ctcctttaga ggctatgtca tgacttgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagga attagtggta gtggtggtag cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtgt 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaggagac 300agctcgaact actactccgg tatggacgtc tggggccaag ggaccacggt catcgtctcc 360tca 363339121PRTHomo sapiens 339Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ala Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Ser Phe Arg Gly Tyr

20 25 30Val Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Cys65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Asp Ser Ser Asn Tyr Tyr Ser Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Ile Val Ser Ser 115 120340340DNAHomo sapiens 340gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacaactcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc ttctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga ggatgtggca atttattact gtcagcaatt ttatggtcct 300cctctcactt ttcggcggag ggaccaaggt ggaaatcaaa 340341113PRTHomo sapiens 341Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Asn 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln 85 90 95Phe Tyr Gly Pro Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys342357DNAHomo sapiens 342caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacccta acaatggtgg cacaaactat 180ggacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagggaac 300tggaacgacg atgcttttga tatctggggc caagggacaa tggtcaccgt ctcttca 357343119PRTHomo sapiens 343Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Gly Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Asn Trp Asn Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110Thr Met Val Thr Val Ser Ser 115344322DNAHomo sapiens 344tcctatgagc tgactcagtc accctcagtg tccgtgtccc caggacagac agccagcatc 60acctgttctg gtgataaatt gggggataaa tttgctttct ggtatcagca gaagccaggc 120cagtcccctg tgctggtcat ctatcaagat agcaagcggc cctcagggat ccctgagcga 180ttctctggct ccaactctgg gaacacagcc actctgacca tcagcgggac ccaggctatg 240gatgaggctg actattactg tcaggcgtgg gacagcagcg ccgggggggt atttcggcgg 300agggaccaag ttgaccgtcc ta 322345107PRTHomo sapiens 345Ser Tyr Glu Leu Thr Gln Ser Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Phe Ala 20 25 30Phe Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Ala Gly Gly 85 90 95Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105346375DNAHomo sapiens 346caggtgcaac tggaggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaatgggg 300tttactatgg ttcggggagc cctctactac ggtatggacg tctggggcca agggaccacg 360gtcaccgtct cctca 375347125PRTHomo sapiens 347Gln Val Gln Leu Glu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Met Gly Phe Thr Met Val Arg Gly Ala Leu Tyr Tyr Gly Met 100 105 110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125348325DNAHomo sapiens 348tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60acatgccaag gagacagcct cagaagctat catgcaagct ggtaccagca gaagccagga 120caggcccctg tacttgtcat ctatggtgaa aacaaccggc cctcagggat cccagaccga 180ttctctgact ccagttcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240gatgaggctg actattattg taattatcgg gacaacagtg gtaaccatct ggtgtttcgg 300cggagggacc aagctgaccg tccta 325349108PRTHomo sapiens 349Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln1 5 10 15Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr His Ala 20 25 30Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45Gly Glu Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Asp Ser 50 55 60Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Asn Tyr Arg Asp Asn Ser Gly Asn His 85 90 95Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105350357DNAHomo sapiens 350gaggtgcagc tgttggaatc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagtcgta gtggtagtac cacatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgt ggaaccgaga 300tattttgact ggttattagg cgactggggc cagggaaccc tggtcaccgt ctcctca 357351119PRTHomo sapiens 351Glu 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 Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Arg Ser Gly Ser Thr Thr Tyr Tyr Ala Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Glu Pro Arg Tyr Phe Asp Trp Leu Leu Gly Asp Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115352369DNAHomo sapiens 352caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt aaatggtatg aaggaagtaa taaatactat 180ggagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ttgcaaatga acagtctgag aggcgaggat acggctgtgt attactgtgc gagaggcgcc 300cacgactacg gtgacttcta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360gtctcctca 369353123PRTHomo sapiens 353Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Lys Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Gly Asp 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 Asn Ser Leu Arg Gly Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ala His Asp Tyr Gly Asp Phe Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120354319DNAHomo sapiens 354tcctatgaac tgactcagcc agcctcagtg tccgtgtccc caggacagat agccagcatc 60acctgctctg gagataattt gggggataaa tatatttgct ggtatcagca gaagccaggc 120cagtcccctg tgcgggtcat ctatcaagat aacaagcggc cctcagggat ccctgagcgt 180ttctctggct ccaattctgg gaacacagcc actctgacca tcagcgggac ccaggctatg 240gatgaggctg actattactg tcaggcgtgg gacagcagca ctgtggtatt tcggcggagg 300gaccaagctg accgtccta 319355106PRTHomo sapiens 355Ser Tyr Glu Leu Thr Gln Pro Ala Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Ile Ala Ser Ile Thr Cys Ser Gly Asp Asn Leu Gly Asp Lys Tyr Ile 20 25 30Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Arg Val Ile Tyr 35 40 45Gln Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser Thr Val Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105356366DNAHomo sapiens 356gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagct attagttata gtggcggtag cacatactac 180gcaggctccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcgg 300gagggagcga cttggtacta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360tcctca 366357122PRTHomo sapiens 357Glu 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 Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Gly 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Glu Gly Ala Thr Trp Tyr Tyr Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120358319DNAHomo sapiens 358tcctatgaac tgactcagcc accctcagtg tccgtgtccc caggacagac agccagcatc 60acctgctctg gagataaatt gggggaaagc tatgcttgct ggtatcagca gaagccaggc 120cagtcccctg tactggtcat ctatcaagat tacaagcggc cctcagggat ccctgagcgc 180ttctctggct ccaactctgg gaacacagcc actctgacca tcagcgggac ccaggctatg 240gatgaggctg actattactg tcaggcgtgg gacagaagta ctgtactatt tcggcggagg 300gaccaagctg accgtccta 319359106PRTHomo sapiens 359Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Glu Ser Tyr Ala 20 25 30Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45Gln Asp Tyr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Arg Ser Thr Val Leu 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105360366DNAHomo sapiens 360cagatgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcaga acctatggca tgcactgggt ccgccaggct 120ccaggcaagg gactggagtg ggtggcagtt atatggtatg atggaagtaa taaacactat 180gcagactccg tgaagggccg attcaccatc accagagaca attccaagaa cactctgaat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagcccct 300cagtgggagc tagttcatga agcttttgat atctggggcc aagggacaat ggtcaccgtc 360tcttca 366361122PRTHomo sapiens 361Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Thr Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Asn65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Pro Gln Trp Glu Leu Val His Glu Ala Phe Asp Ile Trp 100 105 110Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120362325DNAHomo sapiens 362tcctatgtgc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60acctgtgggg gaaacaacct tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcatggat ccctgagcga 180ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggg cgaagccggg 240gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatgt ggtatttcgg 300cggagggacc aagctgaccg tccta 325363108PRTHomo sapiens 363Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln1 5 10 15Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Leu Gly Ser Lys Ser Val 20 25 30His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr 35 40 45Asp Asp Ser Asp Arg Pro Ser Trp Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Gly Glu Ala Gly65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105364981DNAHomo sapiens 364gctagcacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 240tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 300aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 360ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 420gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 480gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 540gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 600aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 660cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 720caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 780gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 840ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 900gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 960tccctgtctc cgggtaaatg a 981365326PRTHomo sapiens 365Ala 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 Asn Phe Gly Thr Gln Thr65 70 75 80Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly145 150 155 160Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn225 230 235 240Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu305 310 315 320Ser Leu Ser Pro Gly Lys 325366324DNAHomo sapiens 366cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300agcttcaaca ggggagagtg ttag 324367107PRTHomo sapiens 367Arg 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 105368321DNAHomo sapiens 368ggccaaccga aagcggcgcc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa 60gccaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120gcctggaagg cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180caaagcaaca acaagtacgc ggccagcagc tatctgagcc tgacgcctga gcagtggaag 240tcccacagaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300gcccctacag aatgttcata g 321369106PRTHomo sapiens 369Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser1 5 10 15Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro 35 40 45Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 50 55 60Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys65 70 75 80Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 10537015DNAHomo sapiens 370agaaaaagga aagtc 153715PRTHomo sapiens 371Arg Lys Arg Lys Val1 5372504DNAHomo sapiens 372atgttccctt ttgccttact atatgttctg tcagtttctt tcaggaaaat cttcatctta 60caacttgtag ggctggtgtt aacttacgac ttcactaact gtgactttga gaagattaaa 120gcagcctatc tcagtactat ttctaaagac ctgattacat atatgagtgg gaccaaaagt 180accgagttca acaacaccgt ctcttgtagc aatcggccac attgccttac tgaaatccag 240agcctaacct tcaatcccac cgccggctgc gcgtcgctcg ccaaagaaat gttcgccatg 300aaaactaagg ctgccttagc tatctggtgc ccaggctatt cggaaactca gataaatgct 360actcaggcaa tgaagaagag gacaaccaat aaatgtctgg aacaagtgtc acaattacaa 420ggattgtggc gtcgcttcaa tcgaccttta ctgaaacaac agcatcacca tcaccatcac 480gactacaaag acgatgacga caaa 504373168PRTHomo sapiens 373Met Phe Pro Phe Ala Leu Leu Tyr Val Leu Ser Val Ser Phe Arg Lys1 5 10 15Ile Phe Ile Leu Gln Leu Val Gly Leu Val Leu Thr Tyr Asp Phe Thr 20 25 30Asn Cys Asp Phe Glu Lys Ile Lys Ala Ala Tyr Leu Ser Thr Ile Ser 35 40 45Lys Asp Leu Ile Thr Tyr Met Ser Gly Thr Lys Ser Thr Glu Phe Asn 50 55 60Asn Thr Val Ser Cys Ser Asn Arg Pro His Cys Leu Thr Glu Ile Gln65 70 75 80Ser Leu Thr Phe Asn Pro Thr Ala Gly Cys Ala Ser Leu Ala Lys Glu 85 90 95Met Phe Ala Met Lys Thr Lys Ala Ala Leu Ala Ile Trp Cys Pro Gly 100 105 110Tyr Ser Glu Thr Gln Ile Asn Ala Thr Gln Ala Met Lys Lys Arg Thr 115 120 125Thr Asn Lys Cys Leu Glu Gln Val Ser Gln Leu Gln Gly Leu Trp Arg 130 135 140Arg Phe Asn Arg Pro Leu Leu Lys Gln Gln His His His His His His145 150 155 160Asp Tyr Lys Asp Asp Asp Asp Lys 165374519DNAHomo sapiens 374atgttccctt ttgccttact atatgttctg tcagtttctt tcaggaaaat cttcatctta 60caacttgtag ggctggtgtt aacttacgac ttcactaact gtgactttga gaagattaaa 120gcagcctatc tcagtactat ttctaaagac ctgattacat atatgagtgg gaccaaaagt 180accgagttca acaacaccgt ctcttgtagc aatcggccac attgccttac tgaaatccag 240agcctaacct tcaatcccac cgccggctgc gcgtcgctcg ccaaagaaat gttcgccatg 300aaaactaagg ctgccttagc tatctggtgc ccaggctatt cggaaactca gataaatgct 360actcaggcaa tgaagaagag gagaaaaagg aaagtcacaa ccaataaatg tctggaacaa 420gtgtcacaat tacaaggatt gtggcgtcgc ttcaatcgac ctttactgaa acaacagcat 480caccatcacc atcacgacta caaagacgat gacgacaaa 519375173PRTHomo sapiens 375Met Phe Pro Phe Ala Leu Leu Tyr Val Leu Ser Val Ser Phe Arg Lys1 5 10 15Ile Phe Ile Leu Gln Leu Val Gly Leu Val Leu Thr Tyr Asp Phe Thr 20 25 30Asn Cys Asp Phe Glu Lys Ile Lys Ala Ala Tyr Leu Ser Thr Ile Ser 35 40 45Lys Asp Leu Ile Thr Tyr Met Ser Gly Thr Lys Ser Thr Glu Phe Asn 50 55 60Asn Thr Val Ser Cys Ser Asn Arg Pro His Cys Leu Thr Glu Ile Gln65 70 75 80Ser Leu Thr Phe Asn Pro Thr Ala Gly Cys Ala Ser Leu Ala Lys Glu 85 90 95Met Phe Ala Met Lys Thr Lys Ala Ala Leu Ala Ile Trp Cys Pro Gly 100 105 110Tyr Ser Glu Thr Gln Ile Asn Ala Thr Gln Ala Met Lys Lys Arg Arg 115 120 125Lys Arg Lys Val Thr Thr Asn Lys Cys Leu Glu Gln Val Ser Gln Leu 130 135 140Gln Gly Leu Trp Arg Arg Phe Asn Arg Pro Leu Leu Lys Gln Gln His145 150 155 160His His His His His Asp Tyr Lys Asp Asp Asp Asp Lys 165 17037628PRTHomo sapiens 376Met Phe Pro Phe Ala Leu Leu Tyr Val Leu Ser Val Ser Phe Arg Lys1 5 10 15Ile Phe Ile Leu Gln Leu Val Gly Leu Val Leu Thr 20 25377481DNAHomo sapiens 377atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccggt 60tacgacttca ctaactgtga ctttcagaag attgaagcag actatctccg tactatttct 120aaagacctga ttacatatat gagtgggact aaaagtaccg acttcaacaa caccgtctcc 180tgtagcaatc ggccacactg ccttactgaa atccagagcc taaccttcaa tcccaccccc 240cgctgcgcgt cgctcgccaa ggaaatgttc gccaggaaaa ctaaggctac cctcgctctc 300tggtgcccag gctattcgga aactcagata aatgctactc aggcaatgaa gaagaggaca 360accaataaat gtctggaaca agtgtcacaa ttactaggat tgtggcgtcg cttcattcga 420actttactga aacaacagca ccaccaccac caccatgact ataaagacga tgacgacaaa 480t 481378160PRTHomo sapiens 378Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro1 5 10 15Gly Ser Thr Gly Tyr Asp Phe Thr Asn Cys Asp Phe Gln Lys Ile Glu 20 25 30Ala Asp Tyr Leu Arg Thr Ile Ser Lys Asp Leu Ile Thr Tyr Met Ser 35 40 45Gly Thr Lys Ser Thr Asp Phe Asn Asn Thr Val Ser Cys Ser Asn Arg 50 55 60Pro His Cys Leu Thr Glu Ile Gln Ser Leu Thr Phe Asn Pro Thr Pro65 70 75 80Arg Cys Ala Ser Leu Ala Lys Glu Met Phe Ala Arg Lys Thr Lys Ala 85 90 95Thr Leu Ala Leu Trp Cys Pro Gly Tyr Ser Glu Thr Gln Ile Asn Ala 100 105 110Thr Gln Ala Met Lys Lys Arg Thr Thr Asn Lys Cys Leu Glu Gln Val 115 120 125Ser Gln Leu Leu Gly Leu Trp Arg Arg Phe Ile Arg Thr Leu Leu Lys 130 135 140Gln Gln His His His His His His Asp Tyr Lys Asp Asp Asp Asp Lys145 150 155 160379495DNAHomo sapiens 379atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccggt 60tacgacttca ctaactgtga ctttcagaag attgaagcag actatctccg tactatttct 120aaagacctga ttacatatat gagtgggact aaaagtaccg acttcaacaa caccgtctcc 180tgtagcaatc ggccacactg ccttactgaa atccagagcc taaccttcaa tcccaccccc 240cgctgcgcgt cgctcgccaa ggaaatgttc gccaggaaaa ctaaggctac cctcgctctc 300tggtgcccag gctattcgga aactcagata aatgctactc aggcaatgaa gaagaggaga 360aaaaggaaag tcacaaccaa taaatgtctg gaacaagtgt cacaattact aggattgtgg 420cgtcgcttca ttcgaacttt actgaaacaa cagcaccacc accaccacca tgactataaa 480gacgatgacg acaaa 495380165PRTHomo sapiens 380Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro1 5 10 15Gly Ser Thr Gly Tyr Asp Phe Thr Asn Cys Asp Phe Gln Lys Ile Glu 20 25 30Ala Asp Tyr Leu Arg Thr Ile Ser Lys Asp Leu Ile Thr Tyr Met Ser 35 40 45Gly Thr Lys Ser Thr Asp Phe Asn Asn Thr Val Ser Cys Ser Asn Arg 50 55 60Pro His Cys Leu Thr Glu Ile Gln Ser Leu Thr Phe Asn Pro Thr Pro65 70 75 80Arg Cys Ala Ser Leu Ala Lys Glu Met Phe Ala Arg Lys Thr Lys Ala 85 90 95Thr Leu Ala Leu Trp Cys Pro Gly Tyr Ser Glu Thr Gln Ile Asn Ala 100 105 110Thr Gln Ala Met Lys Lys Arg Arg Lys Arg Lys Val Thr Thr Asn Lys 115 120 125Cys Leu Glu Gln Val Ser Gln Leu Leu Gly Leu Trp Arg Arg Phe Ile 130 135 140Arg Thr Leu Leu Lys Gln Gln His His His His His His Asp Tyr Lys145 150 155 160Asp Asp Asp Asp Lys 16538120PRTHomo sapiens 381Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro1 5 10 15Gly Ser Thr Gly 203828PRTArtificial SequenceDescription of Artificial Sequence Synthetic linker peptide 382Ser Gly Gly Ala Pro Met Leu Ser1 5

Claims

1. An isolated antigen binding protein comprising an amino acid sequence selected from the group consisting of: a. a light chain CDR3 sequence selected from the group consisting of: i. a light chain CDR3 sequence that differs by no more than a total of two amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences of A1 to All; ii. QQAX.sub.8SFPLT (SEQ ID NO: 251); and b. a heavy chain CDR3 sequence selected from the group consisting of: i. a heavy chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences of A1 to A27; ii. GGGIX.sub.12VADYYX.sub.13YGMDV (SEQ ID NO: 255); and iii. DX.sub.21GX.sub.22SGWPLFX.sub.23Y (SEQ ID NO: 259); wherein X.sub.8 is an N residue or a D residue; Xi.sub.2 is a P residue or an A residue; Xi.sub.3 is a Y residue or an F residue; X.sub.21 is a G residue or an R residue; X.sub.22 is an S residue or a T residue; X.sub.23 is an A residue or a D residue, and wherein said antigen binding protein specifically binds to TSLP.

2. The isolated antigen binding protein of claim 1, further comprising an amino acid sequence selected from the group consisting of: a. a light chain CDRI sequence selected from the group consisting of: i. a light chain CDRI sequence that differs by no more than three amino acids additions, substitutions, and/or deletions from a light chain CDRI sequence of A1 -A27; ii. RSSQSLX.sub.1YSDGX.sub.2TYLN (SEQ ID NO: 246); iii. RASQX.sub.4X.sub.5SSWLA (SEQ ID NO: 249); and b. a light chain CDR2 sequence selected from the group consisting of: i. a light chain CDR2 sequence that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDR2 sequence of A1 -A27; ii. KVSX.sub.3WDS (SEQ ID NO: 247); iii. X.sub.6X.sub.7SSLQS (SEQ ID NO: 250); and iv. QDX.sub.9KRPS (SEQ ID NO: 252); c. a heavy chain CDRI sequence selected from the group consisting of: i. a heavy chain CDRI sequence that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDRI sequence of A1 -A27; ii. X.sub.10YGMH (SEQ ID NO: 253); and iii. X.sub.15X.sub.16YMX.sub.17 (SEQ ID NO: 257); d. a heavy chain CDR2 sequence selected from the group consisting of: i. a heavy chain CDR2 sequence that differs by no more than three amino acid additions, substitutions, and/or deletions from a CDR2 sequence of A1 -A27; ii. VIWX.sub.11DGSNKYYADSVKG (SEQ ID NO: 254); iii. VISYDGSX.sub.14KYYADSVKG (SEQ ID NO: 256); and iv. WrNPNSGGTNXi.sub.8X.sub.19X.sub.20KFQG (SEQ ID NO: 258); wherein X.sub.1 is a V residue or an I residue; X.sub.2 is an N residue or a D residue; X.sub.3 is a Y residue or an N residue; X.sub.4 is a G residue or a S residue; X.sub.5 is a L residue or an I residue; X.sub.6 is an N residue or a T residue; X.sub.7 is a T residue or an A residue; X.sub.9 is a K residue or an N residue; X.sub.10 is an S residue or an N residue; X.sub.11 is a Y residue or an F residue; X.sub.14 is a Y residue or a N residue; X.sub.15 is a D residue or G residue; X.sub.16 is a Y residue or a D residue; X.sub.17 is a Y residue or an H residue; X.sub.18 is a Y residue or an H residue; X.sub.19 is a V residue or an A residue; X.sub.20 is a Q residue or an R residue, and wherein said antigen binding protein specifically binds to TSLP.

3. The isolated antigen binding protein of claim 1 comprising either: a. a light chain variable domain comprising: i. a light chain CDRI sequence selected from A1 -A27; ii a light chain CDR2 sequence selected from A1 -A27; iii. a light chain CDR3 sequence selected from A1 -A27, or b. a heavy chain variable domain comprising: i. a heavy chain CDRI sequence selected from A1 -A27; ii. a heavy chain CDR2 sequence selected from Al-All, and iii. a heavy chain CDR3 sequence selected from A1 -A27; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

4. The isolated antigen binding protein of claim 1 comprising either: a. a light chain variable domain sequence selected from the group consisting of; i. amino acids having a sequence at least 80% identical to a light chain variable domain sequence selected from L1-L27; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the light chain variable domain sequence of L1-L27; iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a light chain variable domain sequence of L1-L27; b. a heavy chain variable domain sequence selected from the group consisting of: i. a sequence of amino acids that is at least 80% identical to a heavy chain variable domain sequence of H1-H27; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the heavy chain variable domain sequence of H1-H27; iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a heavy chain variable domain sequence of H1-H27; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein said antigen binding protein specifically binds to TSLP.

5. An isolated antigen binding protein, comprising either: a. a light chain variable domain sequence selected from the group consisting of: L1-L27 b. a heavy chain variable domain sequence selected from the group consisting of: H1-H27; or, c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antigen binding protein specifically binds to TSLP.

6. (canceled)

7. The isolated antigen binding protein of claim 1, wherein the binding protein binds to TSLP with substantially the same Kd as a reference antibody selected from the group of antibodies consisting of A2, A3, A4 and A5.

8. The isolated antigen binding protein of claim 1, wherein the binding protein inhibits TSLP activity according to the primary cell OPG assay with the same IC50 as a reference antibody selected from the group of antibodies consisting of A2, A3, A4, and A5.

9. The isolated antigen binding protein of claim 1, wherein the antigen binding protein is selected from the group consisting of a human antibody, a humanized antibody, chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an F(fa')x fragment, a domain antibody, an IgD antibody, an IgE antibody, and IgM antibody, and IgG1 antibody, and IgG2 antibody, and IgG3 antibody, and IgG4 antibody, and IgG4 antibody having at least one mutation in the hinge region that alleviates a tendency to for intra H-chain disulfide bonds.

10. (canceled)

11. A pharmaceutical composition comprising the antibody of claim 9.

12. An isolated nucleic acid comprising a polynucleotide sequence encoding the light chain variable domain, the heavy chain variable domain, or both, of the antigen binding agent of claim 5.

13. (canceled)

14. A recombinant expression vector comprising the nucleic acid of claim 12.

15-17. (canceled)

18. A method of treating a TSLP-related inflammatory condition or a TSLP-related fibrotic disorder in a subject in need of such treatment comprising administering a therapeutically effective amount of composition of claim 11 to the subject.

19. The method of claim 18, wherein the inflammatory condition is selected from the group consisting of allergic asthma, allergic rhinosinusitis, allergic conjunctivitis, and atopic dermatitis.

20-21. (canceled)

22. An isolated antigen binding protein that cross-competes for binding TSLP with an antibody selected from the group consisting of A1 -A27.

23-33. (canceled)

34. An isolated antigen binding protein that binds wild-type TSLP with a wild-type affinity, wherein the antigen binding protein binds to any of a group of mutated TSLP with an affinity lower than the wild-type affinity, wherein the group of mutated TSLP includes mutated TSLP comprising a mutation selected from the group consisting of KIOE, A14R, K21E, D22R, K73E, K75E, and A76R.

35. The isolated antigen binding protein of claim 34, wherein antigen binding protein has a lower binding affinity for any two or more members of the group of mutated TSLP than the wild-type affinity.

36. The isolated antigen binding protein of claim 35, wherein antigen binding protein has a lower binding affinity for all members of the group of mutated TSLP than the wild-type affinity.

37-63. (canceled)