New masked cytokines and their applications

Abstract

The present invention provides a prodrug, a preparation method thereof, and use thereof in stimulating the immune system, treating cancer, autoimmune diseases, or infectious diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application also claims priority to U.S. Provisional Application No. 62 / 959,973 filed on January 11, 2020, U.S. Provisional Application No. 63 / 027,138 filed on May 19, 2020, U.S. Provisional Application No. 63 / 029,473 filed on May 23, 2020, and U.S. Provisional Application No. 63 / 126,393 filed on December 16, 2020, the contents of the above U.S. Provisional Applications 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, which is hereby incorporated by reference in its entirety. The ASCII copy created on January 11, 2021 is named 025471_WO008_SL.txt and is 240,322 bytes in size. Background Art

[0005] Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21 have important effects on the proliferation, differentiation and survival of immune cells. The receptors of the above cytokines share the γ chain (γC), that is, CD132, so these cytokines are also called γC family cytokines.

[0006] IL-2 plays an important role in the generation, survival and in vivo stability of lymphocytes. The IL-2 has 133 amino acids and is composed of four antiparallel, amphipathic α-helices. The tetrameric structure formed by it is a necessary condition for the function of IL-2 (Smith, Science (1988) 240: 1169-76; Bazan, Science (1992) 257: 410-13). IL-2 achieves its activity by binding to the IL-2 receptor (IL-2R), which is composed of up to three independent subunits: a trimer composed of α (CD25 or Tac antigen), β (CD122), and γC subunits, forming a high affinity (K) for IL-2. D ~0.01nM) receptor. The IL-2 dimer receptor composed of β and γ subunits is called the intermediate affinity IL-2 receptor (K D ~1nM). The α subunit monomer constitutes a low affinity IL-2 receptor (K D~10nM) (See, eg, Kim et al., Cytokine Growth Factor Rev. (2006) 17:349-66). Although the affinity of the dimeric intermediate affinity IL-2 receptor binding to IL-2 is reduced to about 1 / 100 compared to the trimeric high affinity receptor, both the dimeric and trimeric IL-2 receptors can transmit signals when bound to IL-2 (Minami et al., Annu Rev Immunol. (1993) 11:245-68).

[0007] IL-15 is a cytokine with a similar structure to IL-2. IL-15 is secreted by phagocytes and other immune cells after viral infection. IL-15 can induce the proliferation of natural killer cells and other cells of the immune system, and participate in killing virus-infected cells and tumor cells. Like IL-2, IL-15 binds to the IL-2 receptor (IL-2R) β / γ complex, also known as the intermediate affinity receptor, with K D IL-15 binds with an affinity of about 1 nM (Giri et al., EMBO J. (1994) 13: 2822-30). D ~0.05nM) and IL-15 receptor (IL-15R) α, IL-15Rα can form a specific, high-affinity (αβγ) functional receptor for IL-15 together with the IL-2Rβ / γ complex (Minami et al., Annu. Rev. Immunol. (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).

[0008] IL-21 is produced by activated CD4+ T cells, T-follicular helper cells and natural killer cells (NKT) (Spolski and Leonard, Ann Rev Immunol. (2008) 26:57008). IL-21 has been shown to exert pleiotropic effects on the proliferation, differentiation and cytotoxicity of various types of lymphocytes. Recently, IL-21 has been further shown to play a role in CD4 + T cells differentiate into helper T cells 17 (TH 17), which is a subtype of T cells associated with inflammation and autoimmune responses (Korn et al., Nature (2007) 448 (7152): 484-87; Nurieva et al., Nature (2007) 448 (7152): 480-83). The IL-21 receptor composition consists of a private chain IL-21Rα and a common chain γC (or Rγ). Human IL-21 binds to the IL-21 receptor with a very high affinity (K D ~70pM; Zhang et al., Biochem Biophys Res Commun. (2003) 300(2):291-6) and IL-21Rα, but with relatively low affinity (K D ~160μM) binds to IL-21Rγ.

[0009] The therapeutic potential of the above cytokines, their mutants and their fusions is being studied and developed, among which recombinant IL-2 is the first cytokine approved for cancer treatment. However, cytokine drugs and candidate drugs have obvious side effects. In addition, these drugs usually have a short half-life in the body, and even exist in the form of antibody-cytokine fusion proteins. The reason may be the "PK sedimentation" formed by cytokine receptors on immune cells.

[0010] Therefore, further research and development of cytokine-based tumor treatments with higher tumor site selectivity, improved PK, and efficacy to reduce side effects is necessary. SUMMARY OF THE INVENTION

[0012] The present invention provides a prodrug, comprising a cytokine portion, a masking portion, and a carrier portion, wherein the masking portion binds to the cytokine portion and inhibits the biological activity of the cytokine; the carrier portion comprises an antigen binding portion that can bind to an antigen expressed on the surface of a target cell; and the masking portion is not connected to the carrier portion via a cleavable linker (such as indirectly connected to the carrier portion via a non-cleavable peptide linker, or directly connected to the carrier portion via a peptide linker).

[0013] In some embodiments, the prodrug can be activated by a cell, the cell surface expressing antigens and cytokine receptors at the same time. In some embodiments, the biological activity of the prodrug at the lesion containing the above-mentioned cells is increased by at least 2 times, 5 times or 10 times compared to the biological activity at the site without the above-mentioned cells. In some specific embodiments, the receptor of the cytokine part includes two or more subunits.

[0014] In some embodiments, the antigen is selected from PD-1, PD-L1, CTLA-4, TIGIT, TIM-3, LAG-3, CD25, CD16a, CD16b, NKG2D, NKP44, NKP30, CD19, CD20, CD30, CD38, BCMA, and signal regulatory protein alpha (SIRPα, named CD172a).

[0015] In some embodiments, the cytokine portion comprises an IL-2 agonist polypeptide, an IL-7 agonist polypeptide, an IL-9 agonist polypeptide, an IL-15 agonist polypeptide, an IL-21 agonist polypeptide, an IL-1α agonist polypeptide, an IL-1β agonist polypeptide, an IL-4 agonist polypeptide, an IL-5 agonist polypeptide, an IL-6 agonist polypeptide, an IL-8 agonist polypeptide, an IL-10 agonist polypeptide, an IL-12 agonist polypeptide, an IL-17 agonist polypeptide, an IL-18 agonist polypeptide, an IL-22 agonist polypeptide, an IL-23 agonist polypeptide, an IL-31 agonist polypeptide, an IL-33 agonist polypeptide, an IL-36 agonist polypeptide, an interferon-α agonist polypeptide, an interferon gamma agonist polypeptide, a 4-1BB ligand, an OX-40 ligand, or a CD-40 ligand.

[0016] In some embodiments, the cytokine portion comprises an IL-2 agonist polypeptide or an IL-15 agonist polypeptide, and the masking portion comprises an IL-2 receptor β extracellular domain (IL-2RβECD) or a functional fragment thereof. In other embodiments, the cytokine portion comprises an IL-21 agonist polypeptide, and the masking portion comprises an anti-IL-21 antibody Fab, a single-chain Fv (scFv), or a single-domain antibody thereof. In other embodiments, the cytokine portion comprises an IL-2 agonist polypeptide, and the masking portion comprises an anti-IL-2 antibody Fab, scFv, or a single-domain antibody thereof. In other embodiments, the cytokine portion comprises an IL-15 agonist polypeptide, and the masking portion comprises an anti-IL-15 antibody Fab, scFv, or a single-domain antibody thereof. In other embodiments, the cytokine portion comprises an IL-15 agonist polypeptide, and the masking portion comprises an IL-15 receptor α Sushi domain (IL-15RαSushi domain).

[0017] In some embodiments, the cytokine portion comprises an IL-21 agonist polypeptide having a sequence of SEQ ID NO: 1, or an amino acid sequence having at least 90% homology thereto. In other embodiments, the cytokine portion comprises an IL-2 agonist polypeptide having a sequence of SEQ ID NO: 6 or 62, or an amino acid sequence having at least 95% homology thereto. In other embodiments, the cytokine portion comprises an IL-15 agonist polypeptide having a sequence of SEQ ID NO: 7, or an amino acid sequence having at least 95% homology thereto.

[0018] In some embodiments, the masking portion includes the extracellular domain (ECD) of the cytokine receptor. In specific embodiments, the cytokine includes an IL-7 agonist polypeptide, and the masking portion includes the extracellular domain of IL-7 receptor α (IL-7RαECD) or a functional analog thereof. In specific embodiments, the cytokine portion is an IL-21 agonist polypeptide, and the masking portion includes the extracellular domain of IL-21 receptor α (IL-21RαECD) or a functional analog thereof. In specific embodiments, the masking portion includes IL-21RαECD or a functional analog thereof, and its amino acid sequence is selected from SEQ ID NO: 12, 13 and 63-73 or an amino acid sequence having at least 90% (such as at least 95%) homology thereto. In some embodiments, the masking portion includes IL-2RβECD or a functional analog thereof, including SEQ ID NO: 11 or an amino acid sequence having at least 95% homology thereto.

[0019] In some embodiments, the masking portion includes an scFv that can bind to a cytokine portion and inhibit or interfere with the interaction of the cytokine with its receptor. In a specific embodiment, the masking portion is an scFv that can bind to human IL-21, which includes the amino acid sequence SEQ ID NO: 20 or 21. In a specific embodiment, the masking portion includes an scFv that can bind to IL-2, and inhibits the interaction of IL-2 with IL-2Rα, the interaction of IL-2 with IL-2Rβ, and / or the interaction of IL-2 with IL-2Rγ by binding to IL-2, wherein the scFv optionally includes the complementary determining region (CDR) of the light chain and heavy chain of the antibody 4E12B2D10. In some embodiments, the scFv includes the light chain and heavy chain of the antibody 4E12B2D10. In a specific embodiment, the antibody 4E12B2D10, the amino acid sequences of its heavy chain and light chain are SEQ ID NO: 60 and 61, respectively. In some embodiments, the masking moiety is a scFv that can bind to IL-2, which includes SEQ ID NO: 22 or 23, or an amino acid sequence having at least 95% homology thereto. In a specific embodiment, the masking moiety includes a scFv that can bind to IL-15, which inhibits or interferes with the interaction of IL-15 with IL-2Rβ, and / or the interaction of IL-15 with IL-2Rγ by binding to the scFv, wherein the scFv optionally includes the CDRs of the light and heavy chains of antibodies 146B7, 146H5, or 404E4, or the scFv optionally includes the light and heavy chains of anti-IL-15 antibodies 146B7, 146H5, or 404E4, or the scFv optionally includes SEQ ID NO: 18 or 19. In some embodiments, the IL-15 agonist scFv or Fab comprises CDR1-3 of the heavy chain and CDR1-3 of the light chain of an anti-IL-15 antibody selected from 146B7, 146H5, or 404E4, all of which are described in WO2003 / 017935A2.

[0020] In a specific embodiment, the masking portion includes a scFv that can bind to IL-21, which inhibits or interferes with the interaction between IL-21 and IL-21Rα, and / or the interaction between IL-21 and IL-2Rγ by binding to IL-21. In a specific embodiment, the masking portion includes a scFv that can bind to a cytokine selected from IL-2, IL-7, IL-9, IL-15 or IL-21, and inhibits or interferes with the interaction between the cytokine and IL-2Rγ.

[0021] In some embodiments, the prodrug has a half-life increased by at least 20-fold, at least 50-fold, at least 100-fold, at least 150-fold, or at least 200-fold compared to the corresponding wild-type cytokine in a non-human primate or human.

[0022] In certain embodiments, the prodrug comprises two light chains having an amino acid sequence of SEQ ID NO:44, and two heavy polypeptide chains having amino acid sequences comprising SEQ ID NOs:24 and 25; SEQ ID NOs:35 and 36; SEQ ID NOs:37 and 36; SEQ ID NOs:37 and 38; SEQ ID NOs:39 and 41, or SEQ ID NOs:42 and 43, respectively.

[0023] In certain embodiments, the prodrug comprises two light chains having an amino acid sequence of SEQ ID NO:50, and two heavy polypeptide chains having amino acid sequences comprising SEQ ID NO:51 and 54; SEQ ID NO:51 and 55; SEQ ID NO:51 and 56; SEQ ID NO:52 and 54; SEQ ID NO:53 and 58; SEQ ID NO:53 and 59; or SEQ ID NO:52 and 57, respectively.

[0024] In some embodiments, the present invention provides a pharmaceutical composition comprising a prodrug disclosed herein and a pharmaceutically acceptable excipient.

[0025] On the other hand, the present invention provides a polynucleotide encoding the prodrug, an expression vector comprising the polynucleotide, and a host cell (such as a mammalian host cell, such as a CHO cell, a NS0 cell, and a 293T cell) comprising the expression vector. The present invention also provides a method for preparing the prodrug, comprising culturing the mammalian host cell under conditions that allow the expression of the prodrug, and isolating (purifying) the prodrug.

[0026] Under the premise of ensuring that the cytokine part is masked, the Fc-based IL-21 prodrug cannot interact with the expression of IL-21 receptor ( Figure 2 The study further showed that the masked molecules with the antibody PD-1 as carrier had little activity against NK92 cells that did not express PD-1 ( Figure 3 The inventors surprisingly found that the IL-21 prodrug molecule based on PD-1 antibody has obvious activity against Mino cells before activation ( Figure 4A and Figure 4B IL-2 prodrug ( Fig. 6A and Figure 6B ) and IL-15 prodrug ( Figure 5A-C) has a similar phenomenon. Although not wishing to be bound by theory, it can be assumed that when cells express antigens and cytokine receptors at the same time, the cis binding of PD-1 antibodies to antigens and cytokines to cytokine receptors relieves the masking effect of the masking part. Therefore, the prodrug containing the targeting functional part has obvious selectivity for cells expressing specific antigens compared to cells without the corresponding antigen, wherein the antigen has targeting to the carrier molecule of the prodrug. Based on this, the prodrug can be constructed without the need for protease cleavage or removal of the masking part.

[0027] The present invention provides a prodrug that is selectively activated without the need for protease to cleave or remove the masking portion at the lesion. On the one hand, the present invention provides a completely new prodrug, which includes a cytokine portion (cytokine agonist polypeptide), a masking portion, and a carrier portion, wherein the masking portion inhibits the biological activity of the cytokine by binding to the cytokine agonist polypeptide, the carrier portion includes an antigen binding portion, and the masking portion is directly or indirectly connected to the carrier portion through a non-cleavable peptide connector or without a peptide connector, wherein the prodrug has a higher activity in activated cells that simultaneously express a cytokine receptor and a targeting antigen to the carrier portion than in activated cells that only express a cytokine receptor but do not express a targeting antigen to the carrier portion.

[0028] On the other hand, the prodrug provided by the present invention includes a cytokine portion (cytokine agonist polypeptide), a masking portion and a carrier portion, wherein the masking portion inhibits the biological activity of the cytokine by binding to the cytokine agonist polypeptide, and the carrier portion includes an antigen binding portion, and the masking portion is directly or indirectly connected to the carrier portion through a non-cleavable peptide connector or without a peptide connector, wherein the prodrug is activated at the lesion site (the cells at this site simultaneously express cytokine receptors and antigens that are targeted to the carrier portion), or the prodrug is activated at the lesion site (the cells at this site simultaneously express cytokine receptors and antigens that are targeted to the carrier portion), and its biological activity at the lesion site is increased by at least 2 times, at least 5 times, or at least 10 times.

[0029] In some embodiments, the prodrug does not contain any cleavable peptide linker.

[0030] In some embodiments, the carrier portion includes a binding portion for an antigen expressed by an immune cell. In some embodiments, the carrier portion includes a binding portion for an antigen selected from PD-1, PD-L1, CTLA-4, TIGIT, TIM-3, LAG-3, CD25, CD16a, and CD16b.

[0031] In some embodiments, the cytokine portion includes a cytokine selected from an IL-2 agonist polypeptide, an IL-17 agonist polypeptide, an IL-9 agonist polypeptide, an IL-15 agonist polypeptide, and an IL-21 agonist polypeptide. In some embodiments, the cytokine is selected from an IL-1α agonist polypeptide, an IL-1β agonist polypeptide, an IL-4 agonist polypeptide, an IL-5 agonist polypeptide, an IL-6 agonist polypeptide, an IL-8 agonist polypeptide, an IL-10 agonist polypeptide, an IL-12 agonist polypeptide, an IL-15 agonist polypeptide, an IL-17 agonist polypeptide, an IL-18 agonist polypeptide, an IL-22 agonist polypeptide, an IL-23 agonist polypeptide, an IL-31 agonist polypeptide, an IL-33 agonist polypeptide, an IL-36 agonist polypeptide, an interferon α agonist polypeptide, an interferon γ, a 4-1BB ligand, an OX-40 ligand, and a CD-40 ligand.

[0032] In some embodiments, the masking moiety is an extracellular domain (ECD) of a cytokine receptor and the masking moiety comprises an anti-cytokine antibody or a binding fragment of an antibody.

[0033] In some embodiments, the cytokine is an IL-21 agonist polypeptide, wherein the masking portion is an IL-21 receptor extracellular domain (IL-21RαECD) or a functional analog thereof. In some embodiments, the cytokine is an IL-2 agonist polypeptide or an IL-15 agonist polypeptide, wherein the masking portion is an IL-2 receptor extracellular domain (IL-2RβECD). In some embodiments, the cytokine is an IL-21 agonist polypeptide, wherein the masking portion is an anti-IL-21 Fab, a single-chain antibody (scFv) or a single-domain antibody.

[0034] In some embodiments, the cytokine is an IL-2 agonist polypeptide, wherein the masking moiety is an anti-IL-2 Fab, a single chain antibody (scFv), or a single domain antibody.

[0035] In some embodiments, the cytokine is an IL-15 agonist polypeptide, wherein the masking moiety is an anti-IL-15 Fab, a single chain antibody (scFv) or a single domain antibody. In some embodiments, the cytokine comprises an IL-15 agonist polypeptide, wherein the chimeric molecule further comprises the sushi domain of the α of the IL-15 receptor (IL-15Rαsushi domain).

[0036] In some embodiments, the IL-21 agonist polypeptide comprises SEQ ID NO: 1 or an amino acid sequence having at least 90% homology thereto. In some embodiments, the masking moiety is IL-21RαECD or a functional analog thereof, comprising an amino acid sequence selected from SEQ ID NO: 12, 63-72 and 73, or an amino acid sequence having at least 90% homology thereto with SEQ ID NO: 12. In some embodiments, the masking moiety is a scFv that binds to human IL-21, comprising the amino acid sequence SEQ ID NO: 20 or 21.

[0037] In some embodiments, the IL-2 agonist polypeptide comprises SEQ ID NO: 6 or 61, or an amino acid sequence having at least 95% homology to SEQ ID NO: 6 or 61. In some embodiments, the masking moiety comprises an IL-2RβECD or a functional analog thereof, wherein the IL-2RβECD comprises SEQ ID NO: 11 or an amino acid sequence having at least 95% homology thereto. In some embodiments, the masking moiety is an scFv that binds to IL-2, and the scFv affects the interaction between IL-2 and IL-2Rα. In some embodiments, the masking moiety is an scFv that binds to IL-2, and the scFv affects the interaction between IL-2 and IL-2Rβ. In some embodiments, the masking moiety is an scFv that binds to IL-2, and the scFv affects the interaction between IL-2 and IL-2Rγ. In some embodiments, the masking moiety is an scFv that binds to IL-2, and the scFv has the same light chain and heavy chain as the hybridoma 4E12B2D10. In some embodiments, the masking moiety is a scFv that binds IL-2, the scFv comprising SEQ ID NO: 22, 23, or an amino acid sequence having at least 95% homology thereto.

[0038] In some embodiments, the IL-15 agonist polypeptide comprises SEQ ID NO: 7, or an amino acid sequence having at least 95% homology thereto. In some embodiments, the IL-15 prodrug further comprises a sushi domain, the amino acid sequence of which is SEQ ID NO: 8, or an amino acid sequence having at least 95% homology thereto. In some embodiments, the masking moiety comprises an IL-2RβECD or a functional analog thereof, wherein the IL-2RβECD comprises SEQ ID NO: 11 or an amino acid sequence having at least 95% homology thereto. In some embodiments, the masking moiety is an scFv that binds to IL-15, and the scFv affects the interaction between IL-15 and IL-2Rβ. In some embodiments, the masking moiety is an scFv that binds to IL-15, and the scFv affects the interaction between IL-15 and IL-2Rγ. In some embodiments, the masking moiety is an scFv that binds to IL-15, and the scFv has the same light chain and heavy chain as the IL-15 antibody 146B7, 146H5 or 404E4. In some embodiments, the masking moiety is a scFv that binds IL-15, wherein the scFv comprises the amino acid sequence of SEQ ID NO: 18 or 19.

[0039] In some embodiments, the human IL-21 agonist polypeptide comprises one or more mutations selected from D18, Q19, E109 and K117 (sequence numbers are consistent with SEQ ID NO: 1). In a specific embodiment, the human IL-21 agonist polypeptide comprises an amino acid sequence selected from SEQ ID NO: 1, 2, 3, 4, and 5.

[0040] In some embodiments of the prodrug, the cytokine portion and the masking portion are fused to the carrier portion via a non-cleavable peptide linker, for example, the non-cleavable peptide linker is selected from SEQ ID NOs: 27-34.

[0041] In some embodiments of the prodrug, the carrier portion is an IgG1 antibody comprising L234A and L235A ("LALA") (EU numbering) mutations or an IgG4 antibody comprising S228P / L234A / L235A (PAA) mutations. When the carrier portion is an Fc domain or an antibody Fc, other mutations that can reduce Fc functionality may also be included, such as the mutations described in Tam et al., Antibodies (2017) 6 (12): 1-34.

[0042] In certain embodiments, the carrier portion is an antibody comprising knobs-into-holes mutations, and the cytokine portion and the masking portion are fused to different heavy chains of the antibody, respectively. In certain embodiments, the knobs-into-holes mutation comprises a T366Y "knob" mutation on one polypeptide of the antibody heavy chain or Fc domain, and a Y407T "hole" mutation on another polypeptide of the antibody heavy chain or Fc domain (EU numbering). In certain embodiments, the knobs-into-holes mutation comprises a Y349C and / or T366W mutation in the CH3 domain of the "knob" chain, and an E356C, T366S, L368A, and / or Y407V mutation in the CH3 domain of the "hole" chain (EU numbering).

[0043] In some embodiments, the carrier portion is an antibody or antigen-binding fragment that specifically binds to a protein selected from amidinocyclase 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), proteoglycan-3 (GPC3), c-MET, vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), nectin-4, Li v-1, glycoprotein NMB (GPNMB), prostate-specific membrane antigen (PSMA), Trop-2, carbonic anhydrase IX (CA9), endothelin B receptor (ETBR), 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), phosphodiesterase family member 3 (ENPP3), mesothelin, trophoblast glycoprotein (TPBG), CD19, CD20, CD22, CD33, CD40, CD56, CD66e, CD70, CD74, CD79b, CD98, CD123, CD138, CD352, CD47, signal regulatory protein (SIRPα), PD1, Claudin 18.2, Claudin 6, 5T4, BCMA, PD-L1, PD-1, fibroblast activation protein alpha (FAPα), melanoma-associated chondroitin sulfate proteoglycan (MCSP), epithelial cell adhesion molecule (EPCAM) or one or more antigens. In a specific embodiment, the carrier portion is an antibody or a fragment thereof that binds to FAPα or 5T4.

[0044] On the other hand, the present invention provides a polynucleotide encoding the prodrug or fusion molecule, an expression vector comprising the polynucleotide, and a host cell (such as a mammalian host cell CHO, NS0 cell and 293T cell) comprising the expression vector. The present invention also provides a method for preparing the prodrug or fusion molecule, comprising culturing the host cell under conditions allowing the expression of the prodrug or fusion molecule and isolating the prodrug or fusion molecule.

[0045] The present invention also provides a method for treating cancer, infectious diseases, or stimulating the immune system for a patient (such as a patient) in need thereof, comprising administering to the patient a therapeutically effective amount of a cytokine prodrug or a pharmaceutical composition provided by the present invention. The patient may suffer from, for example, a viral infection (such as HIV, HBV, HCV or HPV infection) or any cancer selected from breast cancer, lung cancer, pancreatic cancer, esophageal cancer, medullary thyroid cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, colorectal cancer and gastric cancer. Also provided are the use of cytokine prodrugs in treating cancer, infectious diseases, or stimulating the immune system, the use of cytokine prodrugs in preparing drugs for treating cancer, infectious diseases, or stimulating the immune system, and products (such as kits) comprising one or more dosage units of the cytokine prodrug.

[0046] The present invention also provides the use of prodrugs in treating cancer, infectious diseases, or stimulating the immune system, the use of prodrugs in preparing drugs for treating cancer, infectious diseases, or stimulating the immune system, and preparations (such as kits) comprising one or more dosage units of the prodrug.

[0047] Other features, purposes and beneficial effects of the present invention may be apparent from the following detailed description, and it should be understood that the detailed descriptions describing the embodiments and aspects of the present invention are intended to be illustrative only and not limiting. Various changes and modifications within the scope of the present invention will be apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1A -E lists heterodimeric cytokine prodrugs using antibodies as carriers. Figure 1A It is a prodrug with a typical antibody having two light chains and two heavy chains as its carrier; Figure 1B It is a prodrug with a bispecific antibody as its carrier, each antigen-binding portion is a monomer, one antigen-binding portion includes a Fab domain, and the other antigen-binding portion includes a scFv or a single-domain antibody; Figure 1C It is a prodrug with a bispecific antibody as its carrier, in which each antigen-binding part is a dimer; Figure 1D A prodrug in which one polypeptide chain of a dimeric Fc domain is fused to a Fab domain, and the other polypeptide chain is fused to a cytokine polypeptide, wherein the cytokine is fused to a masking portion at the N-terminus; Figure 1E It is a prodrug in which one polypeptide chain of the dimer Fc domain is fused to the Fab domain, and the other polypeptide chain is fused to the cytokine polypeptide, wherein the N-terminus of the masking part is fused to the cytokine.

[0049] Figure 2 The binding results of PD-1 antibody, Fc-IL-21 fusion molecule and control molecule to Mino cells were analyzed by FACS.

[0050] Figure 3 The results show the effects of IL-21 prodrug and control molecules on the biological activity of NK-92 cells before and after MMP2 protease activation. PW04-38αPD1-IL21-a* and PW09-16αPD1-IL21-a* are the same molecule from different batches, which are PD-1 antibody-IL-21 prodrugs with IL-21Rα-ECD as the masking part; PW05-68αPD1-IL21-scFv is a PD-1 antibody-IL-21 prodrug with scFv as the masking part; one of the control molecules, PW04-67αPD1-IL21, is a PD-1 antibody-IL-21 fusion molecule without a masking part, in which IL-21 is wild-type; another control molecule, PW09-02αPD1-IL21 R9ER76A mutant, is a PD-1 antibody-IL-21 fusion molecule without a masking part, in which IL-21 has R9E and R76A amino acid mutations (sequence number and SEQ ID NO:1 is consistent); activated PW04-38αPD1-IL21-a* and activated PW09-16αPD1-IL21-a* are PD-1 antibody-IL-21 fusion molecules without mutations, and their masking parts are cut off by protease.

[0051] Figure 4A and Figure 4B The results show the effects of PD-1-IL-21 prodrug and control molecules on the biological activity of Mino cells before and after MMP2 protease activation. Figure 4A The results are shown after the cytokine fusion molecules and Mino cells were incubated for 72 hours; Figure 4B The results are shown after 120 hours of incubation.

[0052] Figure 5A , Figure 5B and Figure 5C CD4 +Ki67 activity of T cells, wherein PBMCs were pretreated with PD-1 antibody (PD-1), scFv-masked Fc-IL-15 fusion molecule (215β), scFv-masked PD-1 antibody-IL-15 fusion molecule (215γ), Fc-IL-15 fusion molecule without masking part (215βref), and PD-1 antibody-IL-15 fusion molecule without masking part (PD1 / IL15mutein (M2)). Figure 5A CD4 that does not express PD-1 + Ki67 activity in T cells; Figure 5B CD4 expressing PD-1 + Ki67 activity in T cells; Figure 5C CD4 expressing and not expressing PD-1 treated with different samples + T cell EC 50 The values ​​of CD4 expressing and not expressing PD-1 are also listed. + T cell EC 50 Multiples of value.

[0053] Fig. 6A and Figure 6B CD4 + Ki67 activity of T cells, in which PBMCs were pretreated with PD-1 antibody (PD-1), negative control (IgG1 antibody), and PD-1 antibody-IL-2 mutant protein fusion molecule (PD-1 / IL2V*) with IL-2 receptor β extracellular domain (IL-2Rβ-ECD) as the masking part. Fig. 6A CD4 that does not express PD-1 + Ki67 activity in T cells; Figure 6B CD4 expressing PD-1 + Ki67 activity in T cells.

[0054] Figure 7 The principle of prodrug activation through "cis-binding" is explained. The target cell (right side) expresses both antigens and cytokine receptors that are targeted to the carrier part. The prodrug approaches the cytokine receptor on the cell surface by binding to the cell surface antigen, allowing the cytokine receptor to replace the masking part with a competitive advantage, thereby achieving its signal transduction effect by binding to the cytokine receptor. The prodrug does not require protease cleavage to remove the masking part. In cells that only express cytokine receptors but not antigens (left side), the cytokine of the prodrug is in a masked and inactive state. DETAILED DESCRIPTION OF THE INVENTION

[0056] As used herein and in the claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0057] Reference to a value or parameter "about" herein includes (and describes) variations of the value or parameter itself. For example, a description of "about X" includes a description of "X". In addition, the use of "about" in front of any set of numbers also includes the use of "about" in the set of numbers cited. For example, a description of "about X, Y, or Z" is intended to describe "about X, about Y, or about Z".

[0058] The term "antigen binding portion" refers to a polypeptide or a group of interacting polypeptides that specifically bind to an antigen, including but not limited to antibodies (e.g., monoclonal antibodies, polyclonal antibodies, multispecific antibodies, 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), diabodies, single chain antibodies and Fc-containing polypeptides (such as immunoadhesins)). In some embodiments, the antibody can be any heavy chain type (e.g., IgG, IgA, IgM, IgE or IgD) or subtype (e.g., IgG1, IgG2, IgG3 or IgG4). In some embodiments, the antibody can be any light chain type (e.g., kappa or lambda). The antibody can be human, non-human (e.g., from mouse, rat, rabbit, goat or other 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, a human framework and a constant region). In some embodiments, the antibody is a derivatized antibody.

[0059] The terms "anti", "binding" and "specific binding" used in the present invention to describe the interaction between two molecules refer to the K measured by conventional means in the art (such as surface plasmon resonance, Elisa, etc.). D The value does not exceed 1000 nM (eg, does not exceed 100, 10, or 1 nM, for example, less than 1 nM, 1-10 nM, 10-100 nM, or 100-1000 nM).

[0060] The term "cytokine agonist polypeptide" 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 cells), although its activity level may be different from that of the wild-type cytokine. An analog may be, for example, a mutant protein (i.e., a mutant polypeptide) of a wild-type cytokine and may include at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mutations relative to the wild-type cytokine.

[0061] "Cytokine antagonists", "masking moieties", or "cytokine masking moieties" refer to moieties (such as polypeptides) that bind to cytokines. When the antagonist or masking moiety binds to the cytokine, it can inhibit the cytokine from binding to the target cell surface receptor and / or inhibit its biological function. Examples of cytokine antagonists or masking moieties include, but are not limited to, polypeptides that interact with cytokines and are derived from the extracellular domain of the natural receptor of the cytokine.

[0062] 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 (e.g., to improve, alleviate, reduce and / or delay one or more symptoms). With respect to diseases such as cancer, an effective amount may be an amount sufficient to delay cancer development or progression (e.g., reduce the growth rate of a tumor, and / or delay or prevent tumor angiogenesis, metastasis, or tumor cell infiltration into peripheral organs), reduce epithelial cells, achieve cancer regression (e.g., reduce or eliminate a tumor), and / or prevent or delay the occurrence or recurrence of cancer. An effective dose may be administered once or more than once.

[0063] A "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.

[0064] The term "fused" or "fusion" with respect to two polypeptide sequences refers to the connection of two polypeptide sequences through a backbone peptide bond. Two polypeptides can be fused directly or through a peptide connector of one or more amino acids in length. Fusion polypeptides can be prepared by recombinant technology from a coding sequence comprising the respective coding sequences of the two fused moieties, with or without the coding sequences of the peptide connector in between. In some embodiments, fusion encompasses chemical conjugation.

[0065] The term "pharmaceutically acceptable excipient" is used to refer to an ingredient in a composition that is suitable for administration to a subject, including a human, without undue adverse side effects to the subject and without affecting the biological activity of the active pharmaceutical ingredient (API).

[0066] The term "prodrug" refers to a therapeutic substance that has no activity or low activity in vitro or in the blood circulation, but has enhanced activity in the environment of the disease site.

[0067] The term "subject" refers to a mammal, including but not limited to a human, a pet (eg, a dog, a cat), a farm animal (eg, a cow, a horse), a rodent, or a primate.

[0068] As used herein, "treatment" or "treating" is a method of obtaining a beneficial or expected clinical outcome. Beneficial or expected clinical outcomes include, but are not limited to, one or more of the following: alleviating one or more symptoms of a disease, reducing the extent of a disease, improving the disease state, stabilizing a disease (e.g., preventing or delaying the deterioration or progression of a disease), preventing or delaying the spread of a disease (e.g., metastasis), preventing or delaying the recurrence of a disease, achieving partial or complete remission of a disease, reducing the dose of one or more other drugs required to treat the disease, improving the patient's quality of life, and / or prolonging survival. The disclosed method contemplates one or more aspects of treatment.

[0069] It should be understood that one, some or all of the attributes in the various embodiments described herein may be combined to form other embodiments of the present invention.The section headings used herein are for organizational purposes and should not be construed as limiting the subject matter described in this application.

[0070] I. Cytokine Prodrugs

[0071] The activity of the cytokine prodrug provided by the present invention is enhanced at the lesion site. The prodrug includes a cytokine agonist polypeptide (cytokine part), a carrier part and a masking part. The cytokine part is connected to the carrier part by or without a peptide connector (such as an uncuttable peptide connector) and is masked (combined) by the masking part. The masking part is connected to the cytokine part or the carrier part by or without a peptide connector (such as an uncuttable peptide connector). Or the cytokine part is connected to the masking part by or without a peptide connector (such as an uncuttable peptide connector), and the masking part is connected to the carrier part by or without a peptide connector (such as an uncuttable peptide connector).

[0072] The carrier portion includes an antigen binding domain that can bind to an antigen on a target cell (e.g., a tumor cell or an immune cell). In some embodiments, the carrier includes an antibody, such as Figure 1A In some embodiments, the carrier portion includes a bispecific antibody that can bind to two different antigens, such as Figure 1B and Figure 1C shown.

[0073] For example, the masking moiety may include a cytokine receptor extracellular domain (ECD), wherein the ECD and the cytokine moiety (e.g. Figure 1D and Figure 1E ) and / or connected to the carrier portion via a non-cleavable peptide linker (e.g. Figure 1A -C and Figure 1E). The masking portion binds to the cytokine portion and inhibits its biological function. The prodrug attracts the target cell by binding to the cytokine receptor and antigen expressed on the cell surface in cis, which can increase the activity of the prodrug without cutting off or removing the masking portion. The activity of the cytokine portion of the prodrug is increased at the target site (such as at the tumor site or the surrounding environment), where the antigen targeted to the carrier and the cytokine receptor are expressed on the same cell. Examples of related prodrugs are described in Figure 1A -E, Figure 7 The principle of the cis-binding is explained.

[0074] A. Cytokine portion of the prodrug

[0075] In some embodiments, the cytokine portion includes an IL-2 agonist polypeptide. In some embodiments, the IL-2 agonist polypeptide is an IL-2 mutant with R38S / F42A / Y45A / E62A or F42A / Y45A / L72G mutations (sequence number and SEQ ID NO: 6 consistent). In some embodiments, the IL-2 mutant disclosed in the present invention includes mutations selected from T3, D20, K35, R38, F42, F44, Y45, E62, E68, L72, A73, N88, N90, C125, and Q126 (sequence number and SEQ ID NO: 6 consistent) sites. In certain embodiments, the new IL-2 mutant includes mutations at R38, F42, Y45, and A73 (sequence number and SEQ ID NO: 6 consistent) sites.

[0076] In some embodiments, the cytokine portion of the prodrug comprises an IL-15 agonist polypeptide. In some embodiments, the human IL-15 polypeptide comprises a polypeptide selected from the group consisting of N1A, N1D, N4A, N4D, I6T, S7A, D8A, D8T, D8E, D8N, K10A, K10D, K11A, K11D, E46, V49, L45, S51, L52, D61A, D61N, T62L, T62A, E64A, E64L, E64K, E64Q, N65A, N65L, N65D, L66D, L66E, I 67D,I67E,I68S,I68E,L69S,L69E,N72A,N72D,V63E,V63D,L66E,L66D,I67E,I67 D,Q108E,N112A,N1D / D61N,N1D / E64Q,N4D / D61N,N4D / E64Q,D8N / D61N,D8N / E64Q , D61N / E64Q, E64Q / Q108E, N1D / N4D / D8N, D61N / E64Q / N65D, N1D / D61N / E64Q, N1D / Q108E, N1D / D61N / E64Q / Q108E, N4D / D61N / E64Q / Q108E, and D30N / E64Q / N65D (sequence number and SEQ ID NO: 7 are consistent). In some embodiments, the IL-15 prodrug further includes a Sushi domain. In some embodiments, the Sushi domain includes SEQ ID NO: 8 or an amino acid sequence having at least 95% homology thereto.

[0077] In some embodiments, the cytokine portion includes an IL-21 agonist polypeptide. In some embodiments, the IL-21 agonist polypeptide can be a wild-type IL-21 polypeptide, such as a wild-type human IL-21 (such as SEQ ID NO: 1), or an IL-21 mutant derived from human IL-21, such as selected from any one of SEQ ID NO: 2-5 amino acid sequences. The IL-21 mutant significantly reduces its affinity for IL-2Rα or IL-21RαRγ compared to wild-type IL-21. In some embodiments, the affinity of the IL-21 mutant for high-affinity IL-2Rα compared to wild-type IL-21 is reduced to 1 / 5, 1 / 10, 1 / 20, 1 / 50, 1 / 100, 1 / 300, 1 / 500, 1 / 1000 or 1 / 10000. Unless otherwise specified, the residue numbers in the IL-21 and IL-21 mutants involved in the present invention are consistent with SEQ ID NO: 1.

[0078] B. Masking Moieties of Prodrugs

[0079] The masking part in the present invention includes a peptide, an antibody or an antibody fragment that binds to the cytokine part of the prodrug, and inhibits its biological function by masking the cytokine. In some embodiments, the masking part is operably connected to the other part of the prodrug through a non-cleavable peptide connector.

[0080] For example, the prodrug includes an IL-2 agonist polypeptide, and the masking portion includes a peptide, an antibody, or an antigen-binding fragment thereof that binds to IL-2 to affect the binding of IL-2 to its cognate receptor. In some embodiments, the masking portion reduces the biological activity of the masked IL-2 portion. In some embodiments, the IL-2 antagonist includes an IL-2Rβ or IL-2Rγ extracellular domain or a functional analog thereof, for example, it can be from human IL-2Rβ or human IL-2Rγ (such as SEQ ID NO: 11 or 13). In some embodiments, the IL-2 masking portion includes a peptide screened from a peptide library. In some embodiments, the IL-2 masking portion includes an antibody or fragment thereof that inhibits the binding of IL-2 or IL-2 mutants to IL-2 receptors. In some embodiments, the masking portion includes an scFv of an anti-IL-2 antibody. In some embodiments, the masking portion includes SEQ ID NO: 22 or 23, or an amino acid sequence having at least 95% homology thereto.

[0081] For example, the prodrug includes an IL-21 agonist polypeptide, and the masking portion includes a peptide, an antibody, or an antigen-binding fragment thereof that binds to IL-21 to affect the binding of IL-21 to its cognate receptor. In some embodiments, the masking portion reduces the biological activity of the masked IL-21 portion. In some embodiments, the IL-21 antagonist includes an IL-21Rα or IL-21Rγ extracellular domain or a functional analog thereof, for example, it can be derived from human IL-21Rα or human IL-21Rγ (such as SEQ ID NO: 12 or 13). In some embodiments, the IL-21 masking portion includes a peptide screened from a peptide library. In some embodiments, the IL-21 masking portion includes an antibody or fragment thereof that inhibits the binding of IL-21 or IL-21 mutants to IL-21 receptors. In some embodiments, the masking portion includes an scFv of an anti-IL-21 antibody. In some embodiments, the masking portion includes SEQ ID NO: 20 or 21, or an amino acid sequence having at least 95% homology thereto.

[0082] For another example, the prodrug includes a masking portion of any cytokine disclosed in the present invention, wherein the cytokine includes but is not limited to an IL-7 agonist polypeptide, an IL-9 agonist polypeptide, an IL-15 agonist polypeptide, an IL-1α agonist polypeptide, an IL-1β agonist polypeptide, an IL-4 agonist polypeptide, an IL-5 agonist polypeptide, an IL-6 agonist polypeptide, an IL-8 agonist polypeptide, an IL-10 agonist polypeptide, an IL-12 agonist polypeptide, an IL-17 agonist polypeptide, an IL-18 agonist polypeptide, an IL-22 agonist polypeptide, an IL-23 agonist polypeptide, an IL-31 agonist polypeptide, an IL-33 agonist polypeptide, an IL-36 agonist polypeptide, an interferon α agonist polypeptide, an interferon γ agonist polypeptide, a 4-1BB ligand, an OX-40 ligand or a CD-40 ligand.

[0083] C. Carrier Moiety of Prodrug

[0084] The carrier portion of the prodrug includes an antigen binding domain and optional other domains. The carrier portion can improve PK, such as the half-life of the cytokine agonist polypeptide in serum, and target the cytokine agonist polypeptide to a target site in the body, such as a tumor site.

[0085] 1. Antigen binding domain of the carrier part

[0086] The carrier portion includes an antigen binding domain, which can be an antibody or an antigen binding fragment thereof, or an immunoadhesin. In some embodiments, the antigen binding carrier portion is a full-length antibody having two heavy chains and two light chains, a Fab fragment, a Fab' fragment, a F(ab') 2 A fragment, an Fv fragment, a disulfide bonded Fv fragment, a single domain antibody, a nanobody or a single chain variable fragment (scFv). 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. The antigen binding portion may provide additional and potential synergistic therapeutic effects for the cytokine agonist polypeptide.

[0087] The cytokine agonist polypeptide and its masking part can be fused to the N-terminus or C-terminus of the light chain and / or heavy chain of the antigen binding portion. For example, the IL-21 agonist polypeptide and its masking part can be fused to the antibody heavy chain or its antigen binding fragment, or it can be fused to the antibody light chain or its antigen binding fragment. For example, the IL-21 agonist polypeptide and its masking part can be fused to the antibody heavy chain or its antigen binding fragment, or it can be fused to the antibody light chain or its antigen binding fragment. In some embodiments, one end of the IL-21 agonist polypeptide is fused to the C-terminus of one or two heavy chains of the antibody, and the IL-21 masking is fused to the other end of the IL-21 agonist polypeptide through a non-cut peptide connector. In some embodiments, the IL-21 receptor agonist polypeptide is fused to the C-terminus of one heavy chain of the antibody, and the IL-21 protection unit is fused to the C-terminus of another heavy chain of the antibody through a non-cut peptide connector, wherein the two heavy chains contain mutations, allowing special pairing of two different heavy chains.

[0088] Strategies for forming heterodimers are well known (see, e.g., Spies et al., Mol Imm. 67(2)(A):95-106(2015)). For example, two heavy chain polypeptides in a prodrug can form a stable heterodimer by a "knobs-into-holes" mutation. The "knobs-into-holes" mutation is performed to promote the formation of heterodimers of antibody heavy chains and is commonly used to make bispecific antibodies (see, e.g., U.S. Patent No. 8,642,745). For example, the Fc domain of an antibody may 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". Another interchain disulfide bridge between the CH3 domains can also be used, for example, by introducing a Y349C mutation into the CH3 domain of the "knobs chain" and an E356C or S354C mutation into the CH3 domain of the "hole chain" (see, e.g., Merchant et al., Nature Biotech 16: 677-81 (1998)). In other embodiments, the antibody portion can comprise 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 specific embodiments, the antibody portion may comprise Y349C and / or T366W mutations in one of the two CH3 domains, and S354C (or E356C), T366S, L368A and / or Y407V mutations in the other CH3 domain; when an additional Y349C mutation on one CH3 domain, and an additional E356C or S354C mutation on the other CH3 domain, an interchain disulfide bond is formed (numbering is always according to the EU index numbering of Kabat; Kabat et al., "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Other knobs-in-holes technologies, such as those described in EP1870459A1, may be used alternatively or additionally. Thus, another example of knobs-in-holes mutations in the antibody portion is with 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).

[0089] In some embodiments, the antigen binding portion of the prodrug comprises an antibody having an Fc domain with L234A and L235A ("LALA") mutations. The LALA mutation can abolish complement binding and fixation and Fcγ-dependent ADCC (see Hezareh et al. J. Virol. (2001) 75(24): 12161-8). In further embodiments, the antibody portion has a LALA mutation in addition to the knobs-into-holes mutation.

[0090] In some embodiments, the antigen binding portion includes M252Y / S254T / T256E ("YTE") mutations in the Fc domain. The YTE mutation allows for simultaneous modulation of serum half-life, tissue distribution, and IgG1 activity (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, in addition to the knobs-into-holes mutation, a YTE mutation is present in the antibody portion. In specific embodiments, the antibody portion has YTE, LALA, and knobs-into-holes mutations or any combination thereof.

[0091] In certain embodiments, the antigen binding portion is an antibody or antigen binding fragment thereof that binds to an antigen on the surface of a target cell (such as an immune cell), wherein immune cells are common knowledge. In non-limiting embodiments, immune cells include T cells, NK cells, and macrophages. The antigen binding portion can activate immune cells and enhance their anti-tumor activity. The antibody may or may not have ADCC activity. The antigen binding portion can further bind to a cytotoxic drug. In some embodiments, the antigen binding portion can bind to PD-1, LAG-3, TIM-3, TIGIT, CTLA-4, or TGF-beta. In other embodiments, the antigen binding portion can bind to an antigen on the surface of a target cell (such as a tumor cell). For example, the antigen binding portion can bind to FAPα, 5T4, Trop-2, PD-L1, HER-2, EGFR, Claudin18.2, DLL-3, GCP3, or carcinoembryonic antigen (CEA). -

[0092] In some embodiments, the antigen binding portion can bind to amidinocyclase C (GCC), carbohydrate antigen 19-9 (CA19-9), glycoprotein A33 (gpA33), mucin 1 (MUC1), 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), proteoglycan-3 (GPC3), c-MET, vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), nectin-4, Liv-1, glycoprotein N MB (GPNMB), prostate-specific membrane antigen (PSMA), Trop-2, carbonic anhydrase IX (CA9), endothelin B receptor (ETBR), 6 transmembrane epithelial antigen of the prostate 1 (STEAP1), folate receptor alpha (FR-α), SLIT and NTRK-like protein 6 (SLITRK6) carbonic anhydrase VI (CA6), phosphodiesterase family member 3 (ENPP3), mesothelin, trophoblast glycoprotein (TPBG), CD19, CD20, CD22, CD33, CD40, CD56, CD66e, CD70, CD74, CD79b, CD98, CD123, CD138, CD352, CD47, signal regulatory protein (SIRPα), Claudin 18.2, Claudin 6, BCMA or EPCAM. 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 the 374th amino acid of GPC3. In some embodiments, the antigen binding portion binds to heparin sulfate glycans 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 has a binding affinity to Claudin 18.1 that is at least 10 times weaker than the binding affinity to Claudin 18.2.

[0093] Exemplary antigen binding portions include trastuzumab, rituximab, bertuximab, cetuximab, panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), anti-dPNAG antibody F598, and antigen binding fragments thereof. In some embodiments, the antigen binding portion is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to trastuzumab, rituximab, bertuximab, cetuximab or panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), anti-dPNAG antibody F598, or a fragment 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% identical to the antibody heavy chain of trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), anti-dPNAG antibody F598 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% identical to the antibody light chain of trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33 (or a humanized version thereof), anti-EGFR antibody mAb806 (or a humanized version thereof), anti-dPNAG antibody F598 or a fragment thereof. The antigen binding portion is fused to the IL-2 agonist polypeptide. In some embodiments, the antigen binding portion includes 6 complementary determining regions (CDRs) of trastuzumab, rituximab, brentuximab, cetuximab, panitumumab, GC33, anti-EGFR antibody mAb806 or anti-dPNAG antibody F598.

[0094] Many CDR descriptions are known in the art and are covered herein. One skilled in the art can easily determine the CDRs of a given description based on the sequence of the heavy or light chain variable region. "Kabat" CDRs are based on sequence variability and are most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). "Chothia" CDRs refer to the positions of structural loops (Chothia & Lesk, Canonical structures for the hypervariable regions of immunoglobulins, J. Mol. Biol., vol. 196, pp. 901-917 (1987)). "AbM" CDRs represent a compromise between Kabat CDRs and Chothia structural loops, and are also used by AbM antibody modeling software from Oxford Molecular. "Contact" CDRs are based on analysis of available complex crystal structures. The individual residues of these CDRs are listed in Table 1 below with reference to common antibody numbering schemes. Unless otherwise specified herein, the amino acid numbering in antibodies refers to the Kabat numbering scheme as described by Kabat et al. above, including when CDR descriptions are performed 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, which correspond to shortening or insertion of the framework region (FR) or CDR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat), and also includes an inserted residue after heavy chain FR residue 82 (e.g., residues 82a, 82b and 82c, etc. according to Kabat). For a given antibody, the Kabat numbering of its antibody residues can be determined by comparing the homologous region of the antibody sequence with the "standard" Kabat numbering sequence.

[0095] Table 1: CDR descriptions for different numbering schemes

[0096] CDR Kabat AbM Chothia Contact VL-CDR1 L24 - L34 L24 - L34 L26 - L32 L30 - L36 VL-CDR2 L50—L56 L50—L56 L50—L52 L46—L55 VL-CDR3 L89—L97 L89—L97 L91—L96 L89—L96 VH-CDR1 (Kabat nos.) H31—H35B H26—H35B H26—H32 H30—H35B VH-CDR1 (Chothia nos.) H31—H35 H26 - H35 H26 - H32 H30 - H35 VH-CDR2 H50—H65 H50—H58 H53—H55 H47—H58 VH-CDR3 H95—H102 H95—H102 H95 - H101 H93 - H101

[0097] In some embodiments, the CDRs are "extended CDRs" that include regions that start 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).

[0098] In some embodiments, the antigen binding portion that binds to PDL1 comprises a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 45 or a fragment thereof, and a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 46 or a fragment thereof. In some embodiments, the antigen binding domain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 45, and CDR1, CDR2, and CDR3 of SEQ ID NO: 46.

[0099] In some embodiments, the antigen binding portion that binds to PD-1 comprises a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 44 or a fragment thereof, and a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 47 or a fragment thereof. In some embodiments, the antigen binding domain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 44, and CDR1, CDR2, and CDR3 of SEQ ID NO: 47.

[0100] In some embodiments, the antigen binding portion that binds to PD-1 comprises a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 48 or a fragment thereof, and a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 49 or a fragment thereof. In some embodiments, the antigen binding domain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 48, and CDR1, CDR2, and CDR3 of SEQ ID NO: 49.

[0101] In some embodiments, the antigen binding portion includes one, two or three antigen binding domains. For example, the antigen binding portion is bispecific and can bind to two different antigens, which are selected from CD3, HER2, HER3, EGFR, 5T4, FAP alpha, Trop-2, GPC3, VEGFR2, Claudin 18.2 and PD-L1. In some embodiments, the bispecific antigen binding portion binds to two different epitopes of HER2. In other embodiments, the antigen binding portion is bispecific and can bind to two different antigens, which are selected from PD-1, PD-L1, CTLA-4, CD47, CD3, TIM-3, LAG-3 and TIGIT.

[0102] 2. Other carrier parts

[0103] The carrier portion may also include other non-antigen binding domains. For example, an antibody Fc domain (e.g., human IgG1, IgG2, IgG3 or IgG4 Fc), a polymer (e.g., PEG), an albumin (e.g., human albumin), or a fragment thereof, or a nanoparticle may be used.

[0104] For example, a cytokine agonist polypeptide (such as IL-2, IL-21, IL-5, or any other cytokine disclosed herein) and its antagonist can be fused to an antibody Fc domain to form an Fc fusion protein. In some embodiments, the cytokine agonist polypeptide is fused to the C-terminus or N-terminus of one of the polypeptide chains of the Fc domain (directly or through a peptide connector), and the cytokine masking portion is fused to the corresponding C-terminus or N-terminus of the other Fc domain polypeptide chain through a cleavable peptide connector, wherein the two Fc domain polypeptide chains contain mutations that allow specific pairing of two different Fc chains. In some embodiments, the Fc domain contains the above-mentioned holes-into-holes mutation. In some further embodiments, the Fc domain may also contain the above-mentioned YTE and / or LALA mutations.

[0105] The carrier portion of the prodrug may comprise albumin (e.g., human serum albumin) or a fragment thereof. In some embodiments, the carrier portion comprises an albumin fragment (e.g., a human serum albumin fragment) having about 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 120 or more, 140 or more, 160 or more, 180 or more, 200 or more, 250 or more, 300 or more, 350 or more, 400 or more, 450 or more, 500 or more, or 550 or more amino acids in length. In some embodiments, the length of the albumin fragment is between about 10 amino acids and about 584 amino acids (e.g., between about 10 and about 20, about 20 and about 40, about 40 and about 80, about 80 and about 160, about 160 and about 250, about 250 and about 350, about 350 and about 450, or about 450 and about 550 amino acids). In some embodiments, the albumin fragment comprises a Sudlow I domain or a fragment thereof, or a Sudlow II domain or a fragment thereof.

[0106] D. Linking moiety of prodrug

[0107] The cytokine agonist polypeptide can be fused to the carrier portion 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: 27-34. In some specific embodiments, the peptide linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 30)

[0108] The masking moiety can be fused to the cytokine moiety or the carrier moiety via a non-cleavable peptide linker or without a peptide linker.

[0109] II. Pharmaceutical Compositions

[0110] Pharmaceutical compositions including the prodrugs and mutant proteins described herein (e.g., active pharmaceutical ingredients or APIs) can be prepared by mixing the API of the desired purity with one or more optional pharmaceutically acceptable excipients (e.g., see Remington's Pharmaceutical Sciences, 16th Edition., Osol, A. Ed. (1980)) into lyophilized formulations or aqueous solutions. Pharmaceutically acceptable excipients (or carriers) are generally non-toxic to the administering agent at the dosages and concentrations used, and include, but are not limited to: buffers containing, for example, phosphate, citrate, succinate, histidine, acetate or another inorganic or organic acid or salt thereof; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; resorcinol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including sucrose, 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., zinc-protein complexes); and / or nonionic surfactants, such as polyethylene glycol (PEG).

[0111] Buffer is used to control pH within the optimal therapeutic effect range, especially when stability depends on pH. Buffer concentration is preferably between 50mM and 250mM. Buffers suitable for use with the present invention include organic and inorganic acids and salts thereof, such as citrate, phosphate, succinate, tartrate, fumarate, gluconate, oxalate, lactate and acetate. In addition, the buffer may include histidine and trimethylamine salts, such as tris(hydroxymethyl)aminomethane.

[0112] Preservatives are added to slow the growth of microorganisms and are generally present in the range of 0.2% to 1.0% (w / v). Suitable preservatives for use in the present invention include octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium halides (e.g., chlorine, bromine, iodine), benzalkonium chloride; thimerosal, phenol, butyl or benzyl alcohol; methyl or propyl paraben; catechol; resorcinol; cyclohexanol, 3-pentanol and m-cresol.

[0113] Tonicity agents, sometimes called "stabilizers," are used to adjust or maintain the tonicity of the liquid in the composition. When used with charged biomacromolecules such as proteins and antibodies, they are often referred to as "stabilizers" because they can interact with the charged groups of the amino acid side chains, thereby reducing the possibility of intermolecular and intramolecular interactions. When considering the relative amounts of the other ingredients, the tonicity agent can be used in any amount between 0.1% and 25% by weight, or more preferably between 1% and 5% by weight. Preferred tonicity agents include polyols, more preferably trivalent or higher sugar alcohols, such as glycerol, erythritol, arabitol, xylitol, sorbitol and mannitol.

[0114] Nonionic surfactants or detergents (also called "wetting agents") are used to help dissolve the therapeutic agent and protect the therapeutic protein from aggregation caused by agitation, 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 used 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.

[0115] Suitable nonionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamer (184, 188, etc.), pluronic polyols, triaton, polyoxyethylene sorbitol monoethers (Tween-20, Tween-80, etc.), lauromacrogol 400, polyoxyalkylene stearate 40, polyoxyethylene hydrogenated castor oil 10, 50 and 60, monostearate, sucrose fatty acid esters, methyl cellulose and carboxymethyl cellulose. Anionic detergents that can be used include sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents include benzalkonium chloride or benzethonium chloride.

[0116] The choice of pharmaceutical carrier, excipient or diluent can be based on the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition may also include a suitable binder, lubricant, suspending agent, coating agent or solubilizer.

[0117] Depending on the drug delivery system, different composition / formulation requirements may be required. For example, the pharmaceutical ingredients useful in the present invention can be formulated to be suitable for micropumps or delivered via mucosal routes, for example, as inhalers or absorbable solutions for nasal sprays or aerosols, or as injectable forms of ingredients for parenteral administration, which are delivered by, for example, intravenous, intramuscular or subcutaneous routes.

[0118] In some embodiments, the pharmaceutical composition of the present invention is a lyophilized protein preparation. In other embodiments, the pharmaceutical composition can be an aqueous liquid preparation.

[0119] III. Treatment Methods

[0120] Cytokine prodrugs and fusion molecules can be used to treat diseases, depending on the antigen to which the antigen binding domain binds. In some embodiments, cytokine prodrugs or fusion molecules are used to treat cancer. In some embodiments, cytokine prodrugs or fusion molecules are used to treat infection.

[0121] In some embodiments, a method of treating a disease (eg, cancer, parasitic infection, viral infection, or bacterial infection) comprises administering to a subject an effective amount of a cytokine prodrug or fusion molecule.

[0122] In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a blood cancer or a solid tumor. 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 (e.g., non-small cell lung cancer), bile duct cancer, breast cancer, and ovarian cancer.

[0123] In some embodiments, the cytokine prodrug or fusion molecule is used to treat viral infection. In some embodiments, the virus causing the viral infection is hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV) or human papillomavirus (HPV). In some embodiments, the antigen binding portion binds to a viral antigen.

[0124] In some embodiments, the cytokine prodrug or fusion molecule is used to treat bacterial infection, 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.

[0125] In general, the dosage and route of administration of existing drugs are determined according to the conditions and conditions of the subject in accordance with standard pharmaceutical practice. In some embodiments, the drug composition is administered by a route of administration, including oral, subcutaneous, inhaled, intravenous, intraarterial, intramuscular, directly applied to the wound, applied to the surgical site, intraperitoneal, suppository, subcutaneous, intradermal injection, transdermal, aerosol, intrapleural, intraventricular, intraarticular, intraocular, intracranial or intraspinal. In some embodiments, the drug is intravenously administered to the subject.

[0126] In certain embodiments, the dosage of the pharmaceutical composition is a single dose or multiple doses. In certain embodiments, the dosage is once a day, twice a day, three times a day, or four times a day or more. In some embodiments, about 1 or more (e.g., about 2, 3, 4, 5, 6 or 7 or more) doses are administered in a week. In certain embodiments, the pharmaceutical composition is administered once a week, once every two weeks, once every three weeks, once every four weeks, once a week (weekly in two weeks of three weeks), or once a week (weekly in three weeks of four weeks). In certain embodiments, multiple doses are administered in a few days, weeks, months or years. In certain embodiments, the course of treatment is about 1 or more doses (e.g., about 2, 3, 4, 5, 7, 10, 15 or 20 or more doses).

[0127] Unless otherwise defined herein, scientific and technical terms related to the present invention shall have the meanings commonly 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 may also be used in the practice or testing of the present invention. In the event of a conflict, the specification description, including definitions, shall prevail. Generally, the terms and techniques related to cell and tissue culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medical and pharmaceutical chemistry, and protein and nucleic acid chemistry, as well as hybridization and mixing described herein are well known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to the manufacturer's specifications, as generally achieved in the art or as described herein. In addition, unless the context otherwise requires, singular terms shall include plural terms, and plural terms shall include singular terms. Throughout the specification description and embodiments, the words "having" and "comprising", or their synonyms, alternatives and variants, will be understood to imply that the integer or integer group is included, but any other integer or integer group is not excluded. It will be appreciated that aspects and variations of the invention described herein include "consisting of" and / or "consisting essentially of" aspects and variations. 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.

[0128] IV. Exemplary Embodiments

[0129] Other specific embodiments of the present invention are described below. These embodiments are intended to illustrate the components and methods described in the present invention, but are not intended to limit the scope of the present invention.

[0130] 1. A prodrug comprising a cytokine portion, a masking portion and a carrier portion, wherein:

[0131] a) the masking moiety binds to the cytokine moiety and inhibits the biological activity of the cytokine;

[0132] b) the carrier portion includes an antigen binding portion that can bind to an antigen expressed on the cell surface, and

[0133] c) the masking moiety is directly or indirectly linked to the carrier moiety via a non-cleavable peptide linker or without a peptide linker;

[0134] Among them, the prodrug has a higher activity on the activation of cells that express both the antigen targeting the carrier portion and the cytokine receptor than on the activation of cells that only express the cytokine receptor but not the antigen targeting the carrier portion.

[0135] 2. A prodrug comprising a cytokine portion, a masking portion and a carrier portion, wherein:

[0136] a) the masking portion binds to the cytokine portion and inhibits the biological activity of the cytokine;

[0137] b) the carrier portion includes an antigen binding portion that can bind to an antigen expressed on the cell surface; and,

[0138] c) the masking moiety is directly or indirectly linked to the carrier moiety via a non-cleavable peptide linker or without a peptide linker;

[0139] Wherein, the prodrug is activated at the lesion site, or the biological function of the prodrug at the lesion site is increased by at least 2 times, at least 5 times or at least 10 times, and the cells at the lesion site simultaneously express antigens and cytokine receptors that are targeted to the vector portion.

[0140] 3. The prodrug of embodiment 1 or 2, wherein the receptor of the cytokine portion comprises two or more subunits.

[0141] 4. The prodrug of embodiment 1 or 2, wherein the carrier portion comprises an antigen binding portion of an immune cell expressing an antigen,

[0142] 5. The prodrug described in Example 1 or 2, wherein the carrier portion includes an antigen binding portion, and the antigen is selected from PD-1, PD-L1, CTLA-4, TIGIT, TIM-3, LAG-3, CD25, CD16a, CD16b, NKG2D, NKP44, NKP30, CD19, CD20, CD38 and BCMA.

[0143] 6. The prodrug described in any one of Examples 1-5, wherein the cytokine portion comprises a cytokine selected from an IL-2 agonist polypeptide, an IL-7 agonist polypeptide, an IL-9 agonist polypeptide, an IL-15 agonist polypeptide and an IL-21 agonist polypeptide.

[0144] 7. The prodrug of any one of Examples 1-5, wherein the cytokine is selected from IL-1α agonist polypeptide, IL-1β agonist polypeptide, IL-4 agonist polypeptide, IL-5 agonist polypeptide, IL-6 agonist polypeptide, IL-8 agonist polypeptide, IL-10 agonist polypeptide, IL-12 agonist polypeptide, IL-17 agonist polypeptide, IL-18 agonist polypeptide, IL-22 agonist polypeptide, IL-23 agonist polypeptide, IL-31 agonist polypeptide, IL-33 agonist polypeptide, IL-36 agonist polypeptide, interferon-α agonist polypeptide, interferon-γ agonist polypeptide, 4-1BB ligand, OX-40 ligand and CD-40 ligand.

[0145] 8. The prodrug of any one of Examples 1-7, wherein the masking moiety is the extracellular domain of a cytokine receptor.

[0146] 9. The prodrug of any one of Examples 1-6, wherein the cytokine is an IL-7 agonist polypeptide, and the masking portion is an IL-7 receptor α extracellular domain (IL-7RαECD) or a functional analog thereof.

[0147] 10. The prodrug of any one of Examples 1-6, wherein the cytokine is an IL-21 agonist polypeptide, and the masking portion is an IL-21 receptor α extracellular domain (IL-21RαECD) or a functional analog thereof.

[0148] 11. The prodrug of any one of Examples 1-6, wherein the cytokine is an IL-2 agonist polypeptide or an IL-15 agonist polypeptide, and the masking portion is an IL-2 receptor β extracellular domain (IL-2RβECD).

[0149] 12. The prodrug of any one of Examples 1-6, wherein the cytokine is an IL-21 agonist polypeptide, and the masking portion is an anti-IL-21 Fab, a single-chain Fv (scFv), or a single-domain antibody.

[0150] 13. The prodrug of any one of Examples 1-6, wherein the cytokine is an IL-2 agonist polypeptide, and the masking portion is an anti-IL-2 Fab, a single-chain Fv (scFv), or a single-domain antibody.

[0151] 14. The prodrug of any one of Examples 1-6, wherein the cytokine is an IL-15 agonist polypeptide, and the masking portion is an anti-IL-15 Fab, a single-chain Fv (scFv), or a single-domain antibody.

[0152] 15. The prodrug of any one of Examples 1-6, 11 or 14, wherein the cytokine comprises an IL-15 agonist polypeptide, and the fusion molecule further comprises the sushi domain of the IL-15 receptor α (IL-15Rαsushi domain).

[0153] 16. The prodrug of any one of embodiments 10 or 12, wherein the IL-21 agonist polypeptide comprises SEQ ID NO: 1 or an amino acid sequence having at least 90% homology thereto.

[0154] 17. The prodrug of embodiment 10 or 16, wherein the masking moiety is IL-21RαECD or a functional analog thereof, which includes SEQ ID NO: 12, 63-72 and 73, or an amino acid sequence having at least 90% homology with SEQ ID NO: 12.

[0155] 18. The prodrug of embodiment 12 or 16, wherein the masking moiety is a scFv that binds to human IL-21, and the scFv comprises the amino acid sequence of SEQ ID NO: 20 or 21.

[0156] 19. The prodrug of embodiment 11 or 13, wherein the IL-2 agonist polypeptide comprises SEQ ID NO: 6 or 61, or an amino acid sequence having at least 95% homology thereto.

[0157] 20. The prodrug of embodiment 11 or 14, wherein the IL-15 agonist polypeptide comprises SEQ ID NO: 7 or an amino acid sequence having at least 95% homology thereto.

[0158] 21. The prodrug of embodiment 11, 19 or 20, wherein the masking moiety comprises IL-2Rβ-ECD or a functional analog thereof, and IL-2Rβ-ECD comprises SEQ ID NO: 11 or an amino acid sequence having at least 95% homology thereto.

[0159] 22. The prodrug of any one of Examples 6, 13 or 19, wherein the masking portion is a scFv that binds to IL-2, and the scFv inhibits or interferes with the interaction between IL-2 and IL-2Rγ, the interaction between IL-2 and IL-2Rβ, and / or the interaction between IL-2 and IL-2Rγ.

[0160] 23. The prodrug of any one of Examples 6, 14, 15 or 20, wherein the masking portion is a scFv that binds to IL-15, and the scFv inhibits or interferes with the interaction between IL-15 and IL-2Rβ, and / or IL-2 and IL-2Rγ.

[0161] 24. The prodrug of any one of Examples 6, 12 or 16, wherein the masking portion is a scFv that binds to IL-21, and the scFv inhibits or interferes with the interaction between IL-21 and IL-21Rα, and / or IL-21 and IL-2Rγ.

[0162] 25. The prodrug of Example 6, wherein the masking portion is a scFv that binds to a cytokine selected from IL-2, IL-7, IL-9, IL-15, or IL-21, and the scFv inhibits or interferes with the interaction between the cytokine and IL-2Rγ, and the half-life of the prodrug in non-human primates or humans is increased by at least 20 times, at least 50 times, at least 100 times, at least 150 times, or at least 200 times compared to the wild-type cytokine.

[0163] 26. A prodrug comprising a carrier portion, a cytokine portion, and a masking portion, wherein:

[0164] a) cytokine is selected from IL-2 agonist polypeptide, IL-7 agonist polypeptide, IL-9 agonist polypeptide, IL-15 agonist polypeptide, IL-21 agonist polypeptide;

[0165] b) the masking portion is a scFv that binds to the cytokine portion;

[0166] c) the scFv inhibits or interferes with the interaction between cytokines and IL-2Rγ; and

[0167] d) the half-life of the prodrug in non-human primates or humans is increased by at least 20 times, at least 50 times, at least 100 times, at least 150 times, or at least 200 times compared to the wild-type cytokine.

[0168] 27. The prodrug of any one of embodiments 22-25, wherein the scFv is K D 1-10nM and cytokine binding.

[0169] 28. The prodrug of any one of embodiments 22-25, wherein the scFv is K D It is 10-100nM and binds to cytokines.

[0170] 29. The prodrug of any one of embodiments 22-25, wherein the scFv is K D It is 100-1000nM and binds to cytokines.

[0171] 30. The prodrug of embodiment 13 or 19, wherein the masking moiety is a scFv that binds IL-2, wherein the scFv comprises the same heavy and light chain CDRs as hybridoma 4E12B2D10.

[0172] 31. The prodrug of embodiment 13 or 19, wherein the masking moiety is an scFv that binds to IL-2, and the scFv comprises SEQ ID NO: 22 or 23, or an amino acid sequence having at least 95% homology thereto.

[0173] 32. The prodrug of embodiment 14 or 20, wherein the masking portion is a scFv that binds IL-15, and the scFv includes the same heavy chain and light chain CDRs as the IL-15 antibody 146B7, 146H5, or 404E4.

[0174] 33. The prodrug of embodiment 14 or 20, wherein the masking moiety is a scFv that binds IL-15, and the scFv comprises the amino acid sequence of SEQ ID NO: 18 or 19.

[0175] 34. The prodrug of any one of embodiments 1-32, wherein the prodrug does not contain a cleavable peptide linker.

[0176] 35. The prodrug of Example 1, wherein the amino acid sequence of the two light chains included in the prodrug is SEQ ID NO: 44, and the amino acid sequences of the heavy chain polypeptide chains are:

[0177] SEQ ID NO:33 and 36;

[0178] SEQ ID NO:37 and 36;

[0179] SEQ ID NO:37 and 38;

[0180] SEQ ID NO:39 and 41; or

[0181] SEQ ID NO:42 and 43.

[0182] 36. The prodrug of Example 1, wherein the amino acid sequence of the two light chains included in the prodrug is SEQ ID NO: 50, and the amino acid sequences of the heavy chain polypeptide chains are:

[0183] SEQ ID NO: 51 and 54;

[0184] SEQ ID NO: 51 and 55;

[0185] SEQ ID NO: 51 and 56;

[0186] SEQ ID NO: 52 and 54;

[0187] SEQ ID NO: 53 and 58;

[0188] SEQ ID NO: 53 and 59; or

[0189] SEQ ID NO:52 and 57.

[0190] 37. A pharmaceutical composition comprising the prodrug described in any one of Examples 1-36 and a pharmaceutically acceptable excipient.

[0191] 38. A polynucleotide encoding the prodrug described in any one of Examples 1-36.

[0192] 39. An expression vector comprising the polynucleotide described in Example 38.

[0193] 40. A host cell comprising the expression vector described in Example 39.

[0194] 41. A method for preparing the prodrug of any one of Examples 1-36, comprising:

[0195] Culturing the host cell of Example 46 under conditions that allow expression of the prodrug, wherein the host cell is a mammalian cell, and

[0196] and isolating the prodrug.

[0197] 42. A method for treating cancer, autoimmune disease or infectious disease or stimulating the immune system in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition described in Example 37.

[0198] 43. Use of the prodrug described in any one of Examples 1-36 in treating cancer, autoimmune diseases, infectious diseases or stimulating the immune system in patients in need.

[0199] 44. Use of the prodrug described in any one of Examples 1-36 in the preparation of a drug for treating cancer, autoimmune diseases, infectious diseases or stimulating the immune system for a patient in need thereof.

[0200] 45. The method described in Example 41, the use of the prodrug in claim 42 or the use of the fusion molecule in claim 43, or the use of the prodrug in claim 44, wherein the patient suffers from an infectious disease such as HIV, HBV, HCV or HPV; an autoimmune system disease selected from lupus erythematosus, type I diabetes, psoriasis, dermatomyositis, GvHD, rheumatoid disease; or a cancer selected from breast cancer, lung cancer, pancreatic cancer, esophageal cancer, medullary thyroid cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, colorectal cancer and gastric cancer.

[0201] 46. ​​A prodrug comprising a carrier portion, a cytokine portion and a masking portion, wherein:

[0202] a) the cytokine portion is selected from an IL-2 agonist polypeptide, an IL-7 agonist polypeptide, an IL-9 agonist polypeptide, an IL-15 agonist polypeptide, an IL-21 agonist polypeptide;

[0203] b) the masking portion is a scFv that binds to a cytokine;

[0204] c) the scFv inhibits or interferes with the interaction between cytokines and IL-2Rγ, and

[0205] d) the area under the curve (AUC) of the prodrug in non-human primates or humans is increased by at least 20 times, at least 50 times, at least 100 times, at least 150 times or at least 200 times compared to the wild-type cytokine.

[0206] In order that the present invention can be better understood, the following examples are described herein. These examples are for illustrative purposes only and should not be interpreted in any way as limiting the scope of the present invention. Example

[0207] The materials and methods used in Examples 1 and 2 are as follows:

[0208] SEC-HPLC analysis

[0209] SEC-HPLC analysis was performed on an Agilent 1100 series HPLC system equipped with a TSKgel G3000SWXL column (7.8 mmIDX 30 cm, particle size 5 μm) from Tosoh Bioscience. A maximum of 100 μl was loaded, and the mobile phase of the column was 200 mM K 3 PO 4 , 250 mM KCl, pH 6.5 buffer. The flow rate was set at 0.5 ml / min. The column temperature was room temperature.

[0210] Proteolytic treatment

[0211] Protease, human MMP2, human MMP9, mouse MMP2 and mouse MMP9 were purchased from R&D systems. The steps of protease digestion were as follows: 10 μg-50 μg of prodrug protein and 1 μg of human MMP2, human MMP9, mouse MMP2 or mouse MMP9 were added to 2 mM CaCl 2 and 10 μM ZnCl 2 HBS buffer (20 mM HEPES, 150 mM NaCl 2 , pH 7.4), and cultured at 37°C for 12 h.

[0212] Cell viability assay

[0213] Prodrugs and control samples before and after protease digestion were tested using a cell viability assay. Briefly, NK92 cells were grown in PRMI-1640 medium supplemented with L-glutamine, 10% fetal bovine serum, 10% non-essential amino acids, 10% sodium pyruvate, and 55 μM mercaptoethanol. NK92 cells were non-adherent and maintained at 1 x 10 in medium containing 100 ng / ml IL-2. 5 -1x 10 6cells / ml. In general, cells were split twice a week. For bioassays, it is best to use cells no less than 48 hours after passaging. NK92 cells were cultured at 5×10 4 The samples were serially diluted and cultured for 2 days in the presence of a fixed amount of IL-2 to determine the functional activity of IL-21. The supernatant was then tested for interferon-γ by ELISA.

[0214] Mino IL-21 activity assay

[0215] Mino cell viability assay was performed as follows:

[0216] a) Add the sample to be tested, serially diluted in 50 μL of assay medium (RPMI 1640, 10% fetal bovine serum, NEAA, sodium pyruvate, 55 μM b-mercaptoethanol) to a 96-well plate;

[0217] b) Add 50 μL of assay medium containing 20,000 Mino cells to each well;

[0218] c) culturing for 3 to 5 days;

[0219] d) Add 100 μL of Cell Titer Glo (Promega) to each well. Cell Titer Glo provides a measure of cell viability by quantitatively evaluating ATP.

[0220] e) Measure fluorescence.

[0221] Analysis of Ki67 activity in PBMC primary cells

[0222] Human PBMCs were activated with anti-CD3 antibody (OKT3) at a concentration of 100 ng / mL for 2 days, washed 3 times, and incubated with regular cell culture medium at 37°C, 5% CO 2 The activated / rested PBMCs were seeded into 96-well plates at a density of 200K cells / well, and the PBMCs were treated with different concentrations of the test samples. After five days of culture, the PD-1 was stained and analyzed by flow cytometry. + CD4 + Cells and PD-1 - CD4 + Ki67 in cells (all mAbs used for cell staining were purchased from BD).

[0223] Example 1: Construction of anti-PD-1 antibody-IL-21 prodrug fusion molecule

[0224] An IL-21 prodrug based on an anti-PD-1 antibody was constructed using two identical light chains (amino acid sequence as shown in SEQ ID NO: 44), a first heavy chain polypeptide chain (amino acid sequence as shown in SEQ ID NO: 42) and a second heavy chain polypeptide chain (amino acid sequence as shown in SEQ ID NO: 76). The molecule was transiently expressed and purified (lot # PW04-38).

[0225] The second anti-PD-1 antibody-based IL-21 prodrug was masked with a scFv moiety, which was expressed and purified (Lot#PW05-68).

[0226] In addition, the control was an anti-PD-1 antibody-IL-21 fusion molecule without the masking moiety, which was expressed and purified (Lot#PW05-67).

[0227] Furthermore, the second control was an anti-PD-1 antibody-IL-21 mutant (R9ER76A) fusion molecule without the masking moiety, which was expressed and purified (Lot#PW09-02).

[0228] Example 2. Biological activity of anti-PD-1 antibody-IL-21 prodrug fusion molecules

[0229] The binding of the prodrug molecules and various control molecules to Mino cells was analyzed by FACS detection. Figure 2 The results shown show that both the PD-1 antibody and the Fc-IL-21 fusion molecule can bind to Mino cells, indicating that Mino cells can express PD-1 and IL-21 receptors. The results show that the Fc-IL-21 prodrug molecule does not bind to the cells, indicating that the IL-21 cytokine is masked by the corresponding masking part. However, the PD-1 antibody-IL-21 prodrug molecule and fusion molecule can bind to Mino cells.

[0230] The cellular activity of the molecules was analyzed using NK92 cells and natural killer (NK) cells. Figure 3 The results shown show that, under non-activated conditions, the prodrug molecule with IL-21α ECD as the masking part (Lot#PW04-38) has minimal activity, while the activity of the scFv as the masking part (Lot#PW05-68) is about 1 / 1000 of that without the masking part (PW04-67). The results show that the biological activity of the prodrug after treatment with the protease MMP2 is significantly enhanced.

[0231] Mino cells were used to detect the tumor-killing activity of the fusion molecule. Mino is a mantle cell lymphoma cell line that can express PD-1 and IL-21 receptors (Harington et al., Leuk Lymphoma (2019) 60 (10): 2498-2507 and Gelebart et al., Leukemia (2009) 23: 1836-1846). Figure 4A and Figure 4B Results of Mino cell viability analysis. Surprisingly, anti-PD-1 antibody-IL-21 prodrugs (Lots#PW04-38 and PW05-68) had significant activity before activation, while the control molecule (PD-1 antibody-IL-21R9E / R76A fusion molecule, Lot#PW09-02) had no or negligible activity. The results showed that the anti-PD-1-IL-21 fusion molecule was activated by "cis-binding", such as by binding to PD-1 and IL-21 receptors at the same time. The cis-binding of PD-1 antibody and cell surface PD-1 antigen and cytokine and cytokine receptor on the same cell surface can remove the masking effect of the masking part. Since the corresponding local immune cells simultaneously express antigens that target the carrier and receptors that bind to the cytokine part, the prodrug without a cleavable peptide linker is activated at the lesion site (such as a tumor).

[0232] Example 3. Construction of anti-PD-1 antibody-IL-15 prodrug fusion molecule

[0233] A group of anti-PD-1 antibody-IL-15 prodrugs were constructed, wherein the IL-15 molecule (i) was masked by scFv 215β; (ii) was masked by scFv 215γ; (iii) did not contain a masking portion (215βRef); or (iv) included a mutation but did not contain a masking portion (PD1 / IL15 mutant (M2)). The anti-PD-1 antibody of the prodrug includes two identical light chains, the amino acid sequence of which is SEQ ID NO: 44, and two identical heavy chains, the amino acid sequence of which is SEQ ID NO: 47.

[0234] The Fc-based prodrug 215β is a heterodimer comprising the amino acid sequences of SEQ ID NOs: 16 and 17.

[0235] The anti-PD-1 antibody-based prodrug 215γ includes two identical light chains (SEQ ID NO: 44), the amino acid sequence of the first heavy chain fusion polypeptide chain is SEQ ID NO: 37, and the amino acid sequence of the second heavy chain fusion polypeptide chain is SEQ ID NO: 75.

[0236] 215βRef is an IL-15 mutant (D30N / E64Q / N65D) Fc fusion molecule.

[0237] PD1 / IL15 mutant (M2) is an anti-PD-1 antibody fused to an IL-15 mutant, wherein the IL-15 agonist includes E46G, V49R, E64Q, D30N, and N1G mutations.

[0238] The above substances are all expressed by CHO cells and purified in sequence by protein A column affinity chromatography and additional chromatography steps.

[0239] Example 4. Biological activity of anti-PD-1 antibody-IL-15 prodrug fusion molecules

[0240] To evaluate and analyze the effect of IL-15 prodrug on activating Ki67 expression in human PBMCs. Figures 5A-5C CD4 + Ki67 activity of T cells; Figure 5A CD4 that does not express PD-1 + Ki67 activity of T cells; Figure 5B CD4 expressing PD-1 + Ki67 activity of T cells; Figure 5C CD4 expressing and not expressing PD-1 treated with different samples + T cell EC 50 The values ​​of CD4 expressing and not expressing PD-1 are also listed. + T cell EC 50 The data showed that 215γ has a multiple relationship with CD4 + The activity of Ki67 in cells was significantly higher than that in CD4 + The Ki67 activity of cells indicated that the prodrug 215γ was activated in cells expressing both the PD-1 antigen and the IL-15 cytokine receptor without the need for protease hydrolysis.

[0241] Example 5. Anti-PD-1 Antibody-IL-2 Prodrug Fusion Molecule

[0242] An anti-PD-1 antibody-IL-2 prodrug was constructed in a similar manner, wherein the prodrug PD-1 / IL-2v* includes two identical light chains (SEQ ID NO: 44) and two heavy chain fusion polypeptides (SEQ ID NO: 24 and 25, respectively). The IL-2 portion is an IL-2 mutant, and the masking portion in the prodrug is an IL-2 receptor β extracellular domain. The activity of the IL-2 prodrug on activating the expression of Ki67 in human PBMC was analyzed.

[0243] Fig. 6A and Figure 6B The CD4 + Ki67 activity of T cells. Negative control was IgG1 antibody against human Claudin 18.2. The above substances were expressed by CHO cells and purified by protein A column affinity chromatography and additional chromatography steps. Fig. 6A CD4 that does not express PD-1 + Ki67 activity of T cells; Figure 6B CD4 expressing PD-1 + Ki67 activity of T cells. The data show that the prodrug PD-1 / IL2V* has an inhibitory effect on CD4 + The Ki67 induction activity of the cells was significantly higher than that of cells that did not express PD-1, indicating that PD-1 / IL-2v* was activated in cells that simultaneously expressed PD-1 antigen and IL-2 cytokine receptor without the need for protease hydrolysis.

[0244] The above data indicate that cytokine prodrugs can be activated in cells that express both cytokine receptors and antigens that target the carrier portion. Prodrugs with antigen binding moieties as carriers can be activated without the need for protease hydrolysis. Although not wishing to be bound by theory, it can be predicted that the antigen binding domain of the carrier portion targets the prodrug molecule to the surface of cells expressing the antigen, thereby allowing the cytokine receptors on the cell surface and the masking portion of the prodrug to competitively bind to the cytokine. Figure 7 As shown, the prodrug that does not undergo proteolysis replaces the masking moiety through the cytokine receptor on the cell surface to complete the entire activation process.

[0245] Cells, such as exhausted Teff cells, express both antigens (such as PD-1) and cytokine receptors (such as IL-2Rβ and IL-2Rγ). Exhausted Teff cells are generally present in the tumor microenvironment rather than normal tissues. The differences in the distribution of cells expressing antigens and cytokine receptors in the body enable the prodrug to be specifically activated at the lesion site. The target specificity also further enhances the safety of cytokine therapy.

[0246] Sequence Listing

[0247] SEQ ID NO: 1—Human IL-21

[0248]

[0249] SEQ ID NO:2—IL-21 mutant A

[0250]

[0251] SEQ ID NO:3 - IL-21 mutant B

[0252]

[0253] SEQ ID NO:4 - IL-21 mutant C

[0254]

[0255] SEQ ID NO:5 - IL-21 mutant D

[0256]

[0257] SEQ ID NO:6—Human IL-2

[0258]

[0259] SEQ ID NO:7—Human IL-15

[0260]

[0261] SEQ ID NO:8—Human IL-15Rαsushi domain

[0262]

[0263] SEQ ID NO:9—Human IL-7

[0264]

[0265] SEQ ID NO: 10—Human IL-9

[0266]

[0267] SEQ ID NO:11 - IL-2Rβ ECD

[0268]

[0269] SEQ ID NO:12 – IL-21Rα ECD (Source: uniprot.org / uniprot / Q9HBE5)

[0270]

[0271] SEQ ID NO: 13—Human IL-21Rγ ECD

[0272]

[0273] SEQ ID NO:14 – IL-7α receptor ECD (Source: https: / / www.uniprot.org / uniprot / P16871)

[0274]

[0275] SEQ ID NO:15 – IL-9α receptor ECD (Source: )

[0276]

[0277] SEQ ID NO: 16 Fc-anti-IL-15 scFv2

[0278]

[0279] SEQ ID NO: 17Fc-IL-15N65D

[0280]

[0281] SEQ ID NO: 18 Anti-IL-15 scFv1 (italic parts: VH and VL)

[0282]

[0283] SEQ ID NO: 19 Anti-IL-15 scFv2 (italic parts: VH and VL)

[0284]

[0285] SEQ ID NO: 20 Anti-IL-21 scFv1 (italic parts: VH and VL)

[0286]

[0287] SEQ ID NO: 21 Anti-IL-21 scFv2 (italic parts: VH and VL)

[0288]

[0289] SEQ ID NO: 22 Anti-IL-2 scFv1 (underlined: HCDR1-3 and LCDR1-3; italics: VH and VL)

[0290]

[0291] SEQ ID NO: 23 Anti-IL-2 scFv2 (underlined: LCDR1-3 and HCDR1-3; italics: VL and VH)

[0292]

[0293] SEQ ID NO:24PD1-HC–IL-2v(CX3.58.1)

[0294]

[0295] SEQ ID NO:25PD1-HC–IL-2Rβ-ECD(CX3.58.3)

[0296]

[0297] SEQ ID NO:26 PD1-HC–IL-21RαECD containing a non-cleavable peptide linker

[0298]

[0299] SEQ ID NO:27-34 Peptide connector (GGGGS) n (SEQ ID NO: 27), wherein n = 1, 2, 3, and 4 GGGGS (SEQ ID NO: 28)

[0300] GGGGSGGGGS (SEQ ID NO: 29)

[0301] GGGGSGGGGSGGGGS (SEQ ID NO:30)

[0302] GGGGSGGGGSXXGGGGSGGGGS (SEQ ID NO:31),X=A or N

[0303] GGGGSGGGGSGGGGSXXGGGGSGGGGS (SEQ ID NO:32),X=A or N

[0304] GGGGSGGGGSGGGGSXXGGGGSGGGGSGGGGS (SEQ ID NO:33),X=A or N

[0305] GGGGSGGGGXGGGGYGGGGS (SEQ ID NO:34), X=S,A or N, and Y=A or N SEQ ID NO:35PD1-HC–IL-2v

[0306]

[0307] wherein Xaa3 is N or A; Xaa125 is A or S; Xaa35 is selected from K and N; Xaa42 is selected from A, G, S, T, Q, E, N, D, R and K; Xaa45 is selected from A, G, S, T, Q, E, N, D, R and K; Xaa72 is selected from A, GS, T, Q, E, N, D, R and K; Xaa73 is selected from A and T; n 1 =0, 1, 2 or 3; n 2 =0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing.

[0308] SEQ ID NO:36–PD1-HC–IL-2Rβ-ECD

[0309]

[0310] where n 1 =0, 1, 2, or 3; n 2 =0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing.

[0311] SEQ ID NO:37PD1–HC with–sushi-IL-15v

[0312]

[0313] SEQ ID NO:38 PD1-HC—anti-IL-15 scFV2

[0314]

[0315] where n 1 =0, 1, 2 or 3; n 2 =0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing.

[0316] SEQ ID NO:39PD1-HC–IL-21

[0317]

[0318] SEQ ID NO:40 PD1-HC–IL-21RαECD containing a cleavable peptide linker

[0319]

[0320] SEQ ID NO:41PD1-HC-anti-IL-21 scFv21

[0321]

[0322] SEQ ID NO:42 PD1-HC-IL-21 including knob mutation

[0323]

[0324] SEQ ID NO:43 PD1-HC–IL-21RαECD including hole mutation

[0325]

[0326] SEQ ID NO:44PD1-LC

[0327]

[0328] SEQ ID NO:45 Anti-PDL1 Atezolizumab LC

[0329]

[0330] SEQ ID NO:46 Anti-PDL1 Atezolizumab HC

[0331]

[0332] SEQ ID NO:47 Anti-PD-1 Nivolumab HC

[0333]

[0334] SEQ ID NO:48 anti-PD-1 Pembrolizumab LC

[0335]

[0336] SEQ ID NO:49 Anti-PD-1 Pembrolizumab HC

[0337]

[0338] SEQ ID NO:50 CTLA-4 antibody Ipilimumab LC

[0339]

[0340] SEQ ID NO:51 CTLA-4 antibody Ipilimumab HC-IL2v

[0341]

[0342] wherein Xaa3 is N or A; Xaa125 is A or S; Xaa35 is selected from K and N; Xaa42 is selected from A, G, S, T, Q, E, N, D, R and K; Xaa45 is selected from A, G, S, T, Q, E, N, D, R and K;

[0343] Xaa72 is selected from A, G, S, T, Q, E, N, D, R and K; Xaa73 is selected from A and T; n 1 =0, 1, 2 or 3; n 2 = 0, 1, 2 or 3; and X 1 Alanine or missing; X 2 Alanine or missing.

[0344] SEQ ID NO:52 CTLA-4 antibody Ipilimumab HC-IL15v

[0345]

[0346] SEQ ID NO:53 CTLA-4 antibody Ipilimumab HC-IL-21

[0347]

[0348] where n 1 =0, 1, 2 or 3; n 2 =0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing. SEQ ID NO: 54 CTLA-4 antibody Ipilimumab HC-IL-2Rβ-ECD

[0349]

[0350] where n 1 =0, 1, 2 or 3; n 2 =0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing.

[0351] SEQ ID NO:55 CTLA-4 antibody Ipilimumab HC-anti-IL-2 scFv1 (in scFV, the underlined parts are: HCDR1-3 and LCDR1-3; the italic parts are: VH and VL)

[0352]

[0353] where n 1 =0, 1, 2 or 3; n 2=0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing.

[0354] SEQ ID NO: 56 CTLA-4 antibody Ipilimumab HC-anti-IL-2 scFv2 (underlined parts: LCDR1-3 and HCDR1-3; italic parts: VL and VH)

[0355]

[0356] where n 1 =0,1,2,or3;n 2 =0,1,2,or3;X 1 Alanine or missing; X 2 Alanine or missing.

[0357] SEQ ID NO:57 CTLA-4 antibody Ipilimumab HC-anti-IL-15 scFv2

[0358]

[0359] where n 1 =0, 1, 2 or 3; n 2 =0, 1, 2 or 3; X 1 Alanine or missing; X 2 Alanine or missing.

[0360] SEQ ID NO:58CTLA-4 antibody Ipilimumab HC-IL-21Rα-ECD

[0361]

[0362] SEQ ID NO:59 CTLA-4 antibody Ipilimumab HC-anti-IL-21 scFv2

[0363]

[0364] SEQ ID NO:604E12B2D10 Anti-IL2 HC variable region (underlined portion: HCDR1-3)

[0365]

[0366] SEQ ID NO:614E12B2D10 anti-IL2LC variable region (underlined portion: LCDR1-3)

[0367]

[0368] SEQ ID NO:62 IL-2 agonist polypeptide

[0369]

[0370] wherein Xaa3 is N or A; Xaa125 is C, A or S; Xaa35 is selected from K and N; Xaa42 is selected from A, G, S, T, Q, E, N, D, R and K; Xaa45 is selected from A, G, S, T, Q, E, N, D, R and K; Xaa72 is selected from A, G, S, T, Q, E, N, D, R and K; and Xaa73 is selected from A and T.

[0371] SEQ ID NO:63 IL-21 receptor α ECD mutant 1 (the mutant part is underlined)

[0372]

[0373] SEQ ID NO:64 IL-21 receptor α ECD mutant 2 (the mutant part is underlined)

[0374]

[0375] SEQ ID NO:65 IL-21 receptor α ECD mutant 3 (the mutant part is underlined)

[0376]

[0377] SEQ ID NO:66 IL-21 receptor α ECD mutant 4 (the mutant part is underlined)

[0378]

[0379] SEQ ID NO:67 IL-21 receptor α ECD mutant 5 (the mutant part is underlined)

[0380]

[0381] SEQ ID NO:68 IL-21 receptor α ECD mutant 6 (the mutant part is underlined)

[0382]

[0383] SEQ ID NO:69 IL-21 receptor α ECD mutant 7 (the mutant part is underlined)

[0384]

[0385] SEQ ID NO:70 IL-21 receptor α ECD mutant 8 (the mutant part is underlined)

[0386]

[0387] SEQ ID NO:71 IL-21 receptor α ECD mutant 9 (the mutant part is underlined)

[0388]

[0389] SEQ ID NO:72 IL-21 receptor α ECD mutant 10 (the mutant part is underlined)

[0390]

[0391] SEQ ID NO:73 IL-21 receptor α ECD mutant 11

[0392]

[0393] SEQ ID NO:74 PD1-HC–IL-21RαECD containing hole mutation

[0394]

[0395] SEQ ID NO: 75 Anti-IL-15 scFv2-PD1-HC fusion polypeptide

[0396]

[0397] SEQ ID NO:76 Anti-IL-15 antibody 146B7HC CDR1 (protein sequence)

[0398] TYWIG

[0399] SEQ ID NO:77 Anti-IL-15 antibody 146B7HC CDR2 (protein sequence)

[0400] IIYPGDSDTR YSPSFQG

[0401] SEQ ID NO:78 Anti-IL-15 antibody 146B7HC CDR3 (protein sequence)

[0402] GNWNCFDY

[0403] SEQ ID NO:79 Anti-IL-15 antibody 146B7LC CDR1 (protein sequence)

[0404] RASQSVSSSY LA

[0405] SEQ ID NO:80 Anti-IL-15 antibody 146B7LC CDR2 (protein sequence)

[0406] GASRRAT

[0407] SEQ ID NO:81 Anti-IL-15 antibody 146B7LC CDR3 (protein sequence)

[0408] QRYGSSHT

[0409] SEQ ID NO:82 Version 2 of anti-IL-15 antibody 146B7HC CDR3 (protein sequence) GNWNSFDY

[0410] SEQ ID NO: 83 Anti-IL-15 antibody 146B7HC variable region (underlined portion: HCDR1-3)

[0411]

[0412] SEQ ID NO: 84 Anti-IL-15 antibody 146B7 LC variable region (underlined portion: LCDR1-3)

[0413] Sequence Listing <110> Ogilvy Pharmaceuticals Ltd. <120> New masked cytokines and their applications <130> 025471.WO008 <140> <141> <150> 63 / 126,393 <151> 2020-12-16 <150> 63 / 029,473 <151> 2020-05-23 <150> 63 / 027,138 <151> 2020-05-19 <150> 62 / 959,973 <151> 2020-01-11 <160> 84 <170> PatentIn version 3.5 <210> 1 <211> 133 <212> PRT <213> Homo sapiens <400> 1 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> 2 <211> 133 <212> PRT <213> Artificial Sequence <220> <221> Source <223> Artificial sequence description: synthetic peptide <400> 2 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Ala Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> 3 <211> 133 <212> PRT <213> Artificial sequence <220> <221> source <223> Synthetic polypeptide description: Synthetic polypeptide <400> 3 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Lys Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> 4 <211> 133 <212> PRT <213> Synthetic sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 4 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> 5 <211> 133 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 5 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Lys Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Arg Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> 6 <211> 133 <212> PRT <213> Homo sapiens <400> 6 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> 7 <211> 113 <212> PRT <213> Homo sapiens <400> 7 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr <210> 8 <211> 75 <212> PRT <213> Homo sapiens <400> 8 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 65 70 75 <210> 9 <211> 152 <212> PRT <213> Homo sapiens <400> 9 Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu 1 5 10 15 Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser 20 25 30 Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp 35 40 45 Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg 50 55 60 Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu 65 70 75 80 Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val 85 90 95 Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser 100 105 110 Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu 115 120 125 Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys 130 135 140 Ile Leu Met Gly Thr Lys Glu His 145 150 <210> 10 <211> 126 <212> PRT <213> Homo sapiens <400> 10 Gln Gly Cys Pro Thr Leu Ala Gly Ile Leu Asp Ile Asn Phe Leu Ile 1 5 10 15 Asn Lys Met Gln Glu Asp Pro Ala Ser Lys Cys His Cys Ser Ala Asn 20 25 30 Val Thr Ser Cys Leu Cys Leu Gly Ile Pro Ser Asp Asn Cys Thr Arg 35 40 45 Pro Cys Phe Ser Glu Arg Leu Ser Gln Met Thr Asn Thr Thr Met Gln 50 55 60 Thr Arg Tyr Pro Leu Ile Phe Ser Arg Val Lys Lys Ser Val Glu Val 65 70 75 80 Leu Lys Asn Asn Lys Cys Pro Tyr Phe Ser Cys Glu Gln Pro Cys Asn 85 90 95 Gln Thr Thr Ala Gly Asn Ala Leu Thr Phe Leu Lys Ser Leu Leu Glu 100 105 110 Ile Phe Gln Lys Glu Lys Met Arg Gly Met Arg Gly Lys Ile 115 120 125 <210> 11 <211> 214 <212> PRT <213> Homo sapiens <400> 11 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> 12 <211> 213 <212> PRT <213> Homo sapiens <400> 12 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 13 <211> 240 <212> PRT <213> Homo sapiens <400> 13 Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly Asn Glu Asp Thr Thr Ala 1 5 10 15 Asp Phe Phe Leu Thr Thr Met Pro Thr Asp Ser Leu Ser Val Ser Thr 20 25 30 Leu Pro Leu Pro Glu Val Gln Cys Phe Val Phe Asn Val Glu Tyr Met 35 40 45 Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro Gln Pro Thr Asn Leu Thr 50 55 60 Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn Asp Lys Val Gln Lys Cys 65 70 75 80 Ser His Tyr Leu Phe Ser Glu Glu Ile Thr Ser Gly Cys Gln Leu Gln 85 90 95 Lys Lys Glu Ile His Leu Tyr Gln Thr Phe Val Val Gln Leu Gln Asp 100 105 110 Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln Met Leu Lys Leu Gln Asn 115 120 125 Leu Val Ile Pro Trp Ala Pro Glu Asn Leu Thr Leu His Lys Leu Ser 130 135 140 Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn Arg Phe Leu Asn His Cys 145 150 155 160 Leu Glu His Leu Val Gln Tyr Arg Thr Asp Trp Asp His Ser Trp Thr 165 170 175 Glu Gln Ser Val Asp Tyr Arg His Lys Phe Ser Leu Pro Ser Val Asp 180 185 190 Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg Ser Arg Phe Asn Pro Leu 195 200 205 Cys Gly Ser Ala Gln His Trp Ser Glu Trp Ser His Pro Ile His Trp 210 215 220 Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe Leu Phe Ala Leu Glu Ala 225 230 235 240 <210> 14 <211> 219 <212> PRT <213> Homo sapiens <400> 14 Glu Ser Gly Tyr Ala Gln Asn Gly Asp Leu Glu Asp Ala Glu Leu Asp 1 5 10 15 Asp Tyr Ser Phe Ser Cys Tyr Ser Gln Leu Glu Val Asn Gly Ser Gln 20 25 30 His Ser Leu Thr Cys Ala Phe Glu Asp Pro Asp Val Asn Ile Thr Asn 35 40 45 Leu Glu Phe Glu Ile Cys Gly Ala Leu Val Glu Val Lys Cys Leu Asn 50 55 60 Phe Arg Lys Leu Gln Glu Ile Tyr Phe Ile Glu Thr Lys Lys Phe Leu 65 70 75 80 Leu Ile Gly Lys Ser Asn Ile Cys Val Lys Val Gly Glu Lys Ser Leu 85 90 95 Thr Cys Lys Lys Ile Asp Leu Thr Thr Ile Val Lys Pro Glu Ala Pro 100 105 110 Phe Asp Leu Ser Val Val Tyr Arg Glu Gly Ala Asn Asp Phe Val Val 115 120 125 Thr Phe Asn Thr Ser His Leu Gln Lys Lys Tyr Val Lys Val Leu Met 130 135 140 His Asp Val Ala Tyr Arg Gln Glu Lys Asp Glu Asn Lys Trp Thr His 145 150 155 160 Val Asn Leu Ser Ser Thr Lys Leu Thr Leu Leu Gln Arg Lys Leu Gln 165 170 175 Pro Ala Ala Met Tyr Glu Ile Lys Val Arg Ser Ile Pro Asp His Tyr 180 185 190 Phe Lys Gly Phe Trp Ser Glu Trp Ser Pro Ser Tyr Tyr Phe Arg Thr 195 200 205 Pro Glu Ile Asn Asn Ser Ser Gly Glu Met Asp 210 215 <210> 15 <211> 230 <212> PRT <213> Homo sapiens <400> 15 Ser Val Thr Gly Glu Gly Gln Gly Pro Arg Ser Arg Thr Phe Thr Cys 1 5 10 15 Leu Thr Asn Asn Ile Leu Arg Ile Asp Cys His Trp Ser Ala Pro Glu 20 25 30 Leu Gly Gln Gly Ser Ser Pro Trp Leu Leu Phe Thr Ser Asn Gln Ala 35 40 45 Pro Gly Gly Thr His Lys Cys Ile Leu Arg Gly Ser Glu Cys Thr Val 50 55 60 Val Leu Pro Pro Glu Ala Val Leu Val Pro Ser Asp Asn Phe Thr Ile 65 70 75 80 Thr Phe His His Cys Met Ser Gly Arg Glu Gln Val Ser Leu Val Asp 85 90 95 Pro Glu Tyr Leu Pro Arg Arg His Val Lys Leu Asp Pro Pro Ser Asp 100 105 110 Leu Gln Ser Asn Ile Ser Ser Gly His Cys Ile Leu Thr Trp Ser Ile 115 120 125 Ser Pro Ala Leu Glu Pro Met Thr Thr Leu Leu Ser Tyr Glu Leu Ala 130 135 140 Phe Lys Lys Gln Glu Glu Ala Trp Glu Gln Ala Gln His Arg Asp His 145 150 155 160 Ile Val Gly Val Thr Trp Leu Ile Leu Glu Ala Phe Glu Leu Asp Pro 165 170 175 Gly Phe Ile His Glu Ala Arg Leu Arg Val Gln Met Ala Thr Leu Glu 180 185 190 Asp Asp Val Val Glu Glu Glu Arg Tyr Thr Gly Gln Trp Ser Glu Trp 195 200 205 Ser Gln Pro Val Cys Phe Gln Ala Pro Gln Arg Gln Gly Pro Leu Ile 210 215 220 Pro Pro Trp Gly Trp Pro 225 230 <210> 16 <211> 500 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 16 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 20 25 30 Ile Thr Arg Glu 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 Glu Glu Met 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 Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu 225 230 235 240 Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser Gly 245 250 255 Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser 260 265 270 Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 275 280 285 Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 290 295 300 Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro 305 310 315 320 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 325 330 335 Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr 340 345 350 Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Gly 355 360 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val 370 375 380 Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu 385 390 395 400 Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile 405 410 415 Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile 420 425 430 Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly 435 440 445 Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln 450 455 460 Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 465 470 475 480 Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 485 490 495 Thr Val Ser Ser 500 <210> 17 <211> 452 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 17 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 20 25 30 Ile Thr Arg Glu 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 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met 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 Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile 245 250 255 Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn 260 265 270 Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val 275 280 285 Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys 290 295 300 Cys Ile Arg Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 325 330 335 Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp 340 345 350 Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp 355 360 365 Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu 370 375 380 Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr 385 390 395 400 Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly 405 410 415 Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys 420 425 430 Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe 435 440 445 Ile Asn Thr Ser 450 <210> 18 <211> 240 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 18 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 Val Ser Gly Tyr Phe Phe Thr Thr Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg 210 215 220 Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser 225 230 235 240 <210> 19 <211> 240 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 19 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser 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 Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg 145 150 155 160 Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly 165 170 175 Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile 180 185 190 Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu 195 200 205 Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp 210 215 220 Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 225 230 235 240 <210> 20 <211> 247 <212> PRT <213> Artificial Sequence <220> <221> Source <223> Artificial Sequence Description: Synthetic polypeptide <400> 20 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Asp Ser Ser Asp Trp Tyr Gly Asp Tyr Tyr Phe Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val 130 135 140 Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala 145 150 155 160 Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly 180 185 190 Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp 210 215 220 Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Thr Phe Gly Gln 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <210> twenty one <211> 247 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> twenty one Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Phe Ile Trp Tyr Asp Gly 165 170 175 Ser Asp Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 180 185 190 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 195 200 205 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly Asp Ser Ser 210 215 220 Asp Trp Tyr Gly Asp Tyr Tyr Phe Gly Met Asp Val Trp Gly Gln Gly 225 230 235 240 Thr Thr Val Thr Val Ser Ser 245 <210> twenty two <211> 248 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> twenty two Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Asp Arg Tyr Tyr Asn Trp Asn Tyr Phe Leu Gly Ser Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Val Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys Thr Ala Arg Ile 145 150 155 160 Thr Cys Gly Gly Asn Asn Ile Arg Ser Lys Ser Val His Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr Tyr Asp Ser Asp 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp 210 215 220 Tyr Phe Cys Gln Val Trp Asp Ser Ser Ser Asp His His Val Phe Gly 225 230 235 240 Gly Gly Thr Lys Leu Thr Val Leu 245 <210> 23 <211> 248 <212> PRT <213> Artificial Sequence <220> <221> Source <223> Description of artificial sequence: Synthetic polypeptide <400> 23 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Arg Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr 35 40 45 Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Phe Cys Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95 His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly 100 105 110 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val 115 120 125 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser 130 135 140 Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val 145 150 155 160 Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile Ile Pro 165 170 175 Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr 180 185 190 Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser 195 200 205 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val Asp Arg 210 215 220 Tyr Tyr Asn Trp Asn Tyr Phe Leu Gly Ser Phe Asp Tyr Trp Gly Gln 225 230 235 240 Gly Thr Leu Val Thr Val Ser Ser 245 <210> twenty four <211> 588 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> twenty four Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys 450 455 460 Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu 465 470 475 480 Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ser Met Leu Thr 485 490 495 Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 500 505 510 Cys Leu Glu Glu Ala Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala 515 520 525 Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile 530 535 540 Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 545 550 555 560 Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 565 570 575 Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 580 585 <210> 25 <211> 675 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 25 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Lys Gly Gly Gly Gly Ser Gly Pro Leu 435 440 445 Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn 450 455 460 Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser 465 470 475 480 Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val 485 490 495 His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu 500 505 510 Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro 515 520 525 Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu 530 535 540 Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys 545 550 555 560 Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val 565 570 575 His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala 580 585 590 Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser 595 600 605 Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys 610 615 620 Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu 625 630 635 640 Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser 645 650 655 Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly 660 665 670 Lys Asp Thr 675 <210> 26 <211> 692 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 26 Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu 1 5 10 15 Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly 20 25 30 Arg Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn 35 40 45 Ser Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Val Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser 65 70 75 80 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 85 90 95 Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 100 105 110 Cys Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Cys 465 470 475 480 Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys Ile 485 490 495 Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp Gln 500 505 510 Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu His 515 520 525 Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met Asp 530 535 540 Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr Asp 545 550 555 560 Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala Glu 565 570 575 Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser Gly 580 585 590 Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe Tyr 595 600 605 Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg Gly 610 615 620 Asp Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp Ser 625 630 635 640 Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser Tyr 645 650 655 Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln Gly 660 665 670 Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser Glu 675 680 685 Glu Leu Lys Glu 690 <210> 27 <211> 20 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (1)..(20) <223> The sequence contains 1-4 'Gly Gly Gly Gly Ser' repeating units <400> 27 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 <210> 28 <211> 5 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 28 Gly Gly Gly Gly Ser 1 5 <210> 29 <211> 10 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 29 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 30 <211> 15 <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 Gly Gly Gly Gly Ser 1 5 10 15 <210> 31 <211> twenty two <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutation <222> (11)..(12) <223> Replace with "N" <220> <221> SITE <222> (1)..(22) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 31 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly 1 5 10 15 Ser Gly Gly Gly Gly Ser 20 <210> 32 <211> 27 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutation <222> (16)..(17) <223> Replace with "N" <220> <221> SITE <222> (1)..(27) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 32 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 1 5 10 15 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 <210> 33 <211> 32 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutation <222> (16)..(17) <223> Replace with "N" <220> <221> SITE <222> (1)..(32) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 33 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 1 5 10 15 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 30 <210> 34 <211> 20 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutation <222> (10)..(10) <223> Replace with "A" or "N" <220> <221> mutation <222> (15) <223> Replace with "N" <220> <221> SITE <222> (1)..(20) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 34 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ala Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 35 <211> 604 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (440)..(454) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (455)..(455) <223> Replace with " " <220> <221> mutation <222> (456)..(456) <223> Replace with " " <220> <221> SITE <222> (457)..(471) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (474)..(474) <223> Replace with "A" <220> <221> mutation <222> (506)..(506) <223> Replace with "N" <220> <221> mutation <222> (513)..(513) <223> Use "G" o or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (516)..(516) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (543)..(543) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (544)..(544) <223> Replace with "T" <220> <221> mutation <222> (596)..(596) <223> Replace with "S" <220> <221> SITE <222> (1)..(604) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 35 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 435 440 445 Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gly Gly Gly Gly Ser Ala Pro Asn Ser Ser Ser Thr Lys Lys 465 470 475 480 Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu 485 490 495 Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 500 505 510 Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 515 520 525 Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Ala Ala 530 535 540 Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile 545 550 555 560 Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 565 570 575 Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 580 585 590 Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu Thr 595 600 <210> 36 <211> 686 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (441)..(455) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (456)..(456) <223> Replace with " " <220> <221> mutation <222> (457)..(457) <223> Replace with " " <220> <221> SITE <222> (458)..(472) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(686) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 36 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn Gly Thr Ser Gln Phe 465 470 475 480 Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp Ser Gln 485 490 495 Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp Pro Asp 500 505 510 Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser Gln Ala 515 520 525 Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln Lys Leu 530 535 540 Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu Gly Val 545 550 555 560 Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu Asn Leu 565 570 575 Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu Thr His 580 585 590 Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr Phe Glu 595 600 605 Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His Thr Trp 610 615 620 Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp Ile Cys 625 630 635 640 Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val Arg Val 645 650 655 Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser Gln Pro 660 665 670 Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr 675 680 685 <210> 37 <211> 665 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 37 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val 450 455 460 Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu 465 470 475 480 Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser 485 490 495 Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr 500 505 510 Thr Pro Ser Leu Lys Cys Ile Arg Gly Gly Gly Gly Ser Gly Gly Gly 515 520 525 Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly 530 535 540 Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu 545 550 555 560 Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu 565 570 575 Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys 580 585 590 Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala 595 600 605 Ser Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser 610 615 620 Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu 625 630 635 640 Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His 645 650 655 Ile Val Gln Met Phe Ile Asn Thr Ser 660 665 <210> 38 <211> 712 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (441)..(455) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (456)..(456) <223> Replace with " " <220> <221> mutation <222> (457)..(457) <223> Replace with " " <220> <221> SITE <222> (458)..(472) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(712) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 38 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro 465 470 475 480 Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg 485 490 495 Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys 500 505 510 Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala 515 520 525 Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 530 535 540 Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr 545 550 555 560 Cys Gln Arg Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu 565 570 575 Glu Ile Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro 595 600 605 Gly Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr 610 615 620 Thr Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu 625 630 635 640 Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro 645 650 655 Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr 660 665 670 Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr 675 680 685 Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln 690 695 700 Gly Thr Leu Val Thr Val Ser Ser 705 710 <210> 39 <211> 605 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 39 Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu 1 5 10 15 Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly 20 25 30 Arg Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn 35 40 45 Ser Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Val Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser 65 70 75 80 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 85 90 95 Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 100 105 110 Cys Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His Met Ile 465 470 475 480 Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val 485 490 495 Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr 500 505 510 Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys 515 520 525 Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys 530 535 540 Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys 545 550 555 560 His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro 565 570 575 Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His 580 585 590 Gln His Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser 595 600 605 <210> 40 <211> 691 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 40 Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu 1 5 10 15 Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly 20 25 30 Arg Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn 35 40 45 Ser Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Val Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser 65 70 75 80 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 85 90 95 Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 100 105 110 Cys Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Cys Pro 465 470 475 480 Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys Ile Leu 485 490 495 Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp Gln Asp 500 505 510 Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu His Arg 515 520 525 Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met Asp Val 530 535 540 Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr Asp Gln 545 550 555 560 Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala Glu Ser 565 570 575 Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser Gly Gln 580 585 590 Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe Tyr Met 595 600 605 Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg Gly Asp 610 615 620 Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp Ser Arg 625 630 635 640 Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser Tyr Glu 645 650 655 Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln Gly Thr 660 665 670 Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser Glu Glu 675 680 685 Leu Lys Glu 690 <210> 41 <211> 726 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 41 Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu 1 5 10 15 Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly 20 25 30 Arg Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn 35 40 45 Ser Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Val Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser 65 70 75 80 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 85 90 95 Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 100 105 110 Cys Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 465 470 475 480 Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu 485 490 495 Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr 500 505 510 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 515 520 525 Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 530 535 540 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 545 550 555 560 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Thr Phe 565 570 575 Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly 580 585 590 Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly 595 600 605 Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala 610 615 620 Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala 625 630 635 640 Pro Gly Lys Gly Leu Glu Trp Val Ala Phe Ile Trp Tyr Asp Gly Ser 645 650 655 Asp Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 660 665 670 Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala 675 680 685 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly Asp Ser Ser Asp 690 695 700 Trp Tyr Gly Asp Tyr Tyr Phe Gly Met Asp Val Trp Gly Gln Gly Thr 705 710 715 720 Thr Val Thr Val Ser Ser 725 <210> 42 <211> 588 <212> PRT <213> Artificial Sequence <220> <221> Source <223> Artificial Sequence Statement: Synthetic polypeptide <400> 42 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Gly Gly Gly Ser Gln Gly Gln Asp Arg His Met Ile Arg 450 455 460 Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn 465 470 475 480 Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn 485 490 495 Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser 500 505 510 Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys 515 520 525 Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His 530 535 540 Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys 545 550 555 560 Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln 565 570 575 His Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser 580 585 <210> 43 <211> 675 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 43 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Cys Pro 450 455 460 Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys Ile Leu 465 470 475 480 Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp Gln Asp 485 490 495 Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu His Arg 500 505 510 Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met Asp Val 515 520 525 Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr Asp Gln 530 535 540 Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala Glu Ser 545 550 555 560 Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser Gly Gln 565 570 575 Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe Tyr Met 580 585 590 Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg Gly Asp 595 600 605 Pro Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp Ser Arg 610 615 620 Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser Tyr Glu 625 630 635 640 Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln Gly Thr 645 650 655 Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser Glu Glu 660 665 670 Leu Lys Glu 675 <210> 44 <211> 214 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 44 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 45 <211> 214 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 45 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 Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr 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 Leu Tyr His Pro Ala 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 46 <211> 448 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 46 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 47 <211> 440 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 47 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Lys 435 440 <210> 48 <211> 218 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 48 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser 20 25 30 Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg 85 90 95 Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 49 <211> 447 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 49 Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe 50 55 60 Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 50 <211> 215 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 50 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 51 <211> 613 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (449)..(463) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (464)..(464) <223> Replace with " " <220> <221> mutation <222> (465)..(465) <223> Replace with " " <220> <221> SITE <222> (466)..(480) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (483)..(483) <223> "A" replaces <220> <221> mutation <222> (515)..(515) <223> Replace with "N" <220> <221> mutation <222> (522)..(522) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (525)..(525) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (552)..(552) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (553)..(553) <223> Replace with "T" <220> <221> mutation <222> (605)..(605) <223> Replace with "S" <220> <221> SITE <222> (1)..(613) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 51 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 450 455 460 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Ala Pro Asn Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 485 490 495 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 500 505 510 Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 515 520 525 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 530 535 540 Pro Leu Glu Glu Val Leu Asn Ala Ala Gln Ser Lys Asn Phe His Leu 545 550 555 560 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 565 570 575 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 580 585 590 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile 595 600 605 Ile Ser Thr Leu Thr 610 <210> 52 <211> 673 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 52 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile 450 455 460 Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys 465 470 475 480 Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe 485 490 495 Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys 500 505 510 Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg 515 520 525 Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala 530 535 540 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn 545 550 555 560 Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln 565 570 575 Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His Pro 580 585 590 Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln Val 595 600 605 Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu Asp 610 615 620 Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val Thr 625 630 635 640 Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys 645 650 655 Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn Thr 660 665 670 Ser <210> 53 <211> 613 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (449)..(463) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (464)..(464) <223> Replace with " " <220> <221> mutation <222> (465)..(465) <223> Replace with " " <220> <221> SITE <222> (466)..(480) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(613) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 53 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 450 455 460 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 485 490 495 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 500 505 510 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 515 520 525 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 530 535 540 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 545 550 555 560 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 565 570 575 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 580 585 590 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 595 600 605 Gly Ser Glu Asp Ser 610 <210> 54 <211> 694 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (449)..(463) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (464)..(464) <223> Replace with " " <220> <221> mutation <222> (465)..(465) <223> Replace with " " <220> <221> SITE <222> (466)..(480) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(694) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 54 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 450 455 460 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala 485 490 495 Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser 500 505 510 Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys 515 520 525 Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu 530 535 540 Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu 545 550 555 560 Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln 565 570 575 Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu 580 585 590 Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile 595 600 605 Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg 610 615 620 Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu 625 630 635 640 Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr 645 650 655 Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr 660 665 670 Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala 675 680 685 Ala Leu Gly Lys Asp Thr 690 <210> 55 <211> 728 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (449)..(463) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (464)..(464) <223> Replace with " " <220> <221> mutation <222> (465)..(465) <223> Replace with " " <220> <221> SITE <222> (466)..(480) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(728) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 55 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 450 455 460 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 485 490 495 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 500 505 510 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 515 520 525 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 530 535 540 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 545 550 555 560 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 565 570 575 Ala Arg Val Asp Arg Tyr Tyr Asn Trp Asn Tyr Phe Leu Gly Ser Phe 580 585 590 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 595 600 605 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Val Leu 610 615 620 Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys Thr Ala Arg Ile 625 630 635 640 Thr Cys Gly Gly Asn Asn Ile Arg Ser Lys Ser Val His Trp Tyr Gln 645 650 655 Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr Tyr Asp Ser Asp 660 665 670 Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser Asn Ser Gly Asn 675 680 685 Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp 690 695 700 Tyr Phe Cys Gln Val Trp Asp Ser Ser Ser Asp His His Val Phe Gly 705 710 715 720 Gly Gly Thr Lys Leu Thr Val Leu 725 <210> 56 <211> 728 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (449)..(463) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (464)..(464) <223> Replace with " " <220> <221> mutation <222> (465)..(465) <223> Replace with " " <220> <221> SITE <222> (466)..(480) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(728) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 56 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 450 455 460 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 485 490 495 Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Arg Ser Lys Ser Val 500 505 510 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr 515 520 525 Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser 530 535 540 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 545 550 555 560 Asp Glu Ala Asp Tyr Phe Cys Gln Val Trp Asp Ser Ser Ser Asp His 565 570 575 His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly 580 585 590 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val 595 600 605 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser 610 615 620 Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val 625 630 635 640 Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile Ile Pro 645 650 655 Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr 660 665 670 Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser 675 680 685 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val Asp Arg 690 695 700 Tyr Tyr Asn Trp Asn Tyr Phe Leu Gly Ser Phe Asp Tyr Trp Gly Gln 705 710 715 720 Gly Thr Leu Val Thr Val Ser Ser 725 <210> 57 <211> 720 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> SITE <222> (449)..(463) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> mutation <222> (464)..(464) <223> Replace with " " <220> <221> mutation <222> (465)..(465) <223> " "Replace <220> <221> SITE <222> (466)..(480) <223> This region includes 0-3 'Gly Gly Gly Gly Ser' repeating units <220> <221> SITE <222> (1)..(720) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 57 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 450 455 460 Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 465 470 475 480 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 485 490 495 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 500 505 510 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 515 520 525 Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 530 535 540 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 545 550 555 560 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His 565 570 575 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Gly Gly Gly Gly Ser 580 585 590 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln 595 600 605 Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys 610 615 620 Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg 625 630 635 640 Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly 645 650 655 Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile 660 665 670 Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu 675 680 685 Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp 690 695 700 Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 705 710 715 720 <210> 58 <211> 683 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 58 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly 450 455 460 Ser Gly Gly Gly Gly Ser Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr 465 470 475 480 Leu Gln Thr Val Ile Cys Ile Leu Glu Met Trp Asn Leu His Pro Ser 485 490 495 Thr Leu Thr Leu Thr Trp Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu 500 505 510 Ala Thr Ser Cys Ser Leu His Arg Ser Ala His Asn Ala Thr His Ala 515 520 525 Thr Tyr Thr Cys His Met Asp Val Phe His Phe Met Ala Asp Asp Ile 530 535 540 Phe Ser Val Asn Ile Thr Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys 545 550 555 560 Gly Ser Phe Leu Leu Ala Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn 565 570 575 Val Thr Val Thr Phe Ser Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp 580 585 590 Tyr Glu Asp Pro Ala Phe Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu 595 600 605 Leu Gln Tyr Arg Asn Arg Gly Asp Pro Trp Ala Val Ser Pro Arg Arg 610 615 620 Lys Leu Ile Ser Val Asp Ser Arg Ser Val Ser Leu Leu Pro Leu Glu 625 630 635 640 Phe Arg Lys Asp Ser Ser Tyr Glu Leu Gln Val Arg Ala Gly Pro Met 645 650 655 Pro Gly Ser Ser Tyr Gln Gly Thr Trp Ser Glu Trp Ser Asp Pro Val 660 665 670 Ile Phe Gln Thr Gln Ser Glu Glu Leu Lys Glu 675 680 <210> 59 <211> 717 <212> PRT <213> artificial sequence <220> <221> Source <223> Artificial Sequence Description: Synthetic polypeptide <400> 59 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala 435 440 445 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly 450 455 460 Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr 465 470 475 480 Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser 485 490 495 Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 500 505 510 Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly 515 520 525 Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 530 535 540 Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln 545 550 555 560 Gln Tyr Gly Ser Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 565 570 575 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 580 585 590 Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 595 600 605 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly 610 615 620 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 625 630 635 640 Phe Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val Lys 645 650 655 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 660 665 670 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 675 680 685 Arg Asp Gly Asp Ser Ser Asp Trp Tyr Gly Asp Tyr Tyr Phe Gly Met 690 695 700 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 705 710 715 <210> 60 <211> 124 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 60 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp 20 25 30 Tyr Leu His Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Pro Lys Phe 50 55 60 Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80 Leu Gln Leu Ser Ile Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Arg Phe Gly Tyr Phe Tyr Gly Ser Ser Phe Tyr Ala Val Ala 100 105 110 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 61 <211> 106 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 61 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Tyr Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 62 <211> 133 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <220> <221> mutation <222> (3) <223> Replace with "A" <220> <221> mutation <222> (35)..(35) <223> Replace with "N" <220> <221> mutation <222> (42)..(42) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (45)..(45) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (72)..(72) <223> Use "G" or "S" or "T" or "Q" or "E" or "N" or "D" or "R" or "K" replaced <220> <221> mutation <222> (73)..(73) <223> Replace with "T" <220> <221> mutation <222> (125)..(125) <223> Replace with "A" or "S" <220> <221> SITE <222> (1)..(133) <223> The variable residues at variable positions in the sequence do not preferentially use the amino acid residues provided in the annotation. <400> 62 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 Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> 63 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 63 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Gly Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 64 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 64 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Asn Ala Ser Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 65 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 65 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Asn Gly Ser Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 66 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 66 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 Asn Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Asn Ala Ser Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 67 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 67 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Pro Ser Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 68 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 68 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Pro Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 69 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 69 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Ala Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Gly Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 70 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 70 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Ile Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Gly Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 71 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 71 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Trp Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Gly Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 72 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 72 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Phe Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Gly Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 73 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 73 Cys Pro Asp Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys 1 5 10 15 Ile Leu Glu Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp 20 25 30 Gln Asp Gln Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu 35 40 45 His Arg Ser Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met 50 55 60 Asp Val Phe His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr 65 70 75 80 Asp Gln Ser Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala 85 90 95 Glu Ser Ile Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser 100 105 110 Gly Gln Tyr Asn Ile Ser Trp Arg Ser Tyr Tyr Glu Asp Pro Ala Phe 115 120 125 Tyr Met Leu Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg 130 135 140 Gly Asp Gly Ser Gly Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp 145 150 155 160 Ser Arg Ser Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser 165 170 175 Tyr Glu Leu Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln 180 185 190 Gly Thr Trp Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser 195 200 205 Glu Glu Leu Lys Glu 210 <210> 74 <211> 674 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 74 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Cys Pro Asp 450 455 460 Leu Val Cys Tyr Thr Asp Tyr Leu Gln Thr Val Ile Cys Ile Leu Glu 465 470 475 480 Met Trp Asn Leu His Pro Ser Thr Leu Thr Leu Thr Trp Gln Asp Gln 485 490 495 Tyr Glu Glu Leu Lys Asp Glu Ala Thr Ser Cys Ser Leu His Arg Ser 500 505 510 Ala His Asn Ala Thr His Ala Thr Tyr Thr Cys His Met Asp Val Phe 515 520 525 His Phe Met Ala Asp Asp Ile Phe Ser Val Asn Ile Thr Asp Gln Ser 530 535 540 Gly Asn Tyr Ser Gln Glu Cys Gly Ser Phe Leu Leu Ala Glu Ser Ile 545 550 555 560 Lys Pro Ala Pro Pro Phe Asn Val Thr Val Thr Phe Ser Gly Gln Tyr 565 570 575 Asn Ile Ser Trp Arg Ser Asp Tyr Glu Asp Pro Ala Phe Tyr Met Leu 580 585 590 Lys Gly Lys Leu Gln Tyr Glu Leu Gln Tyr Arg Asn Arg Gly Asp Pro 595 600 605 Trp Ala Val Ser Pro Arg Arg Lys Leu Ile Ser Val Asp Ser Arg Ser 610 615 620 Val Ser Leu Leu Pro Leu Glu Phe Arg Lys Asp Ser Ser Tyr Glu Leu 625 630 635 640 Gln Val Arg Ala Gly Pro Met Pro Gly Ser Ser Tyr Gln Gly Thr Trp 645 650 655 Ser Glu Trp Ser Asp Pro Val Ile Phe Gln Thr Gln Ser Glu Glu Leu 660 665 670 Lys Glu <210> 75 <211> 706 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 75 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys 180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala 210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr 340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430 Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly 435 440 445 Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 465 470 475 480 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser 485 490 495 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 500 505 510 Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg 515 520 525 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 530 535 540 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser 545 550 555 560 Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser 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 Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp 610 615 620 Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr 625 630 635 640 Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val 645 650 655 Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser 660 665 670 Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly 675 680 685 Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 690 695 700 Ser Ser 705 <210> 76 <211> 5 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 76 Thr Tyr Trp Ile Gly 1 5 <210> 77 <211> 17 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 77 Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln 1 5 10 15 Gly <210> 78 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 78 Gly Asn Trp Asn Cys Phe Asp Tyr 1 5 <210> 79 <211> 12 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 79 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 80 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 80 Gly Ala Ser Arg Arg Ala Thr 1 5 <210> 81 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 81 Gln Arg Tyr Gly Ser Ser His Thr 1 5 <210> 82 <211> 8 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 82 Gly Asn Trp Asn Ser Phe Asp Tyr 1 5 <210> 83 <211> 118 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 83 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 Val Ser Gly Tyr Phe Phe Thr Thr Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 84 <211> 119 <212> PRT <213> Artificial sequence <220> <221> source <223> Artificial sequence description: synthetic peptide <400> 84 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro 115

Claims

1. A prodrug, characterized in that The prodrug comprises two identical light chains and two heavy chains, the light chain amino acid sequence is SEQ ID NO:44, the first heavy chain fusion polypeptide chain amino acid sequence is SEQ ID NO:37, and the second heavy chain fusion polypeptide chain amino acid sequence is SEQ ID NO:

75.

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.

4. An expression vector comprising the polynucleotide according to claim 3.

5. A host cell comprising the expression vector according to claim 4, wherein the host cell is a mammalian cell.

6. A method for preparing the prodrug according to claim 1, comprising: a) culturing the host cell according to claim 5 under conditions that allow expression of the prodrug, wherein the host cell is a mammalian cell, and b) Isolating the prodrug from the cell culture.

Images