Cytokine prodrugs and dual prodrugs

Abstract

The present application relates to novel prodrugs of IL-12. The present application further comprises methods for preparing and using the novel prodrugs.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 907,615, filed on September 28, 2019, the contents of which are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on September 23, 2020, is named 025471_WO007_SL.txt and is 282,851 bytes in size. Background Art

[0005] Interleukin 12 (IL-12) plays an important role in immunity (Watford et al., Cytokine Growth Factor Rev. (2003) 14(5):361-8). It stimulates the release of interferon gamma and activates T cells and natural killer (NK) cells (Del Vecchio, Clin Cancer Res. (2007) 13(16):4677-85). IL-12 consists of two subunits, p40 and p35. The IL-12 receptor consists of two subunits, IL-12 receptor β1 (IL-12Rβ1) and β2 (IL-12Rβ2). Deficiency of IL-12Rβ1 impairs the IL-12 signaling pathway and may lead to bacterial infections and even autoimmunity, such as Sjögren's syndrome ( Syndrome) (Sogkas et al., Front Immunol. (2017) 8:885). IL-12 has previously been explored as a potential therapy for the treatment of cancer (Colombo and Trinchieri, Cytokine and Growth Factor Review (2002) 13(2):155-68; Del Vecchio, supra; Lasek et al., Cancer Immunol Immunother. (2014) 63(5):419-35). Several clinical trials of IL-12 therapy have shown limited efficacy due to its narrow therapeutic index (Lasek et al., supra).

[0006] IL-2, another important cytokine, plays a central role in lymphocyte production, survival, and homeostasis. IL-2 has 133 amino acids and is composed of four antiparallel, amphipathic α-helices that form a quaternary structure essential for its function (Smith, Science (1988) 240: 1169-76; Bazan, Science (1992) 257: 410-13).

[0007] IL-2 works by binding to the IL-2 receptor (IL-2R), which is composed of up to three separate subunits. The association of α (CD25), β (CD122), and γ (CD132) subunits produces a trimeric, high-affinity IL-2R. The dimeric IL-2R composed of β and γ subunits is called the intermediate-affinity IL-2R. The α subunit forms a monomeric low-affinity IL-2R. Although the affinity of the dimeric intermediate-affinity IL-2 receptor to bind IL-2 is about 1 / 100 of that of the trimeric high-affinity receptor, both dimeric and trimeric IL-2R variants are able to transmit signals when IL-2 binds (Minami et al., Annual Review of Immunology (Annu Rev Immunol) (1993) 11: 245-68). Thus, the α subunit is not required for IL-2 signaling but confers high affinity binding to IL-2R, whereas the β and γ subunits are essential for signaling (Krieg et al., Proc Natl Acad Sci. (2010) 107:11906-11). + FoxP3 + Regulatory T (Treg) cells express trimeric IL-2R. Trimeric IL-2R is also transiently induced on conventionally activated T cells, whereas in the resting state, these cells express only dimeric IL-2R. Treg cells consistently express the highest levels of CD25 in vivo (Fontenot et al., Nature Immunol. (2005) 6:1142-51).

[0008] IL-2 mutant proteins have been prepared to reduce the side effects of IL-2. See, for example, U.S. Patents 6,955,807 and 9,428,567 and EP2639241B1. A high-affinity trimeric IL-2R with reduced affinity for PEGylated IL-2 (US20140328791) has also been disclosed. In addition, IL-2 mutant proteins have been fused to antibodies, such as PD-L1 antibodies (e.g., WO 2017 / 220989) and CEA antibodies (e.g., Klein et al., Oncoimmunology (2017) 6(3):e1277306; U.S. Patent 9,206,260). CEA antibodies are matured from the original mouse CEA antibody PR1A3 (U.S. Patent 8,642,742). Although antibodies may target IL-2 mutant proteins to tumor sites, the amount of antibody-IL-2 fusion at the tumor site may be only a small fraction of the administered dose, with most of the administered dose still in circulation. Circulating IL-2 will bind to so-called "PK deposits" (such as IL-2R) on immune cells located in immune organs (e.g., lymph nodes and spleen). Therefore, even if the antibody has tumor targeting specificity, the total amount of IL-2 that can be administered is still limited.

[0009] IL-15 is a cytokine with a similar structure to IL-2. IL-15 is secreted by mononuclear phagocytes and other immune cells after viral infection. IL-15 induces the proliferation of NK and other immune cells and participates in killing virus-infected cells and cancer cells. D The IL-2Rβ / γ complex is approximately 1 nM, i.e., intermediate affinity receptor binding (Giri et al., EMBO J. (1994) 13:2822-30). IL-15 binds with a higher affinity (K D~0.05nM) binds to the IL-15 receptor (IL-15R) α. IL-15Rα can associate with the IL-2Rβ / γ complex to form an IL-15-specific, functional high-affinity receptor (αβγ) (Minami et al., Annual Review of Immunology (1993) 11:245-67; ​​Giri et al., J Leukoc Biol. (1995) 5745:763-6; and Lehours et al., Eur Cytokine Netw. (2000) 11:207-15). The extracellular region of IL-15Rα contains a Sushi domain, a common motif in protein-protein interactions. It has been shown that an N-terminal fragment of IL-15Rα with the first 65 amino acids is partially active, whereas a fragment with the first 85 amino acids is fully functional (Wei et al., J Immunol. (2001) 167(1):277-82).

[0010] Unfortunately, current cytokine drug candidates have significant side effects, limiting the dosage of these drugs. Furthermore, these drug candidates are not site-specific in their activation of T, NK, and other immune cells. Furthermore, cytokine mutant proteins appear to exhibit "PK degradation," even when their affinity for cytokine receptors is significantly reduced. The production of cytokine-based protein therapeutics also presents numerous challenges.

[0011] Therefore, there is a need to develop improved cytokine-based cancer therapeutics that are more selective for tumor sites, avoid PK degradation, and have fewer severe side effects while improving efficacy. Summary of the Invention

[0012] The present disclosure provides an IL-12 prodrug or ("prodrug") comprising an IL-12 cytokine portion, a masking moiety (M), a dimeric carrier portion (C), and at least one peptide linker, wherein the IL-12 cytokine portion comprises an IL-12 p40 subunit (p40) and an IL-12 p35 subunit (p35), the masking moiety binds to the IL-12 cytokine portion and inhibits the biological activity of the IL-12 cytokine portion, and the masking moiety is optionally fused to one polypeptide chain of the dimeric carrier portion via a peptide linker, and the IL-12 cytokine portion is optionally fused to the other polypeptide chain of the carrier portion via a peptide linker, or the p40 subunit is optionally fused to one polypeptide chain of the carrier portion via a peptide linker, the p35 subunit is optionally fused to the other polypeptide chain of the carrier portion via a peptide linker, and the masking moiety is optionally fused to the C-terminus of the p40 subunit or the p35 subunit via a peptide linker.

[0013] In a specific embodiment, the IL-12 subunit p40 has at least 95% homology to the amino acid sequence of SEQ ID NO: 5. In a specific embodiment, the IL-12 subunit p35 has at least 95% homology to the amino acid sequence of SEQ ID NO: 6.

[0014] In some embodiments, at least one peptide linker is a cleavable peptide linker. In other embodiments, at least one peptide linker is a non-cleavable peptide linker.

[0015] In some embodiments, the masking moiety is a first masking moiety (MM1), optionally fused to the carrier moiety or to the IL-12p40 or p35 subunit via a cleavable peptide linker. In specific embodiments, the first masking moiety (MM1) binds to the IL-12p40 subunit and reduces or inhibits IL-12 binding to the IL-12 receptor β1 (IL-12Rβ1). In some embodiments, the masking moiety is selected from the extracellular domain of the IL-12 receptor β1 (IL-12Rβ1 ECD) or a fragment thereof, a p40-binding peptide discovered from a peptide library screen, and a single-chain antibody (scFv) or Fab domain of an antibody that binds to p40. In other embodiments, the masking moiety is an scFv or Fab domain of an antibody that binds to p40. In specific embodiments, the masking moiety comprises an scFv that binds to p40, wherein the scFv comprises an amino acid sequence that is at least 99% homologous to SEQ ID NOs: 7-11 and 12.

[0016] In some embodiments, the prodrug further comprises a second masking moiety (MM2), optionally fused to the carrier moiety or to the IL-12 p40 or p35 subunit via a cleavable peptide linker. In certain embodiments, the second masking moiety (MM2) binds to p35 and / or p40 and inhibits the binding of IL-12 to IL-12 receptor β2 (IL-12Rβ2). In some embodiments, the second masking moiety is selected from the extracellular domain of IL-12 receptor β2 (IL-12Rβ2 ECD) or a fragment thereof, a p35 or p40 binding peptide discovered from a peptide library screen, and a single chain antibody or Fab domain of an antibody that binds to p35 or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2. In certain embodiments, the second masking moiety comprises the extracellular domain (ECD) of IL-12 receptor β2 (IL-12Rβ2) or a fragment thereof, wherein the IL-12Rβ2 ECD or fragment thereof comprises an amino acid sequence at least 95% homologous to SEQ ID NO: 17, 18 or 19.

[0017] In some embodiments, the second masking moiety comprises a single-chain antibody (scFv) or Fab domain of an antibody that binds to p40 and reduces or inhibits binding of IL-12 to IL-12Rβ2; wherein the scFv of the Fab comprises the same light chain CDRs and heavy chain CDRs as those derived from: IL-12 antibody PMA204, Antibody 1, Antibody 50, Antibody 68, Antibody 80, or Antibody 136.

[0018] In some embodiments, the vector is an antibody or antigen-binding portion that binds to a target expressed on the surface of a cancer cell. In particular embodiments, the antibody or antigen-binding portion binds to an antigen selected from the group consisting of 5T4, Claudin18.2, EGFR, EGFR type III, GPC3, TROP-2, mesothelin, PSMA, CMET, DLL-3, and BCMA.

[0019] In some embodiments, the carrier portion is selected from an Fc domain and an antibody. In certain embodiments, the carrier portion comprises an Fc domain, the Fc domain comprising a first polypeptide chain and a second polypeptide chain, and wherein the polypeptide chains of the prodrug comprise a pair of molecular formulas selected from the following pairs (from N-terminus to C-terminus):

[0020] a.F1-PL1-A-PL2-B, F2-CL1-MM2-CL2-MM1; and

[0021] b.F1-PL1-B-PL2-A, F2-CL1-MM1-CL2-MM2;

[0022] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; CL1 and CL2 are cleavable peptide linkers; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0023] In certain embodiments, the carrier portion comprises an Fc domain comprising a first polypeptide chain and a second polypeptide chain, wherein the polypeptide chains of the prodrug comprise a pair of molecular formulas selected from the following pairs (from N-terminus to C-terminus):

[0024] a. F1-PL1-A-PL2-B, F2-PL3-MM2-CL-MM1; and

[0025] b.F1-PL1-B-PL2-A, F2-PL3-MM1-CL-MM2;

[0026] wherein F1 and F2 are subunits of the carrier portion (e.g., an Fc domain) that forms a heterodimer; PL1, PL2, and PL3 are peptide linkers; CL is a cleavable peptide linker; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0027] In certain embodiments, the carrier portion comprises an Fc domain comprising a first polypeptide chain and a second polypeptide chain, wherein the polypeptide chains of the prodrug comprise a pair of molecular formulas selected from the following pairs (from N-terminus to C-terminus):

[0028] a. F1-PL1-A-CL1-MM2, F2-PL2-B-CL2-MM1; and

[0029] b.F1-PL1-A-CL1-MM1, F2-PL2-B-CL2-MM2;

[0030] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; CL1 and CL2 are cleavable peptide linkers; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0031] In certain embodiments, the carrier portion comprises an Fc domain comprising a first polypeptide chain and a second polypeptide chain, wherein the polypeptide chains comprise a pair of formulas selected from the group consisting of (from N-terminus to C-terminus):

[0032] a. F1-PL1-A-CL-MM2, F2-PL2-B-PL3-MM1; and

[0033] b.F1-PL1-A-PL2-MM1, F2-PL3-B-CL-MM2;

[0034] wherein F1 and F2 are subunits of the carrier portion (e.g., an Fc domain) that forms a heterodimer; PL1, PL2, and PL3 are peptide linkers; CL is a cleavable peptide linker; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0035] In certain embodiments, the carrier portion comprises an Fc domain comprising a first polypeptide chain and a second polypeptide chain, wherein the polypeptide chains comprise a pair of formulas selected from the group consisting of (from N-terminus to C-terminus):

[0036] a.F1-PL1-A-PL2-B, F2-CL-M; and

[0037] b.F1-PL1-B-PL2-A, F2-CL-M;

[0038] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; CL is a cleavable peptide linker; M is a masking portion that binds to the p40 subunit and inhibits the biological activity of IL-12; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0039] In certain embodiments, the carrier portion comprises an Fc domain comprising a first polypeptide chain and a second polypeptide chain, wherein the polypeptide chains comprise a pair of formulas selected from the group consisting of (from N-terminus to C-terminus):

[0040] a. F1-PL1-A-PL2-M, F2-PL3-B; and

[0041] b.F1-PL1-B-PL2-A, F2-PL3-M;

[0042] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1, PL2, and PL3 are peptide linkers; M is a masking portion that binds to the p40 subunit and inhibits the biological activity of IL-12; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0043] In certain embodiments, the carrier portion comprises an Fc domain comprising a first polypeptide chain and a second polypeptide chain, wherein the polypeptide chains comprise a pair of formulas selected from the group consisting of (from N-terminus to C-terminus):

[0044] a.F1-PL1-M, F2-PL2-A-SS-B; and

[0045] b.F1-CL, F2-PL1-A-SS-B;

[0046] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; M is a masking portion that binds to the p40 subunit and inhibits the biological activity of IL-12; A is the IL-12p35 subunit; and B is the IL-12p40 subunit; and SS is a disulfide bond.

[0047] In some embodiments, the non-cleavable peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 29-33; and wherein the cleavable peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-54.

[0048] In some embodiments, the prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 20; and wherein the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to any one of the amino acid sequences selected from SEQ ID NO: 21-28.

[0049] In some embodiments, the prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 55; and wherein the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to any one of the amino acid sequences selected from SEQ ID NOs: 56-59.

[0050] In some embodiments, the prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 60; and the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to any one of the amino acid sequences selected from SEQ ID NOs: 61-64.

[0051] In some embodiments, the prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 65; and the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to any one of SEQ ID NOs: 66-73.

[0052] In some embodiments, the prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 20; and the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to any one of the amino acid sequences selected from SEQ ID NOs: 76-79.

[0053] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a prodrug of the present invention and a pharmaceutically acceptable excipient.

[0054] In some aspects, the present disclosure provides a polynucleotide encoding a prodrug of the present invention, an expression vector comprising the polynucleotide, and a host cell (e.g., a mammalian host cell, such as a CHO cell, a NSO cell, and a 293T cell) comprising the expression vector. In some embodiments, one or more genes encoding uPA, MMP-2, MMP-9, and / or a protease are knocked out in the host cells described herein. The present disclosure also provides a method for preparing the prodrug of the present invention, comprising culturing the host cell under conditions that allow expression of the prodrug and isolating (also purifying) the prodrug.

[0055] The present disclosure also provides a method for treating a cancer or infectious disease in a patient in need or stimulating the patient's immune system, the method including administering a therapeutically effective amount of the prodrug or the pharmaceutical composition of the present disclosure to the patient. The present disclosure also provides a method for treating cancer, the method including administering a combination of the prodrug or pharmaceutical composition of the present disclosure and a second pharmaceutical composition to a cancer patient, wherein the second pharmaceutical composition includes an active ingredient selected from the following: cytokines other than IL-12 or its fusion molecules, antibodies against PD-1, antibodies against PD-L1, antibodies against CTLA-4, antibodies against CD47, PD-1 antibody-IL-2 fusion molecules, PD-1-IL-7 fusion molecules, PD-1 antibody-IL-15 fusion molecules and PD-1-IL-21 fusion molecules. The patient may suffer from, for example, a viral infection (e.g., HIV, HBV, HCV or HPV infection) or a cancer selected from the group consisting of: brain cancer, breast cancer, lung cancer, pancreatic cancer, esophageal cancer, medullary thyroid cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, colorectal cancer and gastric cancer.

[0056] Also provided herein are uses of prodrugs for treating cancer or infectious diseases or stimulating the immune system; uses of IL-12 prodrugs for preparing medicaments for treating cancer or infectious diseases or stimulating the immune system; and articles of manufacture (e.g., kits) comprising one or more dosage units of an IL-12 prodrug of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1A and 1B Shown is a diagram of the structure of an IL-12 prodrug comprising: an IL-12p40 subunit (p40), an IL-12p35 subunit (p35), a first masking moiety (MM1; white graphics in the illustrated structure), a second masking moiety (MM2; black graphics in the illustrated structure), a carrier (C), and two cleavable peptide linkers. Figure 1A The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain, while the IL-12 subunit p40 is fused to the C-terminus of p35 via a non-cleavable peptide linker. A second masking moiety is fused to the C-terminus of another polypeptide in the Fc domain via a cleavable linker, and the first masking moiety is fused to the C-terminus of the second masking moiety via a cleavable peptide linker. Figure 1B The IL-12 subunit p40 is shown fused to the C-terminus of one polypeptide in the Fc domain, while the IL-12 subunit p35 is fused to the C-terminus of p40 via a non-cleavable peptide linker. A first masking moiety is fused to the C-terminus of another polypeptide in the Fc domain via a cleavable linker, and a second masking moiety is fused to the C-terminus of the first masking moiety via a cleavable peptide linker.

[0058] Figure 2A and 2B Shown is a diagram of the structure of an IL-12 prodrug comprising: an IL-12p40 subunit (p40), an IL-12p35 subunit (p35), a first masking moiety (MM1; white graphics in the illustrated structure, a second masking moiety (MM2; black graphics in the illustrated structure), a carrier (C), and a cleavable peptide linker. Figure 2A The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain, while the IL-12 subunit p40 is fused to the C-terminus of p35 via a non-cleavable peptide linker. A second masking moiety is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable linker, and the first masking moiety is fused to the C-terminus of the second masking moiety via a cleavable peptide linker. Figure 2B The IL-12 subunit p40 is shown fused to the C-terminus of one polypeptide in the Fc domain, while the IL-12 subunit p35 is fused to the C-terminus of p40 via a non-cleavable peptide linker. A first masking moiety is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable linker, and a second masking moiety is fused to the C-terminus of the first masking moiety via a cleavable peptide linker.

[0059] Figure 3A and 3B Shown is a diagram of the structure of an IL-12 prodrug comprising: an IL-12p40 subunit (p40), an IL-12p35 subunit (p35), a first masking moiety (MM1; white graphics in the illustrated structure), a second masking moiety (MM2; black graphics in the illustrated structure), a carrier (C), and two cleavable peptide linkers. Figure 3A The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p40 is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable peptide linker. The second masking moiety is fused to the C-terminus of p35 via a cleavable linker, while the first masking moiety is fused to the C-terminus of p40 via a cleavable peptide linker. Figure 3B The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p40 is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable peptide linker. The second masking moiety is fused to the C-terminus of p40 via a cleavable linker, while the first masking moiety is fused to the C-terminus of p35 via a cleavable peptide linker.

[0060] Figure 4A and 4BShown is a diagram of the structure of an IL-12 prodrug comprising: an IL-12p40 subunit (p40), an IL-12p35 subunit (p35), a first masking moiety (MM1; white graphics in the illustrated structure), a second masking moiety (MM2; black graphics in the illustrated structure), a carrier (C), and a cleavable peptide linker. Figure 4A The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p40 is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable peptide linker. The second masking moiety is fused to the C-terminus of p35 via a cleavable linker, and the first masking moiety is fused to the C-terminus of p40 via a non-cleavable peptide linker. Figure 4B The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p40 is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable peptide linker. The second masking moiety is fused to the C-terminus of p40 via a cleavable linker, and the first masking moiety is fused to the C-terminus of p35 via a non-cleavable peptide linker.

[0061] Figure 5A and 5B Shown is a schematic representation of the structure of an IL-12 prodrug comprising: an IL-12 p40 subunit (p40), an IL-12 p35 subunit (p35), a masking moiety (MM), and a cleavable peptide linker. Figure 5A The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p40 is fused to the C-terminus of p35 via a non-cleavable peptide linker. In addition, a masking moiety is fused to the C-terminus of the second Fc polypeptide via a cleavable linker. Figure 5B The IL-12 subunit p40 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p35 is fused to the C-terminus of p40 via a non-cleavable peptide linker. In addition, a masking moiety is fused to the C-terminus of the second Fc polypeptide via a cleavable linker.

[0062] Figure 6A and 6B Shown is a representation of the structure of an IL-12 prodrug comprising: IL-12 p40 subunit (p40), IL-12 p35 subunit (p35), a masking moiety (MM), a carrier (C), and no cleavable peptide linker. Figure 6AThe IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p40 is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable peptide linker. In addition, a masking moiety is fused to the C-terminus of p35 via a non-cleavable linker. Figure 6B The IL-12 subunit p40 is shown fused to the C-terminus of one polypeptide in the Fc domain via a non-cleavable peptide linker, while the IL-12 subunit p35 is fused to the C-terminus of p40 via a non-cleavable peptide linker. In addition, the masking moiety is fused to the C-terminus of the second Fc polypeptide via a non-cleavable linker.

[0063] Figure 7A and 7B Shown is a schematic representation of the structure of an IL-12 prodrug comprising three polypeptide chains, including an IL-12 p40 subunit (p40), an IL-12 p35 subunit (p35), a masking moiety (MM), and a carrier (C). Figure 7A The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain, optionally via a non-cleavable linker, and the masking moiety is fused to the C-terminus of another polypeptide in the Fc domain, optionally via a non-cleavable linker. p40 is a third polypeptide chain connected to the p35 subunit via a disulfide bond. Figure 7B The IL-12 subunit p35 is shown fused to the C-terminus of one polypeptide in the Fc domain, optionally via a non-cleavable peptide linker, and the masking moiety is fused to the C-terminus of another polypeptide in the Fc domain via a non-cleavable peptide linker. p40 is a third polypeptide chain linked to the p35 subunit via a disulfide bond.

[0064] Figure 8A and 8B SDS-PAGE analysis is shown. Figure 8A The structure is shown in Figure 5B SDS-PAGE analysis of protein A affinity chromatography pool samples of IL-12 prodrugs JR3.105.2, JR3.105.3, JR3.105.4, and JR3.105.5, shown in Figure 2 and with sequences as shown in Table 2. Samples were run under reducing and non-reducing conditions, respectively. Although some prodrug activation was observed, the samples were of reasonable purity. Figure 8B Shown are SDS-PAGE analyses of prodrug JR3.105.5 samples before and after activation by protease treatment. The data show that most of the prodrug samples were activated.

[0065] Figure 9Figure 2 shows a cell-based activity analysis of IL-12 prodrug samples before and after protease treatment. The prodrugs treated with protease are labeled JR3.105.2-Clv, JR3.105.3-Clv, JR3.105.4-Clv, and JR3.105.5-Clv. Significant activity was observed in the prodrug JR3.105.5 treated with protease.

[0066] Figure 10 Shown are the EC values ​​of IL-12 prodrug samples tested in the cell-based assay. 50 Value, as in Figure 9 The EC of prodrug JR3.105.5 is shown in 50 The value was approximately 0.9 nM before activation and approximately 0.05 nM after activation. DETAILED DESCRIPTION

[0067] As used herein and in the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise. Reference herein to "about" a value or parameter includes (and describes) variations on the value or parameter itself. For example, a description referring to "about X" includes a description of "X." Furthermore, the use of "about" before any series of numbers includes "about" each number listed in the series. For example, a description referring to "about X, Y, or Z" is intended to describe "about X, about Y, or about Z."

[0068] The term "antigen-binding portion" refers to a polypeptide or a group of interacting polypeptides that specifically bind to an antigen, and includes, but is not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, multispecific antibodies, bispecific antibodies (dualspecific or bispecific antibodies), anti-idiotypic antibodies, or bifunctional hybrid antibodies) or antigen-binding fragments thereof (e.g., Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibodies (dAb), or bifunctional antibodies), single chain antibodies, and Fc-containing polypeptides, such as immunoadhesins. In some embodiments, the antibody can be of any heavy chain isotype (e.g., IgG, IgA, IgM, IgE, or IgD) or subtype (e.g., IgG1, IgG2, IgG3, or IgG4). In some embodiments, the antibody can be of any light chain isotype (e.g., κ or λ). The antibody can be human, non-human (e.g., from a mouse, rat, rabbit, goat, or another non-human animal), chimeric (e.g., having a non-human variable region and a human constant region), or humanized (e.g., having a non-human CDR and a human framework and constant region). In some embodiments, the antibody is a humanized antibody.

[0069] The term "cytokine agonist polypeptide" or "cytokine portion" refers to a wild-type cytokine or an analog thereof. An analog of a wild-type cytokine has the same biological specificity as the wild-type cytokine (e.g., binds to the same receptor and activates the same target cell), even if the activity level of the analog may be different from the activity level of the wild-type cytokine. An analog can be, for example, a mutant protein (i.e., a mutant polypeptide) of a wild-type cytokine and can include at least one mutation, at least two mutations, at least three mutations, at least four mutations, at least five mutations, at least six mutations, at least seven mutations, at least eight mutations, at least nine mutations, or at least ten mutations relative to the wild-type cytokine.

[0070] The term "cytokine mask" or "masking moiety" refers to a moiety (e.g., a polypeptide) that binds to a cytokine, thereby inhibiting the cytokine from binding to its receptor on the surface of a target cell and / or exerting its biological function when masked. Examples of cytokine masking agents include, but are not limited to, polypeptides derived from the extracellular domain of the natural receptor of the cytokine that contacts the cytokine.

[0071] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or composition sufficient to treat a particular disorder, condition or disease, such as to ameliorate, alleviate, lessen and / or delay one or more of its symptoms.

[0072] The term "functional analog" refers to a molecule that has the same biological specificity (eg, binds to the same ligand) and / or activity (eg, activates or inhibits a target cell) as a reference molecule.

[0073] The term "fused" or "fusion" with respect to two polypeptide sequences refers to the joining of two polypeptide sequences through a backbone peptide bond. The two polypeptides can be fused directly or through a peptide linker of one or more amino acids in length. Fusion polypeptides can be prepared by recombinant technology from coding sequences containing the corresponding coding sequences of the two fusion partners, with or without the coding sequence of a peptide linker therebetween. In some embodiments, fusion encompasses chemical conjugation.

[0074] The term "pharmaceutically acceptable excipient" when used to refer to an ingredient in a composition means that the excipient is suitable for administration to a therapeutic subject, including a human subject, without undue deleterious side effects to the subject and without affecting the biological activity of the active pharmaceutical ingredient (API).

[0075] The term "subject" refers to a mammal, and includes, but is not limited to, a human, a pet (eg, a canine or feline), a farm animal (eg, a bovine or equine), a rodent, or a primate.

[0076] As used herein, "treatment" or "treating" is a method for obtaining a beneficial or desired clinical outcome. A beneficial or desired clinical outcome includes, but is not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, alleviating the extent of the disease, improving the disease state, stabilizing the disease (e.g., preventing or delaying the exacerbation or progression of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, providing partial or complete relief of the disease, reducing the dosage of one or more other drugs required for treating the disease, improving the patient's quality of life, and / or prolonging survival. The methods of the present disclosure encompass any one or more of these therapeutic aspects.

[0077] It should be understood that one, some or all of the features in the various embodiments described herein can be combined to form other embodiments of the present invention.The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described below.

[0078] I. IL-12 Prodrugs

[0079] The present disclosure provides IL-12 prodrugs that are metabolized in vivo into active IL-12 therapeutic drugs. IL-12 prodrugs have fewer side effects, better in vivo PK properties (e.g., longer half-life) and better targeting specificity, and are more effective than prior art IL-12 therapeutic drugs. The IL-12 prodrugs of the present invention include an IL-12 agonist polypeptide, at least one masking portion (M), a carrier (C), and one or more cleavable or non-cleavable peptide linkers that connect the masking portion to the agonist polypeptide or the carrier. In some embodiments, the IL-12 prodrug includes an IL-12 agonist polypeptide, a first masking portion (MM1), a second masking portion (MM2), a carrier (C), and one or more cleavable or non-cleavable peptide linkers that connect the masking portion to the agonist polypeptide or the carrier.

[0080] IL-12 includes subunits p40 and p35. Subunit p40 comprises the amino acids set forth in SEQ ID NO:5, and p35 comprises the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the IL-12 analog comprises subunit p40 having amino acids at least 90% homologous to SEQ ID NO:5. In other embodiments, the IL-12 analog comprises subunit p35 having an amino acid sequence at least 90% homologous to SEQ ID NO:6.

[0081] In some embodiments, the IL-12 prodrug includes at least one masking portion. The masking portion can be connected to the cytokine portion or the carrier portion through a peptide linker. In some embodiments, the peptide linker is a cleavable peptide linker. In some embodiments, the cleavable peptide linker includes one or more cleavable portions, and the one or more cleavable portions are substrates for proteases typically found at the tumor site. When the masking agent is combined with the cytokine portion, the masking agent inhibits the biological function of the cytokine portion. In a specific embodiment, the masking agent inhibits the biological activity of IL-12 or its analogs. The prodrug can be activated at the patient's target site (e.g., at the tumor site or the surrounding environment) by cleaving the linker and subsequently releasing the cytokine masking agent from the prodrug, thereby exposing the previously masked cytokine portion and allowing the cytokine portion to bind to its receptor on the target cell and exert its biological function on the target cell.

[0082] In some embodiments, the carrier of the IL-12 prodrug is an antigen-binding portion that binds to an antigen at a target site (e.g., a tumor surface). In some embodiments, the IL-12 prodrug of the present invention is metabolized to become active in vivo at the target site targeted by the carrier. In other embodiments, the carrier in the prodrug is an antibody that targets a tumor antigen, such that the IL-12 prodrug is delivered to the patient's tumor site and is locally metabolized (e.g., within or near the tumor microenvironment) by cleaving the linker connecting the cytokine masking agent to the carrier or cytokine portion, thereby allowing the cytokine portion to interact with its receptor on the target cell and locally stimulate the target immune cell.

[0083] In some embodiments, the carrier is selected from albumin, an Fc fragment, polyethylene glycol (PEG), or an antibody or antigen-binding fragment thereof.

[0084] A. Masking Moieties of IL-12 Prodrugs

[0085] In some embodiments, the IL-12 masking moiety (M, MM1, or MM2) is derived from the extracellular domain of the IL-12 receptor β1 subunit or a fragment thereof, the extracellular domain of the IL-12 receptor β2 subunit or a fragment thereof, and a scFv or Fab specific for p40 or p35. In some embodiments, the masking moiety inhibits the biological activity of IL-12 or its analogs. In some embodiments, the masking moiety comprises an scFv, wherein the scFv has an amino acid sequence at least 99% homologous to SEQ ID NOs: 7-11 and 12. In some embodiments, the masking moiety is an IL-12 receptor extracellular domain (ECD) or a functional analog thereof, wherein the IL-12 receptor is IL-12 receptor β1. In some embodiments, the masking moiety is an IL-12 receptor extracellular domain (ECD), a functional analog thereof, or a fragment thereof, wherein the IL-12 receptor is IL-12 receptor β1. In some embodiments, the IL-12 receptor β1 has an amino acid sequence at least 95% homologous to SEQ ID NO: 137. In some embodiments, the prodrug comprises two masking moieties, MM1 and MM2; wherein at least one of the masking moieties comprises an scFv or Fab that binds to p40 or p35 and reduces or inhibits IL-12 binding to IL-12Rβ1 or IL-12Rβ2. In some embodiments, the scFv or Fab comprises the same light chain CDRs and heavy chain CDRs as the IL-12 antibodies briakinumab or ustekinumab. In some embodiments, the scFv or Fab comprises the same light chain CDRs and heavy chain CDRs as an IL-12 antibody selected from the group consisting of PMA204, Antibody 1, Antibody 50, Antibody 68, Antibody 80, and Antibody 136 (see U.S. Patent No. 8,563,697).

[0086] In some embodiments, the masking moieties (MM1 and MM2) are both scFv or Fab; wherein the first masking moiety binds to p40 and reduces or inhibits IL-12 binding to IL-12Rβ1, and the second masking moiety binds to p40 or p35 and reduces or inhibits IL-12 binding to IL-12Rβ2. In some embodiments, the first masking moiety comprises the same light chain CDRs and heavy chain CDRs as the IL-12 antibodies Briakinumab or Ustekinumab. In some embodiments, the second masking moiety comprises the same light chain CDRs and heavy chain CDRs as an IL-12 antibody selected from the group consisting of PMA204, Antibody 1, Antibody 50, Antibody 68, Antibody 80, and Antibody 136 (see U.S. Patent No. 8,563,697).

[0087] B. Carrier Moiety of Prodrug

[0088] The carrier portion of the prodrug of the present invention may be an antigen binding portion or a portion that is not antigen binding. The carrier portion can improve the PK properties of the cytokine agonist polypeptide, such as serum half-life, and can also target the cytokine agonist polypeptide to a target site in the body, such as a tumor site.

[0089] 1. Non-antigen binding carrier part

[0090] Non-antigen binding carrier moieties can be used for the prodrugs of the present invention. For example, an antibody Fc domain (e.g., human IgG1, IgG2, IgG3, or IgG4 Fc), a polymer (e.g., PEG), albumin (e.g., human albumin), or a fragment thereof, or nanoparticles can be used.

[0091] The carrier portion of the prodrug can include albumin (e.g., human serum albumin) or a fragment thereof. In some embodiments, the albumin or albumin fragment is about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more identical to human serum albumin or a fragment thereof.

[0092] In some embodiments, the carrier moiety comprises an albumin fragment (e.g., a human serum albumin fragment) that is about 10 amino acids or more, 20 amino acids or more, 30 amino acids or more, 40 amino acids or more, 50 amino acids or more, 60 amino acids or more, 70 amino acids or more, 80 amino acids or more, 90 amino acids or more, 100 amino acids or more, 120 amino acids or more, 140 amino acids or more, 160 amino acids or more, 180 amino acids or more, 200 amino acids or more, 250 amino acids or more, 300 amino acids or more, 350 amino acids or more, 400 amino acids or more, 450 amino acids or more, 500 amino acids or more, or 550 amino acids or more. In some embodiments, the albumin fragment is between about 10 and about 584 amino acids in length (e.g., between about 10 and about 20 amino acids, between about 20 and about 40 amino acids, between about 40 and about 80 amino acids, between about 80 and about 160 amino acids, between about 160 and about 250 amino acids, between about 250 and about 350 amino acids, between about 350 and about 450 amino acids, or between about 450 and about 550 amino acids in length). In some embodiments, the albumin fragment comprises a Sudlow I domain or a fragment thereof, or a Sudlow II domain or a fragment thereof.

[0093] In some embodiments, the vector is an antibody Fc fragment. Fc is a dimeric molecule with two N-termini and two C-termini. In some embodiments, the cytokine moiety can be fused to one Fc polypeptide in the dimeric Fc fragment, and the masking moiety can be fused to the second Fc polypeptide. In preferred embodiments, both the cytokine moiety and the masking moiety are fused to the C-terminus of each polypeptide chain in the dimeric Fc fragment. In some embodiments, both the cytokine moiety and the masking moiety are fused to the N-terminus of each polypeptide chain in the dimeric Fc fragment. In either case, at least one of the masking moieties is fused to the Fc polypeptide directly or indirectly via a cleavable peptide linker.

[0094] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0095] a.F1-PL1-A-PL2-B, F2-CL1-MM2-CL2-MM1( Figure 1A );as well as

[0096] b.F1-PL1-B-PL2-A, F2-CL1-MM1-CL2-MM2( Figure 1B );

[0097] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; CL1 and CL2 are cleavable peptide linkers; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0098] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0099] a.F1-PL1-A-PL2-B, F2-PL3-MM2-CL-MM1( Figure 2A );as well as

[0100] b.F1-PL1-B-PL2-A, F2-PL3-MM1-CL-MM2( Figure 2B );

[0101] wherein F1 and F2 are subunits of the carrier portion (e.g., an Fc domain) that forms a heterodimer; PL1, PL2, and PL3 are peptide linkers; CL is a cleavable peptide linker; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0102] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0103] a.F1-PL1-A-CL1-MM2, F2-PL2-B-CL2-MM1( Figure 3A);as well as

[0104] b.F1-PL1-A-CL1-MM1, F2-PL2-B-CL2-MM2( Figure 3B );

[0105] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; CL1 and CL2 are cleavable peptide linkers; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0106] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0107] a.F1-PL1-A-CL-MM2, F2-PL2-B-PL3-MM1( Figure 4A );as well as

[0108] b.F1-PL1-A-PL2-MM1, F2-PL3-B-CL-MM2( Figure 4B );

[0109] wherein F1 and F2 are subunits of the carrier portion (e.g., an Fc domain) that forms a heterodimer; PL1, PL2, and PL3 are peptide linkers; CL is a cleavable peptide linker; MM1 is a first masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; MM2 is a second masking portion that binds to p35 and / or p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ2; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0110] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0111] a.F1-PL1-A-PL2-B、F2-CL-M( Figure 5A );as well as

[0112] b.F1-PL1-B-PL2-A、F2-CL-M( Figure 5B );

[0113] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; CL is a cleavable peptide linker; M is a masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0114] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0115] a.F1-PL1-A-PL2-M、F2-PL3-B( Figure 6A );as well as

[0116] b.F1-PL1-B-PL2-A、F2-PL3-M( Figure 6B );

[0117] wherein F1 and F2 are subunits of the carrier portion (e.g., Fc domain) that form a heterodimer; PL1, PL2, and PL3 are peptide linkers; M is a masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; A is the IL-12p35 subunit; and B is the IL-12p40 subunit.

[0118] In some embodiments, the carrier moiety is an Fc domain comprising a first polypeptide chain and a second polypeptide chain (i.e., two different heavy chains), wherein the polypeptide chains of the prodrug comprise a pair of formulas selected from the following pairs (from N-terminus to C-terminus):

[0119] a.F1-PL1-M、F2-PL2-A-SS-B( Figure 7A );as well as

[0120] b.F1-CL-M、F2-PL1-A-SS-B( Figure 7B );

[0121] wherein F1 and F2 are subunits of the carrier portion (e.g., an Fc domain) that form a heterodimer; PL1 and PL2 are peptide linkers; M is a masking portion that binds to p40 and reduces or inhibits the binding of IL-12 to IL-12Rβ1; CL is a cleavable peptide linker; A is the IL-12p35 subunit; and B is the IL-12p40 subunit; and SS is a disulfide bond.

[0122] 2. Antigen binding carrier part

[0123] The carrier portion can be an antibody or its antigen binding fragment, or an immunoadhesin. In certain embodiments, the antigen binding portion is a full-length antibody with two heavy chains and two light chains, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a disulfide-linked Fv fragment, a single domain antibody, a nanobody, or a single-chain variable fragment (scFv). In certain embodiments, the antigen binding portion is a bispecific antigen binding portion and can be combined with two different antigens or two different epitopes on the same antigen. The antigen binding portion can provide additional and potentially synergistic therapeutic efficacy for cytokine agonist polypeptides. In certain embodiments, the antigen binding portion includes a full-length antibody heavy chain or a full-length antibody light chain. In certain embodiments, the antigen binding portion comprises an antibody heavy chain fragment or an antibody light chain fragment.

[0124] In some embodiments, the cytokine portion is fused to the C-terminus of one of the heavy chains of the antibody, and the masking agent for the cytokine is fused to the C-terminus of the other heavy chain of the antibody via a peptide linker (optionally a cleavable linker), wherein the two heavy chains optionally contain mutations that allow for specific pairing of the two different heavy chains.

[0125] Strategies for forming heterodimers of Fc fusion polypeptides or bispecific antibodies are well known (e.g., see Spies et al., Mol Immunol. (2015) 67(2)(A):95-106). For example, the two heavy chain polypeptides in a prodrug can form a stable heterodimer by a "knob-hole" mutation. The "knob-hole" mutation is performed to promote the formation of heterodimers of the antibody heavy chains and is commonly used to prepare bispecific antibodies (see, e.g., U.S. Patent 8,642,745). For example, the Fc domain of an antibody can include a T366W mutation in the CH3 domain of the "knob chain" and a T366S, L368A and / or Y407V mutation in the CH3 domain of the "hole chain". Additional interchain disulfide bonds between the CH3 domains can also be used, for example, by introducing a Y349C mutation into the CH3 domain of the "knob chain" and an E356C or S354C mutation into the CH3 domain of the "hole chain" (see, e.g., Merchant et al., Nature Biotech. (1998) 16:677-81). In other embodiments, the antibody portion can include a Y349C and / or T366W mutation in one of the two CH3 domains and an E356C, T366S, L368A, and / or Y407V mutation in the other CH3 domain. In certain embodiments, the antibody portion may include a Y349C and / or T366W mutation in one of the two CH3 domains and an S354C (or E356C), T366S, L368A, and / or Y407V mutation in the other CH3 domain, wherein the additional Y349C mutation is located in one CH3 domain and the additional E356C or S354C mutation is located in the other CH3 domain, thereby forming an interchain disulfide bond (numbering is always according to the EU index of Kabat; Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Other knob-in-mold techniques, such as the knob-in-mold technique described in EP1870459A1, may alternatively or additionally be used. Thus, another example of a knob-to-hole mutation in the antibody portion is one having R409D / K370E mutations in the CH3 domain of the "knob chain" and D399K / E357K mutations in the CH3 domain of the "hole chain" (EU numbering).

[0126] In some embodiments, the antibody portion of the prodrug includes L234A and L235A ("LALA") mutations in its Fc domain. The LALA mutation abolishes complement binding and fixation, as well as Fcγ-dependent ADCC (see, e.g., Hezareh et al., J. Virol. (2001) 75(24):12161-8). In further embodiments, the LALA mutation is present in addition to the knob-to-hole mutation in the antibody portion.

[0127] In some embodiments, the antibody portion includes an M252Y / S254T / T256E ("YTE") mutation in the Fc domain. The YTE mutation allows for simultaneous modulation of serum half-life, tissue distribution, and activity of IgG1 (see Dall'Acqua et al., J Biol Chem. (2006) 281:23514-24; and Robbie et al., Antimicrob Agents Chemother. (2013) 57(12):6147-53). In further embodiments, the YTE mutation is present in the antibody portion in addition to the knob-in-hole mutation. In specific embodiments, the antibody portion has a YTE, LALA, and knob-in-hole mutation, or any combination thereof.

[0128] In some embodiments, the antibody binds to PD-L1. In some embodiments, the antibody binds to CEA. In some embodiments, the antibody binds to antigens on tumor cells, such as 5T4, FAP, Trop-2, PD-L1, HER-2, EGFR, Claudin18.2, DLL-3, GCP3, and CEA. The antibody may or may not have antibody-dependent cellular cytotoxicity (ADCC) activity. The antibody may also be further conjugated to a cytotoxic drug. In some embodiments, the antibody binds to a target on the surface of an immune cell and has the ability to activate the immune cell and enhance its anti-cancer activity, such as PD-1 antibodies, LAG3 antibodies, TIGIT antibodies, TGF-β antibodies, and CTLA4 antibodies.

[0129] The antigen binding portion can bind to an antigen on the surface of a cell, such as a cancer cell. In some embodiments, the antigen binding portion is a bispecific antigen binding portion that can bind to two different antigens or two different epitopes on the same antigen. In some embodiments, the antigen binding portion can bind to guanylate cyclase C (GCC), carbohydrate antigen 19-9 (CA19-9), glycoprotein A33 (gpA33), mucin 1 (MUC1), carcinoembryonic antigen (CEA), insulin-like growth factor 1 receptor (IGF1-R), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), delta-like protein 3 (DLL3), delta-like protein 4 (DLL4), epidermal growth factor receptor (EGFR), glypican-3 (GPC3), c-MET, vascular endothelial growth factor receptor 1 (VEGFR1) 1, vascular endothelial growth factor receptor 2 (VEGFR2), laminin-4, Liv-1, glycoprotein NMB (GPNMB), prostate specific membrane antigen (PSMA), Trop-2, carbonic anhydrase IX (CA9), endothelin B receptor (ETBR), TF antigen (Thomsen-Friedenrech Antigen (TF), sodium-dependent phosphate transporter 2B (NaPi2b), six-transmembrane epithelial antigen of the prostate 1 (STEAP1), folate receptor alpha (FR-α), SLIT and NTRK-like protein 6 (SLITRK6), carbonic anhydrase VI (CA6), ectonucleotide pyrophosphatase / phosphodiesterase family member 3 (ENPP3), mesothelin, trophoblast glycoprotein (TPBG), CD19, CD20, CD22, CD33, CD40, CD56, CD66e, CD70, CD74, CD79b, CD98, CD123, CD138, CD352, programmed death ligand 1 (PD-L1), Claudin 18.2, Claudin 6, PSMA, or FAPα. In some embodiments, the antigen binding portion binds to the epidermal growth factor (EGF)-like domain of DLL3. In some embodiments, the antigen binding portion binds to the Delta / Serrate / Lag2 (DSL)-like domain of DLL3. In some embodiments, the antigen binding portion binds to an epitope located after amino acid 374 of GPC3. In some embodiments, the antigen binding portion binds to the heparin sulfate glycan of GPC3. In some embodiments, the antigen binding portion binds to Claudin 18.2 but not to Claudin 18.1. In some embodiments, the antigen binding portion binds to Claudin 18.1 with an affinity that is at least 10-fold weaker than that of Claudin 18.2.

[0130] The antigen binding portion can bind to an antigen on the surface of a cell, such as an immune cell, e.g., a T cell, a NK cell, and a macrophage. In some embodiments, the antigen binding portion is a bispecific antigen binding portion that can bind to two different antigens or two different epitopes on the same antigen. In some embodiments, the antigen binding portion binds to: PD-1, LAG-3, TIM-3, CTLA-4, or TGF-β.

[0131] In some embodiments, the antigen binding portion (carrier portion) comprises an antibody or fragment thereof known in the art that binds to PD-1 and disrupts the interaction between PD-1 and its ligand (PD-L1) to stimulate an anti-tumor immune response. In some embodiments, the antibody or antigen binding portion thereof specifically binds to PD-1. For example, antibodies that target PD-1 and may find use in the present invention include, but are not limited to, nivolumab (BMS-936558, Bristol-Myers Squibb), pembrolizumab (MK03475 or MK-3475, Merck), humanized anti-PD-1 antibody JS001 (Shanghai Junshi Company), monoclonal anti-PD-1 antibody TSR-042 (Tesaro Company), pidilizumab (anti-PD-1 mAb CT-011, MediVson Medical Company), anti-PD-1 monoclonal antibody BGB-A317 (BeiGene) and / or anti-PD-1 antibody SHR-1210 (Shanghai Hengrui Company), human monoclonal antibody REGN2810 (Regeneron Pharmaceuticals), human monoclonal antibody MDX-1106 (Bristol-Myers Squibb Company) and / or humanized anti-PD-1 IgG4 antibody PDR001 (Novartis). In some embodiments, the PD-1 antibody is from clone: ​​RMP1-14 (rat IgG)—BioXcell catalog number BP0146. Other suitable anti-PD-1 antibodies include those disclosed in U.S. Patent No. 8,008,449. In some embodiments, the antibody or its antigen-binding portion specifically binds to PD-L1 and inhibits its interaction with PD-1, thereby increasing immune activity. Any antibody known in the art that binds to PD-L1 and disrupts the interaction between PD-1 and PD-L1 and stimulates an anti-tumor immune response is suitable for the combined treatment methods disclosed herein. For example, antibodies targeting PD-L1 include BMS-936559 (Bristol-Myers Squibb) and MPDL3280A (Gene Technology; currently undergoing human trials). Other suitable antibodies targeting PD-L1 are disclosed in U.S. Patent No. 7,943,743. One of ordinary skill will understand that any antibody that binds to PD-1 or PD-L1, disrupts the PD-1 / PD-L1 interaction and stimulates an anti-tumor immune response is suitable for the combined treatment methods disclosed herein.

[0132] In some embodiments, the carrier is an anti-human PD-L1 antibody selected from ASKB1296, avelumab, atezolizumab, and durvalumab.

[0133] Exemplary antigen-binding portions include trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), anti-FAPaα antibody sibrotuzumab (BIBH1), and fragments thereof. In some embodiments, the antigen-binding portion has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology to trastuzumab, rituximab, brentuximab, cetuximab, or panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), sibrotuzumab (BIBH1), or fragments thereof. In some embodiments, the antigen binding portion has an antibody heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the heavy chain of trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), sirozumab (BIBH1), or a fragment thereof. In some embodiments, the antigen binding portion has an antibody light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the light chain of trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), sirozumab (BIBH1), or a fragment thereof.

[0134] In certain embodiments, the antigen binding portion thereof includes the following six complementary determining regions (CDRs): trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33, anti-EGFR antibody mAb806 or sirolimus (BIBH1). Many CDR descriptions are well known in the art and are encompassed herein. Those skilled in the art can easily determine the CDR of a given description based on the sequence of the heavy chain or light chain variable region. "Kabat" complementary determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (1991)). "Chothia" CDR refers to the position of the structural loop (Chothia and Lesk, J. Mol. Biol. (1987) 196: 901-917). "AbM" CDR represents a compromise between the Kabat CDR and the Chothia structural loop and is used by the AbM antibody modeling software of Oxford Molecular. "Contact" CDR is based on an analysis of available complex crystal structures. With reference to common antibody numbering schemes, the residues from each of these CDRs are indicated in Table 1 below. Unless otherwise specified herein, the amino acid numbering of antibodies refers to the Kabat numbering scheme described in Kabat et al., supra, including situations where CDRs are depicted with reference to Kabat, Chothia, AbM or Contact schemes. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening of the framework region (FR) or CDR of the variable domain or insertions therein. For example, the heavy chain variable domain may comprise a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat, etc.). The Kabat residue numbering for a given antibody can be determined by aligning the homologous regions of the antibody sequence with the "standard" Kabat numbering sequence.

[0135] Table 1: CDR delineation according to various schemes

[0136]

[0137] In some embodiments, the CDRs are "extended CDRs" and encompass regions that begin or end according to different schemes. For example, the extended CDRs may be as follows: L24-L36, L26-L34, or L26-L36 (VL-CDR1); L46-L52, L46-L56, or L50-L55 (VL-CDR2); L91-L97 (VL-CDR3); H47-H55, H47-H65, H50-H55, H53-H58, or H53-H65 (VH-CDR2); and / or H93-H102 (VH-CDR3).

[0138] In some embodiments, the IL-12 prodrugs of the present disclosure comprise a carrier comprising an antigen-binding portion; wherein the antigen-binding portion binds to Trop-2. In some embodiments, the IL-12 prodrugs are used to treat patients with solid tumors. In some embodiments, the prodrugs are used to treat triple-negative breast cancer, urothelial carcinoma, small cell lung cancer, pancreatic cancer, hilar cholangiocarcinoma, cervical cancer, and gastric cancer.

[0139] In some embodiments, an IL-12 prodrug comprises a carrier comprising an antigen-binding portion; wherein the antigen-binding portion binds to 5T4. In some embodiments, the IL-12 prodrug is used to treat patients with solid tumors. In some embodiments, the prodrug is used to treat triple-negative breast cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, ovarian cancer, and gastric cancer.

[0140] In some embodiments, the IL-12 prodrug comprises a carrier comprising an antigen binding portion; wherein the antigen binding portion binds to Claudin 18.2. In some embodiments, the IL-12 prodrug is used to treat patients with pancreatic cancer and gastric cancer.

[0141] In some embodiments, the IL-12 prodrug comprises a carrier comprising an antigen binding portion; wherein the antigen binding portion binds to EGFR type III. In some embodiments, the IL-12 prodrug is used to treat patients with glioblastoma and colon cancer.

[0142] In some embodiments, IL-12 prodrugs are used in combination with immune checkpoint blockers (such as PD-1 antibodies or PD-1 antibody fragments thereof).

[0143] C. Linker Moiety of Prodrug

[0144] The IL-12 agonist polypeptide can be fused to the carrier moiety with or without a peptide linker. The peptide linker can be non-cleavable. In some embodiments, the peptide linker is selected from SEQ ID NOs: 29-33.

[0145] The IL-12 masking agent can be fused to the cytokine portion, to the carrier, or to another masking agent via a non-cleavable linker or a cleavable linker. The cleavable linker can comprise one or more (e.g., two or three) cleavable moieties (CMs). Each CM can be a substrate for an enzyme or protease selected from the group consisting of legumin, plasmin, TMPRSS-3 / 4, MMP2, MMP9, MT1-MMP, cathepsin, caspase, human neutrophil elastase, β-secretase, uPA, and PSA. Examples of cleavable linkers include, but are not limited to, those comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 34-54.

[0146] D. IL-12 Prodrugs with Additional Effector Polypeptides

[0147] 1. IL-2 agonist peptide

[0148] In some embodiments, the IL-12 prodrugs of the present disclosure further comprise another cytokine or effector moiety. In some embodiments, the second cytokine moiety comprises an IL-2 agonist polypeptide.

[0149] In some embodiments, the IL-2 agonist polypeptide in the prodrug comprises an amino acid sequence that is at least 85%, at least 90%, at least 95%, or 100% homologous to SEQ ID NO: 1. In some embodiments, the IL-2 agonist polypeptide contains mutations that significantly reduce affinity for the high-affinity trimeric IL-2 receptor. The high-affinity trimeric IL-2 receptor comprises α, β, and γ IL-2 receptor subunits. Optionally, the IL-2 agonist polypeptide further comprises mutations that significantly reduce binding affinity for the intermediate-affinity IL-2 receptor, which comprises IL-2 receptor β and γ subunits. In some embodiments, the IL-2 agonist polypeptide comprises one or more mutations at residues R38, F42, F44, Y45, E62, E68, L72, and A73, according to the numbering of human IL-2 having the amino acid sequence of SEQ ID NO: 1. In some embodiments, the IL-2 agonist polypeptide further comprises one or more mutations at residues D20, N88, N90, and Q126, according to the numbering of human IL-2 having the amino acid sequence of SEQ ID NO: 1. Additional mutations at residues T3 and / or C125 are optionally included.

[0150] In some embodiments, the IL-2 agonist polypeptide of the IL-2 prodrug comprises mutations at residues F42N / F44T, A73T, and / or N90T; wherein the mutations are numbered according to human IL-2 having the amino acid sequence of SEQ ID NO: 1.

[0151] In some embodiments, the IL-2 agonist polypeptide of the IL-2 prodrug comprises a mutation selected from one of the following combinations:

[0152] T3A, R38A, F42I, Y45N, E62L, E68V, C125S;

[0153] T3A, R38K, F42K, Y45R, E62L, E68V, C125S;

[0154] T3A, R38A, F42A, Y45A, E62A, C125S;

[0155] T3A, R38S, F42A, Y45A, E62A, C125S; or

[0156] R38S, F42A, Y45A, E62A; and

[0157] The mutations are referred to according to the numbering of human IL-2 having the amino acid sequence of SEQ ID NO: 1.

[0158] In some embodiments, the IL-2 agonist polypeptide has a binding affinity that is at least 30-fold lower than that of a high-affinity trimeric IL-2 receptor comprising α, β, and γ subunits compared to wild-type IL-2; wherein the polypeptide comprises one or more mutations at R38, F42, Y45, E62, E68, and L72; wherein the mutations are numbered according to human IL-2 having the amino acid sequence of SEQ ID NO: 1. In some embodiments, the IL-2 agonist polypeptide further comprises one or more mutations at residues A3, D20, N88, C125, and / or Q126, according to the numbering of human IL-2 having the amino acid sequence of SEQ ID NO: 1.

[0159] In some embodiments, the IL-2 agonist peptide comprises an amino acid sequence selected from SEQ ID NOs: 74 and 75.

[0160] 2. IL-15 agonist peptide

[0161] In some embodiments, the IL-12 prodrugs of the present disclosure further include another cytokine or effector moiety. In some embodiments, the second cytokine moiety includes an IL-15 agonist polypeptide. In some embodiments, the IL-15 agonist polypeptide may optionally include a Sushi domain of the IL-15 receptor α subunit.

[0162] In some embodiments, the IL-15 portion is an IL-15 mutein comprising at least 1, 2, 3, 4, or 5 mutations at positions of human IL-15 selected from the group consisting of: N1, N4, I6, S7, D8, K10, K11, E46, D61, T62, E64, N65, I68, L69, N72, V63, L66, I67, A70, N71, Q108, N112. Exemplary IL-15 mutant proteins are IL-15 mutant proteins having one or more mutations selected from the group consisting of N1A, N1D, N4A, N4D, I6T, S7A, D8A, DAT, D8E, D8N, K10A, K10D, K11A, K11D, D61A, D61N, T62L, T62A, E64A, E64L, E64K, E64Q, N65A, N65L, N65D, L66D, L66E, I67D, I67E, I68S, I68E, L69S, L69E, N72A, N72D, V63E, V63D, L66E, L66D, I67E, I67D, Q108E, and N112A. In some embodiments, the IL-15 portion comprises a mutation at a position selected from the group consisting of E46, V49, L45, S51, and L52. Unless otherwise indicated, all residue numbering in the IL-15 and IL-15 muteins described herein is consistent with that in SEQ ID NO: 4. In other embodiments, the IL-15 portion comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to SEQ ID NO: 4.

[0163] In specific embodiments, the IL-15 mutant protein contains a mutation selected from the group consisting of: N1D / D61N, N1D / E64Q, N4D / D61N, N4D / E64Q, D8N / D61N, D8N / E64Q, D30N / E64Q / N65D, D61N / E64Q, E64Q / Q108E, N1D / N4D / D8N, D61N / E64Q / N65D, N1D / D61N / E64Q, N1D / D61N / E64Q / Q108E, and N4D / D61N / E64Q / Q108E.

[0164] In some embodiments, the IL-15 prodrug of the present invention includes an IL-15Rα Sushi domain. The Sushi domain is optionally fused directly to a carrier or to an IL-15 cytokine portion via a linker (e.g., a non-cleavable or cleavable peptide linker). The masking portion can be fused to the Sushi domain or to a carrier via a cleavable or non-cleavable peptide linker. In specific embodiments, the Sushi domain is fused to a carrier, and the cytokine portion is fused to the Sushi domain via a peptide linker.

[0165] 3. IL-2 / IL-15 masking part

[0166] In some embodiments, the masking moiety of the additional cytokine moiety disclosed herein comprises a peptide, monomer, or dimer of the soluble extracellular domain of the IL-2 receptor β subunit, a soluble extracellular domain of a fusion protein or complex of the IL-2 receptor β and γ subunits, or an antibody that binds to IL-2 or IL-15 and interferes with the binding of IL-2, IL-2 muteins, or IL-15 to the dimeric IL-2 receptor. In some embodiments, the IL-2 masking moiety also inhibits or reduces the biological activity of IL-2 or IL-15. In some embodiments, the IL-2 masking moiety is a peptide identified by screening from a peptide library. In some embodiments, the IL-2 masking moiety is an antibody or fragment thereof that blocks the binding of IL-2 or an IL-2 mutant to the IL-2 receptor. In some embodiments, the IL-2 masking moiety is a scFv, Fab, or single-chain Fab having the same CDR domain sequence as an antibody selected from hybridoma clones 4E12B2D10, 4E12B2, and 4E12.

[0167] II. Examples of IL-12 Prodrugs

[0168] In some embodiments, the IL-12 prodrug comprises an antibody or Fc domain and an IL-12 agonist polypeptide; wherein the IL-12 agonist polypeptide is fused to the C-terminus of one heavy chain or Fc polypeptide chain of the antibody via a peptide linker; wherein the IL-12 masking moiety is fused to the C-terminus of the second heavy chain or Fc polypeptide chain via a cleavable peptide linker. Figure 1A 、 Figure 1B 、 Figure 2A 、 Figure 2B 、 Figure 3A 、 Figure 3B 、 Figure 4A 、 Figure 4B 、 Figure 5A 、 Figure 5B 、 Figure 6A 、 Figure 6B 、 Figure 7A and Figure 7BExamples of prodrugs are shown in . All prodrugs are shown to have cytokine components p35 and p40 and a masking moiety located at the C-terminus of the Fc domain. In some embodiments, the cytokine components p35 and p40 and the masking moiety are located at the N-terminus of the Fc domain. In addition, the prodrug can include both IL-12 and IL-2 agonist polypeptides or both IL-12 and IL-15 agonist polypeptides.

[0169] For example, an IL-12 prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 20; and the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to an amino acid sequence selected from SEQ ID NOs: 21-28.

[0170] By way of another example, an IL-12 prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% homologous to SEQ ID NO: 55; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to an amino acid sequence selected from SEQ ID NOs: 56-59.

[0171] By way of another example, an IL-12 prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% homologous to SEQ ID NO: 60; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to an amino acid sequence selected from SEQ ID NOs: 61-64.

[0172] By way of another example, an IL-12 prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% homologous to SEQ ID NO: 65; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to an amino acid sequence selected from SEQ ID NOs: 66-73.

[0173] By way of another example, an IL-12 prodrug comprises two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% homologous to SEQ ID NO: 20; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to an amino acid sequence selected from SEQ ID NOs: 76-79.

[0174] In some embodiments, in a prodrug further comprising a second cytokine or effector moiety, the second cytokine moiety is an IL-2 agonist polypeptide, such as an IL-2 agonist polypeptide having an amino acid sequence selected from SEQ ID NOs: 74 and 75. For example, Figures 1A-7BAs shown in , the second cytokine can be fused to the N-terminus of one of the Fc domain polypeptides, while the IL-12 agonist polypeptide and the masking moiety are fused to the C-terminus of the Fc domain. In some embodiments, the IL-12 prodrug can further include one or more masking moieties that bind to and inhibit the biological activity of the second cytokine.

[0175] III. Pharmaceutical Compositions

[0176] Pharmaceutical compositions of the prodrug are prepared in the form of lyophilized formulations or aqueous solutions by mixing the prodrug of the present disclosure, or the antibody fusion molecule or antibody fusion molecule drug conjugate having the desired purity, with one or more optional pharmaceutically acceptable carriers (see Osol, A., ed., Remington's Pharmaceutical Sciences, 16th ed. (1980)). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the doses and concentrations employed and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenolic alcohols, butyl alcohols, or benzyl alcohols; alkyl parabens such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues); yl) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG).

[0177] Buffer is used for pH control in the scope of optimizing therapeutic effect, especially when stability depends on pH.Buffer is preferably present in the concentration of about 50mM to about 250mM with the scope.Suitable buffer used together with the present invention comprises organic acid and inorganic acid and salt thereof, such as citrate, phosphate, succinate, tartrate, fumarate, gluconate, oxalate, lactate, acetate.In addition, buffer can comprise histidine and trimethylamine salt, such as Tris.

[0178] Preservatives are added to slow the growth of microorganisms and are typically present in the range of 0.2% to 1.0% (w / v). Suitable preservatives for use with the present invention include: octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium halides (e.g., chloride, bromide, iodide), benzethonium chloride; thimerosal, phenol, butyl alcohol, or benzyl alcohol; alkyl parabens, such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol, 3-pentanol, and m-cresol.

[0179] Tensile agent, sometimes referred to as " stabilizer ", exists in order to regulate or maintain the tension force of liquid in the composition.When used together with large charged biomolecules such as proteins and antibodies, tensile agent is commonly referred to as " stabilizer ", because it can interact with the charged group of amino acid side chain, thus reducing the possibility of intermolecular and intramolecular interaction.In consideration of the relative amount of other ingredients, tensile agent can exist with any amount between 0.1 % by weight to 25 % by weight or more preferably between 1 % by weight to 5 % by weight.Preferred tensile agent comprises polyol, preferably trivalent or higher sugar alcohol, such as glycerol, erythritol, arabitol, xylitol, sorbitol and mannitol.

[0180] A nonionic surfactant or detergent (also known as a "wetting agent") is present to help solubilize the therapeutic agent and protect the therapeutic protein from agitation-induced aggregation, which also allows the formulation to be exposed to shear surface stress without causing denaturation of the active therapeutic protein or antibody. The nonionic surfactant is present in the range of about 0.05 mg / ml to about 1.0 mg / ml, preferably about 0.07 mg / ml to about 0.2 mg / ml.

[0181] Suitable nonionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamers (184, 188, etc.), polyols, Polyoxyethylene sorbitan monoether ( -20, -80, etc.), lauromacrogol 400, polyoxyethylene 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glyceryl monostearate, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. Anionic detergents that can be used include sodium lauryl sulfate, sodium hexadecylsulfosuccinate, and sodium dioctylsulfonate. Cationic detergents include benzalkonium chloride or benzethonium chloride.

[0182] The choice of pharmaceutical carrier, excipient or diluent can be selected according to the intended route of administration and standard pharmaceutical practice.The pharmaceutical composition may include any suitable binder, lubricant, suspending agent, coating agent or solubilizing agent as a carrier, excipient or diluent or in addition to a carrier, excipient or diluent.

[0183] Depending on the delivery system, there may be different composition / formulation requirements. For example, the pharmaceutical compositions useful in the present invention can be formulated to be administered using a micropump or via a mucosal route, such as a nasal spray or aerosol for inhalation or an ingestible solution, or the composition can be formulated in an injectable form for parenteral delivery, such as via an intravenous route, an intramuscular route, or a subcutaneous route. Alternatively, the formulation can be designed to be administered via a variety of routes. In some embodiments, the formulation is administered directly to one or more tumors.

[0184] In some embodiments, the antibody or protein formulation is a lyophilized formulation. In another embodiment, the antibody or protein formulation is an aqueous formulation.

[0185] In some embodiments, the pharmaceutical composition is a combination pharmaceutical composition comprising an IL-12 prodrug of the present disclosure, a pharmaceutically acceptable excipient, and a second active ingredient selected from the group consisting of: a cytokine other than IL-12 or a fusion molecule thereof, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-CD47 antibody, a PD-1 antibody-IL-15 fusion molecule, a PD-1-IL-2 fusion molecule, and a PD-1-IL-21 fusion molecule.

[0186] IV. Treatment Methods

[0187] The currently disclosed prodrugs can be used to treat diseases, depending on the antigen to which the antigen binding domain is bound. In some embodiments, the prodrugs disclosed herein are used to treat cancer. In some embodiments, the prodrugs are used to treat infections, for example, when the drug molecule is an antibacterial or antiviral agent.

[0188] In some embodiments, a method of treating a disease (such as cancer, a viral infection, or a bacterial infection) in a subject comprises administering to the subject an effective amount of a presently disclosed prodrug.

[0189] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood cancer. Exemplary cancers that can be treated include, but are not limited to, leukemia, lymphoma, kidney cancer, bladder cancer, urinary tract cancer, cervical cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, esophageal cancer, liver cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, pancreatic cancer, lung cancer, bile duct cancer, breast cancer, and ovarian cancer.

[0190] In some embodiments, the presently disclosed prodrugs are used to treat bacterial infections, such as sepsis. In some embodiments, the bacteria causing the bacterial infection are drug-resistant bacteria. In some embodiments, the antigen binding portion binds to a bacterial antigen.

[0191] In some embodiments, the prodrug is used to treat viral infections. In some embodiments, the virus causing the viral infection is hepatitis C (HCV), hepatitis B (HBV), human immunodeficiency virus (HIV), human papillomavirus (HPV). In some embodiments, the antigen binding portion binds to a viral antigen.

[0192] Typically, the dosage and route of administration of the pharmaceutical composition of the present invention are determined according to the size and condition of the subject according to standard pharmaceutical practice. In some embodiments, the pharmaceutical composition is administered to the subject by any route, including oral administration, transdermal administration, administration by inhalation, intravenous administration, intraarterial administration, intramuscular administration, direct application to a wound site, application to a surgical site, intraperitoneal administration, administration by suppository, subcutaneous administration, intradermal administration, transdermal administration, administration by aerosolization, intrapleural administration, intraventricular administration, intraarticular administration, intraocular administration, or intraspinal administration. In some embodiments, the composition is administered intravenously to the subject.

[0193] In certain embodiments, the prodrug is administered to the subject in need with a single dose or repeated dose. In certain embodiments, the dosage is administered to the subject once a day, twice a day, three times a day, or four times a day or more. In certain embodiments, about 1 or more (e.g., about 2, 3, 4, 5, 6 or 7 or more) dosages are administered within a week. In certain embodiments, the antibody fusion molecule conjugated to the drug is administered weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every two weeks in 3 weeks, or once every 3 weeks in 4 weeks. In certain embodiments, multiple doses are administered over the course of several days, weeks, months, or years. In certain embodiments, a course of treatment is about 1 dosage or more dosages (e.g., about 2 dosages, 3 dosages, 4 dosages, 5 dosages, 7 dosages, 10 dosages, 15 dosages, or 20 dosages or more).

[0194] In some embodiments, the IL-12 prodrug is administered to a subject in combination with a second pharmaceutical composition, wherein the second pharmaceutical composition comprises an active ingredient selected from the group consisting of a cytokine other than IL-12 or a fusion molecule thereof, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-CD47 antibody, a PD-1 antibody-IL-2 fusion molecule, a PD-1-IL-7 fusion molecule, a PD-1 antibody-IL-15 fusion molecule, and a PD-1-IL-21 fusion molecule.

[0195] V. Methods of Preparing Prodrugs

[0196] The present invention relates to the prodrug of the present invention.Currently disclosed prodrug can be produced using recombinant DNA methods.The nucleic acid molecules encoding the polypeptide of the prodrug or the fusion polypeptide can be separated and inserted into one or more vectors to further clone and / or express in a host cell.Such nucleic acid molecules can be easily separated and sequenced using conventional methods.Suitable host cells for cloning or expressing fusion polypeptide vectors include prokaryotic cells or eukaryotic cells.Exemplary host cells include Chinese hamster ovary (CHO) cells or human embryonic kidney cells (e.g., HEK293).

[0197] The expression host cell expresses the antibody fusion molecule. After the expression phase, the host cell can be lysed and the prodrug or antibody fusion molecule can be purified. Exemplary purification methods include liquid chromatography, such as ion exchange chromatography, affinity chromatography (such as protein A affinity chromatography) or size exclusion chromatography.

[0198] It should be understood that although various aspects of this specification are highlighted by reference to specific embodiments, those skilled in the art will readily appreciate that these disclosed embodiments merely illustrate the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is not intended to be limited to a particular compound, composition, article, or method, unless expressly stated otherwise. Furthermore, those of ordinary skill in the art will recognize that certain changes, modifications, substitutions, alterations, additions, subtractions, and subcombinations thereof may be made in accordance with the teachings herein without departing from the spirit of this specification.

[0199] Unless otherwise defined herein, the scientific and technical terms used in conjunction with the present disclosure should have the meaning generally understood by those of ordinary skill in the art. Exemplary methods and materials are described below, but methods and materials similar or equivalent to those described herein can also be used for practice or testing of the present disclosure. In the event of a conflict, this specification sheet (including definitions) should be taken as the criterion. Typically, the glossary and technology used in conjunction with cell and tissue culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry, and protein and nucleic acid chemistry and hybridization as described herein are well-known and commonly used glossaries and technology in the art. As commonly realized in this area or as described herein, enzymatic reaction and purification techniques are performed according to the instructions of manufacturers. In addition, unless context requires otherwise, singular terms should include plural meanings and plural terms should include singular meanings. Throughout the present specification and examples, the words "have", "comprise" or variations such as "has", "having", "comprises" or "comprising" should be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or groups of integers. It should be understood that aspects and variations of the invention described herein include "consisting of" and / or "consisting essentially of" aspects and variations. All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0200] VI. Exemplary Embodiments

[0201] Non-limiting exemplary embodiments of the present disclosure are described below.

[0202] 1. An IL-12 prodrug comprising an IL-12 p40 subunit (p40), an IL-12 p35 subunit (p35), a first masking moiety (MM), a second masking moiety, a carrier (C), and at least one cleavable peptide linker; wherein:

[0203] a. The IL-12 subunit p40 has an amino acid sequence that is at least 95% homologous to SEQ ID NO: 5;

[0204] b. The IL-12 subunit p35 has an amino acid sequence that is at least 95% homologous to SEQ ID NO: 6;

[0205] c. the first masking moiety comprises a binding moiety that binds to p40, and the second masking moiety comprises a binding moiety that binds to p35; and

[0206] d. The carrier is selected from the group consisting of albumin or an albumin fragment, an Fc domain and an antibody.

[0207] 2. The prodrug of embodiment 1, wherein the first masking moiety is selected from the extracellular domain of IL-12 receptor β1 (IL-12Rβ1ECD) or a fragment thereof, a p40 binding peptide discovered from a peptide library screening, and a single-chain Fv or Fab domain of an antibody that binds to p40.

[0208] 3. The prodrug of embodiment 1 or 2, wherein the second masking moiety is selected from the extracellular domain of IL-12 receptor β2 (IL-12Rβ2ECD) or a fragment thereof, a p35 or p40 binding peptide discovered from a peptide library screening, and an scFv or Fab domain of an antibody that binds to p35.

[0209] 4. The prodrug of any one of embodiments 1 to 3, wherein the first masking moiety comprises the extracellular domain (ECD) of IL-12 receptor β1 (IL-12Rβ1) or a fragment thereof, wherein the IL-12Rβ1 ECD comprises an amino acid sequence at least 95% homologous to SEQ ID NO: 13.

[0210] 5. The prodrug of any one of embodiments 1 to 3, wherein the first masking moiety comprises a fragment of IL-12Rβ1 ECD, wherein the fragment comprises an amino acid sequence at least 95% homologous to SEQ ID NO: 14, 15, or 16.

[0211] 6. The prodrug of any one of embodiments 1 to 3, wherein the second masking moiety comprises the extracellular domain (ECD) of IL-12 receptor β2 (IL-12Rβ2) or a fragment thereof, wherein the IL-12Rβ2 ECD comprises an amino acid sequence at least 95% homologous to SEQ ID NO: 17.

[0212] 7. The prodrug of any one of embodiments 1 to 3, wherein the second masking moiety comprises a fragment of IL-12Rβ2 ECD, wherein the fragment comprises an amino acid sequence at least 95% homologous to SEQ ID NO: 18 or 19.

[0213] 8. The prodrug of any one of embodiments 1 to 3, wherein the first masking moiety comprises a scFv that binds to p40, wherein the scFv comprises an amino acid sequence at least 99% homologous to any one of SEQ ID NOs: 7-11 and 12.

[0214] 9. The prodrug of any one of embodiments 1 to 3, wherein the first masking moiety is selected from the group consisting of an IL-12Rβ1 ECD or a fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13-16; or a scFv having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-12; and wherein the second masking moiety comprises an IL-12Rβ2 ECD or a fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17-19.

[0215] 10. The prodrug of any one of embodiments 1 to 3, wherein the first masking moiety is selected from the group consisting of an IL-12Rβ1 ECD or a fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13-16; or a scFv having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-12; and wherein the second masking moiety comprises a scFv that binds to p35.

[0216] 11. The prodrug of any one of embodiments 1 to 10, wherein the carrier is an antibody that binds to a target expressed on the surface of an immune cell or a cancer cell.

[0217] 12. The prodrug of any one of embodiments 1 to 10, further comprising another cytokine or effector moiety.

[0218] 13. The prodrug of embodiment 12, wherein the cytokine portion comprises an IL-2 agonist polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 75.

[0219] 14. The prodrug of any one of embodiments 1 to 10, wherein the carrier comprises an Fc domain comprising a first polypeptide chain F1 and a second polypeptide chain F2, wherein the F1 and F2 form a heterodimer; wherein the p40 or an analog thereof is optionally fused to the C-terminus of F1 via a non-cleavable peptide linker, and the p35 or an analog thereof is fused to the C-terminus of p40 via a non-cleavable peptide linker; and wherein the first masking moiety is fused to the C-terminus of F2 via a cleavable or non-cleavable peptide linker, and the second masking moiety is fused to the C-terminus of the first masking moiety via a cleavable peptide linker.

[0220] 15. The prodrug of any one of embodiments 1 to 10, wherein the carrier comprises an Fc domain comprising a first polypeptide chain F1 and a second polypeptide chain F2, wherein the F1 and F2 form a heterodimer; wherein the p40 is optionally fused to the C-terminus of F1 via a non-cleavable peptide linker, and the first masking moiety is fused to the C-terminus of p40 via a cleavable or non-cleavable peptide linker; and wherein the p35 is fused to the C-terminus of F2, and the second masking moiety is fused to the C-terminus of p35 via a cleavable peptide linker.

[0221] 16. The prodrug of any one of embodiments 1 to 10, wherein the carrier comprises an Fc domain comprising a first polypeptide chain F1 and a second polypeptide chain F2, wherein the F1 and F2 form a heterodimer; wherein the p35 is optionally fused to the C-terminus of F1 via a non-cleavable peptide linker, and the first masking moiety is fused to the C-terminus of p35 via a cleavable or non-cleavable peptide linker; and wherein the p40 is fused to the C-terminus of F2, and the second masking moiety is fused to the C-terminus of p40 via a cleavable peptide linker.

[0222] 17. The prodrug of any one of embodiments 1 to 16, wherein the non-cleavable peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 29-33; wherein the cleavable peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-54.

[0223] 18. The prodrug of embodiment 1, comprising two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% homologous to a sequence selected from SEQ ID NO: 20; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to a sequence selected from SEQ ID NO: 21-28.

[0224] 19. The prodrug of embodiment 1, comprising two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence that is at least 99% homologous to SEQ ID NO: 55; and the second polypeptide chain comprises an amino acid sequence that is at least 99% homologous to any one of SEQ ID NOs: 56-59.

[0225] 20. The prodrug of embodiment 1, comprising two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% identical to any one selected from SEQ ID NO: 60; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to any one selected from SEQ ID NO: 61-64.

[0226] 21. The prodrug of embodiment 1, comprising two polypeptide chains, wherein the first polypeptide chain comprises an amino acid sequence at least 99% homologous to SEQ ID NO: 65; and the second polypeptide chain comprises an amino acid sequence at least 99% homologous to any one of SEQ ID NOs: 66-73.

[0227] 22. A pharmaceutical composition comprising the prodrug according to any one of embodiments 1 to 21 and a pharmaceutically acceptable excipient.

[0228] 23. A polynucleotide encoding the prodrug of any one of embodiments 1 to 22.

[0229] 24. An expression vector comprising the polynucleotide of embodiment 23.

[0230] 25. A host cell comprising the vector of embodiment 24.

[0231] 26. The host cell of embodiment 25, wherein the gene encoding uPA, MMP-2, MMP-9 and / or matriptase is knocked out in the host cell.

[0232] 27. A method of preparing the prodrug of any one of embodiments 1 to 21, comprising culturing the host cell of embodiment 25 or 26 under conditions allowing expression of the antigen binding molecule and isolating the antigen binding molecule.

[0233] 28. A method of treating cancer or an infectious disease or stimulating the immune system of a patient in need thereof, comprising administering the pharmaceutical composition of embodiment 22.

[0234] 29. Use of a prodrug for treating cancer or infectious diseases or stimulating the immune system in the method according to embodiment 28.

[0235] 30. The method of embodiment 28, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, esophageal cancer, medullary thyroid cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, colorectal cancer, and gastric cancer.

[0236] 31. A method of treating a patient suffering from cancer, the method comprising administering the pharmaceutical composition of embodiment 22 directly into a tumor.

[0237] In order to better understand the present invention, the following examples are described. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0238] Examples

[0239] Example 1: Transient transfection of IL-12 prodrug into HEK293 cells

[0240] The expression plasmid was co-transfected into approximately 4×10 6 Freestyle HEK293 cells were expressed at 10 cells / ml. For Fc-based IL-12 prodrugs, the ratio of Fc-IL-12 fusion polypeptide to Fc masking moiety fusion polypeptide was 1:2. Six days after transfection, cell cultures were harvested by centrifugation at 9,000 rpm for 45 minutes, followed by 0.22 μM filtration. A variety of IL-12 prodrugs were expressed. Sequence numbers are listed in Table 2.

[0241] Table 2. Sequence information of samples.

[0242] Name of prodrug or reference product Sequence number of Fc-IL-12 fusion polypeptide Sequence number of Fc masking part fusion polypeptide JR3.105.2 SEQ ID NO:20 SEQ ID NO:76 JR3.105.3 SEQ ID NO:20 SEQ ID NO:77 JR3.105.4 SEQ ID NO:20 SEQ ID NO:78 JR3.105.5 SEQ ID NO:20 SEQ ID NO:79

[0243] Example 2: Purification of Fc-based IL-12 prodrug

[0244] The purification of the protein of the IL-12 prodrug based on Fc is carried out by using protein A affinity chromatography. In short, the supernatant of transient expression cell culture is loaded on the protein A column, and before applying the sample, the protein A column is balanced with 25mMTris-HCl, 30mM NaCl (buffer A) at a pH of 7.8. The column is washed with 5 column volumes of buffer A, and the bound protein is eluted with 50mM acetic acid at a pH of 3.6. The pH of the eluted protein is adjusted to about 5.2 using 1M Tris alkali. As described below, the sample is analyzed by SDS-PAGE.

[0245] Example 3: SDS-PAGE analysis

[0246] 10 μl of 10-20 μg of purified protein sample was mixed with Bolt TM Mix with LDS sample buffer (Novex). The samples were heated at 70°C for 3 minutes and then loaded onto NuPAGE TM 4-12% BisTris gel (Invitrogen TM ). The gel was run on NuPAGE TM MOPS SDS running buffer (Invitrogen TM ) was run at 200 volts for 40 minutes and then stained with Coomassie. Purified samples of the prodrug were analyzed by SDS-PAGE analysis as in Figure 8A JR3.105.5 (structure as in Figure 5B The samples were analyzed as shown in Figure 8B The data indicate that the masking portion of the prodrug is largely removed by protease digestion and that the activated molecule migrates at the expected molecular weight. In addition, the Protein A column pool sample also appears to contain the activated version of the IL-12 prodrug ( Figure 8B ).

[0247] Example 4: Proteolytic treatment

[0248] Protease, human MMP2, human MMP9, mouse MMP2, and mouse MMP9 were purchased from R&D Systems. Protease digestion was performed by incubating 10 μg to 50 μg of prodrug with 1 μg of human MMP2, human MMP9, mouse MMP2, or mouse MMP9 in HBS buffer (20 mM HEPES, 150 mM NaCl, pH 7.4) containing 2 mM CaCl and 10 μM ZnCl at 37°C for 12 hours. The protease was analyzed by SDS-PAGE ( Figure 8B ) and cell-based activity assays (see below) to analyze the prodrug JR3.105.5 before and after digestion.

[0249] Example 5: Cell-based IL-12 reporter gene assay

[0250] The bioactivity of IL-12 prodrug before and after activation was determined using a secretory alkaline phosphatase reporter gene cell line (HEK Blue IL-12, InvivoGen catalog number hkb-il12). The HEK-blue IL-12 cell line was generated by stably introducing genes encoding the human IL-12 receptor and signal transduction pathway into HEK 293 cells. The cells also expressed a STAT4-induced secretory alkaline phosphatase (SEAP) reporter gene. The test article was diluted in 100 μL / well of culture medium in a 96-well flat-bottom cell culture plate, followed by addition of HEK-blue IL-12 cells at 50,000 cells / well in 100 μL. The culture was incubated overnight at 37°C. 20 μL of culture supernatant was transferred to an ELISA plate, and 180 μL Quanti-Blue (InvivoGen, catalog number rep-qb1) was added. The ELISA plate was incubated at 37°C for 1 hour, and the OD was measured with a microplate reader. 630 The data are shown in Figure 9 and Figure 10 The results show that based on EC 50 The activity of JR3.105.5 is about 18 times that of JR3.105.5clv(activated) ( Figure 10 ). As in Figure 8BAs shown in Figure 2, the IL-12 prodrug JR3.105.5 sample may contain a small amount of the activated version of the prodrug. Therefore, the masking efficiency of the masking part of JR3.105.5 may be lower than that of Figure 9 and 10 The masking efficiency shown in is stronger.

[0251] Compared to the other samples, the IL-12 prodrug JR3.105.5 also had the highest activation. All IL-12 prodrugs have the same Fc-IL-12 chain (SEQ ID NO: 20, Table 2). However, the masking portion of JR3.105.5 has the longest linker between its VL and VH, including (G4S)4, as shown in SEQ ID NO: 80.

[0252] Example 6: In vivo efficacy study using mouse tumor model

[0253] The in vivo anti-tumor effect of the IL-12-Fc prodrug of the present invention was tested in a mouse model. 3×10 6 After tumors were established, 1.5×10 pp-65 expressing MCF-7 cells were implanted intraperitoneally into mice. 6 The mice were then treated with the IL-12 prodrug twice a week, weekly, or biweekly. Tumor volume and body weight were measured every other day. At the end of the study, the mice were sacrificed and blood, serum, and tissue samples (including liver and lung tumors and major organs) were analyzed for PK, safety, cytokine release, and prodrug activation.

[0254] The above non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the disclosed subject matter. These examples should not be construed as limiting any embodiments described in this specification, including embodiments related to antibodies, pharmaceutical compositions, or methods and uses for treating cancer, neurodegenerative diseases, or infectious diseases.

[0255] Sequence Listing

[0256] SEQ ID NO: 1—Human IL-2:

[0257]

[0258] SEQ ID NO: 2—Human IL-2 receptor β subunit extracellular domain (https: / / www.uniprot.org / uniprot / P14784)

[0259]

[0260] SEQ ID NO:3—IL-15 receptor alpha subunit sushi domain

[0261] ITCPPPMSVE HADIWVKSYS LYSRERYICN SGFKRKAGTS SLTECVLNKA TNVAHWTTPSLKCIRDPALV HQRPAPP

[0262] SEQ ID NO 4—human IL15

[0263]

[0264] SEQ ID NO:5—Human IL-12p40 subunit

[0265]

[0266] SEQ ID NO:6—Human IL-12 p35 subunit

[0267]

[0268] SEQ ID NO:7—scFv that binds to IL-12

[0269]

[0270] SEQ ID NO:8—scFv that binds to IL-12

[0271]

[0272] SEQ ID NO:9—scFv that binds to IL-12

[0273]

[0274] SEQ ID NO: 10 - scFv that binds to IL-12

[0275]

[0276] SEQ ID NO: 11 - scFv that binds to IL-12

[0277]

[0278] SEQ ID NO: 12—scFv that binds to IL-12

[0279]

[0280] SEQ ID NO:13—IL-12 receptor β1 extracellular domain (IL-12Rβ1ECD)

[0281]

[0282] SEQ ID NO:14-IL-12Rβ1 ECD D1-D5

[0283]

[0284] SEQ ID NO:15-IL-12Rβ1 ECD D1-D2

[0285]

[0286] SEQ ID NO:16-IL-12Rβ1 ECD D1-D3

[0287]

[0288] SEQ ID NO:17-IL-12Rβ2 ECD D1-D6

[0289]

[0290] SEQ ID NO:18-IL-12Rβ2ECD D1-D2

[0291]

[0292] SEQ ID NO:19-IL-12Rβ2ECD D1-D3

[0293]

[0294] SEQ ID NO:20—Fc-IL-12 with knob mutation (P40-P35)

[0295]

[0296] SEQ ID NO:21 - Fc-IL-12Rβ1-D1D2 / IL-12Rβ2-D1D2 with hole mutation

[0297]

[0298] Where n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0299] SEQ ID NO:22—Fc IL-12Rβ1-D1D2D3 / IL-12Rβ2-D1D2D3 with hole mutation

[0300]

[0301] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0302] SEQ ID NO:23—Fc-IL-12Rβ1-D1D2 / IL-12Rβ2-D1D2 with hole mutation

[0303]

[0304] Where n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0305] SEQ ID NO:24—Fc IL-12Rβ1-D1D2D3 / IL-12Rβ2-D1D2D3 with hole mutation

[0306] ; n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0308] SEQ ID NO:25—Fc scFv / IL-12Rβ2-D1D2D3 with hole mutation

[0309] ; n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0311] SEQ ID NO:26—Fc scFv / IL-12Rβ2-D1D2D3 with hole mutation

[0312] ; n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0314] SEQ ID NO:27 - Fc SCFV / IL-12Rβ2-D1D2D3 with hole mutation

[0315] ; n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0317] SEQ ID NO:28—Fc scFv / IL-12Rβ2-D1D2D3 with hole mutation

[0318] ; n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0320] SEQ ID NO:29-33 Peptide linker

[0321] GGGGS (SEQ ID NO: 29)

[0322] GGGGSGGGGS (SEQ ID NO: 30)

[0323] GGGGSGGGGS GGGGS(SEQ ID NO:31)

[0324] GGGGSGGGGX GGGGSGGGGS (SEQ ID NO:32), X=A or N

[0325] (GGGGSGGGGX1 GGGGX2GGGGS) n (SEQ ID NO: 33), X1 = S, A or N, X2 = A or N, and n = 1, 2 or 3.

[0326] SEQ ID NO:34—Cleavable peptide linker

[0327] GGS LSGRSDN H GGGGS

[0328] SEQ ID NO:35—Cleavable peptide linker

[0329] GGS LSGRSDN H GS

[0330] SEQ ID NO:36 - Cleavable linker

[0331] GGGGSGGGGS GGGGS ISSGL LSS GGSGGS L SGRSDNH GGG GS

[0332] SEQ ID NO:37-43 - MMP-2 / MMP-9 cleavable peptide linker

[0333] GPLGVR (SEQ ID NO:37)

[0334] PLGMWSR (SEQ ID NO:38)

[0335] PLGLWAR (SEQ ID NO:39)

[0336] PQGIAGQR (SEQ ID NO:40)

[0337] PLGLAG (SEQ ID NO:41)

[0338] LALGPR (SEQ ID NO:42)

[0339] GGPLGMLSQS (SEQ ID NO:43)

[0340] SEQ ID NO:44-52 - Urokinase plasminogen activator (uPA) cleavable peptide linker

[0341] GGGGRRGGS (SEQ ID NO:44)

[0342] TGRGPSWV (SEQ ID NO:45)

[0343] SARGPSRW (SEQ ID NO:46)

[0344] TARGPSFK (SEQ ID NO:47)

[0345] TARGPSW (SEQ ID NO:48)

[0346] GGWHTGRN (SEQ ID NO:49)

[0347] HTGRSGAL (SEQ ID NO:50)

[0348] PLTGRSGG (SEQ ID NO:51)

[0349] LTGRSGA (SEQ ID NO:52)

[0350] SEQ ID NO:53 - Proteinase-cleavable peptide linker

[0351] RQARVVNG (SEQ ID NO:53)

[0352] SEQ ID NO:54 - Matriptase-MMP2 / 9 dual cleavable peptide linker

[0353] VHMPLGFLGP RQARVVNG (SEQ ID NO:54)

[0354] SEQ ID NO:55 - Fc-IL-12P35-linker-IL-12Rβ2 fragment with hole mutation ; n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0356] SEQ ID NO:56—Fc-IL-12P40-non-cleavable linker-IL-12Rβ1 fragment with knob mutation

[0357] SEQ ID NO:57—Fc-IL-12P40-cleavable linker-IL-12Rβ1 fragment with knob mutation

[0358] SEQ ID NO:58 - Fc-IL-12P40-cleavable linker-scFv with knob mutation

[0359]

[0360] SEQ ID NO:59—Fc-IL-12P40-cleavable linker-scFv with knob mutation

[0361]

[0362] SEQ ID NO:60—Fc-IL-12P40-linker-IL-12Rβ2 fragment with hole mutation

[0363] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0364] SEQ ID NO:61 - Fc-IL-12P35-non-cleavable linker-IL-12Rβ1 fragment with knob mutation

[0365] SEQ ID NO:62—Fc-IL-12P35-cleavable linker-IL-12Rβ1 fragment with knob mutation

[0366] SEQ ID NO:63 - Fc-IL-12P35-cleavable linker-scFv with knob mutation

[0367]

[0368] SEQ ID NO:64—Fc-IL-12P35-cleavable linker-scFv with knob mutation

[0369]

[0370] SEQ ID NO:65—Fc-IL-12 with knob mutation (P35-P40)

[0371]

[0372] wherein n1=2, 3, 4 or 5; and wherein n2=2, 3, 4 or 5.

[0373] SEQ ID NO:66—Fc-IL-12Rβ2-D1D2 / IL-12Rβ1-D1D2 with hole mutation

[0374]

[0375] Where n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0376] SEQ ID NO:67 - Fc IL-12Rβ2-D1D2D3 / IL-12Rβ1-D1D2D3 with hole mutation

[0377]

[0378] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0379] SEQ ID NO:68—Fc-IL-12Rβ2-D1D2 / IL-12Rβ1-D1D2 with hole mutation

[0380]

[0381] Where n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0382] SEQ ID NO:69 - Fc IL-12Rβ2-D1D2D3 / IL-12Rβ1-D1D2D3 with hole mutation

[0383]

[0384] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0385] SEQ ID NO:70—Fc IL-12Rβ2-D1D2D3 / scFv with hole mutation

[0386]

[0387] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0388] SEQ ID NO:71 - Fc IL-12Rβ2-D1D2D3 / scFv with hole mutation

[0389]

[0390] ; n1 = 1, 2, 3 or 4, and n2 = 1, 2, 3 or 4.

[0391] SEQ ID NO:72—Fc IL-12Rβ2-D1D2D3 scFv with hole mutation

[0392]

[0393] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0394] SEQ ID NO:73 - Fc IL-12Rβ2-D2D2D3 / scFv with hole mutation

[0395]

[0396] n1=1, 2, 3 or 4, and n2=1, 2, 3 or 4.

[0397] SEQ ID NO:74—IL-2 agonist polypeptide

[0398] APX aa3 SSSTKKT QLQLEHLLL X aa20 LQMILNGINN YKNPKLTRML TX aa42 KFX aa45 MPKKATELKHLQCLE EELKPLEEVL NX aa72 X aa73 QSKNFHL RPRDLISX aa88 IX aa90 VIVLELKGSE TTFMCEYADETATIVEFLNR WITFX aa125 X aa126 SIIS TLT

[0399] where X aa3 is N or A; where X aa125 is C or S; where X aa20 is selected from D, H, K, L, M, N, Q, R, S, V and Y; wherein Xaa42 is selected from A, G, S, T, Q, E, N, D, R, and K; wherein X aa45 is selected from A, G, S, T, Q, E, N, D, R, and K; wherein X aa72 is selected from A, G, S, T, Q, E, N, D, R, and K; wherein X aa73 is A; where X aa88 is selected from the group consisting of N, A, E, F, H, K, L, M, S, T, V, W, and Y; wherein X aa90 is N or T; and wherein X aa126 is selected from the group consisting of A, D, F, G, H, I, K, L, P, S, T, W, and Y; and wherein X aa20 、X aa88 、X aa90 and X aa126 At least one of them is mutated.

[0400] SEQ ID NO:75—IL-2 agonist polypeptide

[0401] APX aa3 SSSTKKT QLQLEHLLL X aa20 LQMILNGINN YKNPKLTX aa38 ML TX aa42 KFX aa45 MPKKATELKHLQCLE EX aa62 LKPLEX aa68 VL NLX aa73 QSKNFHL RPRDLISX aa88 IX aa90 VIVLELKGSETTFMCEYADE TATIVEFLNR WITFX aa125 X aa126 SIIS TLT

[0402] where X aa3 is N or A; where X aa125 is C or S; where X aa20 is selected from D, H, K, L, M, N, Q, R, S, V and Y; wherein X aa38 Selected from A, K and S; wherein X aa42 is selected from A, G, I, S, T, Q, E, N, D, R, and K; wherein X aa45 is selected from A, G, S, T, Q, E, N, D, R, and K; wherein X aa62 is selected from E, L, A and I; wherein X aa68 is E or V; where X aa73 is A or T; where X aa88is selected from the group consisting of N, A, E, F, H, K, L, M, S, T, V, W, and Y; wherein X aa90 is N or T; and wherein X aa126 is selected from the group consisting of A, D, F, G, H, I, K, L, P, S, T, W, and Y; and wherein Xaa20, X aa88 、X aa90 and X aa126 At least one of them is mutated.

[0403] SEQ ID NO:76 - scFv that can bind to the IL-12-VH-VL-2 linker

[0404]

[0405] SEQ ID NO:77 - scFv that can bind to the IL-12-VH-VL-3 linker

[0406]

[0407] SEQ ID NO: 78 scFv that binds to the IL-12-VL-VH-3 linker

[0408]

[0409] SEQ ID NO:79 - scFv that can bind to the IL-12-VL-VH-4 linker

[0410]

[0411] SEQ ID NO:80-G4S4 linker

[0412] GGGGSGGGGS GGGGSGGGGS Sequence Listing <110> Ogilvy Pharmaceuticals Co., Ltd. <120> Cytokine prodrugs and dual prodrugs <130> 025471.WO007 <140> <141> <150> 62 / 907,615 <151> 2019-09-28 <160> 80 <170> PatentIn version 3.5 <210> 1 <211> 133 <212> PRT <213> Homo sapiens <400> 1 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> 2 <211> 214 <212> PRT <213> Homo sapiens <400> 2 Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala 1 5 10 15 Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser 20 25 30 Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys 35 40 45 Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu 50 55 60 Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu 65 70 75 80 Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln 85 90 95 Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu 100 105 110 Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile 115 120 125 Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg 130 135 140 Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu 145 150 155 160 Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr 165 170 175 Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr 180 185 190 Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala 195 200 205 Ala Leu Gly Lys Asp Thr 210 <210> 3 <211> 77 <212> PRT <213> Homo sapiens <400> 3 Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val 1 5 10 15 Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly 20 25 30 Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn 35 40 45 Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile 50 55 60 Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro 65 70 75 <210> 4 <211> 133 <212> PRT <213> Homo sapiens <400> 4 Gly Ile His Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys 1 5 10 15 Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 20 25 30 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 35 40 45 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 50 55 60 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 65 70 75 80 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 85 90 95 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 100 105 110 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 115 120 125 Phe Ile Asn Thr Ser 130 <210> 5 <211> 306 <212> PRT <213> Homo sapiens <400> 5 Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser 305 <210> 6 <211> 197 <212> PRT <213> Homo sapiens <400> 6 Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu 1 5 10 15 His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys 20 25 30 Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp 35 40 45 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 50 55 60 Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr 65 70 75 80 Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 85 90 95 Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100 105 110 Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115 120 125 Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu 130 135 140 Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser 145 150 155 160 Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 165 170 175 Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser 180 185 190 Tyr Leu Asn Ala Ser 195 <210> 7 <211> 236 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 7 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile 35 40 45 Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr 65 70 75 80 Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val 130 135 140 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser 145 150 155 160 Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu 165 170 175 Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser 180 185 190 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 195 200 205 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro 210 215 220 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 <210> 8 <211> 236 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val 115 120 125 Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr 130 135 140 Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys 145 150 155 160 Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg 165 170 175 Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser 180 185 190 Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr 195 200 205 Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp 210 215 220 Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 225 230 235 <210> 9 <211> 241 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 9 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile 35 40 45 Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr 65 70 75 80 Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser 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 Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys 165 170 175 Ala Pro Lys Ser Leu Ile Tyr Ala 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 Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys <210> 10 <211> 241 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln 115 120 125 Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys 130 135 140 Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg 145 150 155 160 Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val 165 170 175 Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met 180 185 190 Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu 195 200 205 Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly 210 215 220 Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser 225 230 235 240 Ser <210> 11 <211> 246 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 11 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile 35 40 45 Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr 65 70 75 80 Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln 165 170 175 Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys 245 <210> 12 <211> 246 <212> PRT <213> Synthetic sequence <220> <221> Source <223> Artificial Sequence Description: Synthetic polypeptide <400> 12 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 115 120 125 Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 130 135 140 Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp 145 150 155 160 Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly 165 170 175 Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln 180 185 190 Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu 195 200 205 Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220 Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser 245 <210> 13 <211> 521 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 13 Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp 1 5 10 15 Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser 20 25 30 Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly 35 40 45 Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr 50 55 60 Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly 65 70 75 80 Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg 85 90 95 Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser 100 105 110 Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala 115 120 125 Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala 130 135 140 Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly 145 150 155 160 Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu 165 170 175 Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly 180 185 190 Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro 195 200 205 Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu Gln Leu 210 215 220 Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro Thr Gln 225 230 235 240 Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr Glu Val 245 250 255 Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys Ala Lys 260 265 270 Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser Gly Ala 275 280 285 Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro Gly Leu 290 295 300 Asn Gln Thr Trp His Ile Pro Ala Asp Thr His Thr Glu Pro Val Ala 305 310 315 320 Leu Asn Ile Ser Val Gly Thr Asn Gly Thr Thr Met Tyr Trp Pro Ala 325 330 335 Arg Ala Gln Ser Met Thr Tyr Cys Ile Glu Trp Gln Pro Val Gly Gln 340 345 350 Asp Gly Gly Leu Ala Thr Cys Ser Leu Thr Ala Pro Gln Asp Pro Asp 355 360 365 Pro Ala Gly Met Ala Thr Tyr Ser Trp Ser Arg Glu Ser Gly Ala Met 370 375 380 Gly Gln Glu Lys Cys Tyr Tyr Ile Thr Ile Phe Ala Ser Ala His Pro 385 390 395 400 Glu Lys Leu Thr Leu Trp Ser Thr Val Leu Ser Thr Tyr His Phe Gly 405 410 415 Gly Asn Ala Ser Ala Ala Gly Thr Pro His His Val Ser Val Lys Asn 420 425 430 His Ser Leu Asp Ser Val Ser Val Asp Trp Ala Pro Ser Leu Leu Ser 435 440 445 Thr Cys Pro Gly Val Leu Lys Glu Tyr Val Val Arg Cys Arg Asp Glu 450 455 460 Asp Ser Lys Gln Val Ser Glu His Pro Val Gln Pro Thr Glu Thr Gln 465 470 475 480 Val Thr Leu Ser Gly Leu Arg Ala Gly Val Ala Tyr Thr Val Gln Val 485 490 495 Arg Ala Asp Thr Ala Trp Leu Arg Gly Val Trp Ser Gln Pro Gln Arg 500 505 510 Phe Ser Ile Glu Val Gln Val Ser Asp 515 520 <210> 14 <211> 521 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 14 Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp 1 5 10 15 Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser 20 25 30 Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly 35 40 45 Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr 50 55 60 Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly 65 70 75 80 Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg 85 90 95 Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser 100 105 110 Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala 115 120 125 Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala 130 135 140 Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly 145 150 155 160 Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu 165 170 175 Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly 180 185 190 Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro 195 200 205 Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu Gln Leu 210 215 220 Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro Thr Gln 225 230 235 240 Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr Glu Val 245 250 255 Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys Ala Lys 260 265 270 Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser Gly Ala 275 280 285 Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro Gly Leu 290 295 300 Asn Gln Thr Trp His Ile Pro Ala Asp Thr His Thr Glu Pro Val Ala 305 310 315 320 Leu Asn Ile Ser Val Gly Thr Asn Gly Thr Thr Met Tyr Trp Pro Ala 325 330 335 Arg Ala Gln Ser Met Thr Tyr Cys Ile Glu Trp Gln Pro Val Gly Gln 340 345 350 Asp Gly Gly Leu Ala Thr Cys Ser Leu Thr Ala Pro Gln Asp Pro Asp 355 360 365 Pro Ala Gly Met Ala Thr Tyr Ser Trp Ser Arg Glu Ser Gly Ala Met 370 375 380 Gly Gln Glu Lys Cys Tyr Tyr Ile Thr Ile Phe Ala Ser Ala His Pro 385 390 395 400 Glu Lys Leu Thr Leu Trp Ser Thr Val Leu Ser Thr Tyr His Phe Gly 405 410 415 Gly Asn Ala Ser Ala Ala Gly Thr Pro His His Val Ser Val Lys Asn 420 425 430 His Ser Leu Asp Ser Val Ser Val Asp Trp Ala Pro Ser Leu Leu Ser 435 440 445 Thr Cys Pro Gly Val Leu Lys Glu Tyr Val Val Arg Cys Arg Asp Glu 450 455 460 Asp Ser Lys Gln Val Ser Glu His Pro Val Gln Pro Thr Glu Thr Gln 465 470 475 480 Val Thr Leu Ser Gly Leu Arg Ala Gly Val Ala Tyr Thr Val Gln Val 485 490 495 Arg Ala Asp Thr Ala Trp Leu Arg Gly Val Trp Ser Gln Pro Gln Arg 500 505 510 Phe Ser Ile Glu Val Gln Val Ser Asp 515 520 <210> 15 <211> 210 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 15 Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp 1 5 10 15 Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser 20 25 30 Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly 35 40 45 Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr 50 55 60 Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly 65 70 75 80 Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg 85 90 95 Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser 100 105 110 Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala 115 120 125 Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala 130 135 140 Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly 145 150 155 160 Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu 165 170 175 Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly 180 185 190 Ser Gln Gly Ser Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro 195 200 205 Pro Glu 210 <210> 16 <211> 312 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 16 Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp 1 5 10 15 Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser 20 25 30 Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly 35 40 45 Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr 50 55 60 Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly 65 70 75 80 Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg 85 90 95 Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser 100 105 110 Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala 115 120 125 Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala 130 135 140 Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly 145 150 155 160 Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu 165 170 175 Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly 180 185 190 Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro 195 200 205 Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu Gln Leu 210 215 220 Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro Thr Gln 225 230 235 240 Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr Glu Val 245 250 255 Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys Ala Lys 260 265 270 Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser Gly Ala 275 280 285 Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro Gly Leu 290 295 300 Asn Gln Thr Trp His Ile Pro Ala 305 310 <210> 17 <211> 599 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 17 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 1 5 10 15 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 20 25 30 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 35 40 45 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 50 55 60 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 65 70 75 80 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 85 90 95 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 100 105 110 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 115 120 125 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 130 135 140 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 145 150 155 160 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 165 170 175 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr 180 185 190 Phe Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg 195 200 205 Ile Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg 210 215 220 Asp Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn 225 230 235 240 Ser Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His 245 250 255 Asp Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser 260 265 270 Ser Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser 275 280 285 Leu Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly Met Leu Asp Val 290 295 300 Trp Tyr Met Lys Arg His Ile Asp Tyr Ser Arg Gln Gln Ile Ser Leu 305 310 315 320 Phe Trp Lys Asn Leu Ser Val Ser Glu Ala Arg Gly Lys Ile Leu His 325 330 335 Tyr Gln Val Thr Leu Gln Glu Leu Thr Gly Gly Lys Ala Met Thr Gln 340 345 350 Asn Ile Thr Gly His Thr Ser Trp Thr Thr Val Ile Pro Arg Thr Gly 355 360 365 Asn Trp Ala Val Ala Val Ser Ala Ala Asn Ser Lys Gly Ser Ser Leu 370 375 380 Pro Thr Arg Ile Asn Ile Met Asn Leu Cys Glu Ala Gly Leu Leu Ala 385 390 395 400 Pro Arg Gln Val Ser Ala Asn Ser Glu Gly Met Asp Asn Ile Leu Val 405 410 415 Thr Trp Gln Pro Pro Arg Lys Asp Pro Ser Ala Val Gln Glu Tyr Val 420 425 430 Val Glu Trp Arg Glu Leu His Pro Gly Gly Asp Thr Gln Val Pro Leu 435 440 445 Asn Trp Leu Arg Ser Arg Pro Tyr Asn Val Ser Ala Leu Ile Ser Glu 450 455 460 Asn Ile Lys Ser Tyr Ile Cys Tyr Glu Ile Arg Val Tyr Ala Leu Ser 465 470 475 480 Gly Asp Gln Gly Gly Cys Ser Ser Ile Leu Gly Asn Ser Lys His Lys 485 490 495 Ala Pro Leu Ser Gly Pro His Ile Asn Ala Ile Thr Glu Glu Lys Gly 500 505 510 Ser Ile Leu Ile Ser Trp Asn Ser Ile Pro Val Gln Glu Gln Met Gly 515 520 525 Cys Leu Leu His Tyr Arg Ile Tyr Trp Lys Glu Arg Asp Ser Asn Ser 530 535 540 Gln Pro Gln Leu Cys Glu Ile Pro Tyr Arg Val Ser Gln Asn Ser His 545 550 555 560 Pro Ile Asn Ser Leu Gln Pro Arg Val Thr Tyr Val Leu Trp Met Thr 565 570 575 Ala Leu Thr Ala Ala Gly Glu Ser Ser His Gly Asn Glu Arg Glu Phe 580 585 590 Cys Leu Gln Gly Lys Ala Asn 595 <210> 18 <211> 198 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 18 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 1 5 10 15 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 20 25 30 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 35 40 45 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 50 55 60 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 65 70 75 80 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 85 90 95 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 100 105 110 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 115 120 125 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 130 135 140 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 145 150 155 160 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 165 170 175 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Ser Leu Pro Ser Thr 180 185 190 Phe Thr Phe Leu Asp Ile 195 <210> 19 <211> 300 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 19 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 1 5 10 15 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 20 25 30 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 35 40 45 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 50 55 60 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 65 70 75 80 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 85 90 95 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 100 105 110 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 115 120 125 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 130 135 140 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 145 150 155 160 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 165 170 175 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Ser Leu Pro Ser Thr 180 185 190 Phe Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg 195 200 205 Ile Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg 210 215 220 Asp Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn 225 230 235 240 Ser Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His 245 250 255 Asp Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser 260 265 270 Ser Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser 275 280 285 Leu Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly 290 295 300 <210> 20 <211> 760 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 20 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp 245 250 255 Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr 260 265 270 Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val 275 280 285 Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp 290 295 300 Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser 305 310 315 320 Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile 325 330 335 Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu 340 345 350 Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile 355 360 365 Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp 370 375 380 Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val 385 390 395 400 Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp 405 410 415 Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val 420 425 430 Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe 435 440 445 Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys 450 455 460 Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp 465 470 475 480 Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln 485 490 495 Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp 500 505 510 Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val 515 520 525 Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser 530 535 540 Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 545 550 555 560 Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe 565 570 575 Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met 580 585 590 Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu 595 600 605 Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu 610 615 620 Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser 625 630 635 640 Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys 645 650 655 Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu 660 665 670 Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met 675 680 685 Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile 690 695 700 Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln 705 710 715 720 Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu 725 730 735 Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg 740 745 750 Val Met Ser Tyr Leu Asn Ala Ser 755 760 <210> twenty one <211> 705 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (451)..(470) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (488)..(507) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> twenty one Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp 245 250 255 Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser 260 265 270 Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly 275 280 285 Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr 290 295 300 Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly 305 310 315 320 Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg 325 330 335 Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser 340 345 350 Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala 355 360 365 Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala 370 375 380 Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly 385 390 395 400 Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu 405 410 415 Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly 420 425 430 Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro 435 440 445 Pro Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro 465 470 475 480 Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly 485 490 495 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala Cys 500 505 510 Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly 515 520 525 Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe 530 535 540 His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg 545 550 555 560 Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu 565 570 575 Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser 580 585 590 Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro 595 600 605 Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr 610 615 620 Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu 625 630 635 640 Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln 645 650 655 Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr 660 665 670 Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn 675 680 685 Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp 690 695 700 Ile 705 <210> twenty two <211> 909 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (553)..(572) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (590)..(609) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> twenty two Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp 245 250 255 Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser 260 265 270 Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly 275 280 285 Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr 290 295 300 Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly 305 310 315 320 Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg 325 330 335 Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser 340 345 350 Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala 355 360 365 Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala 370 375 380 Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly 385 390 395 400 Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu 405 410 415 Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly 420 425 430 Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro 435 440 445 Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu Gln Leu 450 455 460 Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro Thr Gln 465 470 475 480 Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr Glu Val 485 490 495 Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys Ala Lys 500 505 510 Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser Gly Ala 515 520 525 Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro Gly Leu 530 535 540 Asn Gln Thr Trp His Ile Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly 545 550 555 560 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met Pro 565 570 575 Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 595 600 605 Ser Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser 610 615 620 His Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys 625 630 635 640 Pro Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu 645 650 655 Tyr Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn 660 665 670 Ser Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys 675 680 685 Leu Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile 690 695 700 Phe Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln 705 710 715 720 Lys Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp 725 730 735 Thr His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn 740 745 750 Leu Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp 755 760 765 Phe Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala 770 775 780 Lys Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser 785 790 795 800 Thr Phe Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile 805 810 815 Arg Ile Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp 820 825 830 Arg Asp Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser 835 840 845 Asn Ser Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg 850 855 860 His Asp Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile 865 870 875 880 Ser Ser Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu 885 890 895 Ser Leu Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly 900 905 <210> 23 <211> 718 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (464)..(483) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (501)..(520) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> twenty three Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Arg Thr Ser 245 250 255 Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser 260 265 270 Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg 275 280 285 Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His 290 295 300 Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala 305 310 315 320 Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val 325 330 335 Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr 340 345 350 Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr 355 360 365 Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu 370 375 380 Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala Glu Val Gln 385 390 395 400 Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly 405 410 415 Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn 420 425 430 Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly 435 440 445 Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro Pro Glu Gly 450 455 460 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 465 470 475 480 Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala 485 490 495 Arg Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 500 505 510 Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala Cys Lys Arg Gly 515 520 525 Asp Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser Thr Val 530 535 540 Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His Tyr Ser 545 550 555 560 Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile Asn Phe 565 570 575 His His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro Leu Gly 580 585 590 Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp Glu Ile 595 600 605 Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu Gln Pro 610 615 620 Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val Ala Cys 625 630 635 640 Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr Thr Leu 645 650 655 Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys Lys Asp 660 665 670 Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro Glu Ser 675 680 685 Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser Leu Gly 690 695 700 Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile 705 710 715 <210> 24 <211> 922 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (566)..(585) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (603)..(622) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> twenty four Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Arg Thr Ser 245 250 255 Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser 260 265 270 Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg 275 280 285 Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His 290 295 300 Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala 305 310 315 320 Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val 325 330 335 Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr 340 345 350 Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr 355 360 365 Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu 370 375 380 Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala Glu Val Gln 385 390 395 400 Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly 405 410 415 Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn 420 425 430 Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly 435 440 445 Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro Pro Glu Asn 450 455 460 Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu Gln Leu Gly Gln Asp 465 470 475 480 Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro Thr Gln Leu Glu Leu 485 490 495 Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr Glu Val Thr Tyr Arg 500 505 510 Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys Ala Lys Ala Thr Arg 515 520 525 Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser Gly Ala Ala Tyr Asn 530 535 540 Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro Gly Leu Asn Gln Thr 545 550 555 560 Trp His Ile Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 565 570 575 Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe 580 585 590 Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser Gly 595 600 605 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile 610 615 620 Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile 625 630 635 640 Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln 645 650 655 Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe 660 665 670 Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val 675 680 685 Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys 690 695 700 Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly 705 710 715 720 Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu 725 730 735 Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu 740 745 750 Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp 755 760 765 Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile 770 775 780 Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr 785 790 795 800 Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr 805 810 815 Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys 820 825 830 Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu 835 840 845 Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg 850 855 860 Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu 865 870 875 880 Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys 885 890 895 Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg 900 905 910 Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly 915 920 <210> 25 <211> 838 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (482)..(501) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (519)..(538) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 25 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 245 250 255 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 260 265 270 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 275 280 285 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 290 295 300 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 305 310 315 320 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr 325 330 335 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 340 345 350 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln 355 360 365 Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys 370 375 380 Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg 385 390 395 400 Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val 405 410 415 Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met 420 425 430 Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu 435 440 445 Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly 450 455 460 Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser 465 470 475 480 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 485 490 495 Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro Arg 500 505 510 Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala Cys Lys 530 535 540 Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser 545 550 555 560 Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His 565 570 575 Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile 580 585 590 Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro 595 600 605 Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp 610 615 620 Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu 625 630 635 640 Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val 645 650 655 Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr 660 665 670 Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys 675 680 685 Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro 690 695 700 Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser 705 710 715 720 Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile 725 730 735 Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala 740 745 750 Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu 755 760 765 Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met 770 775 780 Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys 785 790 795 800 Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr 805 810 815 Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro 820 825 830 Glu Glu Glu Pro Thr Gly 835 <210> 26 <211> 851 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (495)..(514) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (532)..(551) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 26 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Asp Ile Gln 245 250 255 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 260 265 270 Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp 275 280 285 Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala 290 295 300 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 305 310 315 320 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 325 330 335 Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly 340 345 350 Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly 355 360 365 Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala 370 375 380 Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser 385 390 395 400 Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro 405 410 415 Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp 420 425 430 Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp 435 440 445 Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser 450 455 460 Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr 465 470 475 480 Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 485 490 495 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 500 505 510 Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg 515 520 525 Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 530 535 540 Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala Cys Lys Arg Gly Asp 545 550 555 560 Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser Thr Val Asn 565 570 575 Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His Tyr Ser Arg 580 585 590 Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile Asn Phe His 595 600 605 His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro Leu Gly Thr 610 615 620 Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp Glu Ile Gln 625 630 635 640 Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu Gln Pro Gln 645 650 655 Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val Ala Cys Thr 660 665 670 Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr Thr Leu Gln 675 680 685 Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys Lys Asp Ile 690 695 700 Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro Glu Ser Pro 705 710 715 720 Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser Leu Gly Ser 725 730 735 Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile Val Arg Pro 740 745 750 Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala Ser Val Ser 755 760 765 Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu Leu Asn Arg 770 775 780 Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met Val Asn Val 785 790 795 800 Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys Pro Phe Thr 805 810 815 Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr Lys Gly Ser 820 825 830 Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro Glu Glu Glu 835 840 845 Pro Thr Gly 850 <210> 27 <211> 838 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (482)..(501) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (519)..(538) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 27 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 245 250 255 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 260 265 270 Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile 275 280 285 Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 290 295 300 Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr 305 310 315 320 Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 325 330 335 Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly 340 345 350 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 355 360 365 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 370 375 380 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 385 390 395 400 Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys 405 410 415 Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 420 425 430 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 435 440 445 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 450 455 460 Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 465 470 475 480 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 485 490 495 Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro Arg 500 505 510 Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala Cys Lys 530 535 540 Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser 545 550 555 560 Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His 565 570 575 Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile 580 585 590 Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro 595 600 605 Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp 610 615 620 Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu 625 630 635 640 Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val 645 650 655 Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr 660 665 670 Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys 675 680 685 Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro 690 695 700 Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser 705 710 715 720 Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile 725 730 735 Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala 740 745 750 Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu 755 760 765 Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met 770 775 780 Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys 785 790 795 800 Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr 805 810 815 Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro 820 825 830 Glu Glu Glu Pro Thr Gly 835 <210> 28 <211> 851 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (495)..(514) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (532)..(551) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeat units <400> 28 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln 245 250 255 Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys 260 265 270 Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly 275 280 285 Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met 290 295 300 Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln 305 310 315 320 Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp 325 330 335 Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg 340 345 350 Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 385 390 395 400 Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile 405 410 415 Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys 420 425 430 Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg 435 440 445 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 450 455 460 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile 465 470 475 480 Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly 485 490 495 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 500 505 510 Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg 515 520 525 Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 530 535 540 Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala Cys Lys Arg Gly Asp 545 550 555 560 Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser Thr Val Asn 565 570 575 Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His Tyr Ser Arg 580 585 590 Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile Asn Phe His 595 600 605 His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro Leu Gly Thr 610 615 620 Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp Glu Ile Gln 625 630 635 640 Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu Gln Pro Gln 645 650 655 Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val Ala Cys Thr 660 665 670 Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr Thr Leu Gln 675 680 685 Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys Lys Asp Ile 690 695 700 Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro Glu Ser Pro 705 710 715 720 Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser Leu Gly Ser 725 730 735 Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile Val Arg Pro 740 745 750 Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala Ser Val Ser 755 760 765 Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu Leu Asn Arg 770 775 780 Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met Val Asn Val 785 790 795 800 Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys Pro Phe Thr 805 810 815 Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr Lys Gly Ser 820 825 830 Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro Glu Glu Glu 835 840 845 Pro Thr Gly 850 <210> 29 <211> 5 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 29 Gly Gly Gly Gly Ser 1 5 <210> 30 <211> 10 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 30 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 31 <211> 15 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 31 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 32 <211> 20 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutant <222> (10)..(10) <223> Replace with "Asn" <220> <221> Site <222> (1)..(20) <223> At variable sites, there is no preference for variable residues in the sequence listing relative to the amino acids provided in the annotations. <400> 32 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 33 <211> 60 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutant <222> (10)..(10) <223> Replace with "Ala" or "Asn" <220> <221> mutant <222> (15)..(15) <223> Replace with "Asn" <220> <221> mutant <222> (30)..(30) <223> Replace with "Ala" or "Asn" <220> <221> mutant <222> (35)..(35) <223> Replace with "Asn" <220> <221> mutant <222> (50)..(50) <223> Replace with "Ala" or "Asn" <220> <221> mutant <222> (55)..(55) <223> Replace with "Asn" <220> <221> Site <222> (1)..(60) <223> The sequence includes 1-3 'Gly Gly Gly Gly Ser Gly Gly Gly Gly Xaa Gly Gly Gly Gly Xaa Gly Gly Gly Gly Ser' repeating unit <220> <221> Site <222> (1)..(60) <223> At variable sites, there is no preference for variable residues in the sequence listing relative to the amino acids provided in the annotations. <400> 33 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ala Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45 Gly Ser Gly Gly Gly Gly Ala Gly Gly Gly Gly Ser 50 55 60 <210> 34 <211> 16 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 34 Gly Gly Ser Leu Ser Gly Arg Ser Asp Asn His Gly Gly Gly Gly Ser 1 5 10 15 <210> 35 <211> 13 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 35 Gly Gly Ser Leu Ser Gly Arg Ser Asp Asn His Gly Ser 1 5 10 <210> 36 <211> 42 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 36 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile 1 5 10 15 Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser Gly 20 25 30 Arg Ser Asp Asn His Gly Gly Gly Gly Ser 35 40 <210> 37 <211> 6 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 37 Gly Pro Leu Gly Val Arg 1 5 <210> 38 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 38 Pro Leu Gly Met Trp Ser Arg 1 5 <210> 39 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 39 Pro Leu Gly Leu Trp Ala Arg 1 5 <210> 40 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 40 Pro Gln Gly Ile Ala Gly Gln Arg 1 5 <210> 41 <211> 6 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 41 Pro Leu Gly Leu Ala Gly 1 5 <210> 42 <211> 6 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 42 Leu Ala Leu Gly Pro Arg 1 5 <210> 43 <211> 10 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 43 Gly Gly Pro Leu Gly Met Leu Ser Gln Ser 1 5 10 <210> 44 <211> 9 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 44 Gly Gly Gly Gly Arg Arg Gly Gly Ser 1 5 <210> 45 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 45 Thr Gly Arg Gly Pro Ser Trp Val 1 5 <210> 46 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 46 Ser Ala Arg Gly Pro Ser Arg Trp 1 5 <210> 47 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 47 Thr Ala Arg Gly Pro Ser Phe Lys 1 5 <210> 48 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 48 Thr Ala Arg Gly Pro Ser Trp 1 5 <210> 49 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 49 Gly Gly Trp His Thr Gly Arg Asn 1 5 <210> 50 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 50 His Thr Gly Arg Ser Gly Ala Leu 1 5 <210> 51 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 51 Pro Leu Thr Gly Arg Ser Gly Gly 1 5 <210> 52 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 52 Leu Thr Gly Arg Ser Gly Ala 1 5 <210> 53 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 53 Arg Gln Ala Arg Val Val Asn Gly 1 5 <210> 54 <211> 18 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 54 Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val 1 5 10 15 Asn Gly <210> 55 <211> 795 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (439)..(458) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (476)..(495) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 55 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 245 250 255 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 260 265 270 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 275 280 285 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 290 295 300 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 305 310 315 320 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 325 330 335 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 340 345 350 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 355 360 365 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 370 375 380 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 385 390 395 400 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 405 410 415 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 420 425 430 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met Pro Leu Gly 450 455 460 Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser 465 470 475 480 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys 485 490 495 Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val 500 505 510 Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg 515 520 525 Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys 530 535 540 Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln 545 550 555 560 Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala 565 570 575 Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val 580 585 590 Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly 595 600 605 Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His 610 615 620 Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr 625 630 635 640 Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly 645 650 655 Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val 660 665 670 Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe 675 680 685 Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile 690 695 700 Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp 705 710 715 720 Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser 725 730 735 Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His Asp 740 745 750 Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser 755 760 765 Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu 770 775 780 Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly 785 790 795 <210> 56 <211> 875 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 56 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp 245 250 255 Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr 260 265 270 Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val 275 280 285 Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp 290 295 300 Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser 305 310 315 320 Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile 325 330 335 Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu 340 345 350 Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile 355 360 365 Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp 370 375 380 Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val 385 390 395 400 Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp 405 410 415 Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val 420 425 430 Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe 435 440 445 Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys 450 455 460 Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp 465 470 475 480 Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln 485 490 495 Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp 500 505 510 Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val 515 520 525 Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser 530 535 540 Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 545 550 555 560 Gly Gly Ser Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro 565 570 575 Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr 580 585 590 Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro 595 600 605 Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg 610 615 620 Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp 625 630 635 640 Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser 645 650 655 Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu 660 665 670 Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser 675 680 685 Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln 690 695 700 Val Gly Ala Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp 705 710 715 720 Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu 725 730 735 Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg 740 745 750 Gln Leu Gly Ser Gln Gly Ser Ser Ser Trp Ser Lys Trp Ser Ser Pro Val 755 760 765 Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val 770 775 780 Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln 785 790 795 800 Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly 805 810 815 Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys 820 825 830 Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu 835 840 845 Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly 850 855 860 Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala 865 870 875 <210> 57 <211> 887 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 57 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp 245 250 255 Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr 260 265 270 Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val 275 280 285 Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp 290 295 300 Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser 305 310 315 320 Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile 325 330 335 Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu 340 345 350 Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile 355 360 365 Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp 370 375 380 Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val 385 390 395 400 Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp 405 410 415 Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val 420 425 430 Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe 435 440 445 Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys 450 455 460 Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp 465 470 475 480 Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln 485 490 495 Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp 500 505 510 Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val 515 520 525 Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser 530 535 540 Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly 545 550 555 560 Arg Gly Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Arg 565 570 575 Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp Ser 580 585 590 Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser Ser 595 600 605 Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly Val 610 615 620 Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr Phe 625 630 635 640 Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly Val 645 650 655 Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg Asn 660 665 670 Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser Val 675 680 685 Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala Gly 690 695 700 Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala Glu 705 710 715 720 Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly Asp 725 730 735 Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu Glu 740 745 750 Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly Ser 755 760 765 Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro Pro 770 775 780 Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu Gln Leu Gly 785 790 795 800 Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro Thr Gln Leu 805 810 815 Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr Glu Val Thr 820 825 830 Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys Ala Lys Ala 835 840 845 Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser Gly Ala Ala 850 855 860 Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro Gly Leu Asn 865 870 875 880 Gln Thr Trp His Ile Pro Ala 885 <210> 58 <211> 816 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 58 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp 245 250 255 Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr 260 265 270 Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val 275 280 285 Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp 290 295 300 Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser 305 310 315 320 Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile 325 330 335 Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu 340 345 350 Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile 355 360 365 Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp 370 375 380 Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val 385 390 395 400 Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp 405 410 415 Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val 420 425 430 Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe 435 440 445 Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys 450 455 460 Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp 465 470 475 480 Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln 485 490 495 Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp 500 505 510 Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val 515 520 525 Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser 530 535 540 Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly 545 550 555 560 Arg Gly Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu 565 570 575 Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 580 585 590 Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp 595 600 605 Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly 610 615 620 Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln 625 630 635 640 Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu 645 650 655 Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 660 665 670 Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr 675 680 685 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 690 695 700 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 705 710 715 720 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 725 730 735 Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala 740 745 750 Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro 755 760 765 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 770 775 780 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr 785 790 795 800 Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 805 810 815 <210> 59 <211> 816 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 59 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp 245 250 255 Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr 260 265 270 Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val 275 280 285 Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp 290 295 300 Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser 305 310 315 320 Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile 325 330 335 Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu 340 345 350 Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile 355 360 365 Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp 370 375 380 Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val 385 390 395 400 Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp 405 410 415 Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val 420 425 430 Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe 435 440 445 Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys 450 455 460 Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp 465 470 475 480 Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln 485 490 495 Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp 500 505 510 Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val 515 520 525 Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser 530 535 540 Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly 545 550 555 560 Arg Gly Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Asp 565 570 575 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 580 585 590 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu 595 600 605 Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr 610 615 620 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 625 630 635 640 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 645 650 655 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr 660 665 670 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly 675 680 685 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser 690 695 700 Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys 705 710 715 720 Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln 725 730 735 Met Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp 740 745 750 Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser 755 760 765 Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys 770 775 780 Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln 785 790 795 800 Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 805 810 815 <210> 60 <211> 904 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (548)..(567) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (585)..(604) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 60 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp 245 250 255 Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro 260 265 270 Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu 275 280 285 Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala 290 295 300 Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu 305 310 315 320 Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu 325 330 335 Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala 340 345 350 Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser 355 360 365 Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro 370 375 380 Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg 385 390 395 400 Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser 405 410 415 Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp 420 425 430 Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile 435 440 445 Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro 450 455 460 Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr 465 470 475 480 Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val 485 490 495 Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys 500 505 510 Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg 515 520 525 Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val 530 535 540 Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 545 550 555 560 Gly Ser Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly 565 570 575 Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Ile Asp Ala 595 600 605 Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu Leu 610 615 620 Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys 625 630 635 640 Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg 645 650 655 Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr Gly 660 665 670 Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn 675 680 685 Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala 690 695 700 Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly 705 710 715 720 Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr 725 730 735 Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys 740 745 750 Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu 755 760 765 Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val 770 775 780 Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu 785 790 795 800 Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln 805 810 815 Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu 820 825 830 Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp 835 840 845 Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp 850 855 860 Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His 865 870 875 880 Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln 885 890 895 Thr Pro Glu Glu Glu Pro Thr Gly 900 <210> 61 <211> 766 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 61 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro 245 250 255 Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu 260 265 270 Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu 275 280 285 Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala 290 295 300 Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg 305 310 315 320 Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr 325 330 335 Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys 340 345 350 Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp 355 360 365 Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp 370 375 380 Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys 385 390 395 400 Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys 405 410 415 Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val 420 425 430 Met Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 435 440 445 Ser Gly Gly Gly Gly Ser Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro 450 455 460 Pro Tyr Pro Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu 465 470 475 480 Arg Cys Tyr Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr 485 490 495 Glu Gly Pro Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys Leu Ser 500 505 510 Ser Gly Arg Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln 515 520 525 Phe Ser Asp Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr Leu Trp 530 535 540 Val Glu Ser Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu Val Thr 545 550 555 560 Leu Gln Leu Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile 565 570 575 Lys Val Ser Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu Thr Pro 580 585 590 Asp Asn Gln Val Gly Ala Glu Val Gln Phe Arg His Arg Thr Pro Ser 595 600 605 Ser Pro Trp Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu 610 615 620 Ser Cys Leu Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe Gln Leu 625 630 635 640 Arg Arg Arg Gln Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser 645 650 655 Ser Pro Val Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln Val Arg 660 665 670 Phe Ser Val Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu 675 680 685 Lys Glu Gln Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu 690 695 700 Ala Pro Gly Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met Leu Ser 705 710 715 720 Cys Pro Cys Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly Lys Met 725 730 735 Pro Tyr Leu Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser Ser Asn 740 745 750 Gln Phe Gly Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala 755 760 765 <210> 62 <211> 778 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 62 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro 245 250 255 Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu 260 265 270 Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu 275 280 285 Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala 290 295 300 Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg 305 310 315 320 Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr 325 330 335 Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys 340 345 350 Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp 355 360 365 Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp 370 375 380 Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys 385 390 395 400 Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys 405 410 415 Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val 420 425 430 Met Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 435 440 445 Ser Thr Gly Arg Gly Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Ser Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp 465 470 475 480 Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg 485 490 495 Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr 500 505 510 Ala Gly Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys 515 520 525 Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln 530 535 540 Ala Gly Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp 545 550 555 560 Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr 565 570 575 Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys 580 585 590 Leu Ala Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val 595 600 605 Gly Ala Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys 610 615 620 Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys 625 630 635 640 Pro Leu Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln 645 650 655 Leu Gly Ser Gln Gly Ser Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys 660 665 670 Val Pro Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu 675 680 685 Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro 690 695 700 Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr 705 710 715 720 Glu Val Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys 725 730 735 Ala Lys Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser 740 745 750 Gly Ala Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro 755 760 765 Gly Leu Asn Gln Thr Trp His Ile Pro Ala 770 775 <210> 63 <211> 707 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 63 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro 245 250 255 Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu 260 265 270 Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu 275 280 285 Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala 290 295 300 Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg 305 310 315 320 Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr 325 330 335 Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys 340 345 350 Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp 355 360 365 Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp 370 375 380 Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys 385 390 395 400 Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys 405 410 415 Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val 420 425 430 Met Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 435 440 445 Ser Thr Gly Arg Gly Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro 465 470 475 480 Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr 485 490 495 Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp 500 505 510 Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro 515 520 525 Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr 530 535 540 Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr 545 550 555 560 Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly 565 570 575 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 580 585 590 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 595 600 605 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 610 615 620 Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 625 630 635 640 Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 645 650 655 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 660 665 670 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 675 680 685 Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu 690 695 700 Glu Ile Lys 705 <210> 64 <211> 707 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 64 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro 245 250 255 Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu 260 265 270 Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu 275 280 285 Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala 290 295 300 Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg 305 310 315 320 Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr 325 330 335 Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys 340 345 350 Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp 355 360 365 Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp 370 375 380 Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys 385 390 395 400 Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys 405 410 415 Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val 420 425 430 Met Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 435 440 445 Ser Thr Gly Arg Gly Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 465 470 475 480 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser 485 490 495 Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser 500 505 510 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 515 520 525 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 530 535 540 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr 545 550 555 560 Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly 565 570 575 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 580 585 590 Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile 595 600 605 Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp 610 615 620 Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser 625 630 635 640 Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val 645 650 655 Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn 660 665 670 Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg 675 680 685 Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr 690 695 700 Val Ser Ser 705 <210> 65 <211> 780 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (228)..(252) <223> This region includes 2-5 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (450)..(474) <223> This region includes 2-5 'Gly Gly Gly Gly Ser' repeating units <400> 65 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Asn Leu Pro 245 250 255 Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln 260 265 270 Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr 275 280 285 Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile 290 295 300 Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu 305 310 315 320 Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr 325 330 335 Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu 340 345 350 Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe 355 360 365 Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe 370 375 380 Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu 385 390 395 400 Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro 405 410 415 Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe 420 425 430 Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala 435 440 445 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys 465 470 475 480 Asp Val Tyr Val Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu 485 490 495 Met Val Val Leu Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp 500 505 510 Thr Leu Asp Gln Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr 515 520 525 Ile Gln Val Lys Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys 530 535 540 Gly Gly Glu Val Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu 545 550 555 560 Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys 565 570 575 Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe 580 585 590 Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val 595 600 605 Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala 610 615 620 Ala Thr Leu Ser Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu 625 630 635 640 Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu 645 650 655 Ser Leu Pro Ile Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr 660 665 670 Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp 675 680 685 Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val 690 695 700 Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr 705 710 715 720 Phe Ser Leu Thr Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu 725 730 735 Lys Lys Asp Arg Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys 740 745 750 Arg Lys Asn Ala Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser 755 760 765 Ser Ser Trp Ser Glu Trp Ala Ser Val Pro Cys Ser 770 775 780 <210> 66 <211> 705 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (439)..(458) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (476)..(495) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 66 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 245 250 255 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 260 265 270 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 275 280 285 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 290 295 300 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 305 310 315 320 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 325 330 335 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 340 345 350 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 355 360 365 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 370 375 380 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 385 390 395 400 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 405 410 415 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr 420 425 430 Phe Thr Phe Leu Asp Ile Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met Pro Leu Gly 450 455 460 Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser 465 470 475 480 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg 485 490 495 Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp Ser 500 505 510 Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser Ser 515 520 525 Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly Val 530 535 540 Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr Phe 545 550 555 560 Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly Val 565 570 575 Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg Asn 580 585 590 Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser Val 595 600 605 Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala Gly 610 615 620 Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala Glu 625 630 635 640 Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly Asp 645 650 655 Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu Glu 660 665 670 Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly Ser 675 680 685 Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro Pro 690 695 700 Glu 705 <210> 67 <211> 909 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (541)..(560) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (578)..(597) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 67 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 245 250 255 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 260 265 270 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 275 280 285 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 290 295 300 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 305 310 315 320 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 325 330 335 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 340 345 350 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 355 360 365 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 370 375 380 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 385 390 395 400 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 405 410 415 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr 420 425 430 Phe Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg 435 440 445 Ile Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg 450 455 460 Asp Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn 465 470 475 480 Ser Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His 485 490 495 Asp Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser 500 505 510 Ser Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser 515 520 525 Leu Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly Gly Gly Gly Gly 530 535 540 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 545 550 555 560 Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val 565 570 575 Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 580 585 590 Gly Gly Gly Gly Ser Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro 595 600 605 Tyr Pro Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg 610 615 620 Cys Tyr Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu 625 630 635 640 Gly Pro Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser 645 650 655 Gly Arg Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe 660 665 670 Ser Asp Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val 675 680 685 Glu Ser Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu 690 695 700 Gln Leu Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys 705 710 715 720 Val Ser Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp 725 730 735 Asn Gln Val Gly Ala Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser 740 745 750 Pro Trp Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser 755 760 765 Cys Leu Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg 770 775 780 Arg Arg Gln Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser 785 790 795 800 Pro Val Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe 805 810 815 Ser Val Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys 820 825 830 Glu Gln Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala 835 840 845 Pro Gly Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys 850 855 860 Pro Cys Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro 865 870 875 880 Tyr Leu Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln 885 890 895 Phe Gly Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala 900 905 <210> 68 <211> 718 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (452)..(471) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (489)..(508) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeat units <400> 68 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val[ 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Lys Ile Asp 245 250 255 Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu 260 265 270 Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly 275 280 285 Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp 290 295 300 Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr 305 310 315 320 Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile 325 330 335 Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val 340 345 350 Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln 355 360 365 Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr 370 375 380 Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln 385 390 395 400 Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn 405 410 415 Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala 420 425 430 Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe 435 440 445 Leu Asp Ile Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly 465 470 475 480 Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Ser Gly Gly Gly 485 490 495 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Thr Ser Glu 500 505 510 Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser Ala 515 520 525 Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg Tyr 530 535 540 Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His Phe 545 550 555 560 Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala Gly 565 570 575 Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val Leu 580 585 590 Tyr Thr Val Thr Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr Glu 595 600 605 Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr Glu 610 615 620 Pro Pro Leu Gly Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu Arg 625 630 635 640 Met Glu Trp Glu Thr Pro Asp Asn Gln Val Gly Ala Glu Val Gln Phe 645 650 655 Arg His Arg Thr Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly Pro 660 665 670 Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn Val 675 680 685 Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly Ser 690 695 700 Ser Trp Ser Lys Trp Ser Ser Pro Val Cys Val Pro Pro Glu 705 710 715 <210> 69 <211> 922 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (554)..(573) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (591)..(610) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeat units <400> 69 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Lys Ile Asp 245 250 255 Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu 260 265 270 Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly 275 280 285 Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp 290 295 300 Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr 305 310 315 320 Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile 325 330 335 Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val 340 345 350 Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln 355 360 365 Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr 370 375 380 Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln 385 390 395 400 Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn 405 410 415 Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala 420 425 430 Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe 435 440 445 Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe 450 455 460 Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly 465 470 475 480 Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu 485 490 495 Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu Leu 500 505 510 Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu 515 520 525 His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala 530 535 540 Gln Thr Pro Glu Glu Glu Pro Thr Gly Gly Gly Gly Gly Ser Gly Gly 545 550 555 560 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met 565 570 575 Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly 580 585 590 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 595 600 605 Gly Ser Arg Thr Ser Glu Cys Cys Phe Gln Asp Pro Pro Tyr Pro Asp 610 615 620 Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg Asp Leu Arg Cys Tyr Arg 625 630 635 640 Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp Gln Tyr Glu Gly Pro Thr 645 650 655 Ala Gly Val Ser His Phe Leu Arg Cys Cys Leu Ser Ser Gly Arg Cys 660 665 670 Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg Leu Gln Phe Ser Asp Gln 675 680 685 Ala Gly Val Ser Val Leu Tyr Thr Val Thr Leu Trp Val Glu Ser Trp 690 695 700 Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu Val Thr Leu Gln Leu Tyr 705 710 715 720 Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly Asp Ile Lys Val Ser Lys 725 730 735 Leu Ala Gly Gln Leu Arg Met Glu Trp Glu Thr Pro Asp Asn Gln Val 740 745 750 Gly Ala Glu Val Gln Phe Arg His Arg Thr Pro Ser Ser Pro Trp Lys 755 760 765 Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp Thr Glu Ser Cys Leu Cys 770 775 780 Pro Leu Glu Met Asn Val Ala Gln Glu Phe Gln Leu Arg Arg Arg Gln 785 790 795 800 Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys Trp Ser Ser Pro Val Cys 805 810 815 Val Pro Pro Glu Asn Pro Pro Gln Pro Gln Val Arg Phe Ser Val Glu 820 825 830 Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu Thr Leu Lys Glu Gln Pro 835 840 845 Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln Gly Leu Ala Pro Gly Thr 850 855 860 Glu Val Thr Tyr Arg Leu Gln Leu His Met Leu Ser Cys Pro Cys Lys 865 870 875 880 Ala Lys Ala Thr Arg Thr Leu His Leu Gly Lys Met Pro Tyr Leu Ser 885 890 895 Gly Ala Ala Tyr Asn Val Ala Val Ile Ser Ser Asn Gln Phe Gly Pro 900 905 910 Gly Leu Asn Gln Thr Trp His Ile Pro Ala 915 920 <210> 70 <211> 838 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (541)..(560) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (578)..(597) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 70 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 245 250 255 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 260 265 270 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 275 280 285 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 290 295 300 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 305 310 315 320 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 325 330 335 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 340 345 350 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 355 360 365 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 370 375 380 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 385 390 395 400 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 405 410 415 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr 420 425 430 Phe Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg 435 440 445 Ile Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg 450 455 460 Asp Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn 465 470 475 480 Ser Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His 485 490 495 Asp Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser 500 505 510 Ser Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser 515 520 525 Leu Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly Gly Gly Gly Gly 530 535 540 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 545 550 555 560 Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val 565 570 575 Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 580 585 590 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 595 600 605 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 610 615 620 Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala 625 630 635 640 Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro 645 650 655 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 660 665 670 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr 675 680 685 Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 690 695 700 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 705 710 715 720 Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 725 730 735 Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp 740 745 750 Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly 755 760 765 Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln 770 775 780 Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu 785 790 795 800 Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 805 810 815 Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr 820 825 830 Leu Val Thr Val Ser Ser 835 <210> 71 <211> 851 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (554)..(573) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (591)..(610) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 71 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Lys Ile Asp 245 250 255 Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu 260 265 270 Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly 275 280 285 Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp 290 295 300 Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr 305 310 315 320 Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile 325 330 335 Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val 340 345 350 Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln 355 360 365 Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr 370 375 380 Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln 385 390 395 400 Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn 405 410 415 Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala 420 425 430 Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe 435 440 445 Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe 450 455 460 Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly 465 470 475 480 Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu 485 490 495 Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu Leu 500 505 510 Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu 515 520 525 His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala 530 535 540 Gln Thr Pro Glu Glu Glu Pro Thr Gly Gly Gly Gly Gly Ser Gly Gly 545 550 555 560 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met 565 570 575 Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly 580 585 590 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 595 600 605 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 610 615 620 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser 625 630 635 640 Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser 645 650 655 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 660 665 670 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 675 680 685 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr 690 695 700 Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly 705 710 715 720 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 725 730 735 Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile 740 745 750 Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Tyr Trp Leu Gly Trp 755 760 765 Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser 770 775 780 Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val 785 790 795 800 Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn 805 810 815 Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg 820 825 830 Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr 835 840 845 Val Ser Ser 850 <210> 72 <211> 838 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (541)..(560) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (578)..(597) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeat units <400> 72 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser 225 230 235 240 Lys Ile Asp Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His 245 250 255 Val Ile Leu Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro 260 265 270 Arg Gln Gly Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr 275 280 285 Lys Phe Asp Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser 290 295 300 Gln Val Thr Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu 305 310 315 320 Ala Cys Ile Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe 325 330 335 Val Gly Val Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys 340 345 350 Gly Glu Gln Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr 355 360 365 His Leu Tyr Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu 370 375 380 Thr Trp Gln Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe 385 390 395 400 Gly Ile Asn Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys 405 410 415 Val Thr Ala Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr 420 425 430 Phe Thr Phe Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg 435 440 445 Ile Lys Phe Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg 450 455 460 Asp Glu Gly Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn 465 470 475 480 Ser Arg Leu Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His 485 490 495 Asp Leu Leu Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser 500 505 510 Ser Lys Leu His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser 515 520 525 Leu Arg Ala Gln Thr Pro Glu Glu Glu Pro Thr Gly Gly Gly Gly Gly 530 535 540 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 545 550 555 560 Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val 565 570 575 Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 580 585 590 Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val 595 600 605 Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr 610 615 620 Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys 625 630 635 640 Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg 645 650 655 Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser 660 665 670 Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr 675 680 685 Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp 690 695 700 Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 705 710 715 720 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 725 730 735 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 740 745 750 Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln 755 760 765 Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser 770 775 780 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 785 790 795 800 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 805 810 815 Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly 820 825 830 Thr Lys Leu Glu Ile Lys 835 <210> 73 <211> 851 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> Site <222> (554)..(573) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <220> <221> Site <222> (591)..(610) <223> This region includes 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 73 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Arg Gly 225 230 235 240 Pro Ser Trp Val Gly Gly Gly Gly Ser Gly Gly Gly Ser Lys Ile Asp 245 250 255 Ala Cys Lys Arg Gly Asp Val Thr Val Lys Pro Ser His Val Ile Leu 260 265 270 Leu Gly Ser Thr Val Asn Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly 275 280 285 Cys Phe His Tyr Ser Arg Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp 290 295 300 Arg Arg Ile Asn Phe His His Gly His Ser Leu Asn Ser Gln Val Thr 305 310 315 320 Gly Leu Pro Leu Gly Thr Thr Leu Phe Val Cys Lys Leu Ala Cys Ile 325 330 335 Asn Ser Asp Glu Ile Gln Ile Cys Gly Ala Glu Ile Phe Val Gly Val 340 345 350 Ala Pro Glu Gln Pro Gln Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln 355 360 365 Gly Thr Val Ala Cys Thr Trp Glu Arg Gly Arg Asp Thr His Leu Tyr 370 375 380 Thr Glu Tyr Thr Leu Gln Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln 385 390 395 400 Lys Gln Cys Lys Asp Ile Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn 405 410 415 Leu Thr Pro Glu Ser Pro Glu Ser Asn Phe Thr Ala Lys Val Thr Ala 420 425 430 Val Asn Ser Leu Gly Ser Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe 435 440 445 Leu Asp Ile Val Arg Pro Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe 450 455 460 Gln Lys Ala Ser Val Ser Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly 465 470 475 480 Leu Val Leu Leu Asn Arg Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu 485 490 495 Trp Asn Met Val Asn Val Thr Lys Ala Lys Gly Arg His Asp Leu Leu 500 505 510 Asp Leu Lys Pro Phe Thr Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu 515 520 525 His Leu Tyr Lys Gly Ser Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala 530 535 540 Gln Thr Pro Glu Glu Glu Pro Thr Gly Gly Gly Gly Gly Ser Gly Gly 545 550 555 560 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val His Met 565 570 575 Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly 580 585 590 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 595 600 605 Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro 610 615 620 Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr 625 630 635 640 Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp 645 650 655 Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro 660 665 670 Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr 675 680 685 Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr 690 695 700 Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly 705 710 715 720 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 740 745 750 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 755 760 765 Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 770 775 780 Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 785 790 795 800 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 805 810 815 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 820 825 830 Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu 835 840 845 Glu Ile Lys 850 <210> 74 <211> 133 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutant <222> (3)..(3) <223> Replace with "Ala" <220> <221> mutant <222> (20)..(20) <223> Use "His" or "Lys" or "Leu" or "Met" or "Asn" or "Gln" or "Arg" or "Ser" or "Val" or "Tyr" <220> <221> mutant <222> (42)..(42) <223> Use "Gly" or "Ser" or "Thr" or "Gln" or "Glu" or "Asn" or "Asp" or "Arg" or "Lys" <220> <221> mutant <222> (45)..(45) <223> Use "Gly" or "Ser" or "Thr" or "Gln" or "Glu" or "Asn" or "Asp" or "Arg" or "Lys" <220> <221> mutant <222> (72)..(72) <223> Use "Gly" or "Ser" or "Thr" or "Gln" or "Glu" or "Asn" or "Asp" or "Arg" or "Lys" <220> <221> mutant <222> (88)..(88) <223> Use "Ala" or "Glu" or "Phe" or "His" or "Lys" or "Leu" or "Met" or "Ser" or "Thr" or "Val" or "Trp" or "Tyr" <220> <221> mutant <222> (90)..(90) <223> Replace with "Thr" <220> <221> mutant <222> (125)..(125) <223> Replace with "Ser" <220> <221> mutant <222> (126)..(126) <223> Use "Asp" or "Phe" or "Gly" or "His" or "Ile" or "Lys" or "Leu" or "Pro" or "Ser" or "Thr" or "Trp" or "Tyr" <220> <221> Site <222> (1)..(133) <223> At variable sites, there is no preference for variable residues in the sequence listing relative to the amino acids provided in the annotations. <220> <221> source <223> See the detailed description and specific implementation methods in the application document description <400> 74 Ala Pro Asn Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Ala Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Ala Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> 75 <211> 133 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutant <222> (3)..(3) <223> Replace with "Ala" <220> <221> mutant <222> (20)..(20) <223> Use "His" or "Lys" or "Leu" or "Met" or "Asn" or "Gln" or "Arg" or "Ser" or "Val" or "Tyr" <220> <221> mutant <222> (38)..(38) <223> Replace with "Lys" or "Ser" <220> <221> mutant <222> (42)..(42) <223> Use "Gly" or "Ile" or "Ser" or "Thr" or "Gln" or "Glu" or "Asn" or "Asp" or "Arg" or "Lys" substitution <220> <221> mutant <222> (45)..(45) <223> Use "Gly" or "Ser" or "Thr" or "Gln" or "Glu" or "Asn" or "Asp" or "Arg" or "Lys" <220> <221> mutant <222> (62)..(62) <223> Replace with "Leu" or "Ala" or "Ile" <220> <221> mutant <222> (68)..(68) <223> Replace with "Val" <220> <221> mutant <222> (73)..(73) <223> Replace with "Thr" <220> <221> mutant <222> (88)..(88) <223> Use "Ala" or "Glu" or "Phe" or "His" or "Lys" or "Leu" or "Met" or "Ser" or "Thr" or "Val" or "Trp" or "Tyr" <220> <221> mutant <222> (90)..(90) <223> Replace with "Thr" <220> <221> mutant <222> (125)..(125) <223> Replace with "Ser" <220> <221> mutant <222> (126)..(126) <223> Use "Asp" or "Phe" or "Gly" or "His" or "Ile" or "Lys" or "Leu" or "Pro" or "Ser" or "Thr" or "Trp" or "Tyr" <220> <221> Site <222> (1)..(133) <223> At variable sites, there is no preference for variable residues in the sequence listing relative to the amino acids provided in the annotations. <220> <221> source <223> See the detailed description and specific implementation methods in the application document description <400> 75 Ala Pro Asn Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Ala Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Ala Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> 76 <211> 484 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 76 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu 225 230 235 240 Gly Val Arg Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly 260 265 270 Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln Met 275 280 285 Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp Ser 290 295 300 Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser Val 305 310 315 320 Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala 325 330 335 Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly 340 345 350 Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 355 360 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 370 375 380 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 385 390 395 400 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys 405 410 415 Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln 420 425 430 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 435 440 445 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 450 455 460 Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys 465 470 475 480 Leu Glu Ile Lys <210> 77 <211> 489 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 77 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu 225 230 235 240 Gly Val Arg Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly 245 250 255 Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly 260 265 270 Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln Met 275 280 285 Pro Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp Ser 290 295 300 Asp Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser Val 305 310 315 320 Asp Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala 325 330 335 Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly 340 345 350 Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 355 360 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 370 375 380 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 385 390 395 400 Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 405 410 415 Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala 420 425 430 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 435 440 445 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 450 455 460 Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe 465 470 475 480 Gly Gln Gly Thr Lys Leu Glu Ile Lys 485 <210> 78 <211> 489 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 78 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu 225 230 235 240 Gly Val Arg Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 245 250 255 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 260 265 270 Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 275 280 285 Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 290 295 300 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 305 310 315 320 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 325 330 335 Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu 340 345 350 Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 355 360 365 Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro 370 375 380 Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr 385 390 395 400 Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp 405 410 415 Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro 420 425 430 Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr 435 440 445 Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr 450 455 460 Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly 465 470 475 480 Gln Gly Thr Leu Val Thr Val Ser Ser 485 <210> 79 <211> 494 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 79 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu 225 230 235 240 Gly Val Arg Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 245 250 255 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 260 265 270 Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 275 280 285 Glu Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 290 295 300 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 305 310 315 320 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 325 330 335 Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu 340 345 350 Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 355 360 365 Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala 370 375 380 Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser 385 390 395 400 Gly Tyr Ser Phe Thr Thr Tyr Trp Leu Gly Trp Val Arg Gln Met Pro 405 410 415 Gly Lys Gly Leu Asp Trp Ile Gly Ile Met Ser Pro Val Asp Ser Asp 420 425 430 Ile Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Met Ser Val Asp 435 440 445 Lys Ser Ile Thr Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser 450 455 460 Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Arg Pro Gly Gln Gly Tyr 465 470 475 480 Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 485 490 <210> 80 <211> 20 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 80 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20

Claims

1. A prodrug comprising two polypeptide chains, wherein the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20; and the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 76, 77, 78 or 79.

2. A pharmaceutical composition comprising the prodrug according to claim 1 and a pharmaceutically acceptable excipient.

3. A polynucleotide encoding the prodrug according to claim 1. An expression vector comprising the polynucleotide according to claim 3 . A host cell comprising the vector according to claim 4 .

6. The host cell according to claim 5, wherein the gene encoding uPA, MMP-2, MMP-9 and / or matriptase in the cell is knocked out.

7. A method for preparing the prodrug according to claim 1, the method comprising: Cultivating the host cell according to claim 5 or 6 under conditions that allow expression of the prodrug; as well as and isolating the prodrug.

Images