Novel Antibody And Use In Diagnosis And Therapy Of Arthropathies

Abstract

The present invention provides a composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) in which the antibody or fragment thereof is conjugated to a pharmaceutically active moiety. The invention also provides a composition comprising an antibody or fragment thereof against oxidised Collagen II (Gil) and a detectable label. The invention further provides the use of such compositions in medicine, in particular for the treatment of an arthropathy, and in methods of diagnosis.

Description

[0001] The present invention relates to a novel antibody and its use in the diagnosis and therapy of inflammatory diseases of the joints such as rheumatoid arthritis (RA) and osteoarthritis (OA).

INTRODUCTION

[0002] The final outcome of most rheumatic conditions, the leading cause of disabilities in the western world, is breakdown of articular cartilage. This breakdown is the final outcome of inflammatory events in both rheumatoid arthritis (RA) and osteoarthritis (OA) mediated by either influx of activated leukocytes (RA) or activated chondrocytes (OA). Pro-inflammatory cytokine blockade such as anti-TNFa and IL-1Ra is therefore currently used to treat arthritic conditions, mainly RA. These treatments however, are not consistently effective and the number of patients that fail anti-TNF therapy is increasing. Especially for anti-TNFa treatment there is a risk of serious infections and malignancies. These systemic side effects could be minimised by the development of technologies to target therapeutic agents specifically to the inflamed tissues, but has so far been impeded by the lack of proper target epitope(s) that would be present uniquely in the diseased joint and not in the healthy joint.

[0003] RA is a classic inflammatory form of arthritis, which is a chronic autoimmune disease with extensive synovial inflammation. Influx of activated leukocytes infiltrating the inflamed synovial membrane results in up-regulation of inflammatory cytokines such as TNFa, interleukin-1 (IL-1) and interleukin-6 (IL-6) leading to increase in the levels of matrix metalloproteases (MMP). Moreover, infiltrated inflammatory cells consume increased amounts of oxygen, resulting in the generation of reactive oxidant species (ROS) including superoxide radicals (O.sub.2), hydrogen peroxide (H.sub.2O.sub.2), hydroxyl radicals (OH), hypochlorous acid (HOCl), nitric oxide (NO) and peroxynitrite (ONOO). In addition, sequential oxidative reactions generate reactive oxidants such as advanced glycation end-products (AGE). The combined activities of MMP and ROS may be the cause of the excessive degradation of the extracellular matrix leading to cartilage destruction.

[0004] The immuno-pathological events following the ROS reactivity with cartilage specific collagen type II (CII) protein have been studied recently. A substantial increase in binding of RA sera to CII after chemical post-translational modification in vitro by ROS has been demonstrated in comparison to binding to native non-modified CII, which is significantly greater than in non-RA sera. Post-translational modification in the acute and chronic inflammation by ROS has also been postulated by the presence of other ROS damaged proteins and auto-antibodies against other auto-antigens that are post-translationally modified by ROS. Generation of neoantigenic epitopes on modified CII has been reported in Nissim et al Arthritis & Rheumatism, volume 52 (12) pages 3829-3838 (2005)). Antibodies against IgG-AGE and a T cell response against IgG modified by HOCl and peroxynitrite have also been observed.

[0005] Although synovial inflammation in OA is not as extensive as in RA and inflammatory cells are not significant in numbers, low grade synovitis is nearly a constant feature in OA. Abnormal mechanical force appears to stimulate chondrocytes to produce the same inflammatory mediators and ROS as the infiltrated leukocytes present in inflamed RA joints leading to post translational modifications of CII. There is a report of elevated levels of nitrated CII peptide in sera of patients with OA. The presence of strong staining of nitrotyrosine and low antioxidative capacity in the degenerative region of OA cartilage compared with the intact region from the same sample suggests a possible correlation between oxidative damage and cartilage degradation. As in RA, indirect involvement of oxidative stress has also been evidenced in OA by the fact that: (i) OA is strongly linked with age and in aged cartilage there is accumulation of AGE; and (ii) there is accumulation of lipid peroxidation product and nitrotyrosine.

[0006] There is a need for improved means for diagnosing inflammatory diseases of the joints and for improved therapies for arthropathies such as rheumatoid arthritis (RA) and osteoarthritis (OA).

[0007] It has been found that an antibody raised against post-translationally modified Collagen II (CII) can specifically target the antibody to the sites of inflammation in the joints. This degree of specificity is important since native CII may be present in both inflamed and healthy joints also.

[0008] According to a first aspect of the invention, there is provided a composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) in which the antibody or fragment thereof is conjugated to a pharmaceutically active moiety.

[0009] The present invention therefore provides a novel approach to the targeting of drugs to self-epitopes on Collagen II that are a normal component of the tissue but which become immunogenic after post-translational modification by free radicals as part of a disease process affecting Collagen II.

[0010] The antibody may be a polyclonal antibody or a monoclonal antibody. It may be a human or humanized or chimeric antibody with sequences, residues or domains derived from more than one animal species. Fragments of antibodies include Fc, Fab, scFv, single domain (dAb) antibody, diabody, minibody, and scFv-Fc fragments In one embodiment of the invention, the antibody comprises CDR sequences in the Variable Heavy (VH) Chains and Variable Light (VL) chains as shown in Table 1. CDRH2 and CDRH3 are in the VH chain and CDRL2 and CDRL3 are in the VL chain.

TABLE-US-00001 TABLE 1 CDRH2 CDRH3 CDRL2 CDRL3 DISSTGSYTAYADSVKG GAGSFDY AASALQS QQSSSTPTT AISAAGTATAYADSVKG GYDTFDY AASSLQS QQNYGYPNT SISNSGSYTDYADSVKG GYGSFDY AASTLQS QQANSSPDT SINNYGSNTAYADSVKG GYSSFDY AASYLQS QQTSSSPDT SINNYGSNTAYADSVKG GYSSFDY AASYLQS QQTSSSPDT SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT NIATDGTTTYYADSVKG NSTYFDY SASTLQS QQAATSPTT SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST SISNSGTNTDYADSVKG NYASPDY YASYLQS QQGSASPST SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST SISYTGDSTYYADSVKG NYSAFDY YASYLQS QQADSTPTT SINDSGTTTYYADSVKG NYSAFDY AASDLQS QQSDSAPTT SIDSAGASTYYADSVKG NYSAFDY NASSLQS QQSDTYPST SISYTGDSTYYADSVKG NYSAFDY TASNLQS QQSYASPTT SISYTGDSTYYADSVKG NYSAFDY TASNLQS QQSYASPTT SISYTGDSTYYADSVKG NYSAFDY TASNLQS QQTGSYPTT SINATGYGTYYADSVKG NYSDFDY SASALQS QQGDSYPTT SINSNGTDTYYADSVKG NYSDFDY TASALQS QQGYGAPTT SISATGSSTYYADSVKG NYSDFDY SASDLQS QQSSYTPTT SISATGSSTYYADSVKG NYSDFDY SASDLQS QQSSYTPTT SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT SIDTTGTTTYFADSVKG NYSSFDY SASYLQS QQGYSAPTT TISYSGNNTYYADSVKG NYSSFDY TASSLQS QQGYTSPTT SIDAGGNGTYYADSVKG NYSSPDY TASNLQS QQNNYYPTT SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT SIDSAGNATYYADSVKG NYSSFDY AASTLQS TSNYPTTQQ SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT SIATTGDNTYYADSVKG NYSYFDY TASTLQS QQAAGNPTT AINAYGGSTYYADSVKG NYSYFDY AASSLQS QQGSDYPTT AINAYGGSTYYADSVKG NYSYFDY AASSLQS QQGSDYPTT SIATTGTSTTYADSVKG NYSYPDY TASSLQS QQGSTAPTT SIATTGTSTTYADSVKG NYSYFDY TASSLQS QQGSTAPTT TIDTAGSYTDYADSVKG NYSYFDY GASTLQS QQSTASPST SISNNGSSTYYADSVKG NYSYFDY AASNLQS QQTSSYPTT SIAYGGAGTDYADSVKG NYTAFDY AASYLQS QQGAGSPST AIANTGSATNYADSiKG NYTAFDY DASTLQS QQRNTSPTT SISTAGTYTDYADSVKG NYTDFDY SASYLQS QQSNTSPAT SISTAGTYTDYADSVKG NYTDFDY SASYLQS QQSNTSPAT SINDTGYTTYYADSVKG NYTYFDY TASTLQS QQAYTAPTT STASSGTTTYYADSVKG SYADFDY AASNLQS QQADTYPTT TITSTGAATAYADSVKG SYATFDY AASYLQS QQAANSPDT AIDGTGYGTAYADSVKG SYDTFDY GASSLQS QQTSDYPNT SIANAGTATYYADSVKG SYSNFDY SASTLQS QQASTSPTT SIDSAGDSTYYADSVKG SYSYFDY TASYLQS QQASDYPTT SISSSGDTTYYADSVKG SYSYFDY TASTLQS QQSSSNPTT SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT SIDASGANTAYADSVKG TYGTFDY SASYLQS QQSATTPDT

[0011] In one embodiment of the invention, the antibody may be an scFv selected from the group consisting of the following:

[0012] 3-11A, 6-6E, 1-7G, 3-7B, 6-9D, 1-1C, 1-8D, 1-3G, 4-12C, 6-3E, 6-9A, 1-12A, 4-6A, 4-8A, 4-9F, 4-4H, 3-3A, 3-6F, 6-10H, 12E, 3-5G, 3-4D, 3-5D, 6-4E, 3-6B, 3-6G, 4-11F, 6-7H, 1-11E, 1-2F, 1-6H, 3-8D, 1-4D, 4-2F, 3-3B, 3-5C, 6-9C, 4G, 3-12F, 3-4G, 6-11F, 6-11H, 3-2C, 5B, 6-10G, 1-4H, 4-5A, 4-1B, 4-12D, 6-4B, 1-2B, 1-7F, 1-10F, 1-9G, 4-1C, 6-7G, 3-7H, 6-1F, 6-3B, 4H, 3-9A, 6-10D, 3-5H, 3-2F, 1-6G, 3-11H, 6-9F, 3-9D, 4-3H, 3-3E, 3-10C, 3-11E, 6-8C, 6- 11D, 4-5H, 6-5F, 6-7F, 1-10D

[0013] These scFvs are listed in Table 3 in the Examples below and comprise the CDRH2, CDRH3, CDRL2 and CDRL3 sequences shown in Table 1.

[0014] In one embodiment of the invention, the scFv may comprise a sequence as shown in Table 2.

TABLE-US-00002 TABLE 2 Clone I.D. VH-CDR2 VH-CDR3 VL-CDR2 VL-CDR3 1-2E SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT 1-11E SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT 1-4D SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 1-12A SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 12E SINDSGTTTYYADSVKG NYSAFDY AASDLQS QQSDSAPTT 3-9A TIDTAGSYTDYADSVKG NYSYFDY GASTLQS QQSTASPST 3-5C SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 3-11E SIDSAGDSTYYADSVKG SYSYFDY TASYLQS QQASDYPTT 3-2F AIANTGSATNYADSVKG NYTAFDY DASTLQS QQRNTSPTT 3-6G SINSNGTDTYYADSVKG NYSDFDY TASALQS QQGYGAPTT 3-9D SIASSGTFTYYADSVKG SYADFDY AASNLQS QQADTYPTT 6-3B SIATTGTSTTYADSVKG NYSYFDY TASSLQS QQGSTAPTT 6-11D SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT 6-9F SINDTGYTTYYADSVKG NYTYFDY TASTLQS QQAYTAPTT 6-7G SIATTGDNTYYADSVKG NYSYFDY TASTLQS QQAAGNPTT

[0015] Typically, the scFv is 1-11E.

[0016] Oxidised Collagen II (CII) is post-translationally modified Collagen II (CII) that has been oxidised by non enzymatic glycation or by reactive oxidant species (ROS) which may include superoxide radical (O.sub.2), hydrogen peroxide (H.sub.2O.sub.2), hydroxyl radical (OH), hypochlorous acid (HOCl), nitric oxide (NO) and peroxynitrite (ONOO).

[0017] The antigen may therefore be HOCl-Collagen II or Ribose-Collagen II.

[0018] The antibody or fragment thereof is conjugated to the pharmaceutically active moiety which may be a peptide or peptide-based molecule by any suitable means. Where the pharmaceutically active moiety is a peptide or peptide-based molecule the conjugation may be by means of a peptide bond, including the insertion of one or more amino acid residues.

[0019] The conjugation of a peptide or a peptide-based molecule may be achieved by any generally convenient chemical means or biological means (see for example, Wu & Senter Nature Biotechnology, volume 23 (9) pages 1137-1146 (2005); "Chemistry of Protein Conjugation and Crosslinking" by S. S. Wong, CRC Press Inc. (1991)).

[0020] Chemical conjugation typically uses a bifunctional chemical reagent, for example glutaraldehyde can link molecules to the N-terminus of a peptide, carbodiimide can link molecules to the C-terminus of a peptide, succinimide esters (e.g. MBS, SMCC) can bind free amino groups and cysteine residues, benzidine links to tyrosine residues, periodate attaches to carbohydrate groups and isothiocyanate can also link molecules to antibodies.

[0021] Alternatively, a fusion protein may be synthesised using standard recombinant molecular biology techniques (see for example, Sambrook et al "Molecular Cloning: A Laboratory Manual", 3.sup.rd edition, CSHL Press, (2001); Trachsel et al Arthritis Research & Therapy, volume 9 (1) R9 (2007); Nagai Arthritis & Rheumatism, volume 54 (10) pages 3126-3134 (2006)). Methods for producing fusion proteins are described in the Examples herein.

[0022] In certain embodiments of the invention, the insertion of additional amino acid residues between the antibody or fragment thereof and the pharmaceutically active moiety may represent a site for cleavage by a protease. The proteolytic cleavage site may comprise any protease specific cleavage site. The proteolytic cleavage site may include, but is not limited to, a matrix metalloproteinase (MMP) cleavage site, a serine protease cleavage site, a site cleavable by a parasitic protease derived from a pathogenic organism (Zhang et al., J. Mol. Biol. 289, 1239-1251 (1999); Voth et al., Molecular and Biochemical Parasitology, 93, 31-41 (1998); Yoshioka et al., Folia Pharmacologica Japonica, 110, 347-355 (1997); Tort et al., Advances in Parasitology, 43, 161-266 (1999); McKerrow, International Journal for Parasitology, 29, 833-837 (1999); Young et al., International Journal for Parasitology, 29, 861-867 (1999); Coombs and Mottram, Parasitology, 114, 61-80 (1997)) or a site cleavable by the proteins of the complement cascade (Carroll, Annu. Rev. Immunol. 16, 545-568 (1998); Williams et al., Ann. Allergy, 60, 293-300 (1988)).

[0023] The MMP cleavage site may comprise any amino acid sequence which is cleavable by a MMP. The amino acid sequence of the MMP cleavage site may be encoded by a nucleic acid sequence coding for an MMP sequence as shown in FIG. 5 or a sequence of nucleotides which has at least 50%, 60%, 70%, 80%, 90%, 95% or 99% identity, using the default parameters of the BLAST computer program provided by HGMP, thereto. Preferably, the nucleic acid sequence encoding the MMP cleavage site comprises the minimum number of residues required for recognition and cleavage by MMP.

[0024] A MMP cleavage site may comprise a number of amino acid residues recognisable by MMP. Moreover, the amino acids of the MMP site may be linked by one or more peptide bonds which are cleavable, proteolytically, by MMP. MMPs which may cleave the MMP site include, but are not limited to, MMP1, MMP2, MMP3, MMP7, MMP8, MMP9 or MMP10 (Yu and Stamenkovic, Genes and Dev. 14, 163-176 (2000); Nagase and Fields, Biopolymers, 40, 399-416 (1996); Massova et al., J. Mol. Model. 3, 17-30 (1997); reviewed in Vu and Werb, Genes and Dev. 14, 2123-2133 (2000)). The sequences of the protein cleavage sites of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9 and MMP10 are shown in FIG. 5

[0025] Preferably, the proteolytic cleavage site of the present invention is cleaved at sites of inflammation and tissue remodeling. More preferably, the proteolytic cleavage site of the present invention is a MMP cleavage site e.g. any one or more of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9 or MMP10 as shown in FIG. 5.

[0026] The pharmaceutically active moiety may comprise one or more molecules which may be the same or different, one or more radioisotopes which may be the same or different, or one or more non-radioactive elements which may be the same or different.

[0027] In some embodiments of the invention, the pharmaceutically active moiety may comprise a polypeptide or non-polypeptide molecule. References to a polypeptide include a peptide and vice versa unless the context specifies otherwise.

[0028] The polypeptide may be an antibody or a fragment thereof, such as an anti-TNFalpha monoclonal antibody (for example infliximab or adalimumab), a soluble p75 TNF receptor molecule (for example etanercept) or a IL-1 receptor antagonist (for example anakinra). In such embodiments of the invention, the composition will therefore comprise a bispecific antibody which may be a diabody (scFv with a linker which is too short to allow pairing between VH and VL and therefore the domains are forced to pair with the complementary domain of another scFv to create two antigen binding site), a minibody (composed of two scFv moieties linked via a constant heavy chain region (CH3)), a scFv-Fc molecule, or an intact antibody molecule containing the two separate binding regions.

[0029] For example, a bispecific antibody may comprise a first binding region specific for modified Collagen II (CII) and a second binding region specific for anti-TNFa.

[0030] In one embodiment, the polypeptide is a TNF receptor (TNFR) antibody fusion protein, typically a TNFR2-Fc fusion protein.

[0031] A bispecific antibody of the invention may also further comprise another pharmaceutically active moiety. For example, a composition of the invention may comprise a first binding region specific for modified Collagen II, a second binding region specific for CD64, and a toxin, such as Ricin A.

[0032] Alternatively, the polypeptide may be a growth factor (e.g. TGF.beta., epidermal growth factor (EGF), platelet derived growth factor (PDGF), nerve growth factor (NGF), colony stimulating factor (CSF) granulocyte/macrophage colony stimulating factor (GM-CSF), hepatocyte growth factor, insulin-like growth factor, placenta growth factor); differentiation factor, cytokine molecule, for example an interleukin, (e.g. IL1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20 or IL-21, either .alpha. or .beta.), an interferon (e.g. IFN-.alpha., IFN-.beta. and IFN-.gamma.), tumour necrosis factor (TNF), IFN-.gamma. inducing factor (IGIF), a bone morphogenetic protein (BMP); a chemokine (for example a MIP (Macrophage Inflammatory Protein) e.g. MIP1.alpha. and MIP1.beta.; a MCP (Monocyte Chemotactic Protein) e.g. MCP1, 2 or 3; RANTES (regulated upon activation normal T-cell expressed and secreted)); a trophic factor, a cytokine inhibitor, a cytokine receptor (for example, CD20, CD40, CD40L, CD64); a free-radical scavenging enzyme (e.g. superoxide dismutase or catalase), or a toxin (for example Ricin A toxin, or Pseudomonas exotoxin A), or an active fragment or portion thereof. Typically, the polypeptide is an interferon, typically IFN-.beta..

[0033] See for example, Trachsel et al Arthritis Research & Therapy, volume 9 (1) R9 (2007) reporting antibody-IL10 fusion protein; Nagai Arthritis & Rheumatism, volume 54 (10) pages 3126-3134 (2006) reporting antibody-toxin fusion protein. Other examples of antibody-fusion proteins, include but are not limited to, antibody-TNFalpha, antibody-GM-CSF, and antibody-IL2 fusion proteins

[0034] The pharmaceutically active polypeptide may be derived from the species to be treated e.g. human origin for the treatment of humans.

[0035] The composition may also comprise further peptide sequences which can target the composition inside a cell. Such intracellular targeting sequences include, but are not limited to, the TAT sequence YGRKKRQRRR (see for example, Cohen-Saidon et al Blood, volume 102 (7), pages 2506-2512 (2003)).

[0036] As used herein "peptide mimetics" includes, but is not limited to, agents having a desired peptide backbone conformation embedded into a non-peptide skeleton which holds the peptide in a particular conformation. Peptide mimetics, which do not have some of the drawbacks of peptides, are of interest in those cases where peptides are not suitable in medicine.

[0037] Peptide mimetics may comprise a peptide backbone which is of the L or D conformation. Examples of peptide mimetics include melanocortin, adrenocorticotrophin hormone (ACTH) and other peptide mimetic agents which play a role in the central nervous system, endocrine system, in signal transduction and in infection and immunity.

[0038] The pharmaceutically active agent may comprise a chemical compound such as a chemotherapeutic agent or other synthetic drug. Alternatively, the pharmaceutically active agent may comprise a peptide nucleic acid (PNA) sequence e.g. a poly-lysine sequence which binds to nucleic acids and permeabilises lipid bilayers (Wyman et al., Biological Chemistry, 379, 1045-1052 (1998)) or a KALA peptide which facilitates transfer through lipid bilayers (Wyman et al., Biochemistry, 36, 3008-3017 (1997)).

[0039] The non-polypeptide may be a glycosaminoglycan molecule, such as glucosamine (suitably, glucosamine HCl) or chondroitin. Alternatively, the non-polypeptide molecule may be a non-steroidal anti-inflammatory drug (NSAID) such as a non-selective NSAID or a selective NSAID. Examples of non-selective NSAIDs include aspirin, ibuprofen, and naproxen. Examples of selective NSAIDs (also called COX-2 inhibitors) include celecoxib (Celebrex.RTM.), rofecoxib (Vioxx.RTM.) and valdecoxib (Bextra.RTM.)). Other substances may include steroids, such as cortisol, or polymeric molecules such as sodium hyaluronate or hyaluronic acid (for example hyaluronan (Hyalgan.RTM.) and hylan-GF-20 (Synvisc.RTM.)), or drug substances such as colchicine or hydroxychloroquine (Plaquenil.RTM.).

[0040] Non-polypeptides may be conjugated to the antibody or fragment thereof using a linker that may be a labile bond in order to permit release of the pharmaceutically active substance. For example, a hydrazone bond may be used where the drug is released under acidic conditions, or a disulfide bond which is reduced to release the drug, or also a peptide bond which is cleaved enzymatically by a protease as described above.

[0041] In some embodiments, the composition may comprise a radioactive element or a non-radioactive element. The radioisotope may be an alpha particle-emitting radionuclide such as .sup.213Bi or .sup.211At, a beta particle-emitting radionuclide such as .sup.131I, .sup.90Y, .sup.177Lu or .sup.67Cu, a gamma radiation-emitting radionuclide such as .sup.99mTc, .sup.123I or .sup.111In, or a positron-emitting radionuclide such as .sup.18F, .sup.64Cu, .sup.68Ga, .sup.86Y or .sup.124I. Radioisotopes may be used in order to render the composition detectably labelled for diagnostic uses of the composition.

[0042] Alternatively, the non-radioactive element may be Au, Fe, Cu, Pt or Ag.

[0043] Combinations of the various elements and substances described above may also be included as desired.

[0044] According to a second aspect of the invention, there is provided a composition of the first aspect for use in medicine. This aspect of the invention includes a composition of the first aspect for use in the treatment of an arthropathy, such as rheumatoid arthritis (RA) and osteoarthritis (OA). This aspect of the invention therefore extends to a method of treatment of an arthropathy, such as rheumatoid arthritis (RA) and osteoarthritis (OA), comprising the step of administering to a subject a composition of the first aspect of the invention. The present invention therefore also includes the use of a composition of the first aspect of the invention in the manufacture of a medicament for the treatment of an arthropathy, such as rheumatoid arthritis (RA) and osteoarthritis (OA).

[0045] A composition of the first aspect of the invention may therefore be formulated as a pharmaceutical composition. Suitably, a pharmaceutical composition may comprise a diluent, excipient, adjuvant and/or physiologically acceptable buffer.

[0046] The pharmaceutical composition may be administered in any effective, convenient manner effective for treating a disease as described above including, for instance, administration by oral, topical, intravenous, intramuscular, intra-articular, intranasal, or intradermal routes among others. In therapy or as a prophylactic, the composition of the invention may be administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably isotonic. The injection may suitably be made into the joint affected by the disease.

[0047] For administration to mammals, and particularly humans, it is expected that the daily dosage of the composition of the invention will be from 0.01 mg/kg body weight, typically around 1 mg/kg. The physician in any event will determine the actual dosage which will be most suitable for an individual which will be dependant on factors including the age, weight, sex and response of the individual. The above dosages are exemplary of the average case. There can, of course, be instances where higher or lower dosages are merited, and such are within the scope of this invention

[0048] According to a third aspect of the present invention, there is provided a method for the diagnosis of an arthropathy, such as rheumatoid arthritis (RA) and osteoarthritis (OA), comprising the steps of administering a detectably labelled composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) to a subject and subsequently detecting the composition. This aspect of the invention therefore extends to a detectably labelled composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) for use in the diagnosis of an arthropathy, such as rheumatoid arthritis (RA) and osteoarthritis (OA). Such embodiments also extend to the use of such compositions in the manufacture of an agent for the diagnosis of an arthropathy, such as rheumatoid arthritis (RA) and osteoarthritis (OA).

[0049] The detectable label may be a radioactive or a fluorescent label. In some embodiments the radioisotope may be an alpha particle-emitting radionuclide such as .sup.213Bi or .sup.211At, a beta particle-emitting radionuclide such as .sup.131I, .sup.90Y, .sup.177Lu or .sup.67Cu, a gamma radiation-emitting radionuclide such as .sup.99mTc, .sup.123I or .sup.111In, or a positron-emitting radionuclide such as .sup.18F, .sup.64Cu, .sup.68Ga, .sup.86Y or .sup.124I. Radioisotopes may be used in order to render the composition detectably labelled for diagnostic uses of the composition.

[0050] For diagnostic purposes, fluorescent dyes such as Alexa Fluor 488 or the Cy3 monofunctional N-hydroxysuccinimide (NHS) ester could also be used.

[0051] According to a fourth aspect of the invention, there is provided a composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) and a detectable label.

[0052] RA is the most common chronic inflammatory autoimmune disease, with disability occurring usually within 10 years. Over activation of the inflammatory pathway leads to synovitis, joint damage and destruction. Key players in the joint inflammation are inflammatory cytokines such as TNFa and IL-1. The efficacy of anti-TNFa monoclonal antibodies (Infliximab and Adalimumab), soluble p75 TNF receptors (Etanercept) and IL-1 receptor antagonist (Anakinra) in the treatment of RA patients unresponsive to traditional therapy is now well established but unfortunately might be associated with an increase in serious infection and malignancies. It is therefore becoming very important to develop targeted delivery of anti-proinflammatory drugs to the inflamed joint rather than systemic administration because cytokines exert their function as auto or paracrine factors with high concentrations only in close vicinity of the producing cell. Systemic administration of sufficient blocking agents that can block the local high physiological concentration will likely cause severe side effects.

[0053] Although CII is the best candidate to target therapy to the joint one needs to find a way to target the drugs solely to the inflamed joints. The present studies show the development of a targeting antibody that will specifically recognise collagen type II that has been modified by ROS present in inflamed joint which then allows targeting to inflammatory damage joint independently of the aetiology.

[0054] By employing the phage display human antibody library, a panel of human scFvs was developed (FIG. 1) that bind only to CII which was modified in vitro by HOCl or glycation, known reactive oxidants in RA. Most importantly this scFv binds only to damaged cartilage but not to normal cartilage (FIG. 3) and inversely correlates with the staining of safranin-O for the integrity of cartilage-specific proteoglycan. Most importantly, when inflammation was induced in only one paw in CH3 mice with antigen induced arthritis model 1-11E diabody localized only to the inflamed paw without any background to any of the other healthy paws (FIG. 4). This strongly supports the specificity of 1-11E for damaged CII in vivo in inflammation setting and therefore have potential for targeting anti-TNFa, other pro-inflammatory cytokine blockade or cartilage regenerating factors to inflamed joints. This approach is significantly different from targeting citrullinated peptides that appear as a good biomarker for disease in RA but could not be used as a targeting molecule as its tissue expression is not joint specific.

[0055] Preferred features of the second and subsequent aspects of the invention are as for the first aspect mutatis mutandis.

[0056] In one embodiment, a composition of the invention comprises mouse interferon-beta (IFN-.beta.), the scFv 1-11E and a MMP cleavage site. Such a composition can be produced by creating pFastBac1.AH by cutting out a BamHI/HindIII fragment containing multiple cloning sites (MCS) from pFastBac1 (Invitrogen) and replacing this fragment with a linker to give another MCS of BamHI-KpnI-HindIII-ApaI, cloning mouse interferon b (mIFNb) into the HindIII-EcoRI sites and cloning MMP and 1-11E into the NotI and ApaI site as shown in FIG. 10A.

[0057] Mouse interferon-beta is typically amplified using primers having the sequences shown in SEQ ID NO: 129 (forward) and SEQ ID NO: 130 (reverse). 1-11E is typically amplified using primers having the sequences shown in SEQ ID NO: 131 (forward) and SEQ ID NO: 132 (reverse), wherein 1-11E is amplified with NotI/ApaI ends to include a histidine (His) tag.

[0058] 1-11E is typically then cloned into FastBac1.AH mIFN-b/MMP/SP/His and cut with Not/Apa to liberate SP/His. The mIFN-beta/His construct is typically cloned by amplifying mIFN-b with HindIII/ApaI using primers having the sequence shown in SEQ ID NO: 129 (forward) and SEQ ID NO: 133 (reverse).

[0059] The constructs are then typically transformed into DH10Bac cells (Invitrogen).

[0060] In another embodiment, a composition of the invention comprises TNF receptor 2-Fc (TNFR2Fc), an scFv (either 1-11E or C7 as a negative control) and a MMP cleavage site. Such a composition can be produced by creating pFastBac1.AH from pFastBac1 (Invitrogen) by cutting out a BamHI/HindIII fragment containing multiple cloning sites (MCS), and replacing this fragment with a linker to give another MCS of BamHI-KpnI-HindIII-ApaI, cloning TNFR2Fc into the HindIII-EcoRI sites and cloning a MMP cleavage site and scFv (1-11E or C7) into the NotI and ApaI sites as shown in FIG. 10B.

[0061] Mouse TNFR2-Fc is typically amplified using primers having the sequences shown in SEQ ID NO: 141 (forward) and SEQ ID NO: 142 (reverse). 1-11E is typically amplified using primers having the sequences shown in SEQ ID NO: 131 (forward) and SEQ ID NO: 132 (reverse), wherein 1-11E is amplified with NotI/ApaI ends to include a histidine (His) tag.

[0062] Expression of the constructs is typically carried out using a protocol set out in FIG. 11. Such a protocol typically involves the following steps:

[0063] 1. Transforming the constructs into competent DH10Bac cells (Invitrogen) to generate bacmid vectors.

[0064] 2. Confirming recombinant bacmid vectors by blue-white screening and PCR, typically according to Invitrogen instructions.

[0065] 3. Transfecting bacmid DNA into Sf9 insect cells using cellfectin, typically according to Invitrogen instructions.

[0066] 4. Harvesting baculovirus (P1) from the supernatant of transfected cells.

[0067] 5. Using the harvested baculovirus to infect fresh Sf9 cells to amplify the virus stocks.

[0068] 6. Using P3 virus to infect High 5 insect cells, typically for 72 hours.

[0069] In one embodiment, infected High 5 cells are grown for 3 days at 27.degree. C.

[0070] The supernatant is typically then collected and run on an SDS-PAGE gel. Recombinant proteins can be detected by Western blot, for example using anti-tetra-His antibody (Qiagen) and anti-mouse HRP (Sigma).

[0071] The invention will now be described by way of reference to the following Examples which are present for the purposes of illustration only and are not to be construed as being limiting on the present invention. Reference is also made in the Examples to the following drawings in which:

[0072] FIG. 1 shows representative ELISA of unique scFvs

[0073] FIG. 2 shows Western Blotting with scFv 1-11E probe

[0074] FIG. 3 shows specific binding to damaged human cartilage tissue by anti-ROS-modified CII scFv in patients with OA in photographs (A) to (H).

[0075] FIG. 4 shows the localisation of scFv 1-11E in inflamed paw.

[0076] FIG. 5 shows the sequences of the protein cleavage sites of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9 and MMP10.

[0077] FIG. 6 shows specific binding to damaged human cartilage tissue by anti-ROS-modified CII scFv in patients with OA.

[0078] FIG. 7 shows specific binding to damaged human cartilage tissue by anti-ROS-modified CII scFv in patients with RA.

[0079] FIG. 8 shows: (A) and (B) histological staining of the right paw; (C) and (D) 1-11E staining of cartilage in the paw; (E) staining with a non-relevant scFv; all in a mouse RA model.

[0080] FIG. 9 shows staining of a joint surface injury in a mouse OA model.

[0081] FIG. 10 shows the construction of (A) an IFN-.beta./1-11E fusion protein; and (B) a TNFR2Fc/scFv fusion protein.

[0082] FIG. 11 shows the protocol used for expression of the IFN-.beta./1-11E fusion protein and the TNFR2Fc/scFv fusion protein.

[0083] FIG. 12 is a Western blot of the IFN-.beta./1-11E fusion protein.

[0084] FIG. 13 is a Western blot of (A) and (B) TNFR2Fc/1-11E fusion proteins; (C) a TNFR2Fc/C7 fusion protein

EXAMPLE 1: PREPARATION AND MODIFICATION OF CII

[0085] CII was prepared from bovine cartilage as in Miller (Miller, Biochemistry 11(26): 4903-4909, 1972) and subsequently exposed to reactive oxygen generating systems as previously described (Nissim A, 2005). Briefly, CII was modified with (.OH), HOCl (Hawkins C L, 2001; Hawkins C L, 2002), (ONOO.sup.-), or 2M ribose by ON incubation at 37.degree. C. Bovine serum albumin (BSA, Sigma) was also modified as above and was used as control antigen.

EXAMPLE 2: SELECTION OF ANTI-MODIFIED CII SCFV FROM PHAGE-DISPLAY LIBRARY

[0086] Phage display antibody technology (Winter G et al, Annu. Rev. Immunol. 12: 433-455, 1994) was used to raise a single chain fragment variable (scFv) that binds only to CII that has been post-translationally modified by free radicals.

[0087] A human semi-synthetic scFv library constructed from a single human framework for V.sub.H (DP-47 and JH4) and V.sub.L (DPK9 and JK1) was employed, in which diversity was incorporated in CDR3 and CDR2 (de Wildt R. M et al, Nat. Biotechnol. 18(9): 989-994, 2000). To select for phage binding to modified CII and not to native non-modified CII, subtractive selection was performed using native non-modified CII for subtraction. HOCl modified CII was used as a target for panning as binding to HOCl modified CII was strongest in RA sera (Nissim A, 2005). Glycated CH was used in parallel. Briefly, immunotubes (Nunc-Immuno Tubes, Maxi-Sorp, Nunc, Denmark) were coated with 10 .mu.g/ml CII in phosphate-buffered saline (PBS). After blocking with 2% marvel in PBS (MPBS) coated tubes were exposed for 2 hours to 10.sup.13 transforming units (tu) of the phage library in 2% MPBS. Unbound phage were then transferred to a second immunotube previously coated with HOCl or ribose-modified CII for a further 2 hours incubation at room temperature. Modified CII-bound phage were then used to infect E. coli TG-1 and rescued by helper phage as described (Harrison J. L, 1996). The panning process was repeated three times and E. coli TG-1 was infected with the final phage eluted after the third round and individual ampicillin-resistant colonies (phage clones) were selected for further analysis.

EXAMPLE 3: SCREENING AND SEQUENCING OF MODIFIED CII-SPECIFIC PHAGE CLONES

[0088] Screening for positive anti-modified CII phage clones was first performed by enzyme-linked immunosorbent assay (ELISA), as previously described (Harrison J. L, 1996). Microtiter plate (Nunc, Paisley, UK) wells were coated with 10 .mu.g/ml native or modified CII and incubated with 100 .mu.l phage suspension for 90 minutes. In addition, native and modified BSA were used as negative control. After removal of the supernatants, the amount of bound phage was determined using peroxidase-labeled anti-M13 antibodies (GE Healthcare Ltd, Little Chalfont, Buckinghamshire) and developed by using 100 mM 3,3'5,5' tetramethylbenzidine (TMB) as substrate. The reaction was monitored in an ELISA reader at 450 nm with a reference wavelength of 650 nm using GENios plate reader (TECAN, Theale Court, Reading UK) and Magellan software (TECAN, Theale Court, Reading UK) The entire scFv DNA fragment of each modified CII bound phage clone was sequenced using the primers LMB-3 (5'-C AGGAAACAGCTATGAC) and Fd-Seq (5'-GAATITICTGTATGAGG). Sequences were analyzed using Chromas (Technelysium Pty Ltd) and VBASE (http://vbase.mrc-cpe.cam.ac.uk), to identify unique scFv sequences as shown in Table 3.

TABLE-US-00003 TABLE 3 Clone Antigen CDRH2 CDRH3 CDRL2 CDRL3 3-11A HOC1-CII DISSTGSYTAYADSVKG GAGSFDY AASALQS QQSSSTPTT 6-6E HOC1-CII AISAAGTATAYADSVKG GYDTPDY AASSLQS QQNYGYPNT 1-7G Ribose-CII SISNSGSYTDYADSVKG GYGSNDY AASTLQS QQANSSPDT 3-7B HOC1-CII SINNYGSNTAYADSVKG GYSSFDY AASYLQS QQTSSSPDT 6-9D HOC1-CII SINNYGSNTAYADSVKG GYSSFDY AASYLQS QQTSSSPDT 1-1C Ribose-CII SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT 1-8D Ribose-CII SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT 1-3G Ribose-CII SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT 4-12C Ribose-CII SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT 6-3E HOC1-CII SISYTGNSTDYADSVKG GYTAFDY YASYLQS QQADSTPTT 6-9A HOC1-CII NIATDGTTTYYADSVKG NSTYFDY SASTLQS QQAATSPTT 1-12A Ribose-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 4-6A Ribose-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 4-8A Ribose-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 4-9F Ribose-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 4-4H Ribose-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 3-3A HOC1-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 3-6F HOC1-CII SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST 6-10H HOC1-CII SISYTGDSTYYADSVKG NYSAFDY YASYLQS QQADSTPTT 12E Unknown SINDSGTTTYYADSVKG NYSAFDY AASDLQS QQSDSAPTT 3-5G HOC1-CII SIDSAGASTYYADSVKG NYSAFDY NASSLQS QQSDTYPST 3-4D HOC1-CII SISYTGDSTYYADSVKG NYSAFDY TASNLQS QQSYASPTT 3-5D HOC1-CII SISYTGDSTYYADSVKG NYSAFDY TASNLQS QQSYASPTT 6-4E HOC1-CII SISYTGDSTYYADSVKG NYSAFDY TASNLQS QQTGSYPTT 3-6B HOC1-CII SINATGYGTYYADSVKG NYSDFDY SASALQS QQGDSYPTT 3-6G HOC1-CII SINSNGTDTYYADSVKG NYSDFDY TASALQS QQGYOAPTT 4-11F Ribose-CII SISATGSSTYYADSVKG NYSDFDY SASDLQS QQSSYTPTT 6-7H HOC1-CII SISATGSSTYYADSVKG NYSDFDY SASDLQS QQSSYTPTT 1-11E Ribose-CII SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT 1-2F Ribose-CII SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT 1-6H Ribose-CII SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT 3-8D HOC1-CII SIDDSGATTYYADSVKG NYSSFDY YASSLQS QQAANYPTT 1-4D Ribose-CII SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 4-2F Ribose-CII SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 3-3B HOC1-CII SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 3-5C HOC1-CII SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 6-9C HOCI-CII SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 4G Unknown SIASTGDSTYYADSVKG NYSSFDY SASALQS QQASNYPTT 3-12F HOC1-CII SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT 3-4G HOC1-CII SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT 6-11F HOC1-CII SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT 6-11H HOC1-CII SISTNGSSTYYADSVKG NYSSFDY DASGLQS QQGDTSPTT 3-2C HOC1-CII SIDTTGTTTYFADSVKG NYSSFDY SASYLQS QQGYSAPTT 5B Unknown TISYSGNNTYYADSVKG NYSSFDY TASSLQS QQGYTSPTT 6-10G HOC1CII SIDAGGNGTYYADSVKG NYSSFDY TASNLQS QQNNYYPTT 1-4H Ribose-CII SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT 4-5A HOC1-CII SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT 4-1B HOC1-CII SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT 4-12D HOC1-CII SIDAGGNGTYYADSVKG NYSSFDY YASSLQS QQSDAYPTT 6-4B HOC1-CII SIDSAGNATYYADSVKG NYSSFDY AASTLQS TSNYPTTQQ 1-2E Ribose-CII SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT 1-7F Ribose-CII SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT 1-10F Ribose-CII SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT 1-9G Ribose-CII SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT 4-1C Ribose-CII SITDSGDTTYYADSVKG NYSTFDY SASSLQS QQSNATPTT 6-7G HOC1-CII SIATTGDNTYYADSVKG NYSYFDY TASTLQS QQAAGNPTT 3-7H HOC1-CII AINAYGGSTYYADSVKG NYSYFDY AASSLQS QQGSDYPTT 6-1F HOC1-CII AINAYGGSTYYADSVKG NYSYFDY AASSLQS QQGSDYPTT 6-3B HOC1-CII SIATTGTSTTYADSVKG NYSYFDY TASSLQS QQGSTAPTT 4H Unknown SIATTGTSTTYADSVKG NYSYFDY TASSLQS QQGSTAPTT 3-9A HOC1-CII TIDTAGSYTDYADSVKG NYSYFDY GASTLQS QQSTASPST 6-10D HOC1-CII SISNNGSSTYYADSVKG NYSYFDY AASNLQS QQTSSYPTT 3-5H HOC1-CII SIAYGGAGTDYADSVKG NYTAFDY AASYLQS QQGAGSPST 3-2F HOC1-CII AIANTGSATNYADSVKG NYTAFDY DASTLQS QQRNTSPTT 1-6G Ribose-CII SISTAGTYTDYADSVKG NYTDFDY SASYLQS QQSNTSPAT 3-11H HOC1-CII SISTAGTYTDYADSVKG NYTDFDY SASYLQS QQSNTSPAT 6-9F HOC1-CII SINDTGYTTYYADSVKG NYTYFDY TASTLQS QQAYTAPTT 3-9D HOC1-CII SIASSGTTTYYADSVKG SYADFDY AASNLQS QQADTYFTT 4-3H Ribose-CII TITSTGAATAYADSVKG SYATFDY AASYLQS QQAANSPDT 3-3E HOC1-CII ATDGTGYGTAYADSVKG SYDTFDY GASSLQS QQTSDYPNT 3-10C HOC1-CII SIANAGTATYYADSVKG SYSNFDY SASTLQS QQASTSPTT 3-11E HOC1-CII SIDSAGDSTYYADSVKG SYSYFDY TASYLQS QQASDYPTT 6-8C HOC1-CII SISSSGDTTYYADSVKG SYSYFDY TASTLQS QQSSSNPTT 6-11D HOC1-CII SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT 4-5H Ribose-CII SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT 6-5F HOC1-CII SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT 6-7F HOC1-CII SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT 1-10D Ribose-CII SIDASGANTAYADSVKG TYGTFDY SASYLQS QQSATTPDT

EXAMPLE 4: PRODUCTION AND PURIFICATION OF ANTI-MODIFIED CII-SCFV

[0089] The reactive phage clones obtained from E. coli TG-1 bacteria were used to infect E. coli HB2151 non-suppressor bacterial strain to obtain soluble scFv. After overnight induction with 1 mM IPTG at 30.degree. C., the antibody fragments, derived from the V.sub.H3 family, were harvested from the supernatant and periplasmic space as described (Harrison J. L, 1996) and purified on a protein A affinity column (GE Healthcare Ltd, Little Chalfont, Buckinghamshire). Binding of purified scFv to modified CII was first analyzed by ELISA as above except that mouse anti-myc tag antibody (Santa Cruz Biotechnology, INC, Wembley, UK) followed by anti-mouse-HRP conjugate (Sigma, Dorset, UK) were used to probe bound scFv.

Anti-Modified CII scFv Raised by Phage Display Human Antibody Library

[0090] After three rounds of subtractive selection 82 phage clones specific to either glycated CII or HOCl modified CII were selected out of which 42 clones had unique sequences. 15 representative clones with different binding patterns but with good expression were then studied for further analysis (FIG. 1 and Table 1). As shown in FIG. 1, out of these 15 clones there were 9 clones with stronger binding to modified CII, 3 clones bound to all forms of CII and 3 clones had no binding reactivity to any form of CII. Three scFvs that have different binding characteristics were then further studied: Clone 1-11E binds to modified CII (glycated, HOCl and to some extent to peroxynitrated CII), clone 6-11D binds to both native and modified CII and clone 12E that does not bind to any form of CII. None of these scFv bound to native or free radical modified BSA, or to collagen type III (data not shown).

EXAMPLE 5: WESTERN BLOTTING

[0091] Western blot using scFv as probe and modified or native CII as target antigens was done as described (Nissim A, 2005). Briefly, modified and native CII (2 .mu.g of each) were run on a 7.5% denaturing SDS gel and electroblotted into a nitrocellulose membrane. After blocking with 2% MPBS, membranes were incubated with 10 .mu.g/ml purified scFv in 2% MPBS for 2 hr at room temperature, followed by incubation with mouse anti-myc tag (Santa Cruz Biotechnology, INC, Wembley, UK) and then with anti-mouse-HRP (Sigma, Dorset). Membranes were washed three times with 0.1% Tween PBS (5 min each) and three times with PBS (5 min each) before development with ECL (GE Healthcare Ltd, Little Chalfont, Buckinghamshire).

Comparative Analysis of Human RA Serum and scFv Binding to CII by Western Blotting

[0092] 1-11E binds several CII fragments between 50 and 150 kDa as well as to a band >250 kDa which resulted from CII cross linking due to the ROS reactivity (FIG. 2 lane 2-5). 1-11E also binds to native CII corresponding to a band below 150 KDa (FIG. 2 lane 1). Binding to native CII in Western blotting was also seen in sera from RA patients that did not bind to native CII in ELISA but only to ROS modified CII in ELISA (for example sera 33 (Nissim A, 2005)).

EXAMPLE 6: IMMUNOHISTOCHEMISTRY OF HUMAN OA AND RA CARTILAGE USING SELECTED ANTI-MODIFIED CII SCFV

[0093] One osteochondral sample was obtained from the femoral condyle of a patient (female, 63 years old) undergoing prosthetic knee replacement for OA. One sample of normal human cartilage was obtained post-mortem from a preserved area of a knee with unicompartimental OA undergoing joint replacement (female, 54 years old). In both cases, cartilage was fixed overnight at 4.degree. C. in 4% paraformaldehyde, decalcified for 15 days in 0.5M EDTA at 4.degree. C., washed in PBS, and embedded in paraffin according to standard protocols. Safranin O staining was performed according to standard protocols (Rosenberg, 1971). All samples were obtained in accordance with institutional policies and regulations.

[0094] For immunostaining, 5 mm thick sections were cut, deparaffinized and hydrated according to standard protocols. After endogenous peroxidase quenching in 0.5% hydrogen peroxide for 15 min antigen retrieval was done by 45 min incubation of slides with 3 mg/ml pepsin (Zymed, Chandlers Ford, Hampshire, UK) at 37.degree. C. followed by two washes with PBS. Endogenous avidin activity was blocked using a commercially available kit (Vector Laboratories, Orton Southgate, Peterborough, UK) according to the manufacturer's instructions. This was followed by 30 min blocking with 0.5% BSA. Immunostaining was performed using the selected scFv (10 .mu.g/ml and 1 .mu.g/ml) as well as control commercial mouse anti-CII antibodies (diluted 1:100 and 1:1000 dilution; Chemicon International, Chandlers Ford, Hampshire, UK) and polyclonal anti-CII antibodies (diluted 1:100, 1:1000) from collagen induced arthritis (CIA) mice. ScFv or control antibodies were added to the slide in blocking buffer (0.5% BSA in PBS plus 0.05% sodium azide) and left overnight at 4.degree. C. When scFv were used for probing, next day slides were washed with PBS for 2 minutes and incubated for 30 minutes with anti-myc tag mouse antibodies to bind to the myc tag incorporated at the carboxy terminal end of the scFv (diluted 1:200, Santa Cruz Biotechnology Inc, Wembley, UK). After two washes as above anti-mouse biotinylated antibodies were added (Vector kit PK-6102) followed by two washes with PBS and development with DAB substrate (DAKO, Ely, Cambridgeshire, UK) and nuclear counterstaining with Mayer's haematoxylin. Slides were finally dehydrated and mounted with DPX mount (BDH, London, UK)

Specific Binding to Damaged Human Cartilage Tissue by Anti-ROS-Modified CII scFv

[0095] The cartilage extracellular matrix is a complex structure where several molecules interact to form a structural and functional unit. There is therefore the chance that the tertiary and quaternary structure of collagens in the intact tissue may alter the specificity of binding of the phage antibodies that had been selected in vitro. To determine binding specificity in the intact tissue, the capacity of anti-ROS-modified CII scFv to bind to CII within the matrix complex structure and to present immunoreactivity with damaged OA cartilage as opposed to normal cartilage was tested. 1-11E stained the extracellular matrix of cartilage tissue that displayed marked features of OA (FIG. 3A, B) with mostly pericellular staining (FIG. 3 B), with severe damage of the extracellular matrix determined with reduced staining with safranin O (FIG. 3 C). No staining by scFv 1-11E was detected when using histologically normal cartilage from normal cartilage (FIG. 3 D, B). By contrast, polyclonal antibodies from CIA mice bound the OA cartilage in both the damaged and non-damaged regions strongly (FIG. 3 F) and weakly stained with safranin O (FIG. 3 C). A commercial anti-CII mAb did not stain the damaged cartilage areas stained by 1-11E on an adjacent section (FIG. 3 G) but intensely stained a histologically normal cartilage (FIG. 3 H), suggesting that the epitope recognised by the commercial antibody is lost in the OA section.

[0096] FIG. 6 also shows staining of OA cartilage. Although synovial inflammation in OA is not as extensive as in RA and inflammatory cells are not significant in numbers, low grade synovitis is nearly a constant feature in OA. Abnormal mechanical force appears to stimulate chrondocytes to produce some of the same inflammatory mediators and ROS as the infiltrating leukocytes present in inflamed RA joints, leading to post-translational modifications of CII in OA. FIG. 6 confirms the results shown in FIG. 3 and shows that staining of OA cartilage section is only pericellular, around the chrondocytes.

[0097] A further sample was obtained from a patient (female, 47 years old) undergoing total right knee replacement for RA. Fixing and staining protocols were as described above.

[0098] FIG. 7 shows staining of the RA cartilage. In RA, infiltrating inflammatory cells consume increased amounts of oxygen, resulting in the generation of reactive oxygen species (ROS), which may cause excessive degradation of the extracellular matrix leading to cartilage destruction and chemical post-translational modification of CII by ROS. FIG. 7 shows uniteral staining of RA cartilage across the section. This is due to the high influx of immune cells that produce high levels of ROS.

EXAMPLE 7: CONSTRUCTION AND EXPRESSION OF DIABODY

[0099] Out of the unique scFv assessed for specific binding to modified CII as well as best expression in bacteria, the most promising scFv, 1-11E of 25 kDa, was engineered to a larger fragment of 55 KDa. The linker between the V.sub.H and VL was shortened by digesting the phagemid vector with XhoI and SalI and relegation. This results in bivalent diabody, a superior molecule with an increased half life (Hudson, 2005) built from two scFv. Expression and screening of diabody binders was done as above. Molecular weight profile of the resulted expressed diabody was analyzed by gel filtration.

EXAMPLE 8: INDUCING ARTHRITIS IN THE ANIMAL MODELS

[0100] Male C3H mice (age 17-19 weeks) were used. 100 mg of dessicated non-viable T.B. strain H37RA (Difco 231141) was added to 30 ml of incomplete Freunds adjuvant (IFA, Difco 263910) to form complete Freunds adjuvant (CFA). An equal volume of CPA was added to a 2 mg/ml solution (in PBS) of methylated BSA (mBSA) (Sigma A1009). The mixture was then emulsified on ice using an Ultra-Turrax T25 homogeniser at 13500-20500 rpm until a fluffy milky consistency was obtained. Mice were anaesthetised with Hypnorm, and 100 .mu.l of 1 mg/ml (i.e. 100 .mu.g) mBSA in CFA was injected over 2-3 separate sites intradermally. 1 week later, the immunisation was repeated as previously, except that no bacteria were added (i.e. IFA/mBSA). Two weeks after the 2nd immunisation, mice were anaesthetised with nitrous/oxygen and halothane, and inflammation was induced by injecting 50 .mu.l of 1 mg/ml (i.e. 50 .mu.g) mBSA in PBS into the animals' left hind paw. As a control, 50 .mu.l PBS was injected into the right hind paw. Inflammation was measured using calipers to measure the paw thickness. Swelling was seen only in the right paws from 24 hours, and persisted until 1 week later. 2 weeks later, the swelling had totally subsided.

EXAMPLE 9: IMAGING OF ANTI-ROS MODIFIED CII LOCALIZATION

[0101] 50 .mu.g of 1-11E diabody was radiolabelled with 20 MBq of sodium [I-125] iodide (GE Healthcare, Amersham, UK) using the iodogen method (Perbio Science, Cramlingham, UK) and diluted in PBS to a final volume of 240 .mu.l. Radiochemical purity was determined by thin-layer chromatography on silica gel (ITLC, Pall Corporation, Portsmouth, UK) using 85% methanol as mobile phase. A volume of 100 .mu.l of the labeled diabody was injected intravenously via the tail vein into two arthritis-bearing C3H mice 24 hours after injection of the mBSA. Four and 22 hours later the mice were anaesthetized by ip injection of Ketamine/Xylazine. The mice were imaged on a NanoSPECT/CT scanner (Bioscan Inc, Washington, USA) using a four-detector/36.times.1.4 mm pinhole configuration. 30-50,000 counts were acquired for the SPECT study over 20-50 minutes.

Imaging of 1-11E Localisation into the Inflamed Paw

[0102] SPECT and CT images from the NanoSPECT/CT camera were fused and displayed using PMOD software. FIG. 4 shows a representative image acquired 22 hours after injection of the radiotracer. Increased uptake of radioactivity is clearly seen in the rear left (inflamed) paw relative to the right (normal paw).

EXAMPLE 10: STAINING OF CARTILAGE IN MOUSE RA MODEL

[0103] Staining of cartilage was observed in the mouse mBSA model described in Example 8 above, except that C57BL mice were used.

[0104] Mice were sensitised with mBSA (100 .mu.g) in CFA intradermally at the base of the tail, and challenged either intra-articularly (both knees) or intra-plantarly (right, saline left) with 500 .mu.g mBSA in saline 14 days later.

[0105] Staining of cartilage is shown in FIG. 8.

Paw:

[0106] 12 hours post challenge with mBSA, the right paw was grossly inflamed in the subplantar region (seen by haematoxylin and eosin (H&E) staining), as shown in FIGS. 8A and 8B. The cartilage in the mBSA paws is uniformly and strongly stained by 1-11E, as shown in FIGS. 8C and 8D. The left paw injected by saline had no subplantar inflammation. Some cartilage within the left paw joints was stained heterogeneously, perhaps associated with spontaneous osteoarthritis.

EXAMPLE 11: STAINING OF JOINT IN MOUSE OA MODEL

[0107] Staining was observed in mice with joint surface injury.

[0108] Seven week old C57BL/6 male mice were utilized for these experiments (Dell'Accio F et a, Arthritis Res Ther. 2006; 8(5):R139). The mice were anesthetized and subjected to medial para-patellar arthrotomy. The patellar groove was exposed by lateral patellar dislocation. A longitudinal full thickness injury was made in the patellar groove using a custom made device in which the length of a 26G needle was limited by a glass bead (injured knee). The patellar dislocation was then reduced and the joint capsule and the skin sutured in separate layers. The animals were killed after 4 weeks and the knees dissected for histological and histochemical analysis.

[0109] Staining methods are as set out in Example 6 above, except that rabbit anti-myc followed by anti-rabbit-HRP were used to avoid cross-reactivity with mouse antibody in the tissue.

[0110] As shown in FIG. 9, there is strong staining at the site of the injury.

EXAMPLE 12: PRODUCTION OF FUSION PROTEINS: 1-11E WITH ANTI-INFLAMMATORY CYTOKINES

Cloning of IFN-Beta/1-11E

[0111] pFastBac1.AH was created from pFastBac1 (Invitrogen) by cutting out BamHI/HindIII fragment containing multiple cloning sites (MCS), and replacing with a linker to give another MCS of BamHI-KpnI-HindIII-ApaI.

[0112] Mouse interferon b (mIFNb) was cloned into the HindIII-EcoRI sites, followed by a MMP cleavage site and 1-11E which were cloned into the NotI and ApaI sites as shown in FIG. 10A. The MMP cleavage site can be cleaved by MPP-1 and MMP-3.

[0113] Mouse interferon-beta was amplified with the following primers:

TABLE-US-00004 forward: mIFNBHindFOR 5' gct aag ctt atg aac aac agg tgg atT 3' HindIII Start * reverse: mFNBEcoRIREV 5' CGC GAA TTC GTT TTG GAA GTT TCT GGT 3'

[0114] 1-11E was amplified with the following primers:

TABLE-US-00005 forward: NotI1-11Efor: 5'cag GC GGC CGC a ATG GCC GAG GTG CAG CTG 3' NotI * Start reverse: 1-11EApaRev 5' CTTGGGCCCTCAATGGTGGTGGTGATGGTGTCTAGACCGTTTGATTTCCAC CTT 3'

[0115] 1-11E was amplified with NotI/ApaI ends to include a histidine (His) tag and then cloned into FastBac1.AH mIFN-b/MMP/SP/His and cut with Not/Apa to liberate SP/His.

[0116] The mIFN-beta/His construct was cloned by amplifying mIFN-b with HindIII/ApaI with the following primers:

TABLE-US-00006 forward (this primer is the same as the primer used for cloning IFN-b/MMP/1-11E/His): mIFNBHindFOR 5' gct aag ctt atg aac aac agg tgg atT 3' HindIII Start * reverse primer: mIFN-bApaRev 5' CTTGGGCCCTCAATGGTGGTGGTGATGGTGTCTAGAGTTTTGGAAGTTTCT GGT 3'

[0117] These constructs were transformed into DH10Bac cells from Invitrogen and the sequence was confirmed as follows:

IFN-beta/MMP/1-11E/His (50.4 kDa)

TABLE-US-00007 MNNRWILHAAFLLCFSTTALSINYKQLQLQERTNIRKCQELLEQLNGKIN 50 LTYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETI 100 VVRLLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLK 150 LMKYNSYAWMVVRAEIFRNFLIIRRLTRNFQNEFGGGGSPLGLWAGGGSA 200 AAMAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLE 250 WVSSIDDSGATTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 300 AKNYSSFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSAS 350 VGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASSLQSGVPSRFSG 400 SGSGTDFTLTISSLQPEDFATYYCQQAANYPTTFGQGTKVEIKRDIHHHH 450 HH*

[0118] Within this sequence, the IFN-beta portion is from amino acids 1 to 182 as follows:

TABLE-US-00008 MNNRWILHAAFLLCFSTTALSINYKQLQLQERTNIRKCQELLEQLNGKIN 50 LTYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETI 100 VVRLLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLK 150 LMKYNSYAWMVVRAEIFRNFLIIRRLTRNFQN

[0119] The MMP linker portion is from amino acids 183 to 202 as follows:

TABLE-US-00009 EFGGGGSPLGLWAGGGSA 200 AA

[0120] The 1-11E portion is from amino acids 203 to 446 as follows:

TABLE-US-00010 MAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVKAPGKGLE 250 WVSSIDDSGATTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 300 AKNYSSFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSAS 350 VGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASSLQSGVPSRFSG 400 SGSGTDFTLTISSLQPEDFATYYCQQAANYPTTFGQGTKVEIKRDI

[0121] The His tag is from amino acids 448 to 502 as follows:

TABLE-US-00011 HHHH 450 HH*

IFN-Beta/his (23.2 kDa)

TABLE-US-00012 MNNRWILHAAFLLCFSTTALSINYKQLQLQERTNIRKCQELLEQLNGKIN 50 LTYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETI 100 VVRLLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLK 150 LMKYNSYAWMVVRAEIFRNFLIIRRLTRNFQNDIHHHHHH*

[0122] Within this sequence, the IFN-beta portion is from amino acids 1 to 184 as follows:

TABLE-US-00013 MNNRWILHAAFLLCFSTTALSINYKQLQLQERTNIRKCQELLEQLNGKIN 50 LTYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETI 100 VVRLLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLK 150 LMICYNSYAWMVVRAEIFRNFLIIRRLTRNFQNDI

[0123] The His tag is from amino acids 185 to 190 as follows:

TABLE-US-00014 HHHHHH*

[0124] The protocol for expression of the constructs is shown in FIG. 11.

[0125] Briefly, the constructs were transformed into competent DH10Bac cells (Invitrogen) to generate bacmid vectors. Recombinant bacmid vectors were confirmed by blue-white screening and PCR according to Invitrogen instructions. Bacmid DNA was transfected into Sf9 insect cells using cellfectin according to Invitrogen instructions.

[0126] Baculovirus (P1) was harvested from the supernatant of transfected cells, and used to infect fresh Sf9 cells to amplify the virus stocks. P3 virus was used to infect High 5 insect cells for 72 hours, and the supernatant was collected and run on an SDS-PAGE gel. Recombinant proteins were detected by Western blot using anti-tetra-His antibody (Qiagen) and anti-mouse HRP (Sigma).

[0127] The test expression of the fusion constructs is shown in FIG. 12.

Fusion Proteins: 1-11E/C7 with TNFR2-Fc

Cloning of TNFR2-Fell-11E and TNFR2-Fc/C7

[0128] pFastBac1.AH was created from pFastBac1 (Invitrogen) by cutting out BamHI/HindIII fragment containing multiple cloning sites (MCS), and replacing with a linker to give another MCS of BamHI-KpnI-HindIII-ApaI.

[0129] TNFR2Fc was cloned into the HindIII-EcoRI sites, followed by a MMP cleavage site and scFv (1-11E or C7) which were cloned into the NotI and ApaI sites as shown in FIG. 10B.

[0130] Mouse TNFR2-Fc was amplified with the following primers:

TABLE-US-00015 forward primer: 5' GCT aag at ATG GCG CCC GCC GCC CTC 3' reverse primer: 5' CTTGAATTCTTTACCCAGAGACCGGGA 3'

[0131] 1-11E was amplified with the same primers as above for the INFb.

[0132] The sequence of TNFR2Fc/MMP/1-11E is as follows:

TABLE-US-00016 MAPAALWVALVFELQLWATGHTVPAQVVLTPYKPEPGYECQISQEYYDRK AQMCCAKCPPGQYVKHFCNKTSDTVCADCEASMYTQVWNQFRTCLSCSSS CTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFG VASSRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDA VCAPESDGSPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLSPMVTC VVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQ DWMSGKEFKCKVNNRALPSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKK EFSLTCNITGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLR VQKSTWERGSLFACSVVHEGLHNHLTTKTISRSLGK---EFGGGGSPLGL WAGGGSAAA---MAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSW VRQAPGKGLEWVSSIDDSGATTYYADSVKGRFTISRDNSKNTLYLQMNSL RAEDTAVYYCAKNYSSFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQM TQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAANYPTTFGQGTKV EIKRDIHHHHHH

[0133] Of this sequence, the TNFR2Fc portion is as follows:

TABLE-US-00017 MAPAALWVALVFELQLWATGHTVPAQVVLTPYKPEPGYECQISQEYYDRK 50 AQMCCAKCPPGQYVKHFCNKTSDTVCADCEASMYTQVWNQFRTCLSCSSS 100 CTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFG 150 VASSRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDA 200 VCAPESDGSPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLSPMVTC 250 VVVDVSEDDPDVQISWFVENVEVHTAQTQTHREDYNSTLRVVSALPIQHQ 300 DWMSGKEFKCKVNNRALPSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKK 350 EFSLTCMITGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLR 400 VQKSTWERGSLFACSVVHEGLHNHLTTKTISRSLGK*

[0134] The MMP linker portion is as follows:

TABLE-US-00018 EFGGGGSPLGLWAGGGSAAA

[0135] The 1-11E portion is as follows:

TABLE-US-00019 MAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYANSWVRQAPGKGLE WVSSIDDSGATTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKNYSSFDYWGQGTLVTVSSGGGGSGGGGSGGGGSTDIQMTQSPSSLSAS VGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYYASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQAANYPTTFGQGTKVEIKRDI

[0136] The His tag is as follows:

TABLE-US-00020 HHHHHH*

[0137] As a negative control a non specific scFv was developed that binds to Hen Egg Lysosyme (HEL). Clone C7 was the best expressed and was taken forward for TNFR2Fc fusion as done for 1-11E.

Sequence of TNFR2Fc/MMP/C7:

TABLE-US-00021

[0138] MAPAALWVALVFELQLWATGHTVPAQVVLTPYKPEPGYECQISQEYYDFK AQMCCAKCPPGQYVKHFCNKTSDTVCADCEASMYTQVWNQFRTCLSCSSS CTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFG VASSRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDA VCAPESDGSPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLSPMVTC VVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQ DWMSGKEFKCKVNNRALPSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKK EFSLTCMITGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLR VQKSTWERGSLFACSVVHEGLHNHLTTKTISRSLGKEFGGGGSPLGLWAG GGSAAAMAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPG KGLEWVSTISYAGASTAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA VYYCAKTSTSFDYWGQGTLVTVSTDIQMTQSPSSLSASVGDRVTITCRAS QSISSYLNWYQQKPGKAPKLLIYNASYLQSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQAYAGPYTFGQGTKVEIKRDIHHHHHH*

[0139] Of this sequence, the TNFR2Fc portion is as follows:

TABLE-US-00022 MAPAALWVALVFELQLWATGHTVPAQVVLTPYKPEPGYECQISQEYYDRK 50 AQMCCAKCPPGQYVKHFCNKTSDTVCADCEASMYTQVWNQFRTCLSCSSS 100 CTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFG 150 VASSRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDA 200 VCAPESDGSPPLKECPPCAAPDLLGGPSVFIFPPKIKDVLMISLSPMVTC 250 VVVDVSEDDPDVQISWFVNNVEVRTAQTQTHREDYNSTLRVVSALPIQHQ 300 DWMSGKEFKCKVNNRALPSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKK 350 EFSLTCMITGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLR 400 VQKSTWERGSLFACSVVHEGLHNHLTTKTISRSLGK*

[0140] The MMP linker portion is as follows:

TABLE-US-00023 EFGGGGSPLGLWAGGGSAAA

[0141] The C7 portion is as follows:

TABLE-US-00024 MAEVQLLESGGGLVQPGGSLRLSCAASGFT FSSYAMSWVRQAPGKGLEWVSTISYAGASTAYADSVKGRFTISRDNSKNT LYLQMNSLRAEDTAVYYCAKTSTSFDYWGQGTLVTVSTDIQMTQSPSSLS ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYNASYLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQAYAGPYTFGQGTKVEIKRDI

[0142] The His tag is as follows:

TABLE-US-00025 HHHHHH*

[0143] The protocol for expression of the constructs is shown in FIG. 11 and is as described above for the IFN-beta/1-11E fusion protein.

[0144] Infected Hi-5 cells were grown for 3 days at 27.degree. C. After 3 days, different 100, 50, 25 and 12 microliter aliquots of cell supernatant were taken for Western blot analysis. Fusion protein was probed with anti-His tag antibodies. As shown in FIG. 13 the apparent molecular weight of the TNFR2Fc fusion proteins is slightly above 75 kDa which reflects the predicted 50 kDa TNFR2Fc plus 30 kDa scFv.

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 223 <210> SEQ ID NO 1 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 Asp Ile Ser Ser Thr Gly Ser Tyr Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 2 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Ala Ile Ser Ala Ala Gly Thr Ala Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 3 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 Ser Ile Ser Asn Ser Gly Ser Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 4 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Ser Ile Asn Asn Tyr Gly Ser Asn Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 5 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 Ser Ile Ser Tyr Thr Gly Asn Ser Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 6 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Asn Ile Ala Thr Asp Gly Thr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 7 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 Ser Ile Ser Asn Ser Gly Thr Asn Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 8 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Ser Ile Ser Tyr Thr Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 9 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 Ser Ile Asn Asp Ser Gly Thr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 10 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Ser Ile Asp Ser Ala Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 11 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Ser Ile Asn Ala Thr Gly Tyr Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 12 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 Ser Ile Asn Ser Asn Gly Thr Asp Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 13 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 Ser Ile Ser Ala Thr Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 14 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 Ser Ile Asp Asp Ser Gly Ala Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 15 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 Ser Ile Ala Ser Thr Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 16 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Ser Ile Ser Thr Asn Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 17 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Ser Ile Asp Thr Thr Gly Thr Thr Thr Tyr Phe Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 18 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Thr Ile Ser Tyr Ser Gly Asn Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 19 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 Ser Ile Asp Ala Gly Gly Asn Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 20 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Ser Ile Asp Ser Ala Gly Asn Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 21 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Ser Ile Thr Asp Ser Gly Asp Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 22 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 Ser Ile Ala Thr Thr Gly Asp Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 23 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Ala Ile Asn Ala Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 24 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 24 Ser Ile Ala Thr Thr Gly Thr Ser Thr Thr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 25 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 Thr Ile Asp Thr Ala Gly Ser Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 26 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Ser Ile Ser Asn Asn Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 27 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Ser Ile Ala Tyr Gly Gly Ala Gly Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 28 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Ala Ile Ala Asn Thr Gly Ser Ala Thr Asn Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 29 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 Ser Ile Ser Thr Ala Gly Thr Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 30 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Ser Ile Asn Asp Thr Gly Tyr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 31 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Ser Ile Ala Ser Ser Gly Thr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 32 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Thr Ile Thr Ser Thr Gly Ala Ala Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 33 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 Ala Ile Asp Gly Thr Gly Tyr Gly Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 34 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Ser Ile Ala Asn Ala Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 35 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 Ser Ile Asp Ser Ala Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 36 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 36 Ser Ile Ser Ser Ser Gly Asp Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 37 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 37 Ser Ile Asp Thr Gly Gly Ser Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 38 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 Ser Ile Asp Ala Ser Gly Ala Asn Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 39 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 Gly Ala Gly Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 40 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 Gly Tyr Asp Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 41 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 41 Gly Tyr Gly Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 42 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 42 Gly Tyr Ser Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 43 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 43 Gly Tyr Thr Ala Phe Asp Tyr 1 5 <210> SEQ ID NO 44 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 44 Asn Ser Thr Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 45 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 45 Asn Tyr Ala Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 46 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 46 Asn Tyr Ser Ala Phe Asp Tyr 1 5 <210> SEQ ID NO 47 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47 Asn Tyr Ser Asp Phe Asp Tyr 1 5 <210> SEQ ID NO 48 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48 Asn Tyr Ser Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 49 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 49 Asn Tyr Ser Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 50 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 50 Asn Tyr Ser Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 51 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 51 Asn Tyr Thr Ala Phe Asp Tyr 1 5 <210> SEQ ID NO 52 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 Asn Tyr Thr Asp Phe Asp Tyr 1 5 <210> SEQ ID NO 53 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 53 Asn Tyr Thr Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 54 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 54 Ser Tyr Ala Asp Phe Asp Tyr 1 5 <210> SEQ ID NO 55 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 55 Ser Tyr Ala Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 56 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 Ser Tyr Asp Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 57 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 57 Ser Tyr Ser Asn Phe Asp Tyr 1 5 <210> SEQ ID NO 58 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 58 Ser Tyr Ser Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 59 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 Ser Tyr Thr Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 60 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 60 Thr Tyr Gly Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 61 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 61 Ala Ala Ser Ala Leu Gln Ser 1 5 <210> SEQ ID NO 62 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 62 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 63 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 64 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 64 Ala Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 65 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 65 Tyr Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 66 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 66 Ser Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 67 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 67 Ala Ala Ser Asp Leu Gln Ser 1 5 <210> SEQ ID NO 68 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 Asn Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 69 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 69 Thr Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 70 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 70 Ser Ala Ser Ala Leu Gln Ser 1 5 <210> SEQ ID NO 71 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 71 Thr Ala Ser Ala Leu Gln Ser 1 5 <210> SEQ ID NO 72 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 Ser Ala Ser Asp Leu Gln Ser 1 5 <210> SEQ ID NO 73 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 73 Tyr Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 74 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 74 Asp Ala Ser Gly Leu Gln Ser 1 5 <210> SEQ ID NO 75 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 75 Ser Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 76 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 76 Thr Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 77 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 77 Thr Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 78 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 79 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 79 Ser Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 80 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 80 Thr Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 81 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 81 Gly Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 82 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 Ala Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 83 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 83 Asp Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 84 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 84 Gly Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 85 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 85 Thr Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 86 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 86 Gln Gln Ser Ser Ser Thr Pro Thr Thr 1 5 <210> SEQ ID NO 87 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 87 Gln Gln Asn Tyr Gly Tyr Pro Asn Thr 1 5 <210> SEQ ID NO 88 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 88 Gln Gln Ala Asn Ser Ser Pro Asp Thr 1 5 <210> SEQ ID NO 89 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 89 Gln Gln Thr Ser Ser Ser Pro Asp Thr 1 5 <210> SEQ ID NO 90 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 Gln Gln Ala Asp Ser Thr Pro Thr Thr 1 5 <210> SEQ ID NO 91 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 91 Gln Gln Ala Ala Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 92 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 92 Gln Gln Gly Ser Ala Ser Pro Ser Thr 1 5 <210> SEQ ID NO 93 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 93 Gln Gln Ser Asp Ser Ala Pro Thr Thr 1 5 <210> SEQ ID NO 94 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 94 Gln Gln Ser Asp Thr Tyr Pro Ser Thr 1 5 <210> SEQ ID NO 95 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 95 Gln Gln Ser Tyr Ala Ser Pro Thr Thr 1 5 <210> SEQ ID NO 96 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96 Gln Gln Thr Gly Ser Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 97 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 97 Gln Gln Gly Asp Ser Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 98 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 98 Gln Gln Gly Tyr Gly Ala Pro Thr Thr 1 5 <210> SEQ ID NO 99 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 99 Gln Gln Ser Ser Tyr Thr Pro Thr Thr 1 5 <210> SEQ ID NO 100 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 100 Gln Gln Ala Ala Asn Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 101 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 101 Gln Gln Ala Ser Asn Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 102 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 102 Gln Gln Gly Asp Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 103 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 103 Gln Gln Gly Tyr Ser Ala Pro Thr Thr 1 5 <210> SEQ ID NO 104 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104 Gln Gln Gly Tyr Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 105 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 105 Gln Gln Asn Asn Tyr Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 106 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106 Gln Gln Ser Asp Ala Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 107 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 107 Thr Ser Asn Tyr Pro Thr Thr Gln Gln 1 5 <210> SEQ ID NO 108 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 108 Gln Gln Ser Asn Ala Thr Pro Thr Thr 1 5 <210> SEQ ID NO 109 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 109 Gln Gln Ala Ala Gly Asn Pro Thr Thr 1 5 <210> SEQ ID NO 110 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 110 Gln Gln Gly Ser Asp Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 111 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 111 Gln Gln Gly Ser Thr Ala Pro Thr Thr 1 5 <210> SEQ ID NO 112 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 112 Gln Gln Ser Thr Ala Ser Pro Ser Thr 1 5 <210> SEQ ID NO 113 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 113 Gln Gln Thr Ser Ser Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 114 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 114 Gln Gln Gly Ala Gly Ser Pro Ser Thr 1 5 <210> SEQ ID NO 115 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 115 Gln Gln Arg Asn Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 116 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 116 Gln Gln Ser Asn Thr Ser Pro Ala Thr 1 5 <210> SEQ ID NO 117 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 117 Gln Gln Ala Tyr Thr Ala Pro Thr Thr 1 5 <210> SEQ ID NO 118 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 118 Gln Gln Ala Asp Thr Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 119 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 119 Gln Gln Ala Ala Asn Ser Pro Asp Thr 1 5 <210> SEQ ID NO 120 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 120 Gln Gln Thr Ser Asp Tyr Pro Asn Thr 1 5 <210> SEQ ID NO 121 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 121 Gln Gln Ala Ser Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 122 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 122 Gln Gln Ala Ser Asp Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 123 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 123 Gln Gln Ser Ser Ser Asn Pro Thr Thr 1 5 <210> SEQ ID NO 124 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 124 Gln Gln Gly Ser Asn Ser Pro Thr Thr 1 5 <210> SEQ ID NO 125 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 125 Gln Gln Ser Ala Thr Thr Pro Asp Thr 1 5 <210> SEQ ID NO 126 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 126 Tyr Gly Arg Lys Lys Arg Gln Arg Arg Arg 1 5 10 <210> SEQ ID NO 127 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer LMB-3 <400> SEQUENCE: 127 Cys Ala Gly Gly Ala Ala Ala Cys Ala Gly Cys Thr Ala Thr Gly Ala 1 5 10 15 Cys <210> SEQ ID NO 128 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer Fd-Seq <400> SEQUENCE: 128 Gly Ala Ala Thr Thr Thr Thr Cys Thr Gly Thr Ala Thr Gly Ala Gly 1 5 10 15 Gly <210> SEQ ID NO 129 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer mIFNBHindFOR <400> SEQUENCE: 129 gctaagctta tgaacaacag gtggatt 27 <210> SEQ ID NO 130 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer mIFNBEcoRIREV <400> SEQUENCE: 130 cgcgaattcg ttttggaagt ttctggt 27 <210> SEQ ID NO 131 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer NotI1-11Efor <400> SEQUENCE: 131 caggcggccg caatggccga ggtgcagctg 30 <210> SEQ ID NO 132 <211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer 1-11EApaRev <400> SEQUENCE: 132 cttgggccct caatggtggt ggtgatggtg tctagaccgt ttgatttcca cctt 54 <210> SEQ ID NO 133 <211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer mIFN-bApaRev <400> SEQUENCE: 133 cttgggccct caatggtggt ggtgatggtg tctagagttt tggaagtttc tggt 54 <210> SEQ ID NO 134 <211> LENGTH: 452 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 134 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly 180 185 190 Leu Trp Ala Gly Gly Gly Ser Ala Ala Ala Met Ala Glu Val Gln Leu 195 200 205 Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 210 215 220 Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp 225 230 235 240 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Asp 245 250 255 Asp Ser Gly Ala Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 260 265 270 Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn 275 280 285 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asn Tyr 290 295 300 Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 305 310 315 320 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr 325 330 335 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 340 345 350 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 355 360 365 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 370 375 380 Tyr Tyr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 385 390 395 400 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 405 410 415 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ala Asn Tyr Pro Thr 420 425 430 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Asp Ile His His 435 440 445 His His His His 450 <210> SEQ ID NO 135 <211> LENGTH: 182 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 135 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn 180 <210> SEQ ID NO 136 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 136 Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp Ala Gly Gly Gly 1 5 10 15 Ser Ala Ala Ala 20 <210> SEQ ID NO 137 <211> LENGTH: 244 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 137 Met Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 1 5 10 15 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45 Trp Val Ser Ser Ile Asp Asp Ser Gly Ala Thr Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Lys Asn Tyr Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 130 135 140 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 145 150 155 160 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 165 170 175 Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Ser Leu Gln Ser Gly Val 180 185 190 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 210 215 220 Ala Ala Asn Tyr Pro Thr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 225 230 235 240 Lys Arg Asp Ile <210> SEQ ID NO 138 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 138 His His His His His His 1 5 <210> SEQ ID NO 139 <211> LENGTH: 190 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 139 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn Asp Ile His His His His His His 180 185 190 <210> SEQ ID NO 140 <211> LENGTH: 184 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 140 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn Asp Ile 180 <210> SEQ ID NO 141 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Forward Primer for Mouse TNFR2-Fc <400> SEQUENCE: 141 gctaagctta tggcgcccgc cgccctc 27 <210> SEQ ID NO 142 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Reverse primer for Mouse TNFR2-Fc <400> SEQUENCE: 142 cttgaattct ttacccagag accggga 27 <210> SEQ ID NO 143 <211> LENGTH: 706 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 143 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp 435 440 445 Ala Gly Gly Gly Ser Ala Ala Ala Met Ala Glu Val Gln Leu Leu Glu 450 455 460 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 465 470 475 480 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg 485 490 495 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Asp Asp Ser 500 505 510 Gly Ala Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 515 520 525 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 530 535 540 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asn Tyr Ser Ser 545 550 555 560 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 565 570 575 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Asp Ile 580 585 590 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 595 600 605 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 610 615 620 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr 625 630 635 640 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 645 650 655 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 660 665 670 Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ala Asn Tyr Pro Thr Thr Phe 675 680 685 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Asp Ile His His His His 690 695 700 His His 705 <210> SEQ ID NO 144 <211> LENGTH: 436 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 144 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys 435 <210> SEQ ID NO 145 <400> SEQUENCE: 145 000 <210> SEQ ID NO 146 <400> SEQUENCE: 146 000 <210> SEQ ID NO 147 <211> LENGTH: 690 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 147 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp 435 440 445 Ala Gly Gly Gly Ser Ala Ala Ala Met Ala Glu Val Gln Leu Leu Glu 450 455 460 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 465 470 475 480 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg 485 490 495 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Tyr Ala 500 505 510 Gly Ala Ser Thr Ala Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 515 520 525 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 530 535 540 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Thr Ser Thr Ser 545 550 555 560 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Asp Ile 565 570 575 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 580 585 590 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 595 600 605 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asn 610 615 620 Ala Ser Tyr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 625 630 635 640 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 645 650 655 Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Tyr Ala Gly Pro Tyr Thr Phe 660 665 670 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Asp Ile His His His His 675 680 685 His His 690 <210> SEQ ID NO 148 <211> LENGTH: 436 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 148 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys 435 <210> SEQ ID NO 149 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 149 Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp Ala Gly Gly Gly 1 5 10 15 Ser Ala Ala Ala 20 <210> SEQ ID NO 150 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 150 Met Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 1 5 10 15 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45 Trp Val Ser Thr Ile Ser Tyr Ala Gly Ala Ser Thr Ala Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Lys Thr Ser Thr Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 115 120 125 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 130 135 140 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 145 150 155 160 Ala Pro Lys Leu Leu Ile Tyr Asn Ala Ser Tyr Leu Gln Ser Gly Val 165 170 175 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 195 200 205 Ala Tyr Ala Gly Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 210 215 220 Lys Arg Asp Ile 225 <210> SEQ ID NO 151 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 151 Ala Pro Gln Gly Ile Ala Gly Gln 1 5 <210> SEQ ID NO 152 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 152 Gly Pro Gln Gly Leu Leu Gly Ala 1 5 <210> SEQ ID NO 153 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 153 Gly Pro Gln Gly Leu Ala Gly Gln 1 5 <210> SEQ ID NO 154 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 154 Gly Pro Leu Gly Ile Ala Gly Ile 1 5 <210> SEQ ID NO 155 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 155 Gly Pro Glu Gly Leu Arg Val Gly 1 5 <210> SEQ ID NO 156 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Glutamate <400> SEQUENCE: 156 Ala Ala Tyr His Leu Val Ser Xaa 1 5 <210> SEQ ID NO 157 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 157 Met Asp Ala Phe Leu Glu Ser Ser 1 5 <210> SEQ ID NO 158 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 158 Glu Pro Gln Ala Leu Ala Met Ser 1 5 <210> SEQ ID NO 159 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 159 Gln Ala Leu Ala Met Ser Ala Ile 1 5 <210> SEQ ID NO 160 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Gallus sp. <400> SEQUENCE: 160 Pro Ser Tyr Phe Leu Asn Ala Gly 1 5 <210> SEQ ID NO 161 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 161 Tyr Glu Ala Gly Leu Gly Val Val 1 5 <210> SEQ ID NO 162 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 162 Ala Gly Leu Gly Val Val Glu Arg 1 5 <210> SEQ ID NO 163 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 163 Ala Gly Leu Gly Ile Ser Ser Thr 1 5 <210> SEQ ID NO 164 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 164 Gly Ala Met Phe Leu Glu Ala Ile 1 5 <210> SEQ ID NO 165 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 165 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 166 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 166 Thr Glu Gly Glu Ala Arg Gly Ser 1 5 <210> SEQ ID NO 167 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 167 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 168 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 168 Leu Arg Ala Tyr Leu Leu Pro Ala 1 5 <210> SEQ ID NO 169 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Cavia porcellus <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Hydroxyproline Hyp <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Glutamate or Glutamine Glx <400> SEQUENCE: 169 Gly Ala Xaa Gly Leu Xaa Gly His 1 5 <210> SEQ ID NO 170 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 170 Gly Pro Gln Gly Val Arg Gly Glu 1 5 <210> SEQ ID NO 171 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 171 Gly Pro Ala Gly Val Gln Gly Pro 1 5 <210> SEQ ID NO 172 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Hydroxyproline Hyp <400> SEQUENCE: 172 Gly Pro Ser Gly Leu Xaa Gly Pro 1 5 <210> SEQ ID NO 173 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 173 Gly Pro Ala Gly Glu Arg Gly Ser 1 5 <210> SEQ ID NO 174 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 174 Gly Ala Lys Gly Leu Thr Gly Ser 1 5 <210> SEQ ID NO 175 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 175 Gly Pro Ala Gly Gln Asp Gly Pro 1 5 <210> SEQ ID NO 176 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 176 Gly Pro Ala Gly Phe Ala Gly Pro 1 5 <210> SEQ ID NO 177 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 177 Gly Pro Ile Gly Asn Val Gly Ala 1 5 <210> SEQ ID NO 178 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Hydroxylysine Hyl <400> SEQUENCE: 178 Gly Pro Xaa Gly Ser Arg Gly Ala 1 5 <210> SEQ ID NO 179 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 179 Gly Pro Gln Gly Ile Ala Gly Gln 1 5 <210> SEQ ID NO 180 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 180 Gly Pro Gly Gly Leu Leu Gly Ala 1 5 <210> SEQ ID NO 181 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 181 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 182 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 182 Pro Pro Gly Ala Tyr His Gly Ala 1 5 <210> SEQ ID NO 183 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 183 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 184 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 184 Gly Pro His Leu Leu Val Glu Ala 1 5 <210> SEQ ID NO 185 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 185 Leu Arg Ala Tyr Leu Leu Pro Ala 1 5 <210> SEQ ID NO 186 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 186 Gly Pro Glu Gly Leu Arg Val Gly 1 5 <210> SEQ ID NO 187 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 187 Arg Val Gly Phe Tyr Glu Ser Asp 1 5 <210> SEQ ID NO 188 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 188 Leu Leu Ser Ala Leu Val Glu Thr 1 5 <210> SEQ ID NO 189 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 189 Glu Ala Ile Pro Met Ser Ile Pro 1 5 <210> SEQ ID NO 190 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 190 Ile Ala Gly Arg Ser Leu Asn Pro 1 5 <210> SEQ ID NO 191 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Gallus sp. <400> SEQUENCE: 191 Leu Asn Ala Gly Phe Thr Ala Ser 1 5 <210> SEQ ID NO 192 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 192 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 193 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 193 Lys Pro Gln Gln Phe Phe Gly Leu 1 5 <210> SEQ ID NO 194 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 194 Asp Val Ala Gln Phe Val Leu Thr 1 5 <210> SEQ ID NO 195 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 195 Asp Thr Leu Glu Val Met Arg Lys 1 5 <210> SEQ ID NO 196 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 196 Asp Val Gly His Phe Arg Thr Phe 1 5 <210> SEQ ID NO 197 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 197 Asp Ser Gly Gly Phe Met Leu Thr 1 5 <210> SEQ ID NO 198 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 198 Arg Val Ala Glu Met Arg Gly Glu 1 5 <210> SEQ ID NO 199 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 199 Asp Leu Gly Arg Phe Gln Thr Phe 1 5 <210> SEQ ID NO 200 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 200 Pro Phe Ser Pro Leu Val Ala Thr 1 5 <210> SEQ ID NO 201 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 201 Leu Arg Ala Tyr Leu Leu Pro Ala 1 5 <210> SEQ ID NO 202 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 202 Ala Pro Gly Asn Ala Ser Glu Ser 1 5 <210> SEQ ID NO 203 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 203 Phe Ser Ser Glu Ser Lys Arg Glu 1 5 <210> SEQ ID NO 204 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 204 Ala Gly Gly Ala Gln Met Gly Val 1 5 <210> SEQ ID NO 205 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 205 Gln Met Gly Val Met Gln Gly Pro 1 5 <210> SEQ ID NO 206 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 206 Met Ala Ala Ser Leu Lys Arg Pro 1 5 <210> SEQ ID NO 207 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 207 Ala Lys Arg Glu 1 <210> SEQ ID NO 208 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 208 Leu Arg Lys Pro 1 <210> SEQ ID NO 209 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 209 Gln Ala Gln Ala Ile Leu Gln Gln 1 5 <210> SEQ ID NO 210 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 210 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 211 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 211 Leu Val Glu Ala Leu Tyr Leu Val 1 5 <210> SEQ ID NO 212 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 212 Glu Ala Leu Tyr Leu Val Cys Gly 1 5 <210> SEQ ID NO 213 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 213 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 214 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 214 Gly Pro His Leu Leu Val Glu Ala 1 5 <210> SEQ ID NO 215 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 215 Pro Pro Glu Glu Leu Lys Phe Gln 1 5 <210> SEQ ID NO 216 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 216 Gly Pro Pro Gly Val Val Gly Pro 1 5 <210> SEQ ID NO 217 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 217 Gly Pro Pro Gly Leu Arg Gly Glu 1 5 <210> SEQ ID NO 218 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 218 Gly Pro Gly Gly Val Val Gly Pro 1 5 <210> SEQ ID NO 219 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 219 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 220 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 220 Pro Pro Gly Ala Tyr His Gly Ala 1 5 <210> SEQ ID NO 221 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 221 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 222 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 222 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 223 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 223 Gly Pro His Leu Leu Val Glu Ala 1 5

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 223 <210> SEQ ID NO 1 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 Asp Ile Ser Ser Thr Gly Ser Tyr Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 2 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Ala Ile Ser Ala Ala Gly Thr Ala Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 3 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 Ser Ile Ser Asn Ser Gly Ser Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 4 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Ser Ile Asn Asn Tyr Gly Ser Asn Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 5 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 Ser Ile Ser Tyr Thr Gly Asn Ser Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 6 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Asn Ile Ala Thr Asp Gly Thr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 7 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 Ser Ile Ser Asn Ser Gly Thr Asn Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 8 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Ser Ile Ser Tyr Thr Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 9 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 Ser Ile Asn Asp Ser Gly Thr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 10 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Ser Ile Asp Ser Ala Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 11 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Ser Ile Asn Ala Thr Gly Tyr Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 12 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 Ser Ile Asn Ser Asn Gly Thr Asp Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 13 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 Ser Ile Ser Ala Thr Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 14 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 Ser Ile Asp Asp Ser Gly Ala Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 15 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 Ser Ile Ala Ser Thr Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 16 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Ser Ile Ser Thr Asn Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 17 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Ser Ile Asp Thr Thr Gly Thr Thr Thr Tyr Phe Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 18 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Thr Ile Ser Tyr Ser Gly Asn Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 19 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 Ser Ile Asp Ala Gly Gly Asn Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15

Gly <210> SEQ ID NO 20 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Ser Ile Asp Ser Ala Gly Asn Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 21 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Ser Ile Thr Asp Ser Gly Asp Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 22 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 Ser Ile Ala Thr Thr Gly Asp Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 23 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Ala Ile Asn Ala Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 24 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 24 Ser Ile Ala Thr Thr Gly Thr Ser Thr Thr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 25 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 Thr Ile Asp Thr Ala Gly Ser Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 26 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Ser Ile Ser Asn Asn Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 27 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Ser Ile Ala Tyr Gly Gly Ala Gly Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 28 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Ala Ile Ala Asn Thr Gly Ser Ala Thr Asn Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 29 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 Ser Ile Ser Thr Ala Gly Thr Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 30 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Ser Ile Asn Asp Thr Gly Tyr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 31 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Ser Ile Ala Ser Ser Gly Thr Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 32 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Thr Ile Thr Ser Thr Gly Ala Ala Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 33 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 Ala Ile Asp Gly Thr Gly Tyr Gly Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 34 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Ser Ile Ala Asn Ala Gly Thr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 35 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 Ser Ile Asp Ser Ala Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 36 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 36 Ser Ile Ser Ser Ser Gly Asp Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 37 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 37 Ser Ile Asp Thr Gly Gly Ser Tyr Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 38 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 Ser Ile Asp Ala Ser Gly Ala Asn Thr Ala Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 39

<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 Gly Ala Gly Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 40 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 Gly Tyr Asp Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 41 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 41 Gly Tyr Gly Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 42 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 42 Gly Tyr Ser Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 43 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 43 Gly Tyr Thr Ala Phe Asp Tyr 1 5 <210> SEQ ID NO 44 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 44 Asn Ser Thr Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 45 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 45 Asn Tyr Ala Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 46 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 46 Asn Tyr Ser Ala Phe Asp Tyr 1 5 <210> SEQ ID NO 47 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47 Asn Tyr Ser Asp Phe Asp Tyr 1 5 <210> SEQ ID NO 48 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48 Asn Tyr Ser Ser Phe Asp Tyr 1 5 <210> SEQ ID NO 49 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 49 Asn Tyr Ser Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 50 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 50 Asn Tyr Ser Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 51 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 51 Asn Tyr Thr Ala Phe Asp Tyr 1 5 <210> SEQ ID NO 52 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 Asn Tyr Thr Asp Phe Asp Tyr 1 5 <210> SEQ ID NO 53 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 53 Asn Tyr Thr Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 54 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 54 Ser Tyr Ala Asp Phe Asp Tyr 1 5 <210> SEQ ID NO 55 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 55 Ser Tyr Ala Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 56 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 Ser Tyr Asp Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 57 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 57 Ser Tyr Ser Asn Phe Asp Tyr 1 5 <210> SEQ ID NO 58 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 58 Ser Tyr Ser Tyr Phe Asp Tyr 1 5 <210> SEQ ID NO 59 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 Ser Tyr Thr Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 60 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 60 Thr Tyr Gly Thr Phe Asp Tyr 1 5 <210> SEQ ID NO 61 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 61 Ala Ala Ser Ala Leu Gln Ser 1 5

<210> SEQ ID NO 62 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 62 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 63 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 64 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 64 Ala Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 65 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 65 Tyr Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 66 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 66 Ser Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 67 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 67 Ala Ala Ser Asp Leu Gln Ser 1 5 <210> SEQ ID NO 68 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 Asn Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 69 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 69 Thr Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 70 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 70 Ser Ala Ser Ala Leu Gln Ser 1 5 <210> SEQ ID NO 71 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 71 Thr Ala Ser Ala Leu Gln Ser 1 5 <210> SEQ ID NO 72 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 Ser Ala Ser Asp Leu Gln Ser 1 5 <210> SEQ ID NO 73 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 73 Tyr Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 74 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 74 Asp Ala Ser Gly Leu Gln Ser 1 5 <210> SEQ ID NO 75 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 75 Ser Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 76 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 76 Thr Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 77 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 77 Thr Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 78 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 79 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 79 Ser Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 80 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 80 Thr Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 81 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 81 Gly Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 82 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 Ala Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 83 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 83 Asp Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 84 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 84 Gly Ala Ser Ser Leu Gln Ser

1 5 <210> SEQ ID NO 85 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 85 Thr Ala Ser Tyr Leu Gln Ser 1 5 <210> SEQ ID NO 86 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 86 Gln Gln Ser Ser Ser Thr Pro Thr Thr 1 5 <210> SEQ ID NO 87 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 87 Gln Gln Asn Tyr Gly Tyr Pro Asn Thr 1 5 <210> SEQ ID NO 88 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 88 Gln Gln Ala Asn Ser Ser Pro Asp Thr 1 5 <210> SEQ ID NO 89 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 89 Gln Gln Thr Ser Ser Ser Pro Asp Thr 1 5 <210> SEQ ID NO 90 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 Gln Gln Ala Asp Ser Thr Pro Thr Thr 1 5 <210> SEQ ID NO 91 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 91 Gln Gln Ala Ala Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 92 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 92 Gln Gln Gly Ser Ala Ser Pro Ser Thr 1 5 <210> SEQ ID NO 93 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 93 Gln Gln Ser Asp Ser Ala Pro Thr Thr 1 5 <210> SEQ ID NO 94 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 94 Gln Gln Ser Asp Thr Tyr Pro Ser Thr 1 5 <210> SEQ ID NO 95 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 95 Gln Gln Ser Tyr Ala Ser Pro Thr Thr 1 5 <210> SEQ ID NO 96 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96 Gln Gln Thr Gly Ser Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 97 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 97 Gln Gln Gly Asp Ser Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 98 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 98 Gln Gln Gly Tyr Gly Ala Pro Thr Thr 1 5 <210> SEQ ID NO 99 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 99 Gln Gln Ser Ser Tyr Thr Pro Thr Thr 1 5 <210> SEQ ID NO 100 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 100 Gln Gln Ala Ala Asn Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 101 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 101 Gln Gln Ala Ser Asn Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 102 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 102 Gln Gln Gly Asp Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 103 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 103 Gln Gln Gly Tyr Ser Ala Pro Thr Thr 1 5 <210> SEQ ID NO 104 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104 Gln Gln Gly Tyr Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 105 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 105 Gln Gln Asn Asn Tyr Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 106 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106 Gln Gln Ser Asp Ala Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 107 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 107

Thr Ser Asn Tyr Pro Thr Thr Gln Gln 1 5 <210> SEQ ID NO 108 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 108 Gln Gln Ser Asn Ala Thr Pro Thr Thr 1 5 <210> SEQ ID NO 109 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 109 Gln Gln Ala Ala Gly Asn Pro Thr Thr 1 5 <210> SEQ ID NO 110 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 110 Gln Gln Gly Ser Asp Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 111 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 111 Gln Gln Gly Ser Thr Ala Pro Thr Thr 1 5 <210> SEQ ID NO 112 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 112 Gln Gln Ser Thr Ala Ser Pro Ser Thr 1 5 <210> SEQ ID NO 113 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 113 Gln Gln Thr Ser Ser Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 114 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 114 Gln Gln Gly Ala Gly Ser Pro Ser Thr 1 5 <210> SEQ ID NO 115 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 115 Gln Gln Arg Asn Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 116 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 116 Gln Gln Ser Asn Thr Ser Pro Ala Thr 1 5 <210> SEQ ID NO 117 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 117 Gln Gln Ala Tyr Thr Ala Pro Thr Thr 1 5 <210> SEQ ID NO 118 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 118 Gln Gln Ala Asp Thr Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 119 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 119 Gln Gln Ala Ala Asn Ser Pro Asp Thr 1 5 <210> SEQ ID NO 120 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 120 Gln Gln Thr Ser Asp Tyr Pro Asn Thr 1 5 <210> SEQ ID NO 121 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 121 Gln Gln Ala Ser Thr Ser Pro Thr Thr 1 5 <210> SEQ ID NO 122 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 122 Gln Gln Ala Ser Asp Tyr Pro Thr Thr 1 5 <210> SEQ ID NO 123 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 123 Gln Gln Ser Ser Ser Asn Pro Thr Thr 1 5 <210> SEQ ID NO 124 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 124 Gln Gln Gly Ser Asn Ser Pro Thr Thr 1 5 <210> SEQ ID NO 125 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 125 Gln Gln Ser Ala Thr Thr Pro Asp Thr 1 5 <210> SEQ ID NO 126 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 126 Tyr Gly Arg Lys Lys Arg Gln Arg Arg Arg 1 5 10 <210> SEQ ID NO 127 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer LMB-3 <400> SEQUENCE: 127 Cys Ala Gly Gly Ala Ala Ala Cys Ala Gly Cys Thr Ala Thr Gly Ala 1 5 10 15 Cys <210> SEQ ID NO 128 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer Fd-Seq <400> SEQUENCE: 128 Gly Ala Ala Thr Thr Thr Thr Cys Thr Gly Thr Ala Thr Gly Ala Gly 1 5 10 15 Gly <210> SEQ ID NO 129 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer mIFNBHindFOR

<400> SEQUENCE: 129 gctaagctta tgaacaacag gtggatt 27 <210> SEQ ID NO 130 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer mIFNBEcoRIREV <400> SEQUENCE: 130 cgcgaattcg ttttggaagt ttctggt 27 <210> SEQ ID NO 131 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer NotI1-11Efor <400> SEQUENCE: 131 caggcggccg caatggccga ggtgcagctg 30 <210> SEQ ID NO 132 <211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer 1-11EApaRev <400> SEQUENCE: 132 cttgggccct caatggtggt ggtgatggtg tctagaccgt ttgatttcca cctt 54 <210> SEQ ID NO 133 <211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Primer mIFN-bApaRev <400> SEQUENCE: 133 cttgggccct caatggtggt ggtgatggtg tctagagttt tggaagtttc tggt 54 <210> SEQ ID NO 134 <211> LENGTH: 452 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 134 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly 180 185 190 Leu Trp Ala Gly Gly Gly Ser Ala Ala Ala Met Ala Glu Val Gln Leu 195 200 205 Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 210 215 220 Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp 225 230 235 240 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Asp 245 250 255 Asp Ser Gly Ala Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 260 265 270 Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn 275 280 285 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asn Tyr 290 295 300 Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 305 310 315 320 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr 325 330 335 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 340 345 350 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 355 360 365 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 370 375 380 Tyr Tyr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 385 390 395 400 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 405 410 415 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ala Asn Tyr Pro Thr 420 425 430 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Asp Ile His His 435 440 445 His His His His 450 <210> SEQ ID NO 135 <211> LENGTH: 182 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 135 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn 180 <210> SEQ ID NO 136 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 136 Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp Ala Gly Gly Gly 1 5 10 15 Ser Ala Ala Ala 20 <210> SEQ ID NO 137 <211> LENGTH: 244 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 137 Met Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 1 5 10 15 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45 Trp Val Ser Ser Ile Asp Asp Ser Gly Ala Thr Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Lys Asn Tyr Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 130 135 140 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 145 150 155 160 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 165 170 175 Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Ser Leu Gln Ser Gly Val 180 185 190 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 210 215 220 Ala Ala Asn Tyr Pro Thr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 225 230 235 240 Lys Arg Asp Ile <210> SEQ ID NO 138 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 138 His His His His His His 1 5 <210> SEQ ID NO 139 <211> LENGTH: 190 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 139 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn Asp Ile His His His His His His 180 185 190 <210> SEQ ID NO 140 <211> LENGTH: 184 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 140 Met Asn Asn Arg Trp Ile Leu His Ala Ala Phe Leu Leu Cys Phe Ser 1 5 10 15 Thr Thr Ala Leu Ser Ile Asn Tyr Lys Gln Leu Gln Leu Gln Glu Arg 20 25 30 Thr Asn Ile Arg Lys Cys Gln Glu Leu Leu Glu Gln Leu Asn Gly Lys 35 40 45 Ile Asn Leu Thr Tyr Arg Ala Asp Phe Lys Ile Pro Met Glu Met Thr 50 55 60 Glu Lys Met Gln Lys Ser Tyr Thr Ala Phe Ala Ile Gln Glu Met Leu 65 70 75 80 Gln Asn Val Phe Leu Val Phe Arg Asn Asn Phe Ser Ser Thr Gly Trp 85 90 95 Asn Glu Thr Ile Val Val Arg Leu Leu Asp Glu Leu His Gln Gln Thr 100 105 110 Val Phe Leu Lys Thr Val Leu Glu Glu Lys Gln Glu Glu Arg Leu Thr 115 120 125 Trp Glu Met Ser Ser Thr Ala Leu His Leu Lys Ser Tyr Tyr Trp Arg 130 135 140 Val Gln Arg Tyr Leu Lys Leu Met Lys Tyr Asn Ser Tyr Ala Trp Met 145 150 155 160 Val Val Arg Ala Glu Ile Phe Arg Asn Phe Leu Ile Ile Arg Arg Leu 165 170 175 Thr Arg Asn Phe Gln Asn Asp Ile 180 <210> SEQ ID NO 141 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Forward Primer for Mouse TNFR2-Fc <400> SEQUENCE: 141 gctaagctta tggcgcccgc cgccctc 27 <210> SEQ ID NO 142 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial <220> FEATURE: <223> OTHER INFORMATION: Reverse primer for Mouse TNFR2-Fc <400> SEQUENCE: 142 cttgaattct ttacccagag accggga 27 <210> SEQ ID NO 143 <211> LENGTH: 706 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 143 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp 435 440 445 Ala Gly Gly Gly Ser Ala Ala Ala Met Ala Glu Val Gln Leu Leu Glu 450 455 460 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 465 470 475 480 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg 485 490 495 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Asp Asp Ser 500 505 510 Gly Ala Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 515 520 525 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 530 535 540 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asn Tyr Ser Ser 545 550 555 560 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 565 570 575 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Asp Ile 580 585 590

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 595 600 605 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 610 615 620 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr 625 630 635 640 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 645 650 655 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 660 665 670 Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ala Asn Tyr Pro Thr Thr Phe 675 680 685 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Asp Ile His His His His 690 695 700 His His 705 <210> SEQ ID NO 144 <211> LENGTH: 436 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 144 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys 435 <210> SEQ ID NO 145 <400> SEQUENCE: 145 000 <210> SEQ ID NO 146 <400> SEQUENCE: 146 000 <210> SEQ ID NO 147 <211> LENGTH: 690 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 147 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp 435 440 445 Ala Gly Gly Gly Ser Ala Ala Ala Met Ala Glu Val Gln Leu Leu Glu 450 455 460 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 465 470 475 480 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg 485 490 495 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Tyr Ala 500 505 510 Gly Ala Ser Thr Ala Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile 515 520 525 Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu 530 535 540 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Thr Ser Thr Ser 545 550 555 560 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Asp Ile 565 570 575 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 580 585 590 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 595 600 605

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asn 610 615 620 Ala Ser Tyr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 625 630 635 640 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 645 650 655 Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Tyr Ala Gly Pro Tyr Thr Phe 660 665 670 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Asp Ile His His His His 675 680 685 His His 690 <210> SEQ ID NO 148 <211> LENGTH: 436 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 148 Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu 1 5 10 15 Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr 20 25 30 Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp 35 40 45 Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val 50 55 60 Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu 65 70 75 80 Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser 85 90 95 Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr 100 105 110 Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala 115 120 125 Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys 130 135 140 Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn 145 150 155 160 Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser 165 170 175 Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile 180 185 190 Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Asp Gly 195 200 205 Ser Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu 210 215 220 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 225 230 235 240 Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser 245 250 255 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 260 265 270 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 275 280 285 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 290 295 300 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro 305 310 315 320 Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln 325 330 335 Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe 340 345 350 Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val 355 360 365 Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala 370 375 380 Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 385 390 395 400 Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val 405 410 415 Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg 420 425 430 Ser Leu Gly Lys 435 <210> SEQ ID NO 149 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 149 Glu Phe Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp Ala Gly Gly Gly 1 5 10 15 Ser Ala Ala Ala 20 <210> SEQ ID NO 150 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 150 Met Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 1 5 10 15 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45 Trp Val Ser Thr Ile Ser Tyr Ala Gly Ala Ser Thr Ala Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Lys Thr Ser Thr Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 115 120 125 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 130 135 140 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 145 150 155 160 Ala Pro Lys Leu Leu Ile Tyr Asn Ala Ser Tyr Leu Gln Ser Gly Val 165 170 175 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 195 200 205 Ala Tyr Ala Gly Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 210 215 220 Lys Arg Asp Ile 225 <210> SEQ ID NO 151 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 151 Ala Pro Gln Gly Ile Ala Gly Gln 1 5 <210> SEQ ID NO 152 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 152 Gly Pro Gln Gly Leu Leu Gly Ala 1 5 <210> SEQ ID NO 153 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 153 Gly Pro Gln Gly Leu Ala Gly Gln 1 5 <210> SEQ ID NO 154 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 154 Gly Pro Leu Gly Ile Ala Gly Ile 1 5 <210> SEQ ID NO 155 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 155 Gly Pro Glu Gly Leu Arg Val Gly 1 5 <210> SEQ ID NO 156 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Glutamate <400> SEQUENCE: 156 Ala Ala Tyr His Leu Val Ser Xaa 1 5 <210> SEQ ID NO 157 <211> LENGTH: 8

<212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 157 Met Asp Ala Phe Leu Glu Ser Ser 1 5 <210> SEQ ID NO 158 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 158 Glu Pro Gln Ala Leu Ala Met Ser 1 5 <210> SEQ ID NO 159 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 159 Gln Ala Leu Ala Met Ser Ala Ile 1 5 <210> SEQ ID NO 160 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Gallus sp. <400> SEQUENCE: 160 Pro Ser Tyr Phe Leu Asn Ala Gly 1 5 <210> SEQ ID NO 161 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 161 Tyr Glu Ala Gly Leu Gly Val Val 1 5 <210> SEQ ID NO 162 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 162 Ala Gly Leu Gly Val Val Glu Arg 1 5 <210> SEQ ID NO 163 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 163 Ala Gly Leu Gly Ile Ser Ser Thr 1 5 <210> SEQ ID NO 164 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 164 Gly Ala Met Phe Leu Glu Ala Ile 1 5 <210> SEQ ID NO 165 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 165 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 166 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 166 Thr Glu Gly Glu Ala Arg Gly Ser 1 5 <210> SEQ ID NO 167 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 167 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 168 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 168 Leu Arg Ala Tyr Leu Leu Pro Ala 1 5 <210> SEQ ID NO 169 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Cavia porcellus <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Hydroxyproline Hyp <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Glutamate or Glutamine Glx <400> SEQUENCE: 169 Gly Ala Xaa Gly Leu Xaa Gly His 1 5 <210> SEQ ID NO 170 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 170 Gly Pro Gln Gly Val Arg Gly Glu 1 5 <210> SEQ ID NO 171 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 171 Gly Pro Ala Gly Val Gln Gly Pro 1 5 <210> SEQ ID NO 172 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Hydroxyproline Hyp <400> SEQUENCE: 172 Gly Pro Ser Gly Leu Xaa Gly Pro 1 5 <210> SEQ ID NO 173 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 173 Gly Pro Ala Gly Glu Arg Gly Ser 1 5 <210> SEQ ID NO 174 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 174 Gly Ala Lys Gly Leu Thr Gly Ser 1 5 <210> SEQ ID NO 175 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 175 Gly Pro Ala Gly Gln Asp Gly Pro 1 5 <210> SEQ ID NO 176 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 176 Gly Pro Ala Gly Phe Ala Gly Pro 1 5 <210> SEQ ID NO 177 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <400> SEQUENCE: 177 Gly Pro Ile Gly Asn Val Gly Ala 1 5 <210> SEQ ID NO 178 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Rattus sp. <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Hydroxylysine Hyl <400> SEQUENCE: 178

Gly Pro Xaa Gly Ser Arg Gly Ala 1 5 <210> SEQ ID NO 179 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 179 Gly Pro Gln Gly Ile Ala Gly Gln 1 5 <210> SEQ ID NO 180 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 180 Gly Pro Gly Gly Leu Leu Gly Ala 1 5 <210> SEQ ID NO 181 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 181 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 182 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 182 Pro Pro Gly Ala Tyr His Gly Ala 1 5 <210> SEQ ID NO 183 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 183 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 184 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 184 Gly Pro His Leu Leu Val Glu Ala 1 5 <210> SEQ ID NO 185 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 185 Leu Arg Ala Tyr Leu Leu Pro Ala 1 5 <210> SEQ ID NO 186 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 186 Gly Pro Glu Gly Leu Arg Val Gly 1 5 <210> SEQ ID NO 187 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 187 Arg Val Gly Phe Tyr Glu Ser Asp 1 5 <210> SEQ ID NO 188 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 188 Leu Leu Ser Ala Leu Val Glu Thr 1 5 <210> SEQ ID NO 189 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 189 Glu Ala Ile Pro Met Ser Ile Pro 1 5 <210> SEQ ID NO 190 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 190 Ile Ala Gly Arg Ser Leu Asn Pro 1 5 <210> SEQ ID NO 191 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Gallus sp. <400> SEQUENCE: 191 Leu Asn Ala Gly Phe Thr Ala Ser 1 5 <210> SEQ ID NO 192 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 192 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 193 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 193 Lys Pro Gln Gln Phe Phe Gly Leu 1 5 <210> SEQ ID NO 194 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 194 Asp Val Ala Gln Phe Val Leu Thr 1 5 <210> SEQ ID NO 195 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 195 Asp Thr Leu Glu Val Met Arg Lys 1 5 <210> SEQ ID NO 196 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 196 Asp Val Gly His Phe Arg Thr Phe 1 5 <210> SEQ ID NO 197 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 197 Asp Ser Gly Gly Phe Met Leu Thr 1 5 <210> SEQ ID NO 198 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 198 Arg Val Ala Glu Met Arg Gly Glu 1 5 <210> SEQ ID NO 199 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 199 Asp Leu Gly Arg Phe Gln Thr Phe 1 5 <210> SEQ ID NO 200 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 200 Pro Phe Ser Pro Leu Val Ala Thr 1 5 <210> SEQ ID NO 201 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens

<400> SEQUENCE: 201 Leu Arg Ala Tyr Leu Leu Pro Ala 1 5 <210> SEQ ID NO 202 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 202 Ala Pro Gly Asn Ala Ser Glu Ser 1 5 <210> SEQ ID NO 203 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 203 Phe Ser Ser Glu Ser Lys Arg Glu 1 5 <210> SEQ ID NO 204 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 204 Ala Gly Gly Ala Gln Met Gly Val 1 5 <210> SEQ ID NO 205 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 205 Gln Met Gly Val Met Gln Gly Pro 1 5 <210> SEQ ID NO 206 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 206 Met Ala Ala Ser Leu Lys Arg Pro 1 5 <210> SEQ ID NO 207 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 207 Ala Lys Arg Glu 1 <210> SEQ ID NO 208 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 208 Leu Arg Lys Pro 1 <210> SEQ ID NO 209 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 209 Gln Ala Gln Ala Ile Leu Gln Gln 1 5 <210> SEQ ID NO 210 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 210 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 211 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 211 Leu Val Glu Ala Leu Tyr Leu Val 1 5 <210> SEQ ID NO 212 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Bos sp. <400> SEQUENCE: 212 Glu Ala Leu Tyr Leu Val Cys Gly 1 5 <210> SEQ ID NO 213 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 213 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 214 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 214 Gly Pro His Leu Leu Val Glu Ala 1 5 <210> SEQ ID NO 215 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 215 Pro Pro Glu Glu Leu Lys Phe Gln 1 5 <210> SEQ ID NO 216 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 216 Gly Pro Pro Gly Val Val Gly Pro 1 5 <210> SEQ ID NO 217 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 217 Gly Pro Pro Gly Leu Arg Gly Glu 1 5 <210> SEQ ID NO 218 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 218 Gly Pro Gly Gly Val Val Gly Pro 1 5 <210> SEQ ID NO 219 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 219 Ile Pro Glu Asn Phe Phe Gly Val 1 5 <210> SEQ ID NO 220 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 220 Pro Pro Gly Ala Tyr His Gly Ala 1 5 <210> SEQ ID NO 221 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 221 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 222 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 222 Arg Ala Ile His Ile Gln Ala Glu 1 5 <210> SEQ ID NO 223 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 223 Gly Pro His Leu Leu Val Glu Ala 1 5

Claims

1-26. (canceled)

27. A composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) in which the antibody or fragment thereof is conjugated to a pharmaceutically active moiety, wherein the antibody or fragment thereof comprises CDR sequences in the Variable Heavy (VH) chains and Variable Light (VL) chains as shown below, wherein the CDRH1 and CDRL1 sequences are the same as those of scFv 1-11E; TABLE-US-00026 CDRH2 CDRH3 CDRL2 CDRL3 SIDSAGDSTYYADSVKG SYSYFDY TASYLQS QQASDYPTT (SEQ ID NO: 35) (SEQ ID NO: 58) (SEQ ID NO: 85) (SEQ ID NO: 122) SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST (SEQ ID NO: 7) (SEQ ID NO: 45) (SEQ ID NO: 65) (SEQ ID NO: 92) SIASSGTTTYYADSVKG SYADFDY AASNLQS QQADTYPTT (SEQ ID NO: 31) (SEQ ID NO: 54) (SEQ ID NO: 82) (SEQ ID NO: 118) SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT (SEQ ID NO: 37) (SEQ ID NO: 59) (SEQ ID NO: 75) (SEQ ID NO: 124).

28. The composition as claimed in claim 27, in which the antibody is a polyclonal antibody or a monoclonal antibody.

29. The composition as claimed in claim 27, in which the antibody fragment is a Fc, Fab, scFv, single domain (dAb) antibody, diabody, minibody, or scFv-Fc fragment.

30. The composition as claimed in claim 27, in which the antibody is an scFv selected from the group consisting of 1-12A, 4-6A, 4-8A, 4-9F, 4-4H, 3-3A, 3-6F, 3-9D, 3-11E, 6-11D, 4-5H, 6-5F, and 6-7F.

31. The composition as claimed in claim 27, in which the composition comprises a proteolytic cleavage site between the antibody or fragment thereof and the pharmaceutically active moiety.

32. The composition as claimed in claim 31, in which the proteolytic cleavage site is a matrix metalloproteinase (MMP) cleavage site, a serine protease cleavage site, or a site cleavable by a parasitic protease derived from a pathogenic organism.

33. The composition as claimed in claim 32, in which the proteolytic cleavage site is a MMP cleavage site.

34. The composition as claimed in claim 33, in which the MMP cleavage site is one or more of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, and MMP10 as shown in FIG. 5.

35. The composition as claimed in claim 27, in which the pharmaceutically active moiety is an antibody or a fragment thereof, a growth factor, a differentiation factor, a cytokine molecule, an interferon, a bone morphogenetic protein (BMP), a chemokine, a MCP (Monocyte Chemotactic Protein), a cytokine inhibitor, a cytokine receptor, a free-radical scavenging enzyme, or a toxin, or an active fragment or portion thereof.

36. The composition as claimed in claim 35, in which the pharmaceutically active moiety is an interferon.

37. The composition as claimed in claim 36, in which the pharmaceutically active moiety is interferon beta (IFN-.beta.).

38. The composition as claimed in claim 35, in which the pharmaceutically active moiety is a TNF receptor (TNFR) antibody fusion protein.

39. The composition as claimed in claim 38, in which the pharmaceutically active moiety is TNFR2-Fc.

40. The composition as claimed in claim 27, in which the pharmaceutically active moiety is a glycosaminoglycan molecule, chondroitin, a non-steroidal anti-inflammatory drug (NSAID), a steroid, sodium hyaluronate or hyaluronic acid, colchicine, or hydroxychloroquine.

41. A composition comprising an antibody or fragment thereof against oxidised Collagen II (CII) and a detectable label, wherein the antibody or fragment thereof comprises CDR sequences in the Variable Heavy (VH) chains and Variable Light (VL) chains as shown below, wherein the CDRH1 and CDRL1 sequences are the same as those of scFv 1-11E; TABLE-US-00027 CDRH2 CDRH3 CDRL2 CDRL3 SIDSAGDSTYYADSVKG SYSYFDY TASYLQS QQASDYPTT (SEQ ID NO: 35) (SEQ ID NO: 58) (SEQ ID NO: 85) (SEQ ID NO: 122) SISNSGTNTDYADSVKG NYASFDY YASYLQS QQGSASPST (SEQ ID NO: 7) (SEQ ID NO: 45) (SEQ ID NO: 65) (SEQ ID NO: 92) SIASSGTTTYYADSVKG SYADFDY AASNLQS QQADTYPTT (SEQ ID NO: 31) (SEQ ID NO: 54) (SEQ ID NO: 82) (SEQ ID NO: 118) SIDTGGSYTDYADSVKG SYTTFDY SASYLQS QQGSNSPTT (SEQ ID NO: 37) (SEQ ID NO: 59) (SEQ ID NO: 75) (SEQ ID NO: 124).

42. The composition as claimed in claim 41, in which the detectable label is a radionuclide or a dye.

43. The composition as claimed in claim 42, in which the detectable label is a dye.

44. A method of treatment of an arthropathy, comprising administering to a subject a composition as claimed in claim 27.

45. A method for the diagnosis of an arthropathy comprising administering a composition of claim 27 and subsequently detecting the composition.