Heterodimer relaxin fusions and uses thereof

Abstract

The present invention relates to heterodimeric relaxin fusion polypeptides, in particular to heterodimeric relaxin 2 fusion polypeptides and uses thereof. Accordingly, the present invention provides relaxin fusion polypeptides, nucleic acid molecules, vectors, host cells, pharmaceutical compositions and kits comprising the same as well as uses thereof including therapeutic methods. The polypeptides and compositions of the present invention are particularly useful for the treatment of cardiovascular diseases, for example for the treatment of heart failure.

Description

[0001] SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and which is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 11, 2021, is named 201011(PCT)_SL.txt and is 236,203 bytes in size. TECHNICAL FIELD

[0003] The present invention relates to heterodimeric relaxin fusions and uses thereof. In particular, the present invention relates to relaxin-2 fusions and uses thereof. BACKGROUND

[0004] Relaxin is a peptide hormone belonging to the insulin superfamily. In humans, the relaxin peptide family includes seven peptides with high structural similarity but low sequence similarity: relaxins 1, 2, and 3, and insulin-like peptides INSL3, INSL4, INSL5, and INSL6. Naturally occurring relaxin consists of an A polypeptide chain and a B polypeptide chain covalently linked by two interchain disulfide bonds. The A chain has an additional intra-chain disulfide bond. The relaxin gene encodes a prohormone with the structure B-C-A (B and A polypeptide chains connected by a C peptide). The prohormone undergoes endoproteolytic cleavage by the PC1 and PC2 enzymes, removing the C peptide, followed by secretion of the mature relaxin.

[0005] Relaxin is a pleiotropic hormone known to mediate systemic hemodynamic changes and adaptive changes in the kidney during pregnancy. Relaxin also shows anti-fibrotic properties and has beneficial effects in heart failure, such as acute decompensated heart failure (ADHF). Heart failure is associated with significant morbidity and mortality. It is characterized by complex tissue remodeling involving increased cardiomyocyte death and interstitial fibrosis. Relaxin activates a number of signaling cascades that have been shown to be beneficial in the context of ischemia-reperfusion and heart failure. These signaling pathways include activation of the phosphoinositide 3-kinase pathway and activation of the nitric oxide signaling pathway (Bathgate RA et al. (2013) Physiol. Rev. 93(1):405-480; Mentz RJ et al. (2013) Am. Heart J. 165(2):193-199; Tietjens J et al. (2016) Heart 102:95-99; Wilson SS et al. (2015) Pharmacology 35:315-327).

[0006] Clinical trials have been performed using unmodified recombinant human relaxin-2, serelaxin. Continuous intravenous administration of serelaxin to hospitalized patients improved markers of cardiac, renal and hepatic impairment and congestion (Felker GM et al. (2014) J. Am. Coll. Cardiol. 64(15): 1591-1598; Metra M et al. (2013) J. Am. Coll. Cardiol. 61(2): 196-206; Teerlink JR et al. (2013) Lancet 381(9860): 29-39). However, due to the rapid clearance of serelaxin from the patient's circulation, the therapeutic effect was limited and the positive effects rapidly disappeared once intravenous injection was stopped. In addition, approximately one third of patients experienced a significant drop in blood pressure (>40 mm Hg) after receiving serelaxin intravenously, so the dose had to be reduced by half or even more.

[0007] WO 2013 / 004607 and WO 2018 / 138170 describe recombinant relaxin polypeptides in which relaxin A and relaxin B are fused to a linker peptide in a single chain. WO 2013 / 004607 describes recombinant relaxins with a linker peptide of at least 5 amino acids and less than 15 amino acids. WO 2018 / 138170 describes recombinant relaxins with a linker peptide of at least 15 amino acids.

[0008] In view of the promising clinical studies currently performed with unmodified recombinant relaxin, there is still a need for additional recombinant relaxins that retain the biological activity of relaxin and provide advantages such as, for example, an extended half-life and convenient dosing. SUMMARY

[0009] The present invention relates to heterodimeric fusion proteins having relaxin activity.

[0010] Thus, in one aspect, the present invention provides a heterodimeric fusion protein comprising:

[0011] (i) a first heterodimerization domain linked to at least one relaxin A chain polypeptide or variant thereof; and

[0012] (ii) a second heterodimerization domain linked to at least one relaxin B chain polypeptide or variant thereof,

[0013] wherein the first heterodimerization domain heterodimerizes with the second heterodimerization domain, and wherein the heterodimeric fusion protein has relaxin activity.

[0014] In some embodiments, the relaxin A chain and the relaxin B chain are covalently bound by one or more (e.g. two) interchain bonds, preferably one or more (e.g. two) interchain disulfide bonds. In some embodiments, the relaxin A chain and the relaxin B chain are not covalently linked to each other by an amino acid linker.

[0015] In some embodiments, the relaxin A chain is a relaxin-2 A chain and the relaxin B chain is a relaxin-2 B chain.

[0016] In preferred embodiments, the first and second heterodimerization domains are derived from an immunoglobulin Fc region, e.g. an immunoglobulin G (IgG) Fc region (“first Fc region” and “second Fc region”). The first and second Fc regions can comprise constant domains CH2 and / or CH3. Preferably, the first and second Fc regions comprise CH2 and CH3.

[0017] In alternative embodiments, the first and second heterodimerization domains are derived from an immunoglobulin Fab region.

[0018] In yet further alternative embodiments, the first and second heterodimerization domains heterodimerize to form a parallel coiled coil.

[0019] In some embodiments, the relaxin A chain is connected to the first heterodimerization domain (e.g. first Fc region) via a linker, and the relaxin B chain is connected to the second heterodimerization domain (e.g. second Fc region) via a linker. In preferred embodiments, one or preferably both linkers are polypeptides.

[0020] In some embodiments, at least one linker is a polypeptide of 6 to 40 amino acids in length. Preferably, both linkers are polypeptides of 6 to 40 amino acids in length. In preferred embodiments, at least one linker is a polypeptide of 21 amino acids in length. In particularly preferred embodiments, both linkers are polypeptides of 21 amino acids in length. In certain embodiments, both linkers have the sequence GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO: 5].

[0021] In preferred embodiments, the C-terminus of the first heterodimerization domain (e.g. first Fc region) is connected to the N-terminus of the relaxin A chain, and the C-terminus of the second heterodimerization domain (e.g. second Fc region) is connected to the N-terminus of the relaxin B chain. In alternative embodiments, the N-terminus of the first heterodimerization domain (e.g. first Fc region) is connected to the C-terminus of the relaxin A chain, and the N-terminus of the second heterodimerization domain (e.g. second Fc region) is connected to the C-terminus of the relaxin B chain.

[0022] In some embodiments, the first and second heterodimerization domains (e.g., the first and second Fc regions) comprise amino acid mutations and / or modifications that promote heterodimerization, preferably amino acid mutations and / or modifications that promote asymmetric heterodimerization. In preferred embodiments, the amino acid mutations that promote heterodimerization are "Fc Knob" and "Fc Hole" mutations. In particularly preferred embodiments, the "Fc Knob" and "Fc Hole" mutations are present in the CH3 domains. In preferred embodiments, the first Fc region comprises the "Fc Knob" mutations, and the second Fc region comprises the "Fc Hole" mutations. Alternatively, the first Fc region has the "Fc Hole" mutations, and the second Fc region has the "Fc Knob" mutations. Preferably, the amino acid mutations that promote heterodimerization comprise the "Fc Hole" mutations Y349C, T366S, L368A, and Y407V, or conservative substitutions thereof, in one CH3 domain; and the "Fc Knob" mutations S354C and T366W, or conservative substitutions thereof, in the other CH3 domain, wherein the amino acid numbering is according to the EU index as in Kabat.

[0023] In embodiments of any aspect of the application, the relaxin-2A chain polypeptide comprises the sequence set forth in SEQ ID NO: 1 or a variant thereof, and the relaxin-2B chain polypeptide comprises the sequence set forth in SEQ ID NO: 2 or a variant thereof. In some embodiments, the relaxin-2A chain polypeptide comprises the amino acid mutation K9H.

[0024] The present application also provides a heterodimeric fusion comprising:

[0025] (i) an FcX-con-A fusion polypeptide; and

[0026] (ii) an FcY-con-B fusion polypeptide,

[0027] wherein:

[0028] A is a relaxin A chain or a variant thereof, e.g., a relaxin-2A chain or a variant thereof;

[0029] B is a relaxin B chain or a variant thereof, e.g., a relaxin-2B chain or a variant thereof;

[0030] FcY is an immunoglobulin (e.g., IgGl) Fc region having "Fc Hole" amino acid mutations and / or modifications, preferably comprising a CH3 domain having the amino acid mutations Y349C: T366S: L368A: Y407V, or conservative substitutions thereof;

[0031] FcX is an immunoglobulin (e.g., IgGl) Fc region having an“Fc Knob” amino acid mutation and / or modification, preferably comprising a CH3 domain having the amino acid mutations S354C:T366W or conservative substitutions thereof; and

[0032] con is a linker, e.g., a linker polypeptide, preferably having the sequence GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO: 5],

[0033] wherein the amino acid numbering is according to the EU index as in Kabat, wherein FcX and FcY are heterodimerized, and wherein the heterodimeric fusion has relaxin activity.

[0034] In particularly preferred embodiments, the heterodimeric fusion comprises a fusion polypeptide having the amino acid sequence of SEQ ID NO: 11 and a fusion polypeptide having the amino acid sequence of SEQ ID NO: 20.

[0035] In some embodiments of any aspect of the application, the heterodimeric fusion further comprises one or more Fabs, optionally wherein the heterodimeric fusion comprises one Fab linked to the N-terminus of the first heterodimerization domain (e.g., first Fc region) and a second Fab linked to the N-terminus of the second heterodimerization domain (e.g., second Fc region).

[0036] In some embodiments of any aspect of the application, the heterodimeric fusion further comprises a second relaxin A chain polypeptide or variant thereof linked to the N-terminus of the first heterodimerization domain (e.g., first Fc region) and a second relaxin B chain polypeptide or variant thereof linked to the N-terminus of the second heterodimerization domain (e.g., second Fc region), optionally wherein the second relaxin A chain is linked to the first heterodimerization domain (e.g., first Fc region) via a linker polypeptide and the second relaxin B chain is linked to the second heterodimerization domain (e.g., second Fc region) via a linker polypeptide.

[0037] In another aspect, the application provides a heterodimeric fusion comprising:

[0038] (i) FcX-B-L-A and FcY, optionally FcY-B-L-A; or

[0039] (ii) FcY-B-L-A and FcX, optionally FcX-B-L-A;

[0040] wherein:

[0041] FcY is an immunoglobulin (e.g., IgGl) Fc region having "Fc socket" amino acid mutations and / or modifications, preferably comprising a CH3 domain having amino acid mutations Y349C: T366S: L368A: Y407V or conservative substitutions thereof;

[0042] FcX is an immunoglobulin (e.g., IgGl) Fc region having "Fc mace" amino acid mutations and / or modifications, preferably comprising a CH3 domain having amino acid mutations S354C: T366W or conservative substitutions thereof;

[0043] B is a relaxin B chain or variant thereof, e.g., a relaxin-2 B chain or variant thereof;

[0044] A is a relaxin A chain or variant thereof, e.g., a relaxin-2 A chain or variant thereof; and

[0045] L is a linker polypeptide, preferably having the amino acid sequence GGGSGGGSGG [SEQ ID NO: 60],

[0046] wherein the amino acid numbering is according to the EU index as in Kabat, wherein FcX and FcY are heterodimerized, and wherein the heterodimeric fusion has relaxin activity. Alternatively, FcX and FcY are non-Fc heterodimerization domains as described herein. In some embodiments, the relaxin B chain is linked to FcX and / or FcY via a linker, optionally a linker polypeptide of 6 to 40 amino acids in length, e.g., 21 amino acids in length.

[0047] In yet another aspect, the present application provides a heterodimeric fusion comprising:

[0048] (i) FcX-A-L-B and FcY, optionally FcY-A-L-B; or

[0049] (ii) FcY-A-L-B and FcX, optionally FcX-A-L-B;

[0050] wherein:

[0051] FcY is an immunoglobulin (e.g., IgGl) Fc region having "Fc socket" amino acid mutations and / or modifications, preferably comprising a CH3 domain having amino acid mutations Y349C: T366S: L368A: Y407V or conservative substitutions thereof;

[0052] FcX is an immunoglobulin (e.g., IgGl) Fc region having "Fc mace" amino acid mutations and / or modifications, preferably comprising a CH3 domain having amino acid mutations S354C: T366W or conservative substitutions thereof;

[0053] A is a relaxin A chain or a variant thereof, e.g., a relaxin-2 A chain or a variant thereof;

[0054] B is a relaxin B chain or a variant thereof, e.g., a relaxin-2 B chain or a variant thereof; and

[0055] L is a linker polypeptide, preferably having the amino acid sequence GGGSGGGSGG [SEQ ID NO: 60],

[0056] wherein the amino acid numbering is according to the EU index as in Kabat, wherein FcX and FcY are heterodimerized, and wherein the heterodimeric fusion has relaxin activity. Alternatively, FcX and FcY are non-Fc heterodimerization domains as described herein. In some embodiments, the relaxin A chain is linked to FcX and / or FcY via a linker, optionally a linker polypeptide of 6 to 40 amino acids in length, e.g., 21 amino acids in length.

[0057] In some embodiments of any aspect of the application, the ratio of the relaxin activity of the heterodimeric fusion to the relaxin activity of a reference relaxin protein is about 0.001 to about 10.

[0058] In a related aspect, the present application provides nucleic acid molecules (e.g., DNA molecules) encoding the heterodimeric fusions of the present application, vectors comprising the nucleic acid molecules, host cells comprising the vectors or the nucleic acids, and methods of producing the heterodimeric fusions of the present application by culturing these host cells and collecting the fusion proteins.

[0059] In another aspect, the present application provides pharmaceutical compositions comprising the heterodimeric fusions of the present application, kits comprising the same, and uses of the heterodimeric fusions in therapy, including methods of treating subjects having heart failure.

[0060] Various aspects and embodiments of the present application are set forth in the appended claims. Such and other aspects and embodiments of the present application are also described herein.

[0061] BRIEF DESCRIPTION OF DRAWINGS AND SEQUENCE LISTING

[0062] Figure 1Exemplary formats of heterodimeric fusions according to some embodiments of the application are shown. The format of each fusion polypeptide of the heterodimeric fusion is given as FcX, FcY, A, B, con, and L, where FcX ("Fc Knob") and FcY ("Fc Hole") are two Fc regions comprising amino acid mutations and / or modifications that promote heterodimerization; A ("Rlx A") and B ("RlxB") are relaxin A chain and relaxin B chain polypeptides; "con" is a connector polypeptide; L is a linker polypeptide, HC X and HC Y - heavy chains of an antibody, LC - light chain of an antibody, Hinge - hinge region of an antibody, and Fab - Fab fragment of an antibody.

[0063] Figure 2 LC-MS analysis of RELAX0019 and RELAX0023. A) shows the deglycosylated and non-reducing analysis of RELAX0019 and RELAX0023 for the mass of the complete molecule; B) shows the deglycosylated and reducing analysis of RELAX0019 and RELAX0023 for the mass of the individual Fc fusion chains (Knob-Relaxin chain A and Hole-Relaxin chain B).

[0064] Figure 3 Analysis of C-terminal peptides of RELAX0019 and RELAX0023 by non-reducing peptide mapping using LC-MS. The amino acid sequence of the C-terminal peptide with predicted disulfide bonds represented by lines is shown in the top panel. Panel A and E - Extracted ion chromatograms of the C-terminal peptide in the absence of reducing agent (-DTT). Panel C and G - Deconvoluted mass spectra of the C-terminal peptide in the absence of reducing agent. Panel B and F - Extracted ion chromatograms in the presence of reducing agent (+DTT), and Panel D and H - Deconvoluted mass spectra in the presence of reducing agent. Figure 3 SEQ ID NOs 75, 77, and 76 are disclosed in the order of appearance, respectively.

[0065] Figure 4 In vitro biological activity of some heterodimeric fusions of the application is shown, measured by cAMP induction in cells expressing recombinant human RXFP1.

[0066] Figure 5 In vivo pharmacokinetic (PK) curves from a series of ELISA experiments in which heterodimeric fusions of the application were administered intravenously to mice are shown. Data was normalized to % cMax at the 5 min time point (T1).

[0067] Figure 6Reversal of isoprenaline-induced cardiac fibrosis and hypertrophy in mice treated with RELAX0019 and RELAX0023. Shown are the levels of fibrosis and hypertrophy for: (1) vehicle (baseline), (2) isoprenaline, (3) isoprenaline + relaxin-2, (4) isoprenaline + RELAX0019 and (5) isoprenaline + RELAX0023.

[0068] Figure 7 In vitro non-specific binding of the heterodimeric fusions of the application is shown in a baculovirus (BV) ELISA assay.

[0069] Figure 8 Percent purity loss, aggregation and fragmentation of RELAX0023, RELAX0127 and RELAX0128 in solution after storage is shown.

[0070] Figure 9 Stability of RELAX0023, RELAX0127 and RELAX0128 in solution over time assessed by reduced LC-MS analysis is shown. A) Total ion chromatogram B) Mass spectrum of the reduced molecule

[0071] Figure 10 PK profile of RELAX0023 in cynomolgus monkeys after intravenous and subcutaneous injection is shown.

[0072] Figure 11 Nucleotide sequences encoding some of the polypeptides of the application are shown (SEQ ID NOs 80-140 in order of appearance, respectively).

[0073] Table 1 : The hinge region is shown in italics, relaxin A is underlined, relaxin B is double underlined and the FC region is in bold on the sequence listing.

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] DETAILED DESCRIPTION

[0087] Relaxin

[0088] The present application is based, at least in part, on the discovery that the heterodimeric fusions described herein can exhibit relaxin activity when the relaxin A chain and the relaxin B chain are not covalently linked to each other by an amino acid linker. This is surprising based on the disclosure of WO 2013 / 004607 and WO 2018 / 138170, which describe recombinant relaxins in which the relaxin A and B single chains are fused. The present inventors have also discovered that heterodimerization of the heterodimerization domains induces correct folding and heterodimerization of the relaxin A chain and the relaxin B chain (see Example 2). Furthermore, unlike wild-type relaxin proteins, the fusion polypeptides of the present application do not require endoproteolytic processing for biological activity.

[0089] As used herein, the term "heterodimeric fusion" refers to a heterodimer of fusion polypeptides, wherein one fusion polypeptide comprises a first heterodimerization domain linked to a first subunit of a heterodimeric protein (e.g., a relaxin A chain), and the other fusion polypeptide comprises a second heterodimerization domain linked to a second subunit of a heterodimeric protein (e.g., a relaxin B chain).

[0090] The heterodimeric fusions of the present application can comprise a relaxin A chain polypeptide and a relaxin B chain polypeptide from a relaxin group selected from the group consisting of relaxin-1, relaxin-2, and relaxin-3. In preferred embodiments, the relaxin A chain polypeptide of the present application is a relaxin-2 A chain polypeptide or a variant thereof; and the relaxin B chain polypeptide of the present application is a relaxin-2 B chain polypeptide or a variant thereof. In particular embodiments, the relaxin A chain polypeptide comprises a human relaxin-2 A chain polypeptide or a variant thereof and a human relaxin-2 B chain polypeptide or a variant thereof.

[0091] The terms "chain," "polypeptide," and "peptide" are used interchangeably herein to refer to a chain of two or more amino acids linked by peptide bonds.

[0092] In some embodiments, the relaxin-2A chain polypeptide has the sequence as set forth in SEQ ID NO: 1 or a variant thereof, and the relaxin-2B chain polypeptide has the sequence as set forth in SEQ ID NO: 2 or a variant thereof. Variants can comprise one or more amino acid substitutions, deletions and / or insertions. In some embodiments, the relaxin-2A chain polypeptide comprises one or more amino acid mutations selected from the group consisting of K9E, K9H, K9L, K9M, R18E, R18H, R22A, R22I, R22M, R22Q, R22S, R22Y, F23E, F23A and F23I. In preferred embodiments, the relaxin-2A chain comprises the amino acid mutation K9H.

[0093] Relaxin A chain variants and relaxin B chain variants are known in the art. Furthermore, the skilled person has access to guidance on the design of relaxin A chain variants and relaxin B chain variants. For example, it will be appreciated that variants can retain those amino acids necessary for relaxin function. For example, relaxin-2B chain variants can comprise the conserved motif Arg-X-X-X-Arg-X-X-lle (Claasz AA et al. (2002) Eur. J. Biochem. 269(24):6287-6293) or Arg-X-X-X-Arg-X-X-Val (Bathgate RA et al. (2013) Physiol Rev. 93(1):405-480). Variants can comprise one or more amino acid substitutions and / or insertions. For example, relaxin-2B chain variants can have one or more additional amino acids compared to SEQ ID NO: 62, for example K30 and R31 and N-terminal V-2, A-1 and M-1. Alternatively or in addition, variants can comprise one or more amino acid derivatives. For example, the first amino acid of the relaxin-2B chain variant can be pyroglutamic acid.

[0094] In preferred embodiments, the relaxin A chain and the relaxin B chain are covalently bound by two interchain disulfide bonds (see Example 2).

[0095] Relaxin family peptides mediate their biological effects at least in part by activating G protein-coupled receptors (GPCRs), and subsequently stimulating or inhibiting the cAMP signaling pathway through Gs protein subunits or Gi protein subunits, respectively. Relaxin-2 is known to activate the GPCR RXFP1 (also known as LGR7) and to a lesser extent the GPCR RXFP2 (also known as LGR8), thus stimulating the Gs-cAMP dependent signaling pathway leading to an increase in the second messenger molecule cAMP.

[0096] As used herein, the term "relaxin activity" refers to the ability of a relaxin molecule to bind to a relaxin receptor, and / or to activate the relaxin receptor and / or to initiate an intracellular signaling cascade. In embodiments in which the relaxin activity is the activity of relaxin-2, the relaxin activity can refer to the ability to bind to and / or activate the receptors RXFP1 and / or RXFP2. The term "relaxin activity" can be used interchangeably with "biological activity".

[0097] Relaxin activity can be measured by measuring the binding of a relaxin molecule to a relaxin receptor, and / or by measuring downstream events from the binding of a relaxin receptor.

[0098] Relaxin activity can be measured in vitro and / or in vivo. In some embodiments, the relaxin activity is measured in vitro.

[0099] Relaxin activity can be measured by measuring the amount and / or presence of molecules downstream from the activation of a receptor by a relaxin. For example, relaxin activity can be measured by measuring cAMP production followed by measuring the activation of a receptor by a relaxin. Methods for detecting relaxin-induced cAMP production are known in the art. Such methods include cAMP ELISA, HTRF cAMP assay and cAMP assay. In some embodiments, relaxin activity is measured by measuring relaxin-induced cAMP production by means of a HTRF cAMP assay, for example, as performed in Example 3. Relaxin activity can also be measured by measuring nitric oxide (NO) production followed by measuring the activation of a receptor by a relaxin. Relaxin activity can also be measured by measuring the activation of molecules downstream from the activation of a receptor by a relaxin. For example, relaxin activity can be measured by measuring the activation of p42 / 44 MAPK.

[0100] Alternatively or in addition, relaxin activity can be measured by measuring the activation of known relaxin target genes. For example, relaxin activity can be measured by measuring the activation of transcription of a known relaxin target gene (i.e. VEGF) in THP-1 cells. Methods for measuring the activation of gene transcription are known in the art and include quantitative PCR analysis of mRNA. The relative expression of VEGF mRNA can be measured by quantitative real-time PCR induction of VEGF transcripts followed by incubation of THP-1 cells with relaxin, as described in Xiao et al. (2013) Nat Commun. 4: 1953.

[0101] Alternatively or in addition, relaxin activity can be determined by measuring one or more downstream effects of relaxin. For example, a reduction in cardiac hypertrophy can be measured by echocardiography, left ventricular weight relative to body weight, and / or tibia length, according to standard methods. In another example, relaxin activity can be determined by measuring a reduction in fibrosis using Masson’s Trichrome Stain. In another example, relaxin activity can be determined by measuring modulation of connective tissue metabolism, for example, inhibition of profibrotic factors (such as TGF-β), inhibition of fibroblast proliferation and differentiation, and / or activation of MMP-mediated extracellular matrix degradation (Bathgate RA et al. (2013) Physiol Rev. 93(1):405-480).

[0102] In some embodiments, relaxin activity is determined by measuring reversal of isoproterenol-induced cardiac hypertrophy (measured as heart weight relative to tibia length) and fibrosis (measured as collagen content relative to heart weight), for example, as performed in Example 7.

[0103] The activity of the heterodimeric fusion of the application relative to a reference relaxin protein can be determined. In some embodiments, the reference relaxin protein is a recombinant protein. In preferred embodiments, the reference relaxin protein is a relaxin protein having a relaxin A chain and a relaxin B chain array of mature relaxin proteins. Recombinant relaxins having a relaxin A chain and a relaxin B chain array of mature relaxin proteins are commercially available. For example, recombinant human relaxin-2, murine relaxin-1, and INSL3 are available from R&D Systems (catalog numbers 6586-RN, 6637-RN, and 4544-NS, respectively).

[0104] In some embodiments, the reference relaxin protein has the same relaxin A chain and B chain as the heterodimeric fusion of the application, or differs from the relaxin A chain and B chain of the heterodimeric fusion of the application by up to 10 amino acids, for example, 1 or 2 amino acids. In some embodiments, the first amino acid of the B chain of the reference relaxin-2 is D, and this amino acid is missing in the relaxin B chain of the heterodimeric fusion of the application.

[0105] The reference relaxin protein can be selected from:

[0106] (i) recombinant human relaxin-2 (referred to herein as RELAX0013); and

[0107] (ii) recombinant murine relaxin-1 (referred to herein as RELAX0014); and

[0108] (iii) recombinant Fc-fused relaxin-2, wherein relaxin A and relaxin B single chains are fused, and wherein Fc is a half-life extended Fc region (herein referred to as RELAX0010 and described in WO 2018 / 138170); and

[0109] (iv) recombinant Fc-fused relaxin-2, wherein relaxin A and relaxin B single chains are fused, and wherein Fc is a half-life extended Fc region (herein referred to as RELAX0009 and described in WO 2018 / 138170); and

[0110] (v) recombinant Fc-fused relaxin-2, wherein relaxin A and relaxin B single chains are fused (herein referred to as RELAX0126 and described in WO 2013 / 004607); and

[0111] (vi) recombinant Fc-fused relaxin-2, wherein relaxin A and relaxin B single chains are fused (herein referred to as RELAX0127 and described in WO 2013 / 004607); and

[0112] (vii) recombinant Fc-fused relaxin, wherein relaxin A and relaxin B single chains are fused (herein referred to as RELAX0128 and described in WO 2013 / 004607).

[0113] In a particularly preferred embodiment, the reference relaxin protein is a relaxin-2 protein having the relaxin-2 chain A and relaxin-2B chain array of the mature relaxin-2 protein as disclosed under UniProtKB / Swiss-Prot accession number P04090.1.

[0114] Heterodimeric fusions of the application can be considered to have relaxin activity if they exhibit at least a portion of the activity of the reference relaxin protein. For example, a fusion polypeptide can be considered to have relaxin activity if it has at least about half the activity of the reference relaxin protein. A heterodimeric fusion of the application can be considered to have relaxin activity if the ratio of the activity of the fusion polypeptide to the activity of the reference relaxin protein is from about 10 -5 to about 1, about 10 -4 to about 1, about 10 -3 to about 1, about 10 -2 to about 1, about 1 / 50 to about 1, about 1 / 20 to about 1, about 1 / 15 to about 1, about 1 / 10 to about 1, about 1 / 5 to about 1, or about 1 / 2 to about 1. Alternatively, a heterodimeric fusion of the application can be considered to have relaxin activity if the ratio of the activity of the fusion polypeptide to the activity of the reference relaxin protein is from about 1 to about 10 5 , about 1 to about 10 4 , about 1 to about 10 3about 1 to about 100, about 1 to about 50, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, or about 1 to about 2, then the heterodimeric fusion of the application can be considered to have relaxin activity.

[0115] In some embodiments, the relaxin activity of the heterodimeric fusion is about 0.001 to about 10 of the relaxin activity of a reference relaxin protein.

[0116] Relaxin activity can be determined as an EC50value. As used herein, the term "EC50" (half maximal effective concentration) refers to the effective concentration of a therapeutic compound that induces half of the response between the baseline and the maximum after a specified exposure time.

[0117] Heterodimerization domain

[0118] The heterodimeric fusion of the application comprises a first heterodimerization domain and a second heterodimerization domain. In preferred embodiments, the first and second heterodimerization domains are derived from an immunoglobulin Fc region.

[0119] The term "Fc region" defines the C-terminal region of an immunoglobulin heavy chain, which is produced by papain digestion of an intact antibody. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally a CH4 domain.

[0120] The first and second Fc regions can comprise immunoglobulin domains CH2 and / or CH3. In preferred embodiments, the first and second Fc regions comprise immunoglobulin domains CH2 and CH3.

[0121] The Fc region can be derived from an immunoglobulin (e.g. IgG) from any species, preferably a human immunoglobulin (e.g. human IgG). In embodiments where the Fc region is derived from an IgG, the Fc region can be derived from any subclass of IgG (e.g. IgGl, IgG2, IgG3, IgG4), preferably IgGl. Preferably, the first and second Fc regions are derived from a human IgGl immunoglobulin. In other embodiments, the first and second Fc regions are derived from a human IgG4 immunoglobulin.

[0122] In preferred embodiments, the first and second Fc regions comprise amino acid mutations and / or modifications that promote heterodimerization. Such modifications can include the introduction of asymmetric complementary modifications into each of the first and second Fc regions, such that the two chains are compatible with each other and thus able to form a heterodimer, but each chain is not able to dimerize with itself. Such modifications can encompass insertions, deletions, conservative and non-conservative substitutions, and rearrangements. Incorporation of such modifications provides a method of increasing the yield of heterodimers produced by recombinant cell culture relative to other undesired end products, such as homodimers.

[0123] The first and second Fc regions can comprise any amino acid mutations and / or modifications known in the art that promote heterodimerization. Combinations of modifications can be used to maximize assembly efficiency while minimizing effects on antibody stability.

[0124] In the "knob-in-hole" approach, heterodimerization can be promoted by introducing steric hindrance between the contacting residues. A "knob" is created by replacing one or more small amino acid side chains from one Fc region's ("Fc knob") interface with a larger side chain (e.g., tyrosine or tryptophan). A compensating "hole" of the same or similar size as the one or more large side chains is created on the other Fc region's ("Fc hole") interface by replacing the amino acids with large side chains with amino acids having smaller side chains (e.g., alanine or valine). "Knob-in-hole" modifications are described in detail in, e.g., Ridgway JB et al. (1996) Protein Eng. 9(7) 617-621; Merchant AM et al. (1998) Nat. Biotechnol. 16(7): 677-681.

[0125] Other modifications that can be used to produce heterodimers include, but are not limited to, those that create favorable electrostatic interactions between the two Fc regions. For example, one or more positively charged amino acids can be introduced into one Fc region, and one or more negatively charged amino acids can be introduced into a corresponding position in the other Fc region. Alternatively or in addition, the Fc regions can be modified to include mutations that introduce cysteine residues capable of forming disulfide bonds. Alternatively or in addition, the Fc regions can comprise one or more modifications to hydrophilic and hydrophobic residues at the interface between the chains, such that formation of the heterodimer is more favorable in terms of entropy and enthalpy compared to formation of the homodimer.

[0126] Accordingly, in some embodiments, the amino acid mutations and / or modifications that promote heterodimerization create steric hindrance between the contacting residues (e.g., by a "knobs-into-holes" approach), create favorable electrostatic interactions between the two Fc regions, introduce cysteine residues capable of forming disulfide bonds, and / or modify the hydrophilicity and hydrophobicity of residues at the interface between the two Fc regions.

[0127] In preferred embodiments, the amino acid mutations that promote heterodimerization are "Fc knob" and "Fc hole" mutations. In preferred embodiments, the "Fc knob" and "Fc hole" mutations are present in the CH3 domain.

[0128] In some embodiments, the first and second Fc regions are derived from a human IgGl immunoglobulin and comprise "Fc X" and "Fc Y" having mutations in the CH3 domain, wherein the "Fc X" and "Fc Y" mutations are selected from the combinations (or conservative substitutions thereof) shown in Table 2.

[0129] Table 2: "Fc X" and "Fc Y" mutations

[0130]

[0131]

[0132] *wherein the amino acid numbering is according to the EU index as in Kabat.

[0133] In preferred embodiments, "Fc Y" is a "Fc hole" having mutations Y349C, T366S, L368A, and Y407V, or conservative substitutions thereof, and "Fc X" is a "Fc knob" having mutations S354C and T366W, or conservative substitutions thereof, wherein the amino acid numbering is according to the EU index as in Kabat.

[0134] The term "EU index as in Kabat" refers to the numbering system for human IgGl EU antibodies described in Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. All amino acid positions cited in this application refer to EU index positions.

[0135] In some embodiments, the first Fc region has a“Fc knob” mutation and the second Fc region has a“Fc hole” mutation. In alternative and preferred embodiments, the first Fc region has a“Fc hole” mutation and the second Fc region has a“Fc knob” mutation.

[0136] It will be appreciated that these Fc regions can further comprise other amino acid modifications relative to a wild-type Fc region. Fc regions can be modified, for example, to increase the affinity of the IgG molecule for FcRn. WO 02 / 060919 discloses modified immunoglobulins comprising an Fc region having one or more amino acid modifications, and is incorporated herein by reference in its entirety. Methods of making Fc regions having one or more amino acid modifications are known in the art.

[0137] In some embodiments, the first and / or second Fc region can comprise one or more amino acid modifications that reduce or eliminate effector function of the Fc region. In some embodiments, the amino acid modifications reduce or circumvent cytotoxicity, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

[0138] In some embodiments, the first and / or second Fc region can comprise one or more amino acid modifications that increase the half-life of the heterodimeric fusion.

[0139] In some embodiments, the first and / or second Fc region comprises at least one of the following combinations of amino acid mutations:

[0140] (i) M252Y, S254T, and T256E, or conservative substitutions thereof;

[0141] (ii) L234F, L235Q, and K322Q, or conservative substitutions thereof;

[0142] (iii) L234F, L235E, and P331S, or conservative substitutions thereof;

[0143] (iv) M252Y, S254T, T256E, L234F, L235Q, and K322Q, or conservative substitutions thereof; or

[0144] (v) M252Y, S254T, T256E, L234F, L235E, and P331S, or conservative substitutions thereof,

[0145] wherein the amino acid numbering is according to the EU index as in Kabat.

[0146] In some embodiments, the first and / or second Fc region can comprise the amino acid mutations L234F, L235E and P331S or conservative substitutions thereof, wherein the amino acid numbering is according to the EU index as in Kabat.

[0147] In some embodiments, the Fc region comprising the "Fc knob" mutation has the sequence set forth in SEQ ID NO: 3 or a variant thereof, and the Fc region comprising the "Fc hole" mutation has the sequence set forth in SEQ ID NO: 4 or a variant thereof.

[0148] In some embodiments, the Fc region comprises a variant of SEQ ID NO: 3 with the amino acid mutation Y349C reverted to Y349, and a variant of SEQ ID NO: 4 with the amino acid mutation S354C reverted to S354, such that the Fc region is unable to form stable disulfide bonds.

[0149] In some embodiments, the Fc region comprises a variant of SEQ ID NO: 3 and / or a variant of SEQ ID NO: 4, wherein the first five residues DKTHTCPPC (SEQ ID NO: 69) are modified. In some embodiments, this region is replaced with the sequence DKTHTACPPC (SEQ ID NO: 70). In alternative embodiments, this region is replaced with the sequence GGAGGACPPC (SEQ ID NO: 71). In alternative embodiments, this region is replaced with the sequence ACPPC (SEQ ID NO: 72).

[0150] In alternative embodiments, the first and second heterodimerization domains are derived from an immunoglobulin Fab region. In some embodiments, the heterodimerization domain comprises a CH1 and a CL region. It has been found that a Fab region comprising L and Fd chains mediates efficient heterodimerization (Schoonjans R et al. (2000) J. Immunol. 165(12):7050-7057). Thus, in alternative embodiments, the heterodimerization domain comprises L and Fd chains. In some embodiments, the L and Fd chains heterodimerize to form a disulfide bridge stabilized heterodimer.

[0151] In yet further alternative embodiments, the first and second heterodimerization domains heterodimerize to form a parallel coiled coil. For example, heterodimeric coiled coils are described in Aronsson et al. (2015) Sci. Rep. 5: 14063. In some embodiments, the heterodimerization domain comprises amino acid mutations and / or modifications to prevent formation of undesirable fold assemblies and / or to promote formation of a parallel coiled coil.

[0152] The first and second heterodimerization domains (e.g., the first and second Fc regions) can form a half-life extension moiety. Thus, in some embodiments, the heterodimeric fusion of the application has an extended half-life compared to reference relaxin.

[0153] As used herein, the term "half-life" is used to refer to the time taken for the concentration of a fusion protein in plasma to reduce to 50% of its original level. The "half-life" of a protein in plasma can depend on different factors, e.g., the size of the protein, its stability, its clearance rate, turnover rate, proteolytic degradation in vivo, rate of absorption by the body or specific tissues, etc. Methods of determining the half-life of a protein are known in the art and are described in the Examples below.

[0154] The present inventors have shown that the heterodimeric fusion of the application having a first and second heterodimerization domain derived from an immunoglobulin Fc has a half-life of at least 5 hours in a mouse model (see Example 6). In comparison, the half-life of human relaxin-2 in humans after IV administration is about 0.09 + / - 0.04 hours, i.e., 5.4 + / - 2.4 minutes (Chen SA et al. (1993) Pharm. Res. 10(6):834-838).

[0155] It will be appreciated that an extended half-life is advantageous as it allows the therapeutic protein to be administered according to a safe and convenient dosing regimen, e.g., a lower dose that can be administered less frequently. Furthermore, the achievement of a lower dose can provide further advantages, e.g., provide an improved safety profile and / or activate multiple in vivo mechanisms of action.

[0156] Linker

[0157] One or both of the relaxin A and B chains can be linked to their respective heterodimerization domain via a linker polypeptide. In some embodiments, the relaxin A chain is linked to the first heterodimerization domain (e.g., the first Fc region) via a linker polypeptide, and the relaxin B chain is linked to the second heterodimerization domain (e.g., the second Fc region) via a linker polypeptide.

[0158] The linker polypeptide can be of any suitable length, for example, from about 6 to 40 amino acids in length, preferably from about 6 to 21 amino acids in length. In some embodiments, the linker polypeptide is at least 6 amino acid residues in length, preferably at least 11 amino acids in length, preferably at least 16 amino acids in length. In some embodiments, the linker polypeptide is less than 40 amino acids in length. Linker polypeptides of different or identical length can be used for each arm of the heterodimeric fusion of the application. In some embodiments, at least one linker polypeptide is 21 amino acids in length. In preferred embodiments, both linker polypeptides are 21 amino acids in length. The linker polypeptide can have any amino acid sequence. Linker polypeptides of different or identical amino acid composition can be used for each arm of the heterodimeric fusion of the application.

[0159] In some embodiments, one or, preferably, both linker polypeptides comprise a proline and alanine repeat sequence (PA)x(SEQ ID NO: 73), preferably wherein x is 3 to 15, preferably wherein the linker polypeptide is greater than 16 amino acids in length, preferably wherein the linker polypeptide consists of the 21 amino acid sequence PAPAPAPAPAPAPAPAPAPAG (SEQ ID NO: 6).

[0160] In some embodiments, one or, preferably, both linker polypeptides comprise a glycine and serine repeat sequence, for example, those described in Chen X et al. (2013) Adv. Drug. Deliv. Rev. 65(10): 1357-1369. In some embodiments, one or both linker polypeptides comprise the motif (GGGGS)n(SEQ ID NO: 74), wherein n can be between 1 and 8, for example, wherein n is 4. In some embodiments, one or more linker polypeptides consists of the 21 amino acid sequence GGGGSGGGGSGGGGSGGGGGS (SEQ ID NO: 5). In certain embodiments, both linker polypeptides consist of the 21 amino acid sequence GGGGSGGGGSGGGGSGGGGGS (SEQ ID NO: 5).

[0161] In some embodiments, one linker polypeptide comprises a proline and alanine repeat sequence as described herein and the other linker polypeptide comprises a glycine and serine repeat sequence as described herein.

[0162] Alternatively, one or both of the relaxin A and B chains can be linked to their respective heterodimerization domains via a synthetic linker polypeptide, such as a polyethylene glycol (PEG) polymer chain. Thus, a relaxin A chain can be linked to a first heterodimerization domain (e.g., a first Fc region) via a synthetic linker, such as a polyethylene glycol (PEG) polymer chain, and a relaxin B chain can be linked to a second heterodimerization domain (e.g., a second Fc region) via a synthetic linker, such as a polyethylene glycol (PEG) polymer chain, wherein the synthetic linker can be covalently or non-covalently attached to the heterodimerization domain (e.g., Fc region). PEGylation (the process of attaching a PEG polymer chain to a molecule) can be performed according to methods known in the art.

[0163] Stability

[0164] The present inventors have shown that the heterodimeric fusions of the present application have unexpectedly superior physical and chemical stability. Thus, in some embodiments, the heterodimeric fusions of the present application have superior physical and / or chemical stability compared to reference relaxin proteins.

[0165] Physical stability of relaxin can be determined by measuring purity and aggregation, for example by HP-SEC as in Example 9. Chemical stability of relaxin can be determined by measuring fragmentation and modification of the molecule, for example by LC-MS as in Example 9.

[0166] Surprisingly, the present inventors have shown that the heterodimeric fusions of the present application have superior physical and chemical stability compared to recombinant Fc-fused relaxin in which relaxin A and B are single chain fused (in complete contrast to the present application in which relaxin A and B are in separate fusion polypeptides). WO 2013 / 004607 describes recombinant single chain relaxin fusion polypeptides fused to an immunoglobulin Fc region, for example, the fusion polypeptides referred to herein as RELAX0127 and RELAX0128. Thus, in some embodiments, the heterodimeric fusions of the present application have superior physical and / or chemical stability compared to RELAX0127 and RELAX0128.

[0167] In addition to the first and second heterodimerization domains, the heterodimeric fusion can comprise a half-life extending moiety. In some embodiments, the half-life extending moiety is a protein half-life extending moiety. The protein half-life extending moiety can be selected from the group consisting of an Fc region of an immunoglobulin, an albumin binding domain, and serum albumin. In further embodiments, the half-life extending moiety is a chemical entity other than a protein or peptide, such as a polyethylene glycol (PEG) polymer chain.

[0168] The half-life extension moiety can be attached at the N-terminus or C-terminus of the first or second heterodimerization domain. In some embodiments, the half-life extension moiety is attached at the N-terminus of the first or second heterodimerization domain. In other embodiments, the half-life extension moiety is attached at the C-terminus of the first or second heterodimerization domain. Methods of attaching a half-life extension moiety to a heterodimeric fusion are known in the art. For example, the half-life extension moiety can be attached by chemical conjugation or recombinant techniques. The half-life extension moiety can be attached to the heterodimeric fusion directly or through a linker, e.g., a linker polypeptide. The use of a linker polypeptide can be particularly suitable when the fusion polypeptide comprises a protein half-life extension moiety, e.g., an Fc region.

[0169] Exemplary Embodiments

[0170] The heterodimeric fusions of the present invention can have a variety of formats and / or sequences.

[0171] The term "fusion polypeptide of the invention" can be used to refer to a first heterodimerization domain fused to a relaxin A chain, and / or a second heterodimerization domain fused to a relaxin B chain. The fusion polypeptide of the invention can be a recombinant fusion polypeptide, i.e., it has been produced by recombinant DNA technology.

[0172] In preferred embodiments, the C-terminus of the first heterodimerization domain (e.g., first Fc region) is linked to the N-terminus of the relaxin A chain, and the C-terminus of the second heterodimerization domain (e.g., second Fc region) is linked to the N-terminus of the relaxin B chain. In some embodiments, the relaxin A chain polypeptide and / or the relaxin B chain polypeptide has a free C-terminus.

[0173] In alternative embodiments, the N-terminus of the first heterodimerization domain (e.g., first Fc region) is linked to the C-terminus of the relaxin A chain, and the N-terminus of the second heterodimerization domain (e.g., second Fc region) is linked to the C-terminus of the relaxin B chain. In some embodiments, the relaxin A chain polypeptide and / or the relaxin B chain polypeptide has a free N-terminus.

[0174] The heterodimeric fusions of the present invention can further comprise one or more Fabs. In some embodiments, the heterodimeric fusion comprises one Fab linked to the N-terminus of the first heterodimerization domain (e.g., first Fc region) and a second Fab linked to the N-terminus of the second heterodimerization domain (e.g., second Fc region).

[0175] The heterodimeric fusion of the application can further comprise a second relaxin A chain polypeptide or variant thereof and a second relaxin B chain polypeptide or variant thereof. In some embodiments, the second relaxin A chain polypeptide or variant thereof is linked to the N-terminus of a first heterodimerization domain (e.g., a first Fc region), and the second relaxin B chain polypeptide or variant thereof is linked to the N-terminus of a second heterodimerization domain (e.g., a second Fc region), optionally wherein the second relaxin A chain is linked to the first heterodimerization domain (e.g., a first Fc region) via a linker (e.g., a linker polypeptide), and the second relaxin B chain is linked to the second heterodimerization domain (e.g., a second Fc region) via a linker (e.g., a linker polypeptide).

[0176] Thus, in some embodiments, the format of the heterodimeric fusion is selected from:

[0177] (i) FcX-con-A / FcY-con-B (e.g., see Figure 1 ) ;

[0178] (ii) FcX-con-B / FcY-con-A (e.g., see Figure 1 ) ;

[0179] (iii) A-con-FcX / B-con-FcY (e.g., see Figure 1 ) ;

[0180] (iv) B-con-FcX / A-con-FcY (e.g., see Figure 1 ) ;

[0181] (v) Fab-FcX-con-A / Fab-FcY-con-B (e.g., see Figure 1 ) ;

[0182] (vi) Fab-FcX-con-B / Fab-FcY-con-A;

[0183] (vii) A-con-FcX-con-A / B-con-FcY-con-B (e.g., see Figure 1 ) ;

[0184] (viii) B-con-FcX-con-B / A-con-FcY-con-A;

[0185] (ix) FcX-con-B-L-A and FcY, optionally FcY-con-B-L-A (e.g., see Figure 1 ) ;

[0186] (x) FcY-con-B-L-A and FcX, optionally FcX-con-B-L-A;

[0187] (xi) FcX-con-A-L-B and FcY, optionally FcY-con-A-L-B; and

[0188] (xii) FcY-con-A-L-B and FcX, optionally FcX-con-A-L-B,

[0189] wherein:

[0190] FcY is an immunoglobulin Fc region having an "Fc knob" amino acid mutation and / or modification, preferably comprising a CH3 domain having the amino acid mutations Y349C: T366S: L368A: Y407V or conservative substitutions thereof;

[0191] FcX is an Fc region having an "Fc hole" amino acid mutation and / or modification, preferably comprising a CH3 domain having the amino acid mutations S354C: T366W or conservative substitutions thereof;

[0192] "con" is a linker polypeptide;

[0193] B is a relaxin B chain or variant thereof;

[0194] A is a relaxin A chain or variant thereof; and

[0195] L is a linker polypeptide, preferably having the amino acid sequence GGGSGGGSGG (SEQ ID NO: 60).

[0196] In another aspect, the present application provides a heterodimeric fusion comprising:

[0197] (i) X-B-L-A and Y, optionally Y-B-L-A; or

[0198] (ii) Y-B-L-A and X, optionally X-B-L-A;

[0199] wherein:

[0200] X and Y are heterodimerization domains as described herein;

[0201] B is a relaxin B chain or variant thereof, for example a relaxin-2 B chain or variant thereof;

[0202] A is a relaxin A chain or variant thereof, for example a relaxin-2 A chain or variant thereof; and

[0203] L is a linker polypeptide, preferably having the amino acid sequence GGGSGGGSGG (SEQ ID NO: 60),

[0204] wherein X and Y heterodimerize, and wherein the heterodimeric fusion has relaxin activity.

[0205] In yet another aspect, the present application provides a heterodimeric fusion comprising:

[0206] (i) X-A-L-B and Y, optionally Y-A-L-B or

[0207] (ii) Y-A-L-B and X, optionally X-A-L-B,

[0208] wherein:

[0209] X and Y are heterodimerization domains as described herein;

[0210] A is a relaxin A chain or variant thereof, for example a relaxin-2 A chain or variant thereof;

[0211] B is a relaxin B chain or variant thereof, for example a relaxin-2 B chain or variant thereof; and

[0212] L is a linker polypeptide, preferably having the amino acid sequence GGGSGGGSGG (SEQ ID NO: 60),

[0213] wherein X and Y heterodimerize, and wherein the heterodimeric fusion has relaxin activity.

[0214] In particularly preferred embodiments, the heterodimeric fusion comprises the fusion polypeptide Rlx011DD as set forth in SEQ ID NO: 11 and Rlx014DD as set forth in SEQ ID NO: 20. In alternative preferred embodiments, the heterodimeric fusion comprises the fusion polypeptide Rlx013DD as set forth in SEQ ID NO: 17 and Rlx012DD as set forth in SEQ ID NO: 14.

[0215] In one aspect of the application, there is provided a heterodimeric fusion comprising a combination of fusion polypeptides selected from the combinations of FcX and FcY set forth in Table 3.

[0216] Table 3: Fusion polypeptide combinations in heterodimeric fusions of the present application

[0217]

[0218]

[0219]

[0220] * Table 1 shows the sequences of the listed fusion polypeptides.

[0221] ** In this particular embodiment, the heterodimeric fusion is an IgG and comprises an additional polypeptide corresponding to the light chain set forth in SEQ ID NO: 54.

[0222] In one aspect, a heterodimeric fusion is provided comprising a fusion polypeptide of SEQ ID NO: 11 and SEQ ID NO: 20.

[0223] In an alternative aspect, a heterodimeric fusion is provided comprising a fusion polypeptide of SEQ ID NO: 17 and SEQ ID NO: 14.

[0224] The fusion polypeptides of the application can be produced by any method known in the art. In some embodiments, the fusion polypeptides of the application are produced by recombinantly expressing a nucleic acid molecule encoding the fusion polypeptide in a host cell.

[0225] An expression vector containing a nucleic acid molecule of the application can be constructed using methods known to those of skill in the art. Suitable vectors include, for example, a plasmid, a phagemid, a phage, or a viral vector.

[0226] A vector containing a nucleic acid molecule of the application can be transferred to a host cell by conventional techniques. Suitable host cells are known in the art. In some embodiments, the host cell is a mammalian cell, such as a HEK293 cell or a CHO cell.

[0227] Transfected cells can be cultured to produce the fusion polypeptides of the application by conventional techniques.

[0228] Once a fusion polypeptide of the application has been produced, e.g., by recombinant expression, it can be purified by any method known in the art. Exemplary protein purification techniques include chromatography (e.g., ion exchange, affinity, and / or size column chromatography), centrifugation, and differential solubility. The present application provides isolated fusion polypeptides, which are optionally isolated from a cell culture by at least one purification step.

[0229] Methods of treatment

[0230] The fusion polypeptides of the application can be provided in a pharmaceutical composition.

[0231] A pharmaceutical composition of the application can comprise one or more excipients. Pharmaceutically acceptable excipients are known in the art, see, e.g., Remington's Pharmaceutical Sciences (ed. Joseph P. Remington, 18thEdition, Mack Publishing Co., Easton, Pa.), which is incorporated herein in its entirety.

[0232] The present application encompasses therapies involving administration of the fusion polypeptides of the present application to an animal, particularly a mammal, such as a human, for the prevention, treatment, or amelioration of symptoms associated with a disease, disorder, or infection.

[0233] Accordingly, the fusion polypeptides or pharmaceutical compositions of the present application can be used in therapy, for example, for the treatment of a disease or disorder. Also provided is a method of treating a disease or disorder, the method comprising administering to a subject or patient in need thereof a therapeutically effective amount of a fusion polypeptide of the present application. The use or method can comprise administering a therapeutically effective regimen having a lower frequency of doses of the fusion polypeptide of the present application than a therapeutically effective dosing regimen of a wild-type relaxin molecule.

[0234] It will be appreciated that the fusion polypeptides of the present application can be used to treat cardiovascular diseases, for example, for the treatment of heart failure.

[0235] As used herein, the term "heart failure" includes acute heart failure, chronic heart failure (CHF), and acute decompensated heart failure (ADHF). The term "heart failure" can also include more specific diagnoses, for example, heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction, or heart failure with reduced ejection fraction (HFrEF).

[0236] The fusion polypeptides of the present application can also be used to treat renal diseases, pulmonary diseases, and fibrotic disorders, for example, fibrotic disorders of the kidney, heart, lung, and liver, and for wound healing (Sherwood OD (2004) Endocrine Reviews 25(2):205-234). The fusion polypeptides of the present application can also be used to reverse insulin resistance in diabetic patients (Bonner JS et al. (2013) Diabetes 62(9):3251-3260). The fusion polypeptides of the present application can also be used in different forms of pulmonary arterial hypertension. The fusion polypeptides of the present application can also be used in disorders that are a result or cause of arterial stiffness, reduced arterial elasticity, reduced arterial compliance and distensibility (including hypertension), renal disease, peripheral arterial disease, carotid and cerebrovascular disease (i.e., stroke and dementia), diabetes, microvascular disease leading to end-organ damage, coronary artery disease, and heart failure.

[0237] The fusion polypeptides and / or pharmaceutical compositions of the present application are suitable for parenteral administration to a subject or patient. In some embodiments, the subject or patient is a mammal, particularly a human.

[0238] Wild-type human relaxin-2 has a minute half-life in vivo. Thus, it must be administered by continuous intravenous infusion in hospitalized patients and presents severe side effects, including blood pressure reduction. In contrast, it is understood that embodiments of the fusion polypeptides and / or pharmaceutical compositions of the present application can be administered to a subject or patient by injection (e.g., by intravenous, subcutaneous, or intramuscular injection). In some embodiments, the fusion polypeptides and / or pharmaceutical compositions are administered by subcutaneous injection. Administration by injection, e.g., by subcutaneous injection, provides the benefit of greater comfort to the subject or patient and provides the opportunity for administration to subjects or patients outside of a hospital setting. In some embodiments, the fusion polypeptides or pharmaceutical compositions are administered by self-administration.

[0239] In some embodiments, the fusion polypeptides of the present application have an increased half-life compared to wild-type relaxin, which allows for lower total exposure on a molar basis. For example, the fusion polypeptides of the present application can be administered less frequently than wild-type relaxin, thus providing a more convenient dosing regimen.

[0240] The present application provides kits comprising the pharmaceutical compositions of the present application. The kits can include a package comprising the pharmaceutical compositions of the present application and instructions. In some embodiments, the pharmaceutical compositions of the present application are formulated in a single-dose vial or container closure system (e.g., a pre-filled syringe). Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of drugs or biological products, reflecting approval by the agency of the manufacture, use or sale of the

[0241] As used herein, the articles "a" and "an" can refer to one or more than one (e.g., at least one) of the grammatical objects of the article.

[0242] "About" can generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements obtained. An exemplary degree of error is within 10% of a given value or range of values, typically within 5% thereof.

[0243] Embodiments described herein as "comprising" one or more features can also be considered to be disclosed as corresponding embodiments "consisting of those features.

[0244] The term "pharmaceutically acceptable" as used herein means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0245] Concentrations, amounts, volumes, percentages, and other numerical values can be presented in a range format. It is to be understood that such range format is merely for convenience and brevity and should be construed as having been followed to the left and right of the colon. Only ranges of values are being given, as incorporating the upper and lower limits of those ranges or any sub-ranges therein cited as if explicitly written herein.

[0246] The above embodiments are to be understood as illustrative examples. Further embodiments are envisaged. It will be appreciated that any feature described in relation to any one embodiment can be used alone, or in combination with other features described, and can also be used in combination with one or more features of any other of the embodiments, or any combination of any other of the embodiments. Furthermore, equivalents and modifications not described above can also be employed without departing from the scope of the application, which is defined in the claims below.

[0247] Other examples and variations of the fusion polypeptides and methods described herein will be apparent to those skilled in the art in the context of the present disclosure.

[0248] Other examples and variations are within the scope of the present disclosure, as set out in the appended claims. All documents cited herein are incorporated by reference in their entirety, including all data, tables, figures, and texts presented in the cited documents.

[0249] Examples

[0250] Example 1: Production of recombinant heterodimeric Fc relaxin-2 fusion proteins

[0251] The Fc relaxin-2 fusion proteins described herein have been designed using the heterodimerization properties of knob-in-hole Fc domains (Fc knob and Fc hole) to induce proper folding and heterodimerization of the chain A and chain B of relaxin-2.

[0252] More precisely, the relaxin-2 chain A and chain B have been genetically fused to two complementary Fc (at the N- and / or C-terminus of the Fc) via linkers, as Figure 1 indicated. CHO cells are then co-transfected with two expression vectors comprising each of the single Fc-relaxin chains (A and / or B). The two complementary Fc moieties assemble within the CHO cells and thus facilitate the assembly and proper folding of relaxin-2. As demonstrated in Example 2 below, disulfide bonds are then formed between the complementary Fc chains and between chain A and chain B, thereby reconstituting the native relaxin-2 structure.

[0253] The heterodimeric Fc relaxin-2 fusion proteins are secreted in the supernatant and then purified by affinity chromatography using an automated system, in which the Fc region of the protein binds to the column matrix.

[0254] Example 2: LC-MS analysis of Fc relaxin-2 clamshell heterodimers

[0255] LC-MS analysis was performed on both non-reduced and reduced deglycosylated Fc- relaxin-2 heterodimers. For deglycosylation, samples were diluted to 1 mg / ml and buffered using 10 mM Tris-Cl at pH 7.80. Peptide-N-glycosidase F (PNGase F) (Roche) was added to the samples at a concentration of 1 unit of enzyme per 50 pg of Fc-relaxin-2 and incubated overnight at 37 °C. For non-reduced analysis, samples were diluted to 0.05 mg / ml in water and 20 pL was loaded into LC-MS certified total recovery vials with pre-slit caps (Waters part number: 186005663CV). For reduced analysis, 10 mM TCEP was added and samples were incubated at 37 °C for an additional 30 minutes prior to analysis.

[0256] Experiments were performed using an ACQUITY I-Class UPLC coupled to a Xevo G2-XS Q-TOF instrument (Waters, Milford, MA), both operated using UNIFI Scientific Information System. For the LC system, solvent A was water with 0.1% formic acid and solvent B was acetonitrile with 0.1% formic acid (both UPLC-MS grade, BioSolve). The UV detector was set to measure at wavelengths of 220 nm and 280 nm and the vials were placed in a sample chamber maintained at a temperature of 4 °C. A volume of 1 pL was injected onto a reverse phase ACQUITY UPLC protein BEH C4 column, a BEH C4 1.7 pm, 2.1 x 50 mm column (Waters part number: 186004495) and the proteins were eluted using an increasing gradient of solvent B from 5% to 75% over 6 minutes.

[0257] The mass spectrometer was calibrated from 500-5000 m / z by infusing 2 pg / pL sodium iodide in 50% 2-propanol and lockspray was 200 pg / pL Leucine Enkephalin. The instrument was operated in positive ionization mode and instrument mode as follows: Capillary Voltage = 3.0 V; Sample Cone Voltage = 40 V; Source Temperature = 120 °C; Desolvation Temperature = 450 °C; Cone Gas Flow = 120 L / h; Desolvation Gas Flow = 1000 L / h; Mass Range = 500-5000 m / z, Scan Time = 1.0 sec.

[0258] Data were processed in UNIFI software. Spectra were merged from the retention time in the chromatogram where the protein of interest eluted. Raw data were background subtracted and deconvoluted using the MaxEnt 1 algorithm for macromolecules. Experimental data were compared to the mass of the theoretical sequence, in which disulfide bridges were considered for non-reduced analysis and free cysteines for reduced analysis. Deamidation of asparagines (+1 Da) was also considered after peptid-N-glycosidase F deglycosylation.

[0259] LC-MS analysis confirmed that disulfide bonds were formed between the complementary Fc chains and between chain A and chain B, reconstituting the native relaxin-2 structure. As an example, Figure 2 A shows the LC-MS data for RELAX0019 and RELAX0023. Non-reduced analysis confirmed the formation of the heterodimer of the expected mass of 58932 Da and 59361 Da for RELAX0019 and RELAX0023, respectively: no homodimer was detected. Reduced analysis Figure 2 B) confirmed the sequence identity of the two chains and showed that they were not modified.

[0260] Non-reduced peptide mapping to identify disulfide bonds

[0261] The heterodimer Fc-relaxin (50 pg) was placed into a clean sample tube and diluted in 17 pL of 100 mM sodium phosphate (pH 7.0). Alkylation of free cysteines was achieved by adding 0.5 pL of 5 mg / ml iodoacetamide, followed by incubation at room temperature for 20 minutes. After alkylation, an additional 2.5 pL of 100 mM sodium phosphate buffer (pH 7.0) and 2.5 pL of sodium chloride were added. Denaturation of the protein was achieved by adding 40 pL of 8.0 M guanidine hydrochloride and incubation at 37 °C for 30 minutes. Dilution was achieved by adding 125 pL of 100 mM sodium phosphate buffer (pH 7.0), followed by the addition of 0.5 pL of 40 mM EDTA. Endoproteinase Lys-C (Wako Chemicals) was reconstituted in water at a concentration of 1 mg / ml and 5 pL was added to the Fc-relaxin-2. Digestion was performed at 37 °C for 2 hours, after which time an additional 5 pL of Lys-C was added and incubation was continued for a further 2 hours. For peptide analysis, 42.5 pL of the sample was transferred to a UPLC vial and 2.5 pL of water was added. For reduction of disulfide bonds, 2.5 pL of 500 mM DTT was added to another 42.5 pL aliquot of the sample and left at room temperature for 15 minutes before LC-MS analysis.

[0262] Analysis of peptides was performed using an ACQUITY I-Class UPLC coupled to a Xevo G2-XS Q-TOF instrument (Waters Corporation, Milford, MA), both operated using UNIFI Scientific Information System. For the LC system, solvent A was water containing 0.1% formic acid, and solvent B was acetonitrile containing 0.1% formic acid (both UPLC-MS grade, Burdick & Jackson). The UV detector was set to measure at a wavelength of 214 nm, and the vials were placed in a sample chamber maintained at a temperature of 4°C. A volume of 10 μΐ was injected onto a reversed-phase ACQUITY BEH C18 column (Waters Corporation part number: 186003687), and the proteins were eluted using an increasing gradient of solvent B from 5% to 37% B over 73.5 minutes, then increasing to 60% B over a further 2.5 minutes. The column was held at 95% B for 5 minutes after 77.5 minutes.

[0263] The mass spectrometer was calibrated from 100-2600 m / z by infusion of 2 μg / μL sodium iodide in 50% 2-propanol, and the lockspray was 200 pg / μL leucine enkephalin. The instrument was operated in positive ionization mode and instrument mode, with the following key settings: Capillary voltage = 3.0 V; Sample cone voltage = 25 V; Source temperature = 100 °C; Desolvation temperature = 250 °C; Cone gas flow = 0 L / h; Desolvation gas flow = 500 L / h; Mass range = 100-2600 m / z, Scan time = 0.5 sec.

[0264] Data were processed in UNIFI software by entering the sequence with the expected disulfide bonds and performing a search for matching Lys-C generated peptides. The chromatograms obtained in the absence and presence of reducing agent were overlaid, verifying that the identified disulfide bonded peptides were no longer observed once reduced.

[0265] Peptides were identified that matched the expected mass of relaxin-2 peptides with disulfide bonds incorporated into both Chain A and Chain B, as shown at the top of Figure 3 (SLSLSPGGGGGSGGGGSGGGGSGGGGGSQLYSALANKCCHVGCTK = LCGRELVRAQIAICGMSTWS = RSLARFC (SEQ ID NOs 75-77, respectively), with an expected mass of 6836.23 Da including 3 disulfide bonds). Figure 3 (A-D) show the identification of this peptide for RELAX0019, and demonstrate that the peptide is no longer observed when reducing agent is added: panels A and B show extracted ion chromatograms in the absence and presence of DTT, and panels C and D show the corresponding mass spectra of the peptide. Figure 3(E-H) show the identification of the same peptide for RELAX0023 and confirm that this peptide is no longer observed when a reducing agent is added: panels E and F show the extracted ion chromatograms in the absence and presence of DTT, and panels G and H show the corresponding mass spectra of the peptide. These data confirm that relaxin chain A and chain B interact through disulfide bonds within the heterodimer RELAX0019 and RELAX0023.

[0266] Example 3: In vitro activity of Fc-Relaxin-2 fusion proteins (cell-based cAMP activity assay)

[0267] The biological activity of the relaxin-2 fusion polypeptides produced as described above, e.g., stimulating one or more cellular receptor responses, is tested by the following methods.

[0268] Stable cell lines expressing human or mouse receptors produced in CHO cells are purchased from DiscoverX.

[0269] -cAMP Hunter TM CHO-K1 RXFP1 Gs, cell line (DiscoverX catalog #95-0127C2)

[0270] -cAMP Hunter TM CHO-K1 RXFP2 Gs cell line (DiscoverX catalog #95-0140C2)

[0271] -cAMP Hunter TM CHO-K1 mRXFP1 Gs cell line (DiscoverX catalog #95-0180C2)

[0272] Activation of these receptors leads to the production of downstream cAMP second messenger that can be measured in functional activity assays.

[0273] Routine cAMP assays are performed using the following bovine serum albumin (BSA)-based assay buffer: Hanks Balanced Salt Solution (Sigma #H8264) supplemented with 0.1% BSA (Sigma #A9418) and 0.5 mM IBMX (Sigma #I7018), adjusted to pH 7.4 with 1 M NaOH.

[0274] Frozen vials of cells expressing the receptor of interest are quickly thawed in a water bath, transferred to pre-warmed cell culture medium and spun at 240 x g for 5 minutes. Cells are resuspended at an optimized concentration (e.g., 3.33 x 10 4hRXFP1) were resuspended in cell culture medium and 30 pL of cell suspension was added to poly-D-lysine coated 384-well plates (Greiner #781946) and allowed to adhere overnight. The next day, the medium was removed from the plates and replaced with 5 pL assay buffer. An 11-point serial dilution of test recombinant peptide or Fc fusion sample was added to the cells using a non-contact liquid dispenser (ECHO TM , Labcyte). All sample dilutions were made in duplicate. An additional 5 pL of assay buffer was added to each well and the plates were incubated for 30 minutes at room temperature.

[0275] cAMP levels were measured using a commercially available cAMP Dynamic G S LOI kit (Cisbio, Cat. No. 62AM4PEJ) following a two-step protocol as recommended by the manufacturer. Briefly, the anti-cAMP cryptate (donor fluorophore) and cAMP-d2 (acceptor fluorophore) were each made separately by 1 / 20 dilution in the conjugation and lysis buffer provided in the kit. 5 pL of anti-cAMP cryptate was added to all wells of the assay plate and 5 pL of cAMP-d2 was added to all wells except the non-specific binding (NSB) wells to which conjugation and lysis buffer was added. The plates were incubated for one hour at room temperature before reading on an Envision (Perkin Elmer) using an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm. Data was converted to % AF then to % activation of the maximal natural agonist response as described in the manufacturer’s guidelines and analyzed by 4-parameter logistic fit to determine EC50 values. In the case of hRXFP1 cells, these results were compared to the corresponding results for recombinant hrelaxin-2 (R&D Systems, Cat. No. 6586RN); in the case of mRXFP1 cells, to the corresponding results for mrelaxin-1 (R&D Systems, Cat. No. 6637RN); and in the case of hRXFP2 cells, to the corresponding results for INSL3 (R&D Systems, Cat. No. 4544NS).

[0276] Data analysis was performed using statistical analysis software (GraphPad Prism, version 6).

[0277] The biological activity of the constructs tested is provided in Table 4 and Figure 4 Table 4 has summarized the average EC50 measurements from several assays for both recombinant human relaxin-2 and the fusion polypeptides.

[0278] RELAX0013, RELAX0014 and RELAX0010 are reference proteins, wherein RELAX0013 is recombinant human relaxin-2, RELAX0014 is recombinant murine relaxin-1 and RELAX0010 is a single chain fusion protein comprising Chain A, a 15 amino acid linker, Chain B, a 15 amino acid linker and an Fc comprising the amino acid sequence of SEQ ID NO. 8, described in WO2018 / 138170.

[0279] Table 4: Biological activity of heterodimeric Fc relaxin fusion polypeptides (n: number of repeats).

[0280]

[0281] From the results presented in Table 4, it can be concluded that the potency of the tested heterodimeric Fc relaxin fusion proteins is not as good as the single chain fusion RELAX0010 or recombinant human relaxin-2 peptide, but they still retain a high level of biological activity (in the human RXFP1 cell line, ranging from about 10 pM to about 80 pM).

[0282] These results show that the relaxin A and B chains can be fused to either / both termini (the linker can be attached to the N or C terminus of the relaxin chain) and to either chain of the heterodimeric Fc (X or Y) and retain biological activity. Thus, the formats of the heterodimeric Fc relaxin fusion proteins described herein constitute robust formats for generating long half-life active relaxin.

[0283] The presence of a disulfide bond to stabilise the heterodimeric Fc does not affect the potency of the fusion protein (compare RELAX0023 with RELAX0021 and RELAX0024 with RELAX0022).

[0284] The two upper hinge regions used (GGAGGA (SEQ ID NO: 78) and native DKTHT (SEQ ID NO: 79)) do not affect potency (compare RELAX0023 with RELAX0019 and RELAX0024 with RELAX0020). The exact amino acid sequence of the upper hinge is not important for the activity of the fusion protein.

[0285] Example 4: Effect of linker composition and length in heterodimeric relaxin-2 Fc fusion proteins

[0286] Linkers can consist of glycine and serine residues (GS), or can consist of proline and alanine repeats (PA). Linkers used herein are 6 to 21 residues in length. An example of a long GS linker is: GGGGSGGGGSGGGGSGGGGGS (SEQ ID NO: 5) (21 amino acids). An example of a long PA linker is: PAPAPAPAPAPAPAPAPAPAG (SEQ ID NO: 6) (21 amino acids).

[0287] Linkers of varying length and composition can be placed on each Fc chain of a heterodimeric relaxin-2 Fc fusion polypeptide.

[0288] Examples of heterodimeric relaxin-2 Fc fusion proteins with various linkers are shown in Table 5. This table also shows information on developability / manufacturability (expressed yield and percentage of monomeric / non-aggregated relaxin-2 Fc fusion protein after protein A capture from cell culture supernatant) and biological activity.

[0289] Table 5: Effect of linkers on biological activity and developability characteristics of heterodimeric Fc relaxin-2 fusion proteins during small scale expression.

[0290]

[0291]

[0292] The length and composition of the linker does have an impact on the developability aspects of the molecule. As shown in Table 5, heterodimeric relaxin-2 Fc fusion polypeptides with PA linkers of less than or equal to 16 amino acids did not express well. In contrast, a 21 residue long PA linker significantly increased expression yield. Expression yield was more consistent for constructs with GS linkers.

[0293] Heterodimeric relaxin-2 Fc fusion proteins with short and asymmetric (different) linkers retained potency. Reduced biological activity was only observed in fusion proteins with low monomer content (RELAX0109, RELAX0110 and RELAX0111).

[0294] Example 5: Point mutations in the relaxin-2 sequence

[0295] Relaxin single point mutant analogues were prepared as heterodimeric Fc relaxin-2 fusion proteins. Table 6 shows examples of such molecules that retained potency and favourable developability characteristics.

[0296] The targeted natural residues are positively charged and can be susceptible to proteolysis, but do not participate in relaxin binding to its receptor.

[0297] For example, R22X analog heterodimer Fc relaxin-2 fusion proteins consistently appear to have improved developability / manufacturability characteristics.

[0298] Table 6: Examples of relaxin-2 analogs that retain potency and favorable developability characteristics during small scale expression.

[0299]

[0300] The results presented in Table 6 demonstrate that some variability in the amino acid sequence of the relaxin-2 chain A is tolerated without loss of potency while retaining favorable developability characteristics.

[0301] Example 6: PK profiles of Fc-relaxin-2 fusion proteins

[0302] Pharmacokinetic (PK) profiles of relaxin-2 fusion polypeptides are determined using a relaxin ELISA assay and / or a cAMP assay. 6-10 week old male C57BL / 6J (Jax) mice (Jackson Laboratories) are administered relaxin-2 fusion polypeptides at 6 mg / kg via subcutaneous (SC) and / or intravenous (IV) routes. For IV route administration, serum samples are collected at 5 minutes, 30 minutes, and 60 minutes following drug administration, followed by 3 hours and / or 6 hours and / or 8 hours and 24 hours, followed by a series of at least 1 day intervals up to 21 days. For SC route administration, a similar schedule is followed, with collection at a lower frequency for the first 8 hours; for example, the first sample is collected at 30 minutes, then at 3 hours, 8 hours, 24 hours, 30 hours, and 48 hours, followed by a series of at least 1 day intervals up to 21 days. Samples are collected by cardiac puncture into serum tubes and held at room temperature for 15 to 30 minutes, then centrifuged at 10,000 rpm for 10 minutes within 30 minutes of collection. Aliquots of samples are stored at < -80°C and later tested by ELISA or cAMP activity assay.

[0303] For most molecules, PK samples were tested in ELISA using anti-h relaxin-2 capture (pre-coated human relaxin-2 Quantikine ELISA kit, R&D Systems, Cat. No. DRL200) and anti-human Fc detection antibody (AU003 labeled with HR) except for RELAX0010 (described in WO 2018 / 138170) which was tested in ELISA using anti-human Fc capture and anti-h relaxin-2 detection (using polyclonal HR-labeled antibody from human relaxin-2 ELISA kit (R&D Systems, Cat. No. DRL200)). In both assays, plates coated with capture antibody were blocked with 100 pL of RD1-19 assay diluent at room temperature for one hour. 50 pL of standard or sample was added to each well and incubated at room temperature for two hours. The samples were aspirated and the wells were washed three times with assay wash buffer. 50 pL of HR-labeled detection antibody was added to each well, diluted 1 : 1000 in PBS / 1% BSA in the case of anti-human Fc specific detection, or used undiluted in the case of anti-h relaxin-2 detection. After one hour of incubation at room temperature and three washes, 50 pL / well of TMB (SureBlue Reserve KPL 53-00-03) was added and the reaction was stopped by the addition of 50 pL / well of TMB stop solution (KPL 50-85-06) once color change occurred.

[0304] Bioactivity of PK samples in a cell-based cAMP activity assay.

[0305] Serum samples collected from animals as described above were tested for bioactivity, measuring functional relaxin-2, to assess the integrity of the Fc-relaxin-2 fusion polypeptides. A stable cell line expressing human RXFP1 receptor produced in CHO cells was purchased from Dissolvo Kos. Activation of this receptor leads to the production of downstream cAMP second messenger that can be measured in a functional activity assay.

[0306] The cAMP assay was performed using the following bovine serum albumin (BSA)-based assay buffer: Hank’s Balanced Salt Solution (Sigma #H8264) supplemented with 0.1% BSA (Sigma #A9418) and 0.5 mM IBMX (Sigma #I7018), adjusted to pH 7.4 with 1 M NaOH.

[0307] Dose solutions of relaxin-2 fusion polypeptide or recombinant relaxin-2 peptide (R&D Systems, Cat# 6586-RN) were diluted in assay buffer and a non-contact liquid dispenser (ECHO, Labcyte) was used to generate an 11-point standard curve of four matrix concentrations. The matrix used was blank serum from the mock-dosed animals and was added to the wells manually at twice the desired concentration and allowed to add cells. Test samples were transferred from serum tubes to a 384-well source plate which was passed through a non-contact liquid dispenser (ECHO, Labcyte) to set up four dilutions in assay buffer. All sample dilutions were made in duplicate.

[0308] Frozen vials of cells expressing hRXFP1 were rapidly thawed in a water bath, transferred to pre-warmed cell culture medium and spun at 240xg for 5 minutes. Cells were resuspended in 8 mL cell culture medium, seeded in a T75 flask containing 10 mL of medium and allowed to adhere overnight. The next day, cells were detached using accutase and spun at 240xg for 5 minutes. The resulting cell pellet was resuspended at an optimized concentration and 2.5 μL of cell suspension was added to each well of the assay plate using a Combi-drop dispenser.

[0309] cAMP levels were measured using a commercially available cAMP Dynamic 2HTRF kit (Cisbio, Cat# 62AM4PEJ) following a two-step protocol as recommended by the manufacturer. Briefly, anti-cAMP cryptate (donor fluorophore) and cAMP-d2 (acceptor fluorophore) were each made separately by diluting 1 / 20 in the conjugation and lysis buffer provided in the kit. 2.5 μL of anti-cAMP cryptate was added to all wells of the assay plate and 2.5 μL of cAMP-d2 was added to all wells except the non-specific binding (NSB) wells to which conjugation and lysis buffer was added. The plate was incubated at room temperature for one hour before reading on an Envision (Perkin Elmer) using an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm. Data was converted to %ΔF as described in the manufacturer's guidelines and sample values were calculated from the linear portion of the standard curve.

[0310] Results and Conclusions

[0311] Figure 5 A summary of data from a series of in vivo PK experiments in which Fc- relaxin-2 polypeptide IV was administered to mice is shown. Data was normalized for the 5 minute time point.

[0312] The half-life of human relaxin-2 in humans after IV administration is approximately 0.09 + / - 0.04 hours, i.e. 5.4 + / - 2.4 minutes (Chen et al 1993). All of the recombinant relaxin Fc fusion polypeptides showed improved half-life compared to native relaxin-2. Fc-relaxin polypeptides in which the relaxin A and B chains were linked to different heterodimeric Fc chains (examples RELAX0019, RELAX0023, RELAX0034, RELAX0046 and RELAX0117) had improved PK characteristics compared to those in which the relaxin chain was linked to a linker (examples RELAX0010 and RELAX0009). However, as both linker-containing molecules RELAX0088 and RELAX0122 showed good in vivo stability, the presence of a linking linker between the relaxin A and B chains was not directly related to the rapid elimination of Fc-relaxin polypeptides in vivo per se.

[0313] Unexpected in this study was that the heterodimeric Fc-relaxin fusion polypeptides (RELAX0019, RELAX0023, RELAX0034, RELAX0046, RELAX0117, RELAX0088 and RELAX0122) all had significantly improved pharmacokinetic characteristics compared to the Fc-relaxin fusion polypeptides RELAX0010 and RELAX0009.

[0314] Example 7: Reversal of established hypertrophy and fibrosis by RELAX0019 and RELAX0023

[0315] Isoproterenol (15 mg / kg / day) was infused into C57B6 mice via mini-pumps for 10 days to induce cardiac hypertrophy and fibrosis. Mice infused with vehicle for the same duration were used as baseline controls. After 10 days, the mini-pumps were removed and the mice were given a new mini-pump containing r relaxin-2 (500 ug / kg / day), or the mice received the first of two biweekly (QW) subcutaneous injections of RELAX0019 (20 mg / kg) or RELAX0023 (20 mg / kg). After a 14-day treatment period, the mice were sacrificed and their hearts were collected for analysis of hypertrophy and fibrosis. Hearts from baseline control mice were collected after removal of the vehicle mini-pumps. Hypertrophy was determined as a measure of heart weight relative to tibia length, and fibrosis was established by quantifying collagen content relative to heart weight. In this model, infusion of isoproterenol significantly induced both hypertrophy and fibrosis. QW dosing of RELAX0019 and RELAX0023 returned isoproterenol-induced hypertrophy to baseline levels, as did constant infusion of r relaxin-2. All relaxin treatments also reduced cardiac fibrosis by over 50%. N=8 for each group. **p<0.01, ***p<0.001, ****p<0.0001

[0316] Recombinant relaxin Fc fusion proteins RELAX0019 and RELAX0023 were able to reverse hypertrophy and fibrosis in a similar manner to native h relaxin-2 Figure 6 ).

[0317] Example 8: Assessment of non-specific binding of Fc-relaxin-2 proteins using baculovirus ELISA.

[0318] RELAX proteins were expressed in CHO cells and purified as described above. The baculovirus ELISA developed to assess non-specific binding of the monoclonal antibodies (reference: Hotzel et al., 2012 mAbs 4:6, 753-760) was adapted to determine non-specific binding of Fc- relaxin polypeptides with modifications, whereby instead of calculating the “BV score” (baculovirus plate absorbance / blank plate absorbance), the non-specific binding was calculated as signal over background for the baculovirus plate and the blank plate, respectively (where the background is the value obtained in the absence of the Fc-relaxin polypeptide). This measure was introduced to reflect the increased non-specific binding of some Fc peptides to coated and uncoated (blank) plates (compared to the monoclonal antibody). Preparations of each protein were prepared at 100 nM or 10 nM in PBS (Gibco 14190-086) + 0.5% BSA (Sigma A9576) and used in duplicate for the ELISA assay on 96-well Nunc Maxisorp F plates coated overnight with 50 pL / well of 1% baculovirus extract in 50 mM sodium carbonate (BV plates) or with 50 mM sodium carbonate (blank plates) at 4°C. After washing with PBS, the plates were blocked with 300 pL / well of PBS + 0.5% BSA for 1 h at room temperature and washed three times with PBS. 50 pL / well of PBS + 0.5% BSA (background) or RELAX protein dilutions were added and incubated for 1 h at room temperature. After three washes in PBS, 50 pL / well of detection antibody (anti-human Fc-specific-HR Sigma A0170) diluted 1 :5000 in PBS + 0.5% BSA was added. The samples were incubated for 1 h at room temperature and the plates were washed three times in PBS. HR substrate-TMB (SureBlue Reserve KPL 53-00-03) was then added at 50 pL / well and after color change, the reaction was stopped by adding 50 pL / well of 0.5 M sulfuric acid. The absorbance was measured at 450 nm and the non-specific binding was determined for each sample. Non-specific binding (fold binding over background) was defined as the ratio of non-specific binding in the presence of the Fc relaxin-2 protein and in the absence of the Fc relaxin-2 protein (background). Data for Fc-relaxin-2 proteins tested at 2 different concentrations of 100 nM or 10 nM are shown in Table 7.

[0319] Table 7: Binding of Fc-relaxin fusion proteins at 100 nM and 10 nM in baculovirus ELISA (-001, -002, -003 refer to different batches of the same protein)

[0320]

[0321]

[0322]

[0323] As shown in Tables 7 and Figure 7 When the relaxin chains were attached to the C-terminus using the GS linker, the heterodimeric relaxin-2 Fc fusion polypeptides exhibited lower non-specific binding. Some asymmetric PA linkers, certain point mutations, and positioning of the relaxin chains at the N-terminus, particularly in the case of the bivalent molecule (RELAX0117), increased non-specific binding to both the blank and BV-coated plates. At both high (100 nM) and low (10 nM) concentrations, some Fc-relaxin proteins with particularly high non-specific binding exhibited greater non-specific binding to the blank plates compared to the BV-coated plates. Although the control molecules - the linker-containing bivalent RELAX0009, RELAX0010, RELAX0126, RELAX0127, and RELAX0128 - all demonstrated high non-specific binding, the presence of the linker between chain A and chain B of relaxin and the bivalency itself did not drive high non-specific binding, as evidenced by the low non-specific binding of RELAX0122.

[0324] Example 9: Stability in solution

[0325] The stability of RELAX0023 was assessed using high performance size exclusion chromatography (HP-SEC) and liquid chromatography-mass spectrometry (LC-MS) and compared to RELAX0127 and RELAX0128. HP-SEC with detection of absorbance at 280 nm can be used to measure purity, aggregation, and fragmentation. The molecule was buffer exchanged into the optimized formulation composition and then concentrated up to 10 mg / mL. All samples were placed under stress temperature conditions (40 °C) for up to 4 weeks. At 1, 2, and 4 week time points, samples were collected and injected into a size exclusion column and eluted with an aqueous mobile phase at a constant flow rate. Larger molecules are excluded from the pores of the size exclusion column to a greater extent than smaller molecules and thus elute earlier. Peaks that elute earlier than the monomer peak were recorded as aggregates. Peaks that elute after the monomer peak (excluding buffer-related peaks) were recorded as fragments. Results were recorded as percent purity, percent aggregates, and percent fragments and are shown in Table 9. Figure 8RELAX 0023 was the most stable molecule with a % purity loss of only 0.1% per month, while RELAX 0128 and RELAX 0127 were 7.7% and 9.3%, respectively. Both RELAX 0127 and RELAX 0128 showed signs of aggregation, however, the aggregation level of RELAX 0023 did not increase, indicating better physical solution stability. Fragmentation appeared to be the main factor in purity loss, with RELAX 0127 having 6.6% fragmentation per month and RELAX 0128 6.8%. RELAX 0023 had only 0.7% fragmentation per month. At the same time, after 4 weeks of storage at 40°C, the total peak area of RELAX 0128 decreased from 22,403 to 18,216 (19% decrease), while RELAX 0127 decreased from 22,225 to 18,823 (15% decrease). This significant loss of total peak area, coupled with high fragmentation rates, indicates that both molecules can be undergoing high levels of chemical degradation. It should be noted that this loss of total area has a large impact on the chromatogram profile of both molecules. This explains why RELAX 0128 and RELAX 0127 show lower percentages of aggregate at 4 weeks compared to previous time points, despite the apparent increase in aggregate peak area after storage. In contrast, the total peak area of RELAX 0023 decreased only 0.03% from 21,828 to 21,761, indicating a better stability profile compared to RELAX 0128 and RELAX 0127.

[0326] Further validation of the fragmentation of the molecules was performed by LC-MS using reduced mass analysis, which showed an increase in intensity of the fragment peaks of RELAX 0127 and RELAX 0128 after storage at 40°C (A). In contrast, the fragment peaks of RELAX 0023 remained unchanged after stress. Mass spectrometry under reducing conditions also showed modification of RELAX 0127 and RELAX 0128 over time, evidenced by the shift of peaks to larger masses and broadening of peaks indicating greater heterogeneity (B). In contrast, the intact mass spectrum of RELAX 0023 remained unchanged, indicating no modification had occurred. This study indicates that RELAX 0023 has superior physical and chemical stability compared to RELAX 0127 and RELAX 0128. Figure 9 Figure 9 B). In contrast, the intact mass spectrum of RELAX 0023 remained unchanged, indicating no modification had occurred. This study indicates that RELAX 0023 has superior physical and chemical stability compared to RELAX 0127 and RELAX 0128.

[0327] Example 10: PK profile of RELAX 0023 in cynomolgus monkeys

[0328] ​The pharmacokinetic (PK) profiles of RELAX0023 in cynomolgus monkeys were determined using an ELISA-based sandwich immunoassay. Twelve female cynomolgus monkeys were randomly assigned to four groups (n=3 per group) and administered RELAX0023. Animals in groups 1, 2, and 3 were administered RELAX0023 at SC doses of 0.1, 1, and 10 mg / kg, respectively. Animals in group 4 were administered RELAX0023 via intravenous bolus injection of 10 mg / kg. Serum samples were collected at 0.25 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 7 days, 14 days, and 21 days post-administration.

[0329] The assay plate was coated with goat anti-human IgG antibody and incubated with cynomolgus monkey serum from groups 1–4. RELAX0023 bound to the plate was detected by an HRP-conjugated anti-relaxin antibody. The cynomolgus monkey serum was diluted 1:10 before being added to the plate. The lower limit of quantitation (LOQ) in 100% serum was 0.010 μg / mL, and the upper limit of quantitation (UPQ) was 0.300 μg / mL.

[0330] Results and Conclusions

[0331] Figure 10 The mean serum concentration-time curves of RELAX0023 in cynomolgus monkeys after a single dose are shown. Following a single dose administered via SC, RELAX0023 exhibited linear pharmacokinetic activity (PK) across a dose range of 0.01 to 10 mg / kg. C was observed. max The dosage increased proportionally. For the 0.1, 1, and 10 mg / kg SC dose groups, the average C max The values ​​were 0.400, 4.69, and 34.8 μg / mL, respectively. AUC was also observed in the SC group from 0.1 mg / kg to 10 mg / kg. 0-last The value increased proportionally to the dose. For the 0.1, 1, and 10 mg / kg SC dose groups, the mean AUC was... 0-last The values ​​were 2.01, 25.5, and 193 μg / day / mL, respectively. Overall, RELAX0023 PK was linear in the range of 0.1 mg / kg to 10 mg / kg, with an average CL / F of 51.0 mL / day / kg and an average t... 1 / 2 The time to survival was 3.07 days. The estimated SC bioavailability of RELAX0023 was 88.2%. sequence list <110> MEDIMMUNE LIMITED <120> Heterodimeric relaxin fusion compounds and their uses <130> 201011-WO-PCT <140> <141> <150> 63 / 040,250 <151> 2020-06-17 <160> 140 <170> PatentIn version 3.5 <210> 1 <211> twenty four <212> PRT <213> Unknown sequence <220> <221> source <223> / Note="Description of the unknown sequence: relaxin A sequence" / <400> 1 Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 <210> 2 <211> 28 <212> PRT <213> Unknown sequence <220> <221> source <223> / Note="Description of the unknown sequence: relaxin B sequence" / <400> 2 Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 20 25 <210> 3 <211> 226 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 3 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 225 <210> 4 <211> 226 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 4 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 225 <210> 5 <211> twenty one <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 5 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Gly Ser 20 <210> 6 <211> twenty one <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 6 Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 1 5 10 15 Pro Ala Pro Ala Gly 20 <210> 7 <211> 312 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 7 Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala 35 40 45 Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala 50 55 60 Arg Phe Cys Ala Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 65 70 75 80 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Cys Pro Pro Cys Pro 85 90 95 Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 100 105 110 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 115 120 125 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 130 135 140 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 145 150 155 160 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 165 170 175 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 180 185 190 Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 195 200 205 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 210 215 220 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 225 230 235 240 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 245 250 255 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 260 265 270 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 275 280 285 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 290 295 300 Lys Ser Leu Ser Leu Ser Pro Gly 305 310 <210> 8 <211> 309 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 8 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr 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 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 245 250 255 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly Gly Gly Gly Ser Gly 260 265 270 Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile 275 280 285 Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly 290 295 300 Met Ser Thr Trp Ser 305 <210> 9 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 9 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 10 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 10 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 11 <211> 271 <212> PRT <213> Artificial Sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 11 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 12 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 12 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 13 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 13 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 14 <211> 275 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 14 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser 275 <210> 15 <211> 276 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 15 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <210> 16 <211> 276 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 16 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <210> 17 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 17 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 18 <211> 276 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 18 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <210> 19 <211> 276 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 19 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <210> 20 <211> 275 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 20 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser 275 <210> twenty one <211> 266 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> twenty one Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 245 250 255 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 <210> twenty two <211> 270 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> twenty two Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu 245 250 255 Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 270 <210> twenty three <211> 261 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> twenty three Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr 225 230 235 240 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 245 250 255 Leu Ala Arg Phe Cys 260 <210> 24 <211> 265 <212> PRT <213> Artificial Sequence <220> <221> Source <223> / Annotation="Description of artificial sequence: synthetic polypeptide" <400> 24 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met 225 230 235 240 Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile 245 250 255 Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 <210> 25 <211> 256 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 25 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 225 230 235 240 Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 245 250 255 <210> 26 <211> 260 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 26 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 225 230 235 240 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 245 250 255 Ser Thr Trp Ser 260 <210> 27 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 27 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 225 230 235 240 Ala Pro Ala Pro Ala Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 28 <211> 275 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 28 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 225 230 235 240 Ala Pro Ala Pro Ala Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser 275 <210> 29 <211> 266 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 29 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 225 230 235 240 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 245 250 255 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 <210> 30 <211> 270 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 30 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 225 230 235 240 Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu 245 250 255 Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 270 <210> 31 <211> 261 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 31 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Pro Ala Pro Ala Pro Ala Pro Ala Gly Ser Gln Leu Tyr 225 230 235 240 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 245 250 255 Leu Ala Arg Phe Cys 260 <210> 32 <211> 265 <212> PRT <213> Synthetic Sequence <220> <221> Source <223> / Annotation="Description of artificial sequence: synthetic polypeptide" <400> 32 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Pro Ala Pro Ala Pro Ala Pro Ala Gly Ser Ser Trp Met 225 230 235 240 Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile 245 250 255 Ala Ile Cys Gly Met Ser Thr Trp Ser 260 265 <210> 33 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 33 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Glu Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 34 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 34 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 His Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 35 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 35 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Leu Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 36 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 36 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Met Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 37 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 37 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys Glu Ser Leu Ala Arg Phe Cys 260 265 270 <210> 38 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 38 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys His Val Gly Cys Thr Lys His Ser Leu Ala Arg Phe Cys 260 265 270 <210> 39 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 39 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Ala Phe Cys 260 265 270 <210> 40 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 40 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Ile Phe Cys 260 265 270 <210> 41 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 41 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Met Phe Cys 260 265 270 <210> 42 <211> 271 <212> PRT <213> Artificial Sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 42 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Gln Phe Cys 260 265 270 <210> 43 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 43 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Ser Phe Cys 260 265 270 <210> 44 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 44 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Glu Cys 260 265 270 <210> 45 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 45 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Ile Cys 260 265 270 <210> 46 <211> 308 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 46 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gln Leu Tyr Ser 275 280 285 Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu 290 295 300 Ala Arg Phe Cys 305 <210> 47 <211> 308 <212> PRT <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: synthetic polypeptide" <400> 47 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr Trp Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gln Leu Tyr Ser 275 280 285 Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu 290 295 300 Ala Arg Phe Cys 305 <210> 48 <211> 273 <212> PRT <213> Artificial sequence <220> <221> Source <223> / note="Description of artificial sequence: Synthetic polypeptide" <400> 48 Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ala Ala Ala Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 50 55 60 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 65 70 75 80 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 85 90 95 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 100 105 110 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 115 120 125 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 130 135 140 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 145 150 155 160 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 165 170 175 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 180 185 190 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 195 200 205 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 210 215 220 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 225 230 235 240 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 245 250 255 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 260 265 270 Gly <210> 49 <211> 269 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 49 Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys Ala Ala Ala Gly Gly Gly Gly Ser 20 25 30 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 35 40 45 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 50 55 60 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 65 70 75 80 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 85 90 95 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 100 105 110 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 115 120 125 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 130 135 140 Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser 145 150 155 160 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 165 170 175 Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val 180 185 190 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 195 200 205 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 210 215 220 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 225 230 235 240 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 245 250 255 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 260 265 <210> 50 <211> 314 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 50 Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys Ala Ala Ala Gly Gly Gly Gly Ser 20 25 30 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 35 40 45 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 50 55 60 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 65 70 75 80 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 85 90 95 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 100 105 110 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 115 120 125 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 130 135 140 Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser 145 150 155 160 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 165 170 175 Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val 180 185 190 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 195 200 205 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 210 215 220 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 225 230 235 240 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 245 250 255 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly 260 265 270 Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 275 280 285 Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly 290 295 300 Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 305 310 <210> 51 <211> 322 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 51 Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg 1 5 10 15 Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser Ala Ala Ala Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 50 55 60 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 65 70 75 80 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 85 90 95 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 100 105 110 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 115 120 125 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 130 135 140 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 145 150 155 160 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 165 170 175 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 180 185 190 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 195 200 205 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 210 215 220 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 225 230 235 240 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 245 250 255 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 260 265 270 Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 275 280 285 Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys 290 295 300 Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr 305 310 315 320 Trp Ser <210> 52 <211> 273 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 52 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 Thr <210> 53 <211> 272 <212> PRT <213> Artificial Sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 53 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu 245 250 255 Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser 260 265 270 <210> 54 <211> 213 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 54 Glu Leu Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser 85 90 95 Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125 Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130 135 140 Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 55 <211> 494 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 55 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Gly Ile Asn Asn Asn Gly Arg Thr Ala Phe 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 Ile Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Lys Asp Val Arg Phe Ile Ala Val Pro Gly Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys 465 470 475 480 Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 485 490 <210> 56 <211> 498 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 56 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Gly Ile Asn Asn Asn Gly Arg Thr Ala Phe 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 Ile Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Lys Asp Val Arg Phe Ile Ala Val Pro Gly Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys Leu Cys 465 470 475 480 Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr 485 490 495 Trp Ser <210> 57 <211> 292 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 57 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr 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 Lys Gly Gly Ser Pro Gln Leu Tyr Ser Ala Leu Ala Asn Lys 225 230 235 240 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys Gly 245 250 255 Gly Gly Ser Gly Gly Gly Ser Gly Ser Trp Met Glu Glu Val Ile Lys 260 265 270 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 275 280 285 Ser Thr Trp Ser 290 <210> 58 <211> 295 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 58 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr 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 Lys Gly Gly Ser Gly Gly Ser Pro Gln Leu Tyr Ser Ala Leu 225 230 235 240 Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg 245 250 255 Phe Cys Gly Gly Gly Ser Gly Gly Gly Ser Gly Ser Trp Met Glu Glu 260 265 270 Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile 275 280 285 Cys Gly Met Ser Thr Trp Ser 290 295 <210> 59 <211> 298 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 59 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr 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 Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Gln Leu Tyr 225 230 235 240 Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys Arg Ser 245 250 255 Leu Ala Arg Phe Cys Gly Gly Gly Ser Gly Gly Gly Ser Gly Ser Trp 260 265 270 Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val Arg Ala Gln 275 280 285 Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 290 295 <210> 60 <211> 10 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 60 Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 1 5 10 <210> 61 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 61 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Ala Cys 260 265 270 <210> 62 <211> 29 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 62 Asp Ser Trp Met Glu Glu Val Ile Lys Leu Cys Gly Arg Glu Leu Val 1 5 10 15 Arg Ala Gln Ile Ala Ile Cys Gly Met Ser Thr Trp Ser 20 25 <210> 63 <211> twenty four <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 63 Gln Leu Tyr Ser Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr 1 5 10 15 Lys Arg Ser Leu Ala Arg Phe Cys 20 <210> 64 <211> 33 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 64 Met Arg Val Ser Glu Glu Trp Met Asp Gly Phe Ile Arg Met Cys Gly 1 5 10 15 Arg Glu Tyr Ala Arg Glu Leu Ile Lys Ile Cys Gly Ala Ser Val Gly 20 25 30 Arg <210> 65 <211> 25 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 65 Glu Ser Gly Gly Leu Met Ser Gln Gln Cys Cys His Val Gly Cys Ser 1 5 10 15 Arg Arg Ser Ile Ala Lys Leu Tyr Cys 20 25 <210> 66 <211> 272 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 66 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn 245 250 255 Lys Cys Cys Arg Val Gly Cys Thr Lys Arg Ser Leu Ala Arg Phe Cys 260 265 270 <210> 67 <211> 276 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 67 Asp Lys Thr His Thr Ala Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 1 5 10 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 65 70 75 80 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 100 105 110 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 115 120 125 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Gly Ser Ser Trp Met Glu Glu Val Ile Lys 245 250 255 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 260 265 270 Ser Thr Trp Ser 275 <210> 68 <211> 271 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 68 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 225 230 235 240 Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser Ala Leu Ala Asn Lys 245 250 255 Cys Cys His Val Gly Cys Thr Lys Arg Ser Leu Ala Tyr Phe Cys 260 265 270 <210> 69 <211> 9 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 69 Asp Lys Thr His Thr Cys Pro Pro Cys 1 5 <210> 70 <211> 10 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 70 Asp Lys Thr His Thr Ala Cys Pro Pro Cys 1 5 10 <210> 71 <211> 10 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 71 Gly Gly Ala Gly Gly Ala Cys Pro Pro Cys 1 5 10 <210> 72 <211> 5 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 72 Ala Cys Pro Pro Cys 1 5 <210> 73 <211> 30 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <220> <221> site <222> (1)..(30) <223> / Note: This sequence may contain 3-15 "Pro Ala" repeating units. / <400> 73 Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 1 5 10 15 Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala 20 25 30 <210> 74 <211> 40 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <220> <221> site <222> (1)..(30) <223> / Note: This sequence may contain 1–8 repeating units of “Gly Gly Gly Gly Ser”. / <400> 74 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ser Gly Gly Gly Gly Ser 35 40 <210> 75 <211> 45 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic polypeptide" <400> 75 Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly 1 5 10 15 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gln Leu Tyr Ser 20 25 30 Ala Leu Ala Asn Lys Cys Cys His Val Gly Cys Thr Lys 35 40 45 <210> 76 <211> 20 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 76 Leu Cys Gly Arg Glu Leu Val Arg Ala Gln Ile Ala Ile Cys Gly Met 1 5 10 15 Ser Thr Trp Ser 20 <210> 77 <211> 7 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 77 Arg Ser Leu Ala Arg Phe Cys 1 5 <210> 78 <211> 6 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 78 Gly Gly Ala Gly Gly Ala 1 5 <210> 79 <211> 5 <212> PRT <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: synthetic peptide" <400> 79 Asp Lys Thr His Thr 1 5 <210> 80 <211> 72 <212> DNA <213> Unknown sequence <220> <221> source <223> / Note="Description of the unknown sequence: relaxin A sequence" / <400> 80 cagctctact cagcgctcgc taataagtgt tgtcatgtgg gatgcacaaa gcggtctctc 60 gccagattct gc 72 <210> 81 <211> 84 <212> DNA <213> Unknown sequence <220> <221> source <223> / Note="Description of the unknown sequence: relaxin B sequence" / <400> 81 agctggatgg aagaagtgat taaactgtgt ggccgcgaac tggtgcgcgc gcagattgcg 60 atttgcggca tgagcacctg gagc 84 <210> 82 <211> 678 <212> DNA <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 82 gacaagaccc atacatgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaaaagc 660 ttgtccctga gccccggc 678 <210> 83 <211> 678 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 83 gacaagaccc atacatgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaagc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaaaagc 660 ttgtccctga gccccggc 678 <210> 84 <211> 927 <212> DNA <213> Artificial sequence <220> <221> source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 84 gataaaaccc atacctgccc gccgtgcccg gcgccggaac tgctgggcgg cccgagcgtg 60 tttctgtttc cgccgaaacc gaaagatacc ctgatgatta gccgcacccc ggaagtgacc 120 tgcgtggtgg tggatgtgag ccatgaagat ccggaagtga aatttaactg gtatgtggat 180 ggcgtggaag tgcataacgc gaaaaccaaa ccgcgcgaag aacagtataa cagcacctat 240 cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa agaatataaa 300 tgcaaagtga gcaacaaagc gctgccggcg ccgattgaaa aaaccattag caaagcgaaa 360 ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccgcgatga actgaccaaa 420 aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 480 tgggaaagca acggccagcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 540 gatggcagct tttttctgta tagcaaactg accgtggata aaagccgctg gcagcagggc 600 aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 660 ctgagcctga gcccgggcaa aggcggcggc ggcagcggcg gcggcggcag cggcggcggc 720 ggcagccagc tgtatagcgc gctggcgaac aaatgctgcc atgtgggctg caccaaacgc 780 agcctggcgc gcttttgcgg cggcggcggc agcggcggcg gcggcagcgg cggcggcggc 840 agcagctgga tggaagaagt gattaaactg tgtggccgcg aactggtgcg cgcgcagatt 900 gcgatttgcg gcatgagcac ctggagc 927 <210> 85 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 85 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 86 <211> 816 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 86 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 87 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 87 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagattc tgc 813 <210> 88 <211> 816 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 88 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtgc acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 89 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 89 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 90 <211> 825 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 90 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacct ggagc 825 <210> 91 <211> 828 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 91 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <210> 92 <211> 828 <212> DNA <213> Synthetic Sequence <220> <221> Source <223> / Note="Description of synthetic sequence: synthetic polynucleotide" <400> 92 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <210> 93 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note = "Description of artificial sequence: synthetic polynucleotide" <400> 93 gacaagaccc ayacmtgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagattc tgc 813 <210> 94 <211> 828 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 94 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtgc acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <210> 95 <211> 828 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 95 ggaggagcgg gtggagcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <210> 96 <211> 825 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 96 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacct ggagc 825 <210> 97 <211> 798 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 97 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg tggagggggc 720 ggatcccagc tctactcagc gctcgctaat aagtgttgtc atgtgggatg cacaaagcgg 780 tctctcgcca gattctgc 798 <210> 98 <211> 810 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 98 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa aggatcaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcgggagg gtggctctgg tggagggggc 720 ggatccagct ggatggaaga agtgattaaa ctgtgtggcc gcgaactggt gcgcgcgcag 780 attgcgattt gcggcatgag cacctggagc 810 <210> 99 <211> 783 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide"[[ID= seventeen]] <400> 99 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 It should be noted that there may be some inaccuracies in the above translation due to the specific nature of the patent sequence text. It is recommended to double-check with relevant professionals or reference materials for more accurate results.tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggaggtggc tctggtggag ggggcggatc ccagctctac 720 tcagcgctcg ctaataagtg ttgtcatgtg ggatgcacaa agcggtctct cgccagattc 780 tgc 783 <210> 100 <211> 795 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 100 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggaggtggc tctggtggag ggggcggatc cagctggatg 720 gaagaagtga ttaaactgtg tggccgcgaa ctggtgcgcg cgcagattgc gatttgcggc 780 atgagcacct ggagc 795 <210> 101 <211> 768 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 101 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa aggatcaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg tggagggggc ggatcccagc tctactcagc gctcgctaat 720 aagtgttgtc atgtgggatg cacaaagcgg tctctcgcca gattctgc 768 <210> 102 <211> 780 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: synthetic polynucleotide" <400> 102 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg tggagggggc ggatccagct ggatggaaga agtgattaaa 720 ctgtgtggcc gcgaactggt gcgcgcgcag attgcgattt gcggcatgag cacctggagc 780 <210> 103 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 103 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc acctgctccc gcaccagccc ctgctcccgc accagcccct 720 gctcccgcac cagccggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780<000407:ggatgcacaa agcggtctct cgccagattc tgc 813 <210> 104 <211> 825 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 104 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa aggatcaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc acctgctccc gcaccagccc ctgctcccgc accagcccct 720 gctcccgcac cagccggatc cagctggatg gaagagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacct ggagc 825 <210> 105 <211> 798 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 105 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc agctcctgct cccgcaccag cccctgctcc cgcaccagcc 720 ggatcccagc tctactcagc gctcgctaat aagtgttgtc atgtgggatg cacaaagcgg 780 tctctcgcca gattctgc 798 <210> 106 <211> 810 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 106 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc agctcctgct cccgcaccag cccctgctcc cgcaccagcc 720 ggatccagct ggatggaaga agtgattaaa ctgtgtggcc gcgaactggt gcgcgcgcag 780 attgcgattt gcggcatgag cacctggagc 810 ​​​​​​​​​​​​​​​​​​​​tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc accagcccct gctcccgcac cagccggatc ccagctctac 720 tcagcgctcg ctaataagtg ttgtcatgtg ggatgcacaa agcggtctct cgccagattc 780 tgc 783 <210> 108 <211> 795 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Comment="Description of artificial sequence: synthetic polynucleotide" <400> 108 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgc accagcccct gctcccgcac cagccggatc cagctggatg 720 gaagaagtga ttaaactgtg tggccgcgaa ctggtgcgcg cgcagattgc gatttgcggc 780 atgagcacct ggagc 795 <210> 109 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: Synthetic polynucleotide" <400> 109 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaatga gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 110 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 110 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaatca ctgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 111 <211> 816 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Annotation="Description of artificial sequence: synthetic polynucleotide" <400> 111 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660​tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaattt gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 112 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note = "Description of artificial sequence: synthetic polynucleotide" <400> 112 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc y240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaatat gtgttgtcat 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 113 <211> 816 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 113 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaaggagtc tctcgccaga ttctgc 816 [[ID=​​​​​​​​​​ <223> / Annotation="Description of artificial sequence: Synthetic polynucleotide" <400> 114 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcat 780 gtgggatgca caaagcactc tctcgccaga ttctgc 816 <210> 115 <211> 813 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 115 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccgccttc tgc 813 <210> 116 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 116 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600<0004�61>aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccatcttc tgc 813 <210> 117 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Comment="Description of artificial sequence: synthetic polynucleotide" <400> 117 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccatgttc tgc 813 <210> 118 <211> 813 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 118 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgcccagttc tgc 813 <210> 119 <211> 813 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 119 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgcctccttc tgc 813 <210> 120 <211> 813 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Annotation="Description of artificial sequence: synthetic polynucleotide" <400> 120 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgcctacttc tgc 813 <210> 121 <211> 813 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 121 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagagag tgc 813 <210> 122 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 122 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagaatc tgc 813 ggatgcacaa agcggtctct cgccagaatc tgc 813 <210> 123 <210> 123 <211> 924 <211> 924 <212> DNA <212> DNA <213> 人工序列 <213> Artificial sequence <220> <220> <221> 来源 <221> Source <223> / Annotation="Description of artificial sequence: synthetic polynucleotide" <400> 123 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ctcctggatg gaggaggtta tcaagctgtg tggacgcgaa 780 ctggtgcgcg ctcagatcgc gatatgcggg atgtccacat ggtcaggcgg cggcagcggc 840 ggcggcagcg gccagctcta ctcagcgctc gctaataagt gttgtcatgt gggatgcaca 900 aagcggtctc tcgccagatt ctgc 924 <210> 124 <211> 924 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 124 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ctcctggatg gaggaggtta tcaagctgtg tggacgcgaa 780 ctggtgcgcg ctcagatcgc gatatgcggg atgtccacat ggtcaggcgg cggcagcggc 840 ggcggcagcg gccagctcta ctcagcgctc gctaataagt gttgtcatgt gggatgcaca 900 aagcggtctc tcgccagatt ctgc 924 <210> 125 <211> 819 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 125 tcctggatgg aagaagtgat caagctctgc ggcagagaac tcgtgcgggc ccagatcgct 60 atctgcggca tgtctacttg gagcgcggcc gcgggtggag gtggatccgg aggaggtgga 120 agcggaggag gtggaagcgg aggaggtgga agcgcttgtc ctccatgccc ggcgcctgag 180 ttcgagggcg gaccctccgt gttcctgttc cccccaaagc ccaaggacac cctgatgatc 240 tcccggaccc ccgaagtgac ctgcgtggtg gtggacgtgt cccacgagga ccctgaagtg 300 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcccagagag 360 gaacagtaca actccaccta ccgggtggtg tccgtgctga ccgtgctgca ccaggactgg 420 ctgaacggca aagagtacaa gtgcaaggtc tccaacaagg ccctgcccgc ctccatcgaa 480 aagaccatct ccaaggccaa gggccagccc cgcgagcctc aggtgtgcac actgcccccc 540 agccgggaag agatgaccaa gaaccaggtg tccctgtcct gtgccgtgaa aggcttctac 600 ccctccgata tcgctgtgga atgggagtcc aacggccagc ccgagaacaa ctacaagacc 660 accccccctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gaccgtggac 720 aagtcccggt ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 780 aaccactaca cccagaagtc tctgtccctg agccccggc 819 <210> 126 <211> 807 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 126 cagctgtact ctgccctggc caacaagtgt tgccacgtgg gctgcaccaa gagatccctg 60 gccagattct gtgcggccgc gggtggaggt ggatccggag gaggtggaag cggaggaggt 120 ggaagcggag gaggtggaag cgcttgtcct ccatgcccgg cgcctgagtt cgagggcgga 180 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 240 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 300 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 360 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 420 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 480 aaggccaagg gccagccccg cgagcctcag gtgtacacac tgcccccctg ccgggaagag 540 atgaccaaga accaggtgtc cctgtggtgt ctggtgaaag gcttctaccc ctccgatatc 600 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 660 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtcccggtgg 720 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 780 cagaagtctc tgtccctgag ccccggc 807 <210> 127 <211> 942 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 127 cagctgtact ctgccctggc caacaagtgt tgccacgtgg gctgcaccaa gagatccctg 60 gccagattct gtgcggccgc gggtggaggt ggatccggag gaggtggaag cggaggaggt 120 ggaagcggag gaggtggaag cgcttgtcct ccatgcccgg cgcctgagtt cgagggcgga 180 ccctccgtgt tcctgttccc cccaaagccc areacaccc tgatgatctc ccggaccccc 240 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 300 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagaga acagtacaac 360 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 420 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 480 aaggccaagg gccagccccg cgagcctcag gtgtacacac tgcccccctg ccgggaagag 540 atgaccaaga accaggtgtc cctgtggtgt ctggtgaaag gcttctaccc ctccgatatc 600 gctgtggaat gggagtccaa cggccagccc gagaaact aaagaccac cccccctgtg 660 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtcccggtgg 720 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 780 840 gggggtggaa gcggaggtgg aggtggatcc cagctctact cagcgctcgc taataagtgt 900 tgtcatgtgg gatgcacaaa gcggtctctc gccagattct gc 942 <210> 128 <211> 966 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: synthetic polynucleotide" <400> 128 tcctggatgg aagaagtgat caagctctgc ggcagagaac tcgtgcgggc ccagatcgct 60 atctgcggca tgtctacttg gagcgcggcc gcgggtggag gtggatccgg aggaggtgga 120 agcggaggag gtggaagcgg aggaggtgga agcgcttgtc ctccatgccc ggcgcctgag 180 ttcgagggcg gaccctccgt gttcctgttc cccccaaagc ccaaggacac cctgatgatc 240 tcccggaccc ccgaagtgac ctgcgtggtg gtggacgtgt cccacgagga ccctgaagtg 300 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcccagagag 360 gaacagtaca actccaccta ccgggtggtg tccgtgctga ccgtgctgca ccaggactgg 420 ctgaacggca aagagtacaa gtgcaaggtc tccaacaagg ccctgcccgc ctccatcgaa 480 aagaccatct ccaaggccaa gggccagccc cgcgagcctc aggtgtgcac actgcccccc 540​agccgggaag agatgaccaa gaaccaggtg tccctgtcct gtgccgtgaa aggcttctac 600 ccctccgata tcgctgtgga atgggagtcc aacggccagc ccgagaacaa ctacaagacc 660 accccccctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gaccgtggac 720 aagtcccggt ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 780 aaccactaca cccagaagtc tctaagcttg agccccggcg gaggtggtgg aagcggagga 840 ggtggctctg gagggggtgg aagcggaggt ggaggtggat ccagctggat ggaagaagtg 900 attaaactgt gtggccgcga actggtgcgc gcgcagattg cgatttgcgg catgagcacc 960 tggagc 966 <210> 129 <211> 819 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 129 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa aggatcaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagcacc 819 <210> 130 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 130 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 3,60 ggccagcccc gcgagcctca ggtgtgcaca ctgcccccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg tgccgtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctggt gtccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc cagctggatg gaagaagtga ttaaactgtg tggccgcgaa 780 ctggtgcgcg cgcagattgc gatttgcggc atgagc 816 <210> 131 <211> 1482 <212> DNA <213> Artificial sequence <220> <221> Source <223> / note="Description of artificial sequence: synthetic polynucleotide" [[ID=2二十二]]<400> 131 gaggtgcagc tgctcgagtc agggggaggc ttggtacagc cgggggggtc cctgagactc 60 tcctgtacaa cctctggatt cacctttaac acgtatgcca tgagttgggt ccgccaggct 120 ccagggaagg ggctggaatg gctctcaggt attaataaca atggtcggac tgcattctac 180 gcagactccg tgaagggccg cttcaccatc tccagagaca actccaaaaa cacactttat 240 ctgcaaatta atagtctgag agcggacgac acggccgttt atttctgtgc gaaagatgtc 300 agatttatcg cagtgcctgg tgactcctgg ggccagggaa ccctggtcac cgtctcctca 360 gcctccacca agggcccatc ggtcttcccc ctggccccca gcagcaagag caccagcggc 420 ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgtcc 480 tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc 540 ggcctgtaca gcctgagcag cgtggtgaca gtgccaagca gcagcctggg cacccagacc 600 tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaagaccca cacctgtcct ccatgcccgg cgcctgagtt cgagggcgga 720 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 780 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 840 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 900 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 960 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 1020 aaggccaagg gccagccccg cgagcctcag gtgtacacac tgcccccctg ccgggaagag 1080 atgaccaaga accaggtgtc cctgtggtgt ctggtgaaag gcttctaccc ctccgatatc 1140 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtcccggtgg 1260 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 1320 cagaagtctc taagcttgag ccccggcgga ggtggtggaa gcggaggagg tggctctgga 1380 gggggtggaa gcggaggtgg aggtggatcc cagctctact cagcgctcgc taataagtgt 1440 tgtcatgtgg gatgcacaaa gcggtctctc gccagattct gc 1482 <210> 132 <211> 1494 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 132 gaggtgcagc tgctcgagtc agggggaggc ttggtacagc cgggggggtc cctgagactc 60 tcctgtacaa cctctggatt cacctttaac acgtatgcca tgagttgggt ccgccaggct 120 ccagggaagg ggctggaatg gctctcaggt attaataaca atggtcggac tgcattctac 180 gcagactccg tgaagggccg cttcaccatc tccagagaca actccaaaaa cacactttat 240 ctgcaaatta atagtctgag agcggacgac acggccgttt atttctgtgc gaaagatgtc 300 agatttatcg cagtgcctgg tgactcctgg ggccagggaa ccctggtcac cgtctcctca 360 gcctccacca agggcccatc ggtcttcccc ctggccccca gcagcaagag caccagcggc 420 ggcacagccg ccctgggctg cctggtgaag gactacttcc ccgagcccgt gaccgtgtcc 480 tggaacagcg gagccctgac ctccggcgtg cacaccttcc ccgccgtgct gcagagcagc 540 ggcctgtaca gcctgagcag cgtggtgaca gtgccaagca gcagcctggg cacccagacc 600 tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaagaccca cacctgtcct ccatgcccgg cgcctgagtt cgagggcgga 720 ccctccgtgt tcctgttccc cccaaagccc aaggacaccc tgatgatctc ccggaccccc 780 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggacc ctgaagtgaa gttcaattgg 840 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 900 tccacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaacggcaaa 960 gagtacaagt gcaaggtctc caacaaggcc ctgcccgcct ccatcgaaaa gaccatctcc 1020 aaggccaagg gccagccccg cgagcctcag gtgtgcacac tgccccccag ccgggaagag 1080 atgaccaaga accaggtgtc cctgtcctgt gccgtgaaag gcttctaccc ctccgatatc 1140 gctgtggaat gggagtccaa cggccagccc gagaacaact acaagaccac cccccctgtg 1200 ctggactccg acggctcatt cttcctggtg tccaagctga ccgtggacaa gtcccggtgg 1260 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa ccactacacc 1320 cagaagtctc taagcttgag ccccggcgga ggtggtggaa gcggaggagg tggctctgga 1380 gggggtggaa gcggaggtgg aggtggatcc agctggatgg aagaagtgat taaactgtgt 1440 ggccgcgaac tggtgcgcgc gcagattgcg atttgcggca tgagcacctg gagc 1494 <210> 133 <211> 648 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 133 gagctcgtgt tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60 tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120 cacccaggca aagcccccaa actcatgatt tatgatgtca gtaagcggcc ctcaggggtt 180 tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240 caggctgagg acgaggctga ttattactgc agctcatata caagcagcag cactttggta 300 ttcggcggag ggaccaagct gaccgtccta ggtcagccca aggctgcccc ctcggtcact 360 ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420 agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480 gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540 tatctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600 catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca 648 <210> 134 <211> 876 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Comment="Description of artificial sequence: Synthetic polynucleotide" <400> 134 gataaaaccc atacctgccc gccgtgcccg gcgccggaac tgctgggcgg cccgagcgtg 60 tttctgtttc cgccgaaacc gaaagatacc ctgatgatta gccgcacccc ggaagtgacc 120 tgcgtggtgg tggatgtgag ccatgaagat ccggaagtga aatttaactg gtatgtggat 180 ggcgtggaag tgcataacgc gaaaaccaaa ccgcgcgaag aacagtataa cagcacctat 240 cgcgtggtga gcgtgctgac cgtgctgcat caggattggc tgaacggcaa agaatataaa 300 tgcaaagtga gcaacaaagc gctgccggcg ccgattgaaa aaaccattag caaagcgaaa 360 ggccagccgc gcgaaccgca ggtgtatacc ctgccgccga gccgcgatga actgaccaaa 420 aaccaggtga gcctgacctg cctggtgaaa ggcttttatc cgagcgatat tgcggtggaa 480 tgggaaagca acggccagcc ggaaaacaac tataaaacca ccccgccggt gctggatagc 540 gatggcagct tttttctgta tagcaaactg accgtggata aaagccgctg gcagcagggc 600 aacgtgttta gctgcagcgt gatgcatgaa gcgctgcata accattatac ccagaaaagc 660 ctgagcctga gcccgggcaa aggcggcagc ccgcagctgt atagcgcgct ggcgaacaaa 720 tgctgccatg tgggctgcac caaacgcagc ctggcgcgct tttgcggcgg cggcagcggc 780 ggcggcagcg gcagctggat ggaagaagtg attaaactgt gtggccgcga actggtgcgc 840 gcgcagattg cgatttgcgg catgagcacc tggagc 876 <210> 135 <211> 885 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: synthetic polynucleotide" <400> 135 gataagacac acacctgtcc tccatgtcct gctccagaac tgctcggcgg accctctgtg 60 ttcctgtttc ctccaaagcc taaggacacc ctgatgatct ctcggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc tcacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 240 agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggctaag 360 ggccagcctc gggaacctca ggtttacaca ctgcctccat ctcgggacga gctgaccaag 420 aatcaggtgt ccctgacctg cctggtcaag ggcttctacc cttccgatat cgccgtggaa 480 tgggagtcca atggccagcc tgagaacaac tacaagacca cacctcctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg acagtggaca agtctcggtg gcagcagggc 600 aacgtgttct cctgttctgt gatgcacgag gccctgcaca accactacac ccagaagtcc 660 ctgtctctgt cccctggaaa aggcggttct ggtggctctc ctcagctgta ctctgccctg 720 gccaacaagt gttgtcacgt gggctgcacc aagcggtccc tggctagatt ttgtggcggt 780 ggaagtggcg gcggatccgg ctcttggatg gaagaggtta tcaagctgtg cggcagagaa 840 ctcgtgcggg cccagatcgc tatctgtggc atgtccacct ggtcc 885 <210> 136 <211> 894 <212> DNA <213> Artificial sequence <220> <221> Source <223> / Note="Description of artificial sequence: Synthetic polynucleotide" <400> 136 gataagacac atacctgtcc tccatgtcct gctccagagc tgctcggagg cccttccgtg 60 tttctgttcc ctccaaagcc taggcacc ctgatgatct ctcggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc tcacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 240 agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agatcaag 300 tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggccaag 360 ggccagccta gggaacccca ggtttacacc ttgcctccat ctcgggacga gctgaccaag 420 aaccaggtgt ccctgacctg tctggtcaag ggcttctacc cctccgatat cgccgtggaa 480 tgggagtcta atggccagcc tgagaacaac tacaagacca cacctcctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg acagtggaca agtccagatg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca atcactacac ccagaagtcc 660 ctgtctctgt cccctggcaa aggtggcagc ggaggttccg gaggatctcc tcagctgtac 720 tctgccctgg ccaacaagtg ttgccacgtg ggctgcacca agagatccct ggccagattt 780 tgtggcggcg gatctggcgg aggttccggc tcttggatgg aagaagtgat caagctctgc 840 ggcagagaac tcgtgcgggc ccagatcgct atctgcggca tgtctacctg gtcc 894 <210> 137 <211> 516 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / note="Description of artificial sequence: Synthetic polynucleotide" <400> 137 ttcaattggt acgtggacgg cgtggaagtg cacaacgcca agaccaagcc cagagaggaa 60 cagtacaact ccacctaccg ggtggtgtcc gtgctgaccg tgctgcacca ggactggctg 120 aacggcaaag agtacaagtg caaggtctcc aacaaggccc tgcccgcctc catcgaaaag 180 accatctcca aggccaaggg ccagccccgc gagcctcagg tgtacacact gccccccagc 240 cgggaagaga tgaccaagaa ccaggtgtcc ctgacctgtc tggtgaaagg cttctacccc 300 tccgatatcg ctgtggaatg ggagtccaac ggccagcccg agaacaacta caagaccacc 360 ccccctgtgc tggactccga cggctcattc ttcctgtact ccaagctgac cgtggacaag 420 tcccggtggc agcagggcaa cgtgttctcc tgctccgtga tgcacgaggc cctgcacaac 480 cactacaccc agaagtctct gtccctgagc cccggc 516 <210> 138 <211> 828 <212> DNA <213> Artificial sequence <220> <221> Source <223> / note="Description of artificial sequence: Synthetic polynucleotide" <400> 138 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtgc acactgcccc ccagccggga agagatgacc 420 aagaaccagg tgtccctgtc ctgtgccgtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct ggtgtccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atccagctgg atggaagaag tgattaaact gtgtggccgc 780 gaactggtgc gcgcgcagat tgcgatttgc ggcatgagca cctggagc 828 <210> 139 <211> 816 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 139 gacaagaccc acaccgcttg tcctccatgc ccggcgcctg agttcgaggg cggaccctcc 60 gtgttcctgt tccccccaaa gcccaaggac accctgatga tctcccggac ccccgaagtg 120 acctgcgtgg tggtggacgt gtcccacgag gaccctgaag tgaagttcaa ttggtacgtg 180 gacggcgtgg aagtgcacaa cgccaagacc aagcccagag aggaacagta caactccacc 240 taccgggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaagagtac 300 aagtgcaagg tctccaacaa ggccctgccc gcctccatcg aaaagaccat ctccaaggcc 360 aagggccagc cccgcgagcc tcaggtgtac acactgcccc cctgccggga agagatgacc 420 aagaaccagg tgtccctgtg gtgtctggtg aaaggcttct acccctccga tatcgctgtg 480 gaatgggagt ccaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 540 tccgacggct cattcttcct gtactccaag ctgaccgtgg acaagtcccg gtggcagcag 600 ggcaacgtgt tctcctgctc cgtgatgcac gaggccctgc acaaccacta cacccagaag 660 tctctaagct tgagccccgg cggaggtggt ggaagcggag gaggtggctc tggagggggt 720 ggaagcggag gtggaggtgg atcccagctc tactcagcgc tcgctaataa gtgttgtcga 780 gtgggatgca caaagcggtc tctcgccaga ttctgc 816 <210> 140 <211> 813 <212> DNA <213> Artificial Sequence <220> <221> Source <223> / Note="Description of artificial sequence: synthetic polynucleotide" <400> 140 gacaagaccc acacctgtcc tccatgcccg gcgcctgagt tcgagggcgg accctccgtg 60 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 120 tgcgtggtgg tggacgtgtc ccacgaggac cctgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa aggatcaag 300 tgcaaggtct ccaacaaggc cctgcccgcc tccatcgaaa agaccatctc caaggccaag 360 ggccagcccc gcgagcctca ggtgtacaca ctgcccccct gccgggaga gatgaccaag 420 aaccaggtgt ccctgtggtg tctggtgaaa ggcttctacc cctccgatat cgctgtggaa 480 tgggagtcca acggccagcc cgagaacac tacaagacca ccccccctgt gctggactcc 540 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 600 aacgtgttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctaagcttga gccccggcgg aggtggtgga agcggaggag gtggctctgg agggggtgga 720 agcggaggtg gaggtggatc ccagctctac tcagcgctcg ctaataagtg ttgtcatgtg 780 ggatgcacaa agcggtctct cgccagagcg tgc 813

Claims

1. A heterodimer fusion compound, comprising the following: (i) the polypeptide according to SEQ ID NO:11; and (ii) The polypeptide according to SEQ ID NO:20; SEQ ID NO:11 contains a first heterodimerized domain linked to the relaxin A chain polypeptide; SEQ ID NO:20 contains a second heterodimerized domain linked to the relaxin B chain polypeptide; The first heterodimerized domain is heterodimerized with the second heterodimerized domain, and the heterodimer fusion product has relaxin activity.

2. The heterodimer fusion compound according to claim 1, wherein the relaxin A chain polypeptide and the relaxin B chain polypeptide are covalently linked by at least one interchain disulfide bond.

3. The heterodimer fusion compound according to claim 1 or 2, wherein the relaxin A chain and the relaxin B chain are not covalently linked to each other through an amino acid linker.

4. The heterodimer fusion according to claim 1, wherein the heterodimer fusion further comprises one or more Fabs.

5. The heterodimer fusion according to claim 4, wherein the heterodimer fusion comprises a Fab connected to the N-terminus of the Fc region of the first heterodimerization domain and a second Fab connected to the N-terminus of the Fc region of the second heterodimerization domain.

6. The heterodimer fusion compound according to claim 1, wherein the heterodimer further comprises a second relaxin A chain polypeptide or a variant thereof linked to the N-terminus of the Fc region of the first heterodimerization domain and a second relaxin B chain polypeptide or a variant thereof linked to the N-terminus of the Fc region of the second heterodimerization domain.

7. The heterodimer fusion compound according to claim 6, wherein the second relaxin A chain is linked to the Fc region of the first heterodimerization domain via a linker polypeptide, and the second relaxin B chain is linked to the Fc region of the second heterodimerization domain via a linker polypeptide.

8. A nucleic acid molecule encoding a heterodimer fusion compound according to any one of the preceding claims.

9. A vector comprising the nucleic acid molecule according to claim 8.

10. A host cell comprising the vector according to claim 9 or the nucleic acid molecule according to claim 8.

11. A method for producing a heterodimer fusion product according to any one of claims 1 to 7, the method comprising culturing a host cell according to claim 10 and collecting the fusion protein.

12. A pharmaceutical composition comprising a heterodimer fusion according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

13. A kit comprising the pharmaceutical composition according to claim 12.

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