CN111018999B

CN111018999B - Dimeric immune fusion protein, pharmaceutical composition and use

Info

Publication number: CN111018999B
Application number: CN201911231491.XA
Authority: CN
Inventors: 傅文燕; 丁敏; 胡适
Original assignee: Fengchao Medical Technology Shanghai Co ltd
Current assignee: Fengchao Medical Technology Shanghai Co ltd
Priority date: 2019-12-05
Filing date: 2019-12-05
Publication date: 2022-07-12
Anticipated expiration: 2039-12-05
Also published as: WO2021109914A1; CN111018999A

Abstract

The invention relates to the technical field of biomedical engineering, and provides a composition and a method related to soluble dimer immune fusion protein. The dimeric immunological fusion protein comprises a first and a second polypeptide chain which dimerize. Wherein the first polypeptide chain has a general structural formula of Z1-Z2, and the second polypeptide chain has a general structural formula of Y1-Y2. Wherein Z1 is (i) an extracellular domain of a first pattern recognition receptor, or a functional variant or fragment thereof, or (ii) a first co-receptor, a functional variant or fragment thereof; z2 is a dimerization domain or a functional variant or fragment thereof. Y1 is (i) the extracellular domain of a second pattern recognition receptor or a functional variant or fragment thereof, or (ii) a second co-receptor or a functional variant or fragment thereof, Y2 is a dimerization domain or a functional variant or fragment thereof. The dimeric protein can be used for blocking pathogen invasion, limiting generation and expansion of inflammatory mediators, and can be used for preparing a product for preventing or treating diseases related to the inflammatory mediators.

Description

Dimeric immune fusion protein, pharmaceutical composition and use

Technical Field

The invention relates to the technical field of biomedical engineering, in particular to a dimer immune fusion protein, a pharmaceutical composition taking the dimer immune fusion protein as an active component and medical application of the dimer immune fusion protein, especially application of the dimer immune fusion protein to inflammatory mediator-related diseases.

Background

In animals, an inflammatory response occurs when cells or tissues are damaged by bacteria, trauma, toxins, physical or chemical agents (which may be collectively referred to as "inflammatory agents"). The pathophysiological characteristics of the inflammatory response are regulated by complex interactions of a variety of pro-inflammatory or anti-inflammatory stimuli or mediators that are synthesized and released by cells. Some known classes of pro-inflammatory, anti-inflammatory stimuli or mediators include cytokines, nitric oxide, thromboxane (thromboxane), eulene, phospholipid-like platelet activating factor, prostaglandins, kinins, complement factors, coagulation factors, superantigens, monokines, chemokines, interferons, free radicals, proteases, arachidonic acid metabolites, cycloprostanes, beta endorphins, myocardial depressant factors (myocadinal depressor), anadamides, 2-arachidylglycerol (2-arachidonoyl glycerol), tetrahydrobioperids, cell debris, and chemicals including histamine, bradykinin, and serotonin, and the like.

The nature and intensity of the inflammatory response varies according to the site of the infestation, the nature of the inflammatory substance, and the interaction of the involved pro-or anti-inflammatory stimuli or mediators. When regulated and localized, the inflammatory response is beneficial. However, if unregulated and generalized, the inflammatory response can cause significant tissue damage and even death.

In recent years, highly resistant microbial infections have become a common clinical challenge. Because the rescue time of a patient is prolonged, microorganisms further evolve in vivo to generate super drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), and the like, and the drug-resistant microorganisms continuously exist in vivo to cause the regulation and control of a cytokine network involved in inflammation to be disordered, so that the development of a drug capable of inhibiting the action of the whole microorganism-immune system becomes a leading-edge hotspot. Microorganisms can be killed by using overdose of antibiotics, but dead microorganisms can further mediate inflammatory factor storm, and large dose of antibiotics causes damage to liver and kidney of patients and still cannot resist diseases.

Cytokines involved in inflammation are produced primarily by macrophages, monocytes, neutrophils and lymphocytes, a class of proteins that are normally stimulated by viral, bacterial, fungal or parasitic infections of these cells, as well as stimulated by T cells in the immune response for release. Other cells may also release inflammatory cytokines, for example stromal cells such as fibroblasts, endothelial cells and smooth muscle cells, as well as epithelial cells, keratinocytes and hepatocytes. Cytokines are usually present in low concentrations in blood or tissue.

The structure and activity of cytokines are hot spots for immunological studies. It is currently believed that cytokines possess a wide range of immunological and non-immunological activities that can affect a variety of physiological functions, such as cell growth, differentiation, homeostasis, and pathophysiology; meanwhile, the cell factor has various biological activities and participates in various biological regulation processes; in addition, cytokines can promote their own synthesis, as well as the production of other cytokines, a phenomenon known as the "cytokine cascade". The cytokine cascade is usually associated with systemic changes caused by infection and tissue damage, in which case the entire cytokine cascade network produces very complex cellular and biological effects, e.g., multiple cytokines of the Interleukin (IL) class, Interferon (IF) class, and Tumor Necrosis Factor (TNF) class can be produced in immune and inflammatory responses.

In general, cytokine cascades mediate normal host defense responses, cellular regulation, and cellular differentiation. In a cascade environment, the function of cytokine production may become disordered. This disorder can lead to the appearance of cytokines in concentrations above normal, when the effects on the body are twosided: on the one hand against invaders, but on the other hand if it is too strong or lacking in regulation, it can injure the body.

When exogenous infectious agents, endogenous immune stimuli mediate cytokine cascade disturbances, Systemic Inflammatory Response Syndrome (SIRS), sepsis (and so-called severe sepsis (sepsis with organ dysfunction), and even septic shock) can arise.

In conclusion, a drug capable of clearing invaders and inhibiting cytokines which cause excessive production in vivo is in urgent need to be developed, and the inventors do not report any similar drug at present.

Disclosure of Invention

The present invention has been made to solve the above problems, and provides a soluble dimeric immune fusion protein, and specific structures, preparation methods, and uses of the soluble dimeric immune fusion protein are described, that is, a dimeric immune fusion protein, a preparation method, and a use thereof are provided.

In a first aspect of the invention, there is provided a soluble dimeric immune fusion protein comprising a first polypeptide chain and a second polypeptide chain which dimerize, the first polypeptide chain having the general structural formula Z1-Z2, and the second polypeptide chain having the general structural formula Y1-Y2. Wherein Z1 is (i) an extracellular domain of a first pattern recognition receptor, or a functional variant or fragment thereof, or (ii) a first co-receptor, or a functional variant or fragment thereof; z2 is a dimerization domain or a functional variant or fragment thereof, Y1 is (i) an extracellular domain of a second pattern recognition receptor or a functional variant or fragment thereof, or (ii) a second co-receptor or a functional variant or fragment thereof; y2 is a dimerization domain or functional variant or fragment thereof.

The term "pattern recognition receptor" is an immunological concept, and a Pattern Recognition Receptor (PRR) is a type of recognition molecule that is mainly expressed on the surface of innate immune cells, has a non-clonal distribution, and can recognize one or more PAMPs. Is representative of immune receptors in innate immunity, encoded by a limited number of germline genes, which are evolutionarily well conserved, and also suggests that such receptors are of great importance to the survival of organisms. Its recognition and interaction with pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic organisms is critical for the initiation of innate immune responses. PRR has four characteristics compared to lymphocyte receptors in adaptive immunity. In addition to being encoded entirely by germline genes, three additional features are: constitutively expressed, elicited rapid responses and capable of recognizing various pathogens. Any pattern recognition receptor is suitable for use in the fusion protein structural schemes of the present invention.

In certain preferred embodiments of the invention, when both Z1 and Y1 are extracellular domains of pattern recognition receptors or functional variants or fragments thereof, the first pattern recognition receptor and the second pattern recognition receptor are each selected from the group consisting of: TLR1(Gene ID:7096), TLR2(Gene ID:7097), TLR3(Gene ID:7098), TLR4(Gene ID:7099), TLR5(Gene ID:7100), TLR6(Gene ID:10333), TLR7(Gene ID:51284), TLR8(Gene ID:51311), TLR9(Gene ID:54106), TLR10(Gene ID:81793), Dectin-1(Gene ID:64581), Dectin-2(Gene ID:93978), Mincle (Gene ID:26253), CLEC2(Gene ID:51266), CLEC5A (Gene ID:23601), CLEC12A (Gene ID:160364), DCIR (Gene ID: 856), CLEC SF8(Gene ID: 338339).

Where both Z1 and Y1 are extracellular domains of pattern recognition receptors or functional variants or fragments thereof, the first and second pattern recognition receptors may be the same or different.

In some preferred embodiments of the invention, when Z1 and Y1 are both co-receptors or functional variants or fragments thereof, the first co-receptor and the second co-receptor are each selected from any one of CD14(Gene ID:929), MD-2(Gene ID:23643), LBP (Gene ID:3929), CD36(Gene ID: 948).

Where both Z1 and Y1 are co-receptors or functional variants or fragments thereof, the first and second co-receptors may be the same or different.

The dimerization domain Z2 or Y2 includes an immunoglobulin heavy chain constant region. For example, in a particular variation, dimerization domains Z2 and Y2 are Fc fragments of IgG, such as human immunoglobulin γ 1Fc fragment. When Z1 is different from Y1, dimerization domains Z2 and Y2 may be engineered to increase specific heterodimerization formation, such as Z2 and Y2 being Fc fragments of IgG or Fc mutants altering its biological activity, or heterodimeric IgG-Fc fragments constructed using Knob-in-hole technology, ART-Ig technology altering charge polarity, or BiMab technology (review Brinkmann U, Kontermann R E. mabs,2017,9(2): 182. 212.).

With respect to Fc mutants that alter their biological activity, e.g., dimerization domains Z2 and Y2 may be active variants of a human immunoglobulin Fc fragment, e.g., employing Fc domains of IgG2, IgG3, or IgG 4. In certain embodiments, mutants of Fc may be further employed to reduce biological activity of immunoglobulins such as ADCC, complement fixation, etc., such as LALA-PG mutants, L235E, E318A, K320A, K322A mutants, etc.

In addition, dimerization domains Z2 and Y2 further comprise a peptide linker consisting of 15-32 amino acid residues, wherein 1-8 (e.g., 2) of these residues are cysteine residues. In particular variations, Z2 and Y2 comprise an immunoglobulin hinge region or variant thereof, e.g., in one particular embodiment, Z2 and Y2 comprise an immunoglobulin hinge variant (e.g., a human immunoglobulin γ 1 hinge variant) in which the 220 corresponding cysteine residue of the Fc fragment is replaced with serine. Particularly suitable peptide linkers for use according to the above dimerization domains Z2 and Y2 include peptide linkers such as: the linker comprises a plurality of glycine residues, and optionally comprises at least one serine residue.

With respect to the specific structures of Z1 and Y1, the following description is specifically made:

(1) when each of Z1 and Y1 is the same extracellular domain of a pattern recognition receptor or a functional variant or fragment thereof: in a particular variation of the soluble dimeric immunological fusion proteins having the above general formulae Z1-Z2 and Y1-Y2, the amino acid sequences of Z1 and Y1, including any one of the amino acids shown in SEQ ID nos. 1-18, have at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity. The names of the sequences 1-18 are as follows:

(2) when each of Z1 and Y1 is the same co-receptor or functional variant or fragment thereof: in a specific variation of the soluble dimeric immunoaffinity proteins having the general formulae Z1-Z2 and Y1-Y2 described above, the amino acid sequences of Z1 and Y1, including any of the amino acids set forth in SEQ ID nos. 19-22, are at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identical. The sequences 19-22 are named as follows:

sequence of	Name (R)	Sequence of	Name(s)
				19	CD1426-355 amino acid	21	LBP26-481 amino acid
20	MD-217-160 amino acid	22	CD361-472 amino acid

(3) The amino acid sequences of dimerization domains Z2 and Y2 include any one of the amino acids set forth in SEQ ID nos. 23-28 having at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity. The sequences 23-29 are named as follows:

sequence of	Name (R)	Sequence of	Name (R)
				23	IgG-Fc	27	IgG4-Fc
24	IgG-Fc-LALAGP	28	Human IgG4FC-hole mutant
				25	IgG-Fc-hole	29	Human IgG4FC-knob mutant
26	IgG-Fc-knob

Specific sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are exemplified below, based on the sources of Z1 and Y1:

in some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR1 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR1-IgG1-Fc amino acid sequence set forth in SEQ ID No.30, described below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR1 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identical to the TLR1-IgG 1-Fc-lalapc amino acid sequence set forth in SEQ ID No.31 below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR2 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR2-IgG1-Fc amino acid sequence set forth in SEQ ID No.32, described below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR2 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identical to the TLR2-IgG1-Fc-LALA amino acid sequence set forth in SEQ ID No.33, described below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR4 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity to the TLR4-IgG1-Fc amino acid sequence set forth in SEQ ID No.34, described below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR4 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identical to the TLR4-IgG 1-Fc-lalgp amino acid sequence set forth in SEQ ID No.35 below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR6 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to, or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity to, the TLR6-IgG1-Fc amino acid sequence set forth in SEQ ID No.36, described below.

In some particularly preferred embodiments of the invention, Z1 and Y1 are both the extracellular domain of TLR6 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identical to the TLR6-IgG 1-Fc-lalgp amino acid sequence set forth in SEQ ID No.37, described below.

In some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR1 or a functional variant or fragment thereof. Y1 is the extracellular domain of TLR2 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR1-Fc-Knob amino acid sequence set forth in SEQ ID No.38 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or having at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR2-Fc-Hole amino acid sequence set forth in SEQ ID No.39 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR1 or a functional variant or fragment thereof. Y1 is the extracellular domain of TLR6 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity to the TLR1-Fc-Knob amino acid sequence set forth in SEQ ID No.38 described below; said Y1-Y2 polypeptide chain comprises a sequence identical to or having at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR6-Fc-hole amino acid sequence set forth in SEQ ID No.40 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR2 or a functional variant or fragment thereof. Y1 is the extracellular domain of TLR4 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR2-Fc-Hole amino acid sequence set forth in SEQ ID No.39 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or having at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR4-IgG-Knob amino acid sequence set forth in SEQ ID No.41 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR2 or a functional variant or fragment thereof. Y1 is the extracellular domain of TLR6 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR2-Fc-Hole amino acid sequence set forth in SEQ ID No.39 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR6-Fc-knob amino acid sequence set forth in SEQ ID No.42 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR4 or a functional variant or fragment thereof. Y1 is the extracellular domain of TLR6 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR4-IgG-Knob amino acid sequence set forth in SEQ ID No.41 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or having at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR6-Fc-hole amino acid sequence set forth in SEQ ID No.40 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR4 or a functional variant or fragment thereof. Y1 is LBP or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR4-IgG-Knob amino acid sequence set forth in SEQ ID No.41 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the LBD-Fc-hole amino acid sequence set forth in SEQ ID No.43 described below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR4 or a functional variant or fragment thereof. Y1 is the extracellular domain of CD14 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR4-IgG-Knob amino acid sequence set forth in SEQ ID No.41 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CD14 Fc hole amino acid sequence set forth in SEQ ID No.44 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR4 or a functional variant or fragment thereof. Y1 is MD-2 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the TLR4-IgG-Knob amino acid sequence set forth in SEQ ID No.41 below; the Y1-Y2 polypeptide chain comprises a sequence identical to the MD-2Fc hole amino acid sequence set forth in SEQ ID No.45 below or is at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identical;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of CD14 or a functional variant or fragment thereof. Y1 is MD-2 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CD14 Fc knob amino acid sequence set forth in SEQ ID No.46 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the MD-2Fc hole amino acid sequence set forth in SEQ ID No.45 described below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR4 or a functional variant or fragment thereof. Y1 is the extracellular domain of CD36 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity to the TLR4-IgG-Knob amino acid sequence set forth in SEQ ID No.41 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CD36 Fc hole amino acid sequence set forth in SEQ ID No.47 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR6 or a functional variant or fragment thereof. Y1 is the extracellular domain of CD36 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity to the TLR6-Fc-knob amino acid sequence set forth in SEQ ID No.42 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CD36 Fc hole amino acid sequence set forth in SEQ ID No.47 below;

in some particularly preferred embodiments of the invention, both Z1 and Y1 are the extracellular domain of Dectin-1 or a functional variant or fragment thereof. For example, each of the Z1-Z2 and Y1-Y2 polypeptide chains comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-1 IgG Fc amino acid sequence set forth in SEQ ID No.48, described below.

In some particularly preferred embodiments of the invention, both Z1 and Y1 are the extracellular domain of Dectin-2 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-2 IgG Fc amino acid sequence set forth in SEQ ID No.49 below.

In some particularly preferred embodiments of the invention, Z1 is the extracellular domain of Dectin-1 or a functional variant or fragment thereof. Y1 is the extracellular domain of minicle or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-1 IgG Fc-knob amino acid sequence set forth in SEQ ID No.50 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Mincle IgG Fc-hole amino acid sequence shown in SEQ ID No.51 described below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of Dectin-2 or a functional variant or fragment thereof. Y1 is the extracellular domain of CLEC2 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-2 IgG Fc-knob amino acid sequence set forth in SEQ ID No.52 below; the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity with the CLEC2-Fc-hole amino acid sequence shown in SEQ ID No.53 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of Dectin-1 or a functional variant or fragment thereof. Y1 is the extracellular domain of CLEC5A or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to the Dectin-1 IgG Fc-knob amino acid sequence set forth in SEQ ID No.50 below or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CLEC5A-Fc-hole amino acid sequence set forth in SEQ ID No.54 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of Dectin-2 or a functional variant or fragment thereof. Y1 is the extracellular domain of CLEC12A or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-2 IgG Fc-knob amino acid sequence set forth in SEQ ID No.52 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CLEC12AFc hole amino acid sequence set forth in SEQ ID No.55 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of Dectin-1 or a functional variant or fragment thereof. Y1 is the extracellular domain of DCIR or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to the Dectin-1 IgG Fc-knob amino acid sequence set forth in SEQ ID No.50 below or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% identity; said Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the DCIR Fc hole amino acid sequence set forth in SEQ ID No.56 below;

in some particularly preferred embodiments of the invention, Z1 is the extracellular domain of Dectin-2 or a functional variant or fragment thereof. Y1 is the extracellular domain of CLECSF8 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-2 IgG Fc-knob amino acid sequence set forth in SEQ ID No.52 below; said Y1-Y2 polypeptide chain comprises a sequence identical to or having at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the CLECSF8 Fc hole amino acid sequence set forth in SEQ ID No.57 described below;

in some particularly preferred embodiments of the invention, both Z1 and Y1 are the extracellular domain of Dectin-1 or a functional variant or fragment thereof. For example, each of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-1 IgG4Fc amino acid sequence set forth in SEQ ID No.58, below.

In some particularly preferred embodiments of the invention, Z1 is the extracellular domain of TLR2 or a functional variant or fragment thereof. Y1 is the extracellular domain of Dectin-1 or a functional variant or fragment thereof. For example, the Z1-Z2 polypeptide chain comprises a sequence identical to the amino acid sequence set forth in SEQ ID No.39 below or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity; the Y1-Y2 polypeptide chain comprises a sequence identical to or has at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% identity to the Dectin-1 IgG Fc-knob amino acid sequence set forth in SEQ ID No.50, described below.

In a second aspect of the invention, there are provided polynucleotides encoding the dimeric immunological fusion proteins described above, vectors carrying the polynucleotides and cells comprising such vectors.

The present invention provides an expression vector comprising the following operably linked elements: a transcription promoter, a DNA region encoding the dimeric immune fusion protein, and a transcription terminator.

For producing a polypeptide or dimeric protein as disclosed above by culturing a cell comprising a vector, comprising: (i) culturing a cell comprising an expression vector as disclosed above, wherein the cell expresses the dimeric immune fusion protein encoded by the DNA segment and produces the encoded dimeric immune fusion protein; (ii) recovering the soluble dimeric immune fusion protein.

Similarly, the method of preparing a dimeric protein comprises: (i) culturing a cell comprising an expression vector as disclosed above, wherein the cell expresses the dimeric immune fusion protein encoded by the DNA segment and produces the encoded dimeric immune fusion protein as a dimeric protein; and (ii) recovering the dimeric protein.

In a third aspect of the invention, a pharmaceutical composition is provided, comprising the above soluble dimeric immunological fusion protein and at least one pharmaceutically acceptable carrier. The pharmaceutical composition takes soluble dimer immune-mucofusion protein as a main or only active ingredient, and auxiliary materials can ensure the conformation integrity of the amino acid core sequence of the dimer immune-mucofusion protein disclosed by the invention, and simultaneously protect the polyfunctional group of the protein to prevent the protein from degrading (including but not limited to agglomeration, deamination or oxidation), thereby more stably exerting curative effect.

In the form of medicine, the preparation can be suspension, hydro-acupuncture, freeze-drying and the like which are commonly used in the pharmaceutical field, and the hydro-acupuncture or freeze-drying preparation is preferred. The liquid preparation can be stored stably for at least one year at 2-8 deg.C, and the lyophilized preparation can be kept stable at 30 deg.C for at least six months.

For the hydro-acupuncture or freeze-drying preparation of the dimer immune fusion protein disclosed by the invention, pharmaceutically acceptable auxiliary materials comprise one or the combination of a surfactant, a solution stabilizer, an isotonic regulator and a buffer solution. Wherein the surfactant comprises nonionic surfactant such as polyoxyethylene sorbitol fatty acid ester (Tween-20 or Tween-80); poloxamer (such as poloxamer 188); triton; sodium Dodecyl Sulfate (SDS); sodium lauryl sulfate; tetradecyl, oleyl, or octadecyl sarcosine; pluronics; monaquatm, etc., in an amount that minimizes the tendency of the bifunctional bispecific antibody protein to granulate; the solution stabilizer can be saccharides including reducing saccharides and non-reducing saccharides, amino acids include monosodium glutamate or histidine, alcohols include one or a combination of trihydric alcohols, higher sugar alcohols, propylene glycol, polyethylene glycol, and the like, and is added in an amount such that the final formulation remains stable for a period of time deemed stable by one skilled in the art; the isotonic regulator can be one of sodium chloride and mannitol; the buffer may be one of TRIS, histidine buffer, and phosphate buffer.

The dimer immune fusion protein and the composition of the dimer immune fusion protein as an active component have the following purposes: 1) binding to a pathogenic microorganism surface molecule, cell wall or cell surface component, as described in example 1; 2) directly killing pathogenic microorganisms, limiting the growth of pathogenic microorganisms, and improving the resistance of immune cells to the invasion of pathogenic microorganisms, as described in examples 2-9; 3) inhibit and reduce the over-expression, secretion of inflammatory mediators and/or cytokines such as HMGB1, TNF alpha, IFN-gamma, IL-6, COX-2, etc. As in examples 10-11; 4) reducing the over-expression and release of organ inflammation mediators, relieving organ inflammation injury, enhancing the stress resistance of organs, resisting acute and chronic organ injury, resisting toxemia and the like, as in example 12-13; 5) reducing chronic inflammatory mediator damage and reducing organ inflammation fibrosis, as in examples 14-15; 6) suppression of local immune tolerance disorders, such as immune infertility as described in example 16; 7) inhibiting autoimmune tolerance mediated inflammatory mediator excess disease, such as autoimmune diseases like lupus, as in example 17.

Thus, in some aspects of the invention, the dimeric immunological fusion proteins and compositions thereof as active ingredients have the following uses: comprises any one or the combination of at least two of drugs, reagents and kits for preventing, diagnosing and treating diseases related to the removal of inflammatory mediators.

In some methods, the inflammatory mediators comprise: pathogenic microorganisms such as viruses, bacteria or parasites include any one or a combination of at least two of enzymes, cytokines, prostaglandins, eicosanoids, autotrienes, kinins, complements, clotting factors, toxins, endotoxins, enterotoxins, lipopolysaccharides, substances that induce apoptosis, corrosive substances, bile salts, fatty acids, phospholipids, oxidation by-products, reactive oxygen species, oxygen radicals, surfactants, ions, irritant substances, cell debris, interferons, and immunomodulatory antibodies, biologics, and drugs.

In some aspects, the inflammatory mediator is present in a physiological fluid or carrier fluid of the subject, the physiological fluid including fluids of the nasopharynx, oral cavity, esophagus, stomach, pancreas, liver, pleura, pericardium, peritoneum, intestine, prostate, semen, vaginal secretions, tears, saliva, mucus, bile, blood, lymph, plasma, serum, synovial fluid, cerebrospinal fluid, urine, and interstitial, intracellular and extracellular fluids.

The inflammatory mediator-associated diseases include: systemic Inflammatory Response Syndrome (SIRS) or sepsis (e.g., from viral, bacterial, fungal or parasitic infection), autoimmune disease, surgery, cytotoxic chemotherapy, bone marrow manipulation, major tissue injury or trauma, mesenteric hypoperfusion, intestinal mucosal injury, malaria, gastrointestinal inflammatory disease, intestinal infection, uterine cavity infection, influenza, acute pneumonia such as acute respiratory distress syndrome or acute lung injury, pulmonary embolism, pancreatitis, autoimmune and collagen vascular diseases, transfusion related diseases, burns, smoke or inhaled lung injury, graft-versus-host disease, ischemia or infarction, reperfusion injury, hemorrhage, anaphylaxis, drug overdose, radiation injury, or chemical injury. In some embodiments, the inflammatory mediator is produced by a disease caused by a biowarfare pathogen, toxin, or agent, such as viral hemorrhagic fever, aequorin, hantavirus cardiopulmonary syndrome (hantavirus), cholera toxin, botulinum toxin, kenaf toxin, qoloris [ coxiella rickettsii (coxellabuntenuii) ], plaque-specific typhoid (Rickettsia prowaszekii), or psittacosis [ chlamydia psittaci (chlamydialittaci) ].

Inflammatory mediator-related diseases also include: receiving transplantation, immune infertility and other diseases needing to remove the target immune factors.

The invention has the following beneficial guarantee and effects:

the dimer immune fusion protein, the pharmaceutical composition and the application provided by the invention have simple construction and expression processes, and experiments prove that the dimer immune fusion protein can directly kill pathogenic microorganisms, limit the invasion of foreign pathogens, inhibit excessively generated inflammatory factors, relieve tissue damage, have good treatment effect on inflammatory mediator-related diseases and the like, can effectively prevent and/or treat the inflammatory mediator-related diseases by being applied alone or combined with other related disease drugs, and have wide clinical application prospects.

Drawings

FIG. 1 is a schematic diagram of the structure of a dimeric immunological fusion protein.

Detailed Description

The following examples and experimental examples further illustrate the present invention and should not be construed as limiting the present invention. The examples do not include detailed descriptions of conventional methods such as those used to construct vectors and plastron, methods of inserting genes encoding proteins into such vectors and plastron, or methods of introducing plasmids into host cells. Such methods are well known to those having ordinary skill in the art and are described in numerous publications, including Sambrook, j., Fritsch, e.f. and maniis, T. (1989) Molecular Cloning: a Laboratory Manual, 2^ndedition，Cold spring Harbor Laboratory Press。

Example 1 construction, expression, characterization of soluble dimeric immune fusion proteins

As shown in fig. 1, the soluble dimeric immune fusion protein is a dimer with antibody Fc, and the method for constructing and expressing the dimeric immune fusion protein itself is a routine experimental technique in the field, and is briefly described as follows:

(1) the gene synthesizer (Jinweizhi, Suzhou) was entrusted with the codon optimization and full-gene synthesis of the coding nucleotide for the amino acid sequence of the dimeric immune fusion protein required in this example, and the optimized nucleotide sequence was directly loaded onto the PCDNA3.4 vector, and the amino acid sequences encoded by all vectors are described in Table 1.

(2) The protein manufacturer (Cassia corporation) was entrusted with the requirement for expression and purification of dimeric immune fusion protein for this example. The literature Finck B k.science,265 is adopted; mihara M et al. Journal of clinical investigation.2000; 106: 91-101; yu X, et al. nature immunology.2009; liu S, et al, Clin Immunol.2019Jun; 203:72-80.) method, using 293F system to perform transient transfection expression technology to perform protein expression, then using protein A and ion exchange method to obtain a large amount of soluble dimer immune fusion protein, and SDS-PAGE, western blot and mass spectrum to verify the target protein.

(3) Determination of the ligand binding Capacity of the dimeric Immunofusion proteins

The binding capacity of the dimeric immune fusion protein to specific ligands was tested by ELISA as shown in table 2.

TABLE 1 soluble dimer immune fusion protein message

TABLE 2 dimer immuno-fusion protein binding Capacity assay

*+++: the binding force reaches the PM level; the + binding force reaches NM level.

Example 2 action of dimeric immunological fusion proteins on Staphylococcus aureus

Staphylococcus aureus expressing GFP was deposited from the institute of microbiology, China academy of sciences with a multiplicity of infection of 1: 10. Peripheral blood samples were collected from healthy volunteers to isolate peripheral mononuclear cells (PBMCs, isolated using the picrinian lymphocyte isolation kit). Freshly isolated cells in RPMI1640 medium containing 10% fetal bovine serumMedium stability for 2h (37.5 ℃, 5% CO)₂)。

Culturing Staphylococcus aureus according to experimental requirements, centrifuging at 10000g for 30 s in a bench centrifuge to collect bacteria, and resuspending to 10%⁸Bacterial density around CFU/ml. The bacterial suspension was taken for gradient dilution plating to determine the exact bacterial density. After the PBMC cells were replaced with the medium, 10. mu.l of Staphylococcus aureus suspension resuspended in PBS (about 10. mu.l)⁶Left and right bacteria), mixed by gentle shaking, and incubated at 37 ℃ for 2 hours. And (3) sucking the culture medium supernatant, washing the cells for three times by using 1mL of ice PBS, combining the culture medium supernatant and the washing liquid, performing gradient dilution and plate coating counting, and calculating the number of the unophagocytized staphylococcus aureus.

Fresh medium was added, 10. mu.g/ml erythromycin was added and the PBMC were completely cleared of residual bacteria outside the cells for 12 hours, and fresh medium without antibiotics was replaced for 12 hours. Cells at 12 hours, 24 hours, 36 hours, hours and 48 hours after the start of the phagocytosis experiment were taken, washed, added with an aqueous trypsin solution, and the resuspended cells were thoroughly aspirated with a pipette tip, which simultaneously caused the swelling and rupture of macrophages. The lysate was subjected to gradient dilution plating to count the number of bacteria living in macrophages after phagocytosis, and the lysis rate of staphylococcus aureus was calculated, the results of which are shown in tables 3 and 4.

Table 3: phagocytosis rate of Staphylococcus aureus

Table 4: lysis rate of Staphylococcus aureus

Group of	Phagocytosis ratio (% of phagocytosed bacteria)	SD	p value
				Blank control	22.45	2.47
Control IgG	24.62	1.39
				TLR1-Fc	99.15	5.72	p＜0.05
TLR2-Fc	95.61	5.72	p＜0.05
				TLR4-Fc	70.73	9.63	p＜0.05
TLR2/TLR4-Fc	96.60	10.39	p＜0.05
				TLR4/TLR6-Fc	88.31	11.60	p＜0.05
TLR4/MD-2-Fc	75.46	9.83	p＜0.05
				TLR4/CD36-Fc	81.89	8.68	p＜0.05
TLR2/Dectin-1-Fc	94.65	8.66	p＜0.05

These experiments can confirm that the dimeric immune fusion protein can effectively enhance the phagocytic and lytic abilities of macrophages, and that the dimeric immune fusion protein can be used as a product for resisting infection.

Example 3 Effect of immune dimers on methicillin-resistant Staphylococcus aureus

BALB/c mice, SPF grade, female, 6-8 weeks old, weight 18-20 g, International Standard strain MRSA-252, purchased from American Tissue Culture Collection (ATCC). Establishing a mouse model, injecting 0.1mL of washed bacterial liquid (the concentration of the bacterial liquid is 1 multiplied by 10) through tail vein⁹CFU/mL), blank mice were injected with an equal amount of sterile saline via tail vein. The mice were then divided into 10 control groups, to which control IgG was administered, and 10 treated groups, to which the dimeric immune fusion protein of the invention was administeredThe representative was administered at a dose of 10mg/kg intravenously once a day for 10 days. If the mouse dies or all mice are killed after the experiment of the last day, blood is immediately taken out in an aseptic condition to be plated and counted, meanwhile, the whole organs of the kidney, the spleen and the liver are taken out in an aseptic condition, part of tissues are removed, the tissues are grinded by a glass homogenizer to be plated and counted, and meanwhile, pathological examination is carried out. The results are shown in tables 5 to 9:

table 5: survival Rate of mice%

Table 6: relative colony count of blood before death in each group of mice

Group of	Relative colony number%	SD	p value
				Blank control	0	0
Model set	94.65	8.66
				Control IgG	100	7.88
TLR1-Fc	14.94	1.31	p＜0.05
				TLR2-Fc	21.03	3.10	p＜0.05
TLR4-Fc	13.90	0.71	p＜0.05
				TLR2/TLR4-Fc	13.41	1.29	p＜0.05
TLR4/TLR6-Fc	23.31	1.34	p＜0.05
				TLR4/MD-2-Fc	14.75	1.93	p＜0.05
TLR4/CD36-Fc	13.03	1.17	p＜0.05
				TLR2/Dectin-1-Fc	23.17	2.38	p＜0.05

Table 7: relative number of liver colonies before death in each group of mice

Table 8: relative spleen colony count before death of each group of mice

Group of	Relative colony number%	SD	p value
				Blank control	0	0
Model set	107.97	11.57
				Control IgG	100	6.97
TLR1-Fc	5.51	0.37	p＜0.05
				TLR2-Fc	18.70	1.53	p＜0.05
TLR4-Fc	8.29	0.61	p＜0.05
				TLR2/TLR4-Fc	2.40	0.19	p＜0.05
TLR4/TLR6-Fc	11.32	1.12	p＜0.05
				TLR4/MD-2-Fc	1.80	0.25	p＜0.05
TLR4/CD36-Fc	14.27	1.23	p＜0.05
				TLR2/Dectin-1-Fc	17.36	2.40	p＜0.05

Table 9: relative number of colonies in kidney before death in each group of mice

Group of	Relative colony number%	SD	p value
				Blank control	0	0
Model set	108.35	12.42
				Control IgG	100	8.15
TLR1-Fc	5.28	0.29	p＜0.05
				TLR2-Fc	10.12	0.55	p＜0.05
TLR4-Fc	14.27	2.07	p＜0.05
				TLR2/TLR4-Fc	2.22	0.01	p＜0.05
TLR4/TLR6-Fc	19.15	1.47	p＜0.05
				TLR4/MD-2-Fc	16.16	0.89	p＜0.05
TLR4/CD36-Fc	8.00	0.48	p＜0.05
				TLR2/Dectin-1-Fc	15.90	2.36	p＜0.05

These results show that the dimer immune fusion protein has stronger microbial killing effect and anti-infection effect, reduces the colony number of visceral organs, and effectively resists methicillin-resistant golden yellow staphylococcus.

Example 4 experiments on systemic fungal infections in animals treated with dimeric immune fusion proteins

Female C57BL/6 mice were selected as experimental animals (about 20 g) and administered 5X 10 by tail vein injection⁶Cryptococcus neoformans 0.1ml (5X 10) in CFU/ml concentration⁵CFU/ml) to create a systemic fungal infection model. Then grouping is carried out, 10 mice are used in each group, 10mg/kg of the dimer immune fusion protein is applied to the treatment group through veins, once a day, the control group is given control IgG, the administration lasts for 5 days, the mice are killed on the 5 th day, brains are taken out, brain tissues are homogenized evenly, the homogenate is diluted by a certain multiple and then added into a peptone agar base for plating, colonies on the culture medium are counted, the brain fungus load of the mice is calculated, and the results are shown in table 10.

Table 10: brain tissue derived colony count

Group of	Relative colony (%)	SD	p value
				Normal mice	0	0
Model set	95.95	4.82
				Control IgG	100	6.68
TLR1-Fc	17.27	1.36	p＜0.05
				TLR2-Fc	27.88	3.84	p＜0.05
TLR4-Fc	13.40	1.29	p＜0.05
				TLR2/TLR4-Fc	28.48	4.24	p＜0.05
TLR4/TLR6-Fc	21.69	2.80	p＜0.05
				TLR4/MD-2-Fc	12.55	0.69	p＜0.05
TLR4/CD36-Fc	29.82	3.81	p＜0.05
				TLR2/Dectin-1-Fc	27.37	2.29	p＜0.05

As can be seen from Table 10, systemic administration of the dimeric immune fusion protein can effectively inhibit the growth of fungi in brain tissues, and achieve an obvious effect of killing fungi.

Example 5 treatment of dimeric immune fusion protein therapeutic Studies on Trichophyton mentagrophytes infected Guinea pig model

Selecting trichophyton mentagrophytes (ATCC) as pathogenic bacteria, recovering the pathogenicity of the trichophyton mentagrophytes before the experiment, inoculating the trichophyton mentagrophytes into a sandcastle agar (SDA) inclined test tube, culturing at 26 ℃, carefully scraping colonies after 7-10 days, and preparing an infectious fungus suspension by using physiological saline for later use. SDA consisted of 4% glucose, 1% peptone and 2% agar.

48 healthy white guinea pigs are used for both male and female, and the weight of the guinea pigs ranges from 250 g to 350 g. Shearing long hairs on the back and abdomen of all white guinea pigs, removing hairs by a shaver to form a hair removing area of 8cm multiplied by 10cm, coating a proper amount of glycerin on the hair removing area to prevent skin from drying and cracking, repeatedly rubbing the skin on the hair removing area by abrasive paper, wherein the damaged surface is about 3cm multiplied by 5cm, applying the prepared trichophyton mentagrophytes suspension on the damaged skin, observing the pathological change degree of the skin in the infected area of the white guinea pigs on the 10 th day after the infection of fungi, scraping skin rash, scales or crusts, and detecting hypha or spore of the fungi by a microscope. Proves that the scrub wound infection method is successful in infecting a guinea pig animal model.

After the trichophyton mentagrophytes infected guinea pig animal model is prepared, the animals are divided into groups of 10 animals, 10mg/kg of the dimeric immune fusion protein of the invention is applied to the treatment groups through veins respectively, the administration is performed once every 2 days, and the control group is given with control IgG for 5 days. The healing is the regression of skin lesions, the negative result of the fungus microscopic examination is 2 times continuously and the negative result of the fungus culture is obtained; the ineffectiveness is that the skin lesion is not faded away and the fungus is positive by microscopic examination. And recording the cure number of each group of animals, calculating the cure rate, and observing the relapse condition of the cured animals after stopping the medicine.

The clotrimazole cream, the external film preparation of the Fuzhuan tea extract, the control external film preparation and the external blank film preparation are respectively administered to each component, and the treatment observation is carried out for 14d continuously, wherein the cure rates of 7, l0 and 14d are shown in table 11. As shown in the experimental statistics results in Table 11, the dimeric immune fusion protein of the present invention has a good therapeutic effect on trichophyton mentagrophytes infection model of guinea pig.

Table 11: comparison of therapeutic effects of Trichophyton mentagrophytes in various groups on Guinea pig infection

	7d cure rate (%)	10d cure rate (%)	14d cure rate (%)
				Model set	0	0	0
Control IgG	0	0	0
				TLR1-Fc	90	100	100
TLR2-Fc	100	100	100
				TLR4-Fc	80	100	100
TLR2/TLR4-Fc	100	100	100
				TLR4/TLR6-Fc	100	100	100
TLR4/MD-2-Fc	100	100	100
				TLR4/CD36-Fc	100	100	100
TLR2/Dectin-1-Fc	100	100	100

The results show that the dimeric immune fusion protein effectively inhibits the growth of superficial fungi on the skin, and achieves an obvious effect of killing the fungi.

EXAMPLE 6 therapeutic Effect of dimeric immune fusion protein on Vibrio vulnificus

1) Binding experiments

The experiment was carried out with inactivated Vibrio vulnificus and Vibrio anguillarum, Edwardsiella tarda, and Vibrio alginolyticus (all from institute of microbiology, Zhongkojic institute), and the binding force of the representative of the dimeric immune fusion protein of the present invention to the above-mentioned bacteria was detected by ELISA method using control IgG or TIGIT-Ig in the same reference (Goldberg M E, Djavadi-Ohaniance L. Current opinion in immunology,1993,5(2): 278. Olympic experiment 281.), and the detection results are shown in Table 12:

table 12: cell binding force (nM)

2) Protection experiment of suckling mouse

Firstly, establishing animal model, infecting suckling mouse artificially by intraperitoneal injection method, and adopting 3X 10⁹Bacterial load was injected intraperitoneally into suckling mice, and the mice were divided into groups 12h after infection, wherein each group had n-10. IgG was administered to the control group, and the dimeric immune fusion protein of the present invention was administered to each treatment group at 10mg/kg, once every 2 days, and intraperitoneally. The survival rate of mice was calculated for a total of 3 weeks for observation and recording of morbidity and mortality in suckling mice and the results are shown in table 13:

table 13: vibrio vulnificus survival rate

Group of	Survival rate of 0 week%	Survival rate at 1 week%	Survival rate of 2 weeks	Survival rate of 3 weeks	p value
						Blank control	100	0	0	0	-
Control IgG	100	0	0	0	-
						TLR1-Fc	100	60	60	60
TLR2-Fc	100	60	60	60	p＜0.05
						TLR4-Fc	100	60	60	60	p＜0.05
TLR2/TLR4-Fc	100	70	70	70	p＜0.05
						TLR4/TLR6-Fc	100	70	70	70	p＜0.05
TLR4/MD-2-Fc	100	70	70	70	p＜0.05
						TLR4/CD36-Fc	100	70	70	70	p＜0.05
TLR2/Dectin-1-Fc	100	70	70	70	p＜0.05

The result shows that the dimer immune fusion protein effectively inhibits the growth of virulent bacteria represented by vibrio vulnificus, and achieves an obvious effect of killing the microorganisms.

Example 7 dimeric immunological fusion proteins against dengue Virus infection

Dengue-1 virus 128 strain (Gen Bank FJ176780), dengue-4 virus 43 strain (GeneBank AF119661), dengue-3 virus 80-2 strain (Gen Bank AF317645), dengue-4 virus B5 strain (Gen Bank AF289029), C6/36 cells and BHK21 cells: are all provided by virus rooms of institute of microbiological epidemic disease of military medical academy of sciences; the dengue virus culture employs C6/36 cells. And (3) after the cells grow to a monolayer, removing culture solution, adding different virus suspensions, culturing at 37 ℃, and observing cytopathic effect. When the cytopathic effect reaches +++ the virus culture solution is frozen and thawed, centrifuged at 2,000rpm for 5min, and the supernatant is collected as the virus stock solution. Subpackaging and storing at-80 deg.C. To determine the titer of the different viruses, the virus stock was first diluted 10-fold with a cell maintenance solution containing 2% FCS, and then the different dilutions of virus were added to the cell monolayer and incubated for 1h at 37 ℃. The supernatant was discarded, and a DMEM cell-maintaining solution containing 1% low-melting agarose was added thereto, and the culture was continued for 5 days. Observing under a microscope, fixing the cells for 30min by 4% formaldehyde solution after the cells have pathological changes, abandoning the upper agar, washing the cells by deionized water, adding 1% crystal violet for dyeing for 30min, counting the number of plaques after washing the cells by the deionized water, and expressing the virus titer by a plaque forming unit (PFU/ml).

1) In vitro experiments

Plaque reduction neutralization assays were performed using a method of fixing virus dilution antibodies: mixing monoclonal antibody with different concentrations

100PFU of dengue-4 virus suspension was mixed in equal amounts and incubated in a water bath at 37 ℃ for 1 h. The mixture was added to BHK21 cells cultured in 6-well plates, incubated at 37 ℃ for 1h, the mixture was discarded, and the cells were washed with PBS buffer. Adding nutrient agar, continuously culturing for 5d, fixing and dyeing, and counting the plaque number. The treatment group had a drug content of 50. mu.g/ml, the control group was administered IgG and the neutralization rate of each administration group was calculated as (1-treatment group/blank control). times.100%, and the results are shown in Table 14.

Table 14: neutralization rate of dengue virus

Group of	Neutralization rate%	SD	p value
				Blank control	0	4.67	-
Control IgG	3.82	0.57	-
				TLR1-Fc	91.65	9.68
TLR2-Fc	87.90	11.58	p＜0.05
				TLR4-Fc	88.21	8.76	p＜0.05
TLR2/TLR4-Fc	64.82	4.96	p＜0.05
				TLR4/TLR6-Fc	98.16	14.24	p＜0.05
TLR4/MD-2-Fc	91.09	11.45	p＜0.05
				TLR4/CD36-Fc	84.52	12.60	p＜0.05
TLR2/Dectin-1-Fc	93.86	10.43	p＜0.05

2) In vivo experiments

Will be compared with 10⁵PFU/ml of dengue virus of each type are mixed in equal amounts and incubated at 37 ℃ for 1 h. Virus pooled solution was inoculated intracranially to 1 day old Kunming stock suckling mice, each approximately 30 μ L, each group n ═ 10. After infection for 24h, the groups were divided, IgG was administered to the control group, and the dimer immune fusion protein of the present invention was administered to each treatment group at 10mg/kg once a day by intraperitoneal injection. The morbidity and mortality of the suckling mice were observed and recorded for 3 weeks and the survival rate of the mice was calculated as shown in table 15.

Table 15: survival rate of dengue virus

The results show that the dimeric immune fusion protein effectively inhibits the growth of virulent microorganisms represented by dengue virus, and achieves an obvious effect of killing the microorganisms.

Example 8 study of the killing effect of dimeric immunological fusion protein on Schistosoma japonicum-representative parasites

New Zealand white rabbits (Male, 2.5-3.0Kg) were purchased from Shanghai Si Laike laboratory animals, Inc.; 5 week old BALB/c mice (males) were purchased from Shanghai Jersey laboratory animals, Inc.; new Zealand white rabbit is infected with 1000 + -5 pieces of Schistosoma japonicum cercaria by means of abdominal skin patch, and killed by dissection at 14 th day after infection, Schistosoma japonicum bodies with corresponding infection time are collected from hepatic portal vein by aortic perfusion method, and then the bodies are washed thoroughly with RPMI1640 culture medium.

1) In vitro study

Will 10⁵Each PBMC was cultured in RPMI1640 medium containing 10% fetal bovine blood, and the treatment group was administered with a representative of the dimeric immune fusion protein of the present invention, the control group was administered with control IgG, and the blank group was not administered with any drug. The administration concentration is 1mg/ml, 10 (14d) Japanese blood fluke with good activity are respectively added into each hole, and then the mixture is placed at 37 ℃ and 5% CO₂Culturing in an incubator (replacing the culture medium every 24 h), and setting three multiple holes in each group. Observing the activity and morphological change of the schistosoma japonicum of different groups at 24h, 48h, 72h and 96h of culture by using an inverted microscope, and calculating the survival rate of the schistosoma japonicum at corresponding culture time. The death of Schistosoma japonicum was defined as the death of the worm body when the worm body was continuously observed for 2min and the results are shown in Table 16.

Table 16: effect of PBMC on the survival Rate of 14d schistosome

2) In vivo studies

BALB/c mice from 5-week-old males were randomly grouped into healthy control (blank), infected control (model), and control IgG treated with dimeric immune fusion protein. Except for the blank group, 40. + -.2 Schistosoma japonicum cercaria were infected per mouse by the abdominal skin patch method, and administered at 14d of infection, each group was treated with a representative of the dimeric immune fusion protein of the present invention, and the control group was administered with control IgG at an administration dose of 10mg/kg intravenously once every 3 days. And (4) killing at 42d of infection, collecting the bodies, counting the schistosoma japonicum in the mice of each group, and calculating the insect reduction rate. The reduction rate was calculated as follows: the reduction rate was (1-average worm number in experimental group/average worm number in control group) × 100%, and the results are shown in table 17:

table 17: schistosome insect reduction rate

Group of	The insect reduction rate%	SD	p value
				Blank control (healthy mouse)	-	-	-
Model set	-	-
				Control IgG	0	1.25	-
TLR1-Fc	99.47	9.40
				TLR2-Fc	78.08	8.92	p＜0.05
TLR4-Fc	91.02	10.01	p＜0.05
				TLR2/TLR4-Fc	81.87	11.41	p＜0.05
TLR4/TLR6-Fc	78.55	7.01	p＜0.05
				TLR4/MD-2-Fc	97.68	8.06	p＜0.05
TLR4/CD36-Fc	90.50	6.23	p＜0.05
				TLR2/Dectin-1-Fc	92.70	7.82	p＜0.05

The results show that the dimeric immune fusion protein effectively inhibits the growth of the parasitic pathogenic microorganisms represented by the schistosoma so as to achieve the obvious effect of killing the microorganisms.

Example 9 administration of dimeric fusion proteins to patients exposed to unknown pathogens

In the outbreak of public safety or bioterrorism attacks, people are exposed to unknown pathogens or toxins. The exposure mode is one of many different ways, such as food or water intake, aerosol inhalation, or skin contact. The pathogen is one of a number of pathogens, such as bacillus anthracis (anthrax), influenza virus, smallpox virus, yersinia pestis (plague), ebola or marburg virus, francisella tularensis (harLeporis), hantavirus, dengue virus, cholera toxin, botulinum toxin, ricin toxin, salmonella, escherichia coli, e.g., e.coli 0157: H7, shigella, listeria, and the like.

When the threat microorganism is not yet established, some patients have quickly begun to develop severe disease with similar symptoms, including high fever, chills, cough, severe fatigue and diarrhea. The patient may receive standard treatment, e.g. antiviral drugs, antibiotics, antitoxins, immunoglobulins.

The dimeric immune fusion protein of the present invention, e.g., a pharmaceutical composition comprising 10mg/kg TLR2-Fc as an active ingredient, a pharmaceutical composition comprising 10mg/kg TLR2/TLR4-Fc as an active ingredient, a pharmaceutical composition comprising 10mg/kg TLR4/TLR6-Fc as an active ingredient, or the pharmaceutical composition of the dimeric immune fusion protein of example 1, can then be administered intravenously to a patient using the immune dimers of the present invention to rapidly neutralize inflammatory mediators, e.g., as a prophylactic or therapeutic measure for a patient experiencing symptoms of infection and signs of inflammation (fever, chills, etc.). Once the drug is distributed into the body fluids (especially the gut blood), the dimers immunologically fuse and sequester inflammatory mediators in the blood that are introduced exogenously or produced locally or introduced into the gut by physiological fluids such as bile, before these inflammatory mediators can cause further inflammation or toxicity, or cause inflammatory infections, endotoxemia and sepsis that can lead to exacerbations. By removing these inflammatory mediators, the dimeric immune fusion protein reduces the initiation of additional systemic inflammation in the patient, reduces the production of systemic inflammatory mediators (e.g., cytokines), and thereby prevents or limits the occurrence of cytokine or other inflammatory mediator-induced cell death, organ damage, multi-organ failure, and potential death.

Example 10 anti-inflammatory Activity of dimeric immune fusion proteins on macrophages

Raw 264.7 macrophages (cell bank of the Chinese academy of sciences) were cultured in DMEM medium containing 10% fetal bovine serum (FBS; Gibco Laboratories) at 37 ℃ and 5% CO 2. At 1 × 10⁶Density of individual cells/mL Raw 264.7 cells were seeded into 96-well plates and cultured adherent overnight. The following day, the medium was replaced with fresh DMEM medium, and 5. mu.g/mL of the various dimeric immune fusion proteins described in example 1 were added to the cells, and control human IgG (Sigma) was added to the control group. After incubating the cells with the protein for 30 minutes, the medium was supplemented with LPS (final concentration 1. mu.g/mL), and the cells were incubated for another 24 hours before performing the detection experiment.

1) NO level measurement

Nitric Oxide (NO) levels in the above Raw 264.7 cell culture media were measured using the Griess reagent system (Promega, USA). mu.L of the medium was added to a 96-well plate, followed by the addition of the same amounts of Griess reagent I (NED) solution and Griess reagent II (p-aminobenzenesulfonamide solution), and incubated for 10 minutes, after which the optical density at 540nm was measured using a microplate reader (Molecular Devices, USA) over 30 minutes. The concentration of NO was calculated using a sodium nitrite standard curve (0-100. mu.M).

As shown in table 18 below, stimulation of cells with LPS increased NO expression, but decreased levels when LPS was co-treated with the dimeric immune fusion protein of the invention. Supporting the effect of the dimeric immune fusion protein in reducing macrophage autoinflammatory exudation.

TABLE 18 relative NO content

2) Cytokine detection

Supernatant samples containing cell culture media were collected and analyzed for cytokine levels using HMGB1, TNF α, IFN- γ, and IL-6ELISA kits (eBioscience, San Diego). The 96-well plates were coated overnight at 4 ℃ with 100 μ L of capture antibody (diluted in coating buffer to the concentration recommended by the manufacturer's protocol). Next, after washing the plate 5 times, 200 μ L of assay dilution was added to each well and incubated at room temperature for 1 hour for blocking. After washing each well 5 times with wash buffer, the cell culture samples or each cytokine standard protein sample was diluted and 100 μ L of each sample was added to each well. Plates containing samples were incubated overnight at 4 ℃. Subsequently, after washing the plate 5 times with the washing buffer, 100. mu.L of secondary antibody coupled to avidin was added and incubated at room temperature for 1 hour. After incubation with secondary antibody, the plate was washed 5 times and incubated with 100 μ L avidin-hrp (bdbioscience) for 30 minutes at room temperature. After washing the plate 7 times, 100 μ L of TMB solution (Pierce) was added and incubated for 15 minutes at room temperature. The reaction was stopped by adding 50. mu.l of sulfuric acid to each well. Optical density at 450nm was measured using a microplate reader. Statistical analysis was performed using ANOVA procedures of the SPSS program for analysis of variance and the duncan's multiple variable domain test was used to verify significance between analyses. The detection results are shown in tables 19 to 22:

table 19 HMGB1 levels for each treatment group

Group of	HMGB1(pg/ml)	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	26.63	3.21
Control IgG	30.46	2.32
				Control IgG + LPS	575.15	32.18
TLR1-Fc+LPS	144.23	11.13	p＜0.05
				TLR2-Fc+LPS	154.83	19.01	p＜0.05
TLR4-Fc+LPS	155.32	20.34	p＜0.05
				TLR6-Fc+LPS	295.83	39.24	p＜0.05
TLR4-Fc-LALAPG+LPS	147.27	15.17	p＜0.05
				TLR1/TLR2-Fc+LPS	61.96	5.71	p＜0.05
TLR2/TLR4-Fc+LPS	85.82	8.82	p＜0.05
				TLR4/TLR6-Fc	187.14	11.97	p＜0.05
TLR4/MD-2-Fc+LPS	104.50	14.40	p＜0.05
				TLR4/CD36-Fc+LPS	262.44	27.69	p＜0.05
TLR2/Dectin-1-Fc	132.86	10.30	p＜0.05

TABLE 20 TNF α levels in each treatment group

Group of	TNFα(pg/ml)	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	38.81	3.04
Control IgG	26.97	1.55
				Control IgG + LPS	846.19	109.55
TLR1-Fc+LPS	222.31	29.63	p＜0.05
				TLR2-Fc+LPS	283.73	32.10	p＜0.05
TLR4-Fc+LPS	109.83	12.84	p＜0.05
				TLR6-Fc+LPS	280.92	41.07	p＜0.05
TLR4-Fc-LALAPG+LPS	231.82	25.73	p＜0.05
				TLR1/TLR2-Fc+LPS	156.57	13.75	p＜0.05
TLR2/TLR4-Fc+LPS	96.98	10.40	p＜0.05
				TLR4/TLR6-Fc	212.85	10.79	p＜0.05
TLR4/MD-2-Fc+LPS	77.54	5.55	p＜0.05
				TLR4/CD36-Fc+LPS	54.13	5.91	p＜0.05
TLR2/Dectin-1-Fc	176.33	20.53	p＜0.05

TABLE 21 IFN-. gamma.levels in the treatment groups

Group of	IFN-γ(pg/ml)	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	32.19	3.38
Control IgG	41.47	4.76
				Control IgG + LPS	468.55	26.07
TLR1-Fc+LPS	174.12	25.90	p＜0.05
				TLR2-Fc+LPS	70.74	9.15	p＜0.05
TLR4-Fc+LPS	237.00	28.58	p＜0.05
				TLR6-Fc+LPS	174.12	25.90	p＜0.05
TLR4-Fc-LALAPG+LPS	136.35	19.16	p＜0.05
				TLR1/TLR2-Fc+LPS	206.10	30.47	p＜0.05
TLR2/TLR4-Fc+LPS	77.88	6.72	p＜0.05
				TLR4/TLR6-Fc	216.75	28.28	p＜0.05
TLR4/MD-2-Fc+LPS	91.34	10.97	p＜0.05
				TLR4/CD36-Fc+LPS	202.65	15.46	p＜0.05
TLR2/Dectin-1-Fc	199.29	23.21	p＜0.05

TABLE 22 IL-6 levels in each treatment group

Group of	IL-6(pg/ml)	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	31.47	4.69
Control IgG	41.00	3.53
				Control IgG + LPS	634.98	71.06
TLR1-Fc+LPS	160.10	12.29	p＜0.05
				TLR2-Fc+LPS	71.72	7.42	p＜0.05
TLR4-Fc+LPS	295.24	34.62	p＜0.05
				TLR6-Fc+LPS	157.59	8.61	p＜0.05
TLR4-Fc-LALAPG+LPS	211.16	13.26	p＜0.05
				TLR1/TLR2-Fc+LPS	262.55	21.10	p＜0.05
TLR2/TLR4-Fc+LPS	89.26	5.95	p＜0.05
				TLR4/TLR6-Fc	57.33	5.83	p＜0.05
TLR4/MD-2-Fc+LPS	109.77	8.01	p＜0.05
				TLR4/CD36-Fc+LPS	189.63	13.57	p＜0.05
TLR2/Dectin-1-Fc	171.20	21.51	p＜0.05

The inhibitory effect of the dimeric immune fusion protein on cytokine protein expression was further determined. The cells of the control group and the treated group were lysed, and the expression of cytokine mRNA in the cells was analyzed by the qPCR method as shown in tables 23 to 26 below, and the expression of cytokines was increased by stimulating the cells with LPS (HMGB1, TNF-. alpha., IL-6, COX-2). However, if cells are treated simultaneously with LPS and the dimeric immune fusion proteins described in the present invention, the expression levels of the aforementioned pro-inflammatory cytokines are significantly reduced. These results strongly suggest and support the anti-inflammatory effect of the dimeric immunological fusion proteins of the present invention.

TABLE 23 expression level of HMGB1 in cells of each treatment group

TABLE 24 TNF α expression levels in cells of each treatment group

Group of	Relative expression level of TNF alpha%	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	10.67	0.98
Control IgG	10.12	0.69
				Control IgG + LPS	100	7.84
TLR1-Fc+LPS	17.63	1.99	p＜0.05
				TLR2-Fc+LPS	23.04	2.93	p＜0.05
TLR4-Fc+LPS	14.33	1.04	p＜0.05
				TLR6-Fc+LPS	18.87	2.13	p＜0.05
TLR4-Fc-LALAPG+LPS	24.65	2.80	p＜0.05
				TLR1/TLR2-Fc+LPS	13.46	1.47	p＜0.05
TLR2/TLR4-Fc+LPS	14.82	0.75	p＜0.05
				TLR4/TLR6-Fc	20.77	2.98	p＜0.05
TLR4/MD-2-Fc+LPS	35.86	5.38	p＜0.05
				TLR4/CD36-Fc+LPS	18.47	2.62	p＜0.05
TLR2/Dectin-1-Fc	22.18	2.26	p＜0.05

TABLE 25 cellular IL-6 expression levels in the treatment groups

TABLE 26 cellular COX-2 expression levels in the treatment groups

Group of	Relative expression level of COX-2%	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	22.86	3.16
Control IgG	28.89	1.91
				Control IgG + LPS	100	8.81
TLR1-Fc+LPS	30.69	3.44	p＜0.05
				TLR2-Fc+LPS	26.50	3.03	p＜0.05
TLR4-Fc+LPS	29.65	3.21	p＜0.05
				TLR6-Fc+LPS	34.03	3.44	p＜0.05
TLR4-Fc-LALAPG+LPS	28.15	1.65	p＜0.05
				TLR1/TLR2-Fc+LPS	26.32	3.85	p＜0.05
TLR2/TLR4-Fc+LPS	22.44	2.28	p＜0.05
				TLR4/TLR6-Fc	23.45	2.82	p＜0.05
TLR4/MD-2-Fc+LPS	21.64	1.42	p＜0.05
				TLR4/CD36-Fc+LPS	41.09	3.67	p＜0.05
TLR2/Dectin-1-Fc	38.46	3.76	p＜0.05

As can be seen from the results, the dimeric immune fusion protein effectively inhibits inflammatory exudation of immune cells represented by macrophages mediated by foreign stimuli.

Example 11 anti-inflammatory Activity of dimeric immune fusion proteins on peripheral monocytes

PBMCs (peripheral blood mononuclear cells) were isolated from blood samples (50ml) collected from healthy subjects using a Biocoll Separating Solution (Biochrom AG, Berlin, Germany). The results of cell treatment according to the method of example 2 and measurement of the secretion level of cytokines (TNF α and IL-6) and the mRNA level of intracellular cytokines (HMGB1, TNF α) in the culture medium are shown in tables 27 to 30:

TABLE 27 TNF α levels in each treatment group

TABLE 28 IL-6 levels in each treatment group

Group of	IL-6(pg/ml)	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	13.23	1.72
Control IgG	22.60	2.99
				Control IgG + LPS	263.02	32.10
TLR1-Fc+LPS	31.13	3.08	p＜0.05
				TLR2-Fc+LPS	85.98	7.08	p＜0.05
TLR4-Fc+LPS	95.74	8.38	p＜0.05
				TLR6-Fc+LPS	46.93	5.89	p＜0.05
TLR4-Fc-LALAPG+LPS	12.63	1.32	p＜0.05
				TLR1/TLR2-Fc+LPS	84.79	5.11	p＜0.05
TLR2/TLR4-Fc+LPS	15.60	0.96	p＜0.05
				TLR4/TLR6-Fc	45.76	6.01	p＜0.05
TLR4/MD-2-Fc+LPS	44.22	6.54	p＜0.05
				TLR4/CD36-Fc+LPS	19.75	1.16	p＜0.05
TLR2/Dectin-1-Fc	97.01	6.27	p＜0.05

TABLE 29 expression level of HMGB1 in cells of each treatment group

TABLE 30 TNF α expression levels in cells of each treatment group

Group of	Relative expression level of TNF alpha%	SD	p-value (vs. control IgG + LPS)
				Blank control (Medium only)	17.13	1.58
Control IgG	15.71	2.15
				Control IgG + LPS	100	5.57
TLR1-Fc+LPS	40.85	6.10	p＜0.05
				TLR2-Fc+LPS	32.04	2.55	p＜0.05
TLR4-Fc+LPS	27.84	3.89	p＜0.05
				TLR6-Fc+LPS	27.57	2.47	p＜0.05
TLR4-Fc-LALAPG+LPS	21.35	1.33	p＜0.05
				TLR1/TLR2-Fc+LPS	27.30	3.66	p＜0.05
TLR2/TLR4-Fc+LPS	26.88	1.81	p＜0.05
				TLR4/TLR6-Fc	23.46	1.49	p＜0.05
TLR4/MD-2-Fc+LPS	24.63	2.64	p＜0.05
				TLR4/CD36-Fc+LPS	40.76	4.67	p＜0.05
TLR2/Dectin-1-Fc	47.92	3.34	p＜0.05

As can be seen from the results, the dimeric immune fusion protein effectively inhibits inflammatory exudation of immune cells typified by peripheral mononuclear cells due to the mediation of an external stimulus.

Example 12 treatment of acute Lung injury with dimeric immune fusion proteins

BALB/c mice were divided into groups (n-12), PBS was given to the blank group and sham-operated group, control IgG was given to the control group, the dimer immune fusion protein representative of the present invention was given to each treatment group, the mice were injected into the tail vein at a dose of 10mg/kg, the administration was continued for 3 days once a day, the model was started after 1 hour of the last administration, the anesthetized mice were injected intraperitoneally with 2% sodium isopentarbital, and the mice were fixed on a 37 ℃ thermostatic operating table in a supine position. According to the method of the reference literature, the main steps of molding are as follows: carefully shaving off median hair of the neck, disinfecting with alcohol, incising the skin of the neck about 2cm in the median, exposing and separating the trachea, slowly dripping LPS5mg/kg (0.5mL/kg) into the trachea by using an insulin syringe, dripping an equal amount of physiological saline into the trachea of a sham operation group, disinfecting wounds with iodophors and suturing the skin, and establishing an acute lung injury model of the mouse.

And (3) after 24h of molding, picking eyeballs and taking blood, standing in a refrigerator at 4 ℃ for 3h, centrifuging at 3500r/min for 15min, separating serum, storing in liquid nitrogen, and testing. The neck skin was carefully excised and the trachea separated and cannulated with a trachea cannula for each group of mice. The chest was dissected, the right bronchus ligated, the left lung was perfused 3 times, 2 mL/time with phosphate buffer, bronchoalveolar lavage fluid was collected and centrifuged (4 ℃, 1300r/min,5 min).

The following indexes are detected: 1) the BCA protein quantitative kit (Biyuntian) detects the protein content in bronchoalveolar lavage fluid, and the experimental operation is carried out according to the kit specification. 2) Bronchoalveolar lavage fluid leukocyte level, using 800 u L0.01mol/L (pH 7.4) PBS buffer solution heavy suspension bronchoalveolar lavage fluid precipitate, after blowing evenly, 400 u L in the blood analyzer for white blood cell number detection. 3) Lung wet-dry mass ratio (W/D): weighing the upper left lung leaves as wet mass, placing the upper left lung leaves in a constant-temperature drying oven (105 ℃) for baking for 72 hours, drying to constant mass, weighing and recording as dry mass, and calculating according to the following formula, wherein the wet-dry mass ratio of the lung is equal to wet mass/dry mass. 4) Pathological morphology scoring of lung tissue: taking the lower lobe of the right lung,

soaking and fixing with neutral formaldehyde for 24h, washing with running water for 12h, embedding with conventional paraffin, slicing, staining with hematoxylin and eosin, sealing, and performing pathological observation under a microscope. And selecting different visual fields to carry out pathological scoring according to standard pulmonary inflammation scoring, and scoring method references [ Zhusan, Panlinghui, Linfei, and the like.]. 5) Detection of blood biochemical indexes SOD activity and MDA content in serum are strictly detected according to the steps of the corresponding detection kit instruction. 6) Lung tissue TExpression level detection of GF-beta 1 and Smad 2: the BCA kit detects the total protein concentration of the lung tissue homogenate, and an equal amount of sample is added into an electrophoresis tank for SDS-polyacrylamide gel electrophoresis. Performing trans-membrane, sealing and incubation on TGF-beta 1(1:3000) and Smad2(1:2000) for overnight resistance; washing the membrane, incubating the secondary antibody (1:7000) (antibodies were purchased from CST corporation), washing the membrane, developing, and semi-quantitatively analyzing the gray value of each band using ImageJ software. The results are shown in tables 31 to 38:

TABLE 31 protein content of bronchoalveolar lavage fluid in each group

Group of	Protein content (g/L)	SD	p-value (vs. control IgG + LPS)
				Artificial operation group	0.44	0.05
Model group (blank control)	3.16	0.46
				Control IgG	3.41	0.56
TLR1-Fc+LPS	0.77	0.04	p＜0.05
				TLR2-Fc+LPS	1.31	0.16	p＜0.05
TLR4-Fc+LPS	0.74	0.07	p＜0.05
				TLR6-Fc+LPS	0.47	0.07	p＜0.05
TLR4-Fc-LALAPG+LPS	0.35	0.02	p＜0.05
				TLR1/TLR2-Fc+LPS	0.67	0.01	p＜0.05
TLR2/TLR4-Fc+LPS	1.10	0.11	p＜0.05
				TLR4/TLR6-Fc	1.40	0.15	p＜0.05
TLR4/MD-2-Fc+LPS	0.21	0.02	p＜0.05
				TLR4/CD36-Fc+LPS	0.75	0.06	p＜0.05
TLR2/Dectin-1-Fc	0.30	0.01	p＜0.05

TABLE 32 number of neutrophils in bronchoalveolar lavage fluid for each group

TABLE 33 Wet-to-Dry mass ratio of Lung tissue for each group

TABLE 34 pulmonary injury scores for each group

TABLE 35 serum SOD Activity in groups

TABLE 36 serum MDA content (. mu.mol/L) Activity of each group

TABLE 37 relative TGF-. beta.1 expression levels in various groups of tissues

Group of	TGF-. beta.1 relative expression%	SD	p-value (vs. control IgG + LPS)
				Artificial operation group	5.05	0.26
Model group (blank control)	101.53	12.42
				Control IgG	100	8.81
TLR1-Fc+LPS	38.51	2.26	p＜0.05
				TLR2-Fc+LPS	39.78	3.35	p＜0.05
TLR4-Fc+LPS	17.13	2.56	p＜0.05
				TLR6-Fc+LPS	20.69	2.50	p＜0.05
TLR4-Fc-LALAPG+LPS	28.51	2.28	p＜0.05
				TLR1/TLR2-Fc+LPS	12.17	1.67	p＜0.05
TLR2/TLR4-Fc+LPS	12.64	1.70	p＜0.05
				TLR4/TLR6-Fc	28.36	3.45	p＜0.05
TLR4/MD-2-Fc+LPS	15.73	0.91	p＜0.05
				TLR4/CD36-Fc+LPS	39.06	5.50	p＜0.05
TLR2/Dectin-1-Fc	5.04	0.31	p＜0.05

TABLE 38 relative Smad2 expression levels in tissue groups

The experiments prove that the dimer immune fusion protein has the effects of reducing acute inflammatory exudation, inhibiting leucocyte exudation, reducing tissue edema, relieving tissue injury, enhancing SOD activity, reducing serum MDA content, inhibiting Smad2 and TGF-beta 1 expression, and has stronger anti-inflammatory and anti-LPS effects. Can be used for treating acute organ inflammation injury.

Example 13 protocol overview for administration of dimeric immune fusion proteins in a mouse model of caecal ligation for oral toxicity

C57 male mice, surgery was as follows: anesthesia is performed using a short-acting isoflurane hospital to minimize the deleterious effects of anesthesia on cardiovascular function. The procedure included a 5cm midline laparotomy starting 2cm below the chest plate. The cecum was isolated on sterile gauze outside the abdominal cavity to avoid vascular injury. Thereafter, 2-0 vicry tree (vicry1) was used to ligate immediately below the ileocaecal valve and maintain intestinal continuity. The cecal contents were then squeezed into one end of the cecum. The cecum was punctured 3 times with a 20 gauge needle and then a single drop of fecal material was expressed from each puncture site. The abdominal cavity was then closed for two layers, followed by fluid resuscitation, and the animals were returned to the appropriate cages. Sham mice were subjected to the same procedure except that cecal ligation and perforation were not performed. Animals were examined at 2 hours, 6 hours and 12 hours post-surgery. Animals were allowed ad libitum diet. 12 hours after surgery, the animals were divided into a blank group (PBS injection) or intravenous injection containing the representative pharmaceutical composition for the immiscoloration according to the invention as the active ingredient, n-10, at a dose of 10mg/kg, and were administered continuously daily. Mice survival was observed and recorded every 12 hours until 7 days post-surgery. Blood samples were taken from mice at 48 hours of surgery and the plasma levels of TNF α were measured in each group using ELISA kit (CST). The results are shown in tables 39 and 40:

table 39 mouse survival (%)

TABLE 40 TNF α expression levels

Group of	TNFα(pg/ml)	SD	p-value (vs. control IgG + LPS)
				Artificial operation group	27.49	3.15	p＜0.05
Model group (blank control)	793.47	62.44	p＜0.05
				Control IgG	779.51	64.66	p＜0.05
TLR1-Fc	110.02	15.18	p＜0.05
				TLR2-Fc	149.20	15.24	p＜0.05
TLR4-Fc	159.25	22.40	p＜0.05
				TLR2/TLR4-Fc	198.55	27.01	p＜0.05
TLR4/TLR6-Fc	296.06	29.39	p＜0.05
				TLR4/MD-2-Fc	305.86	26.49	p＜0.05
TLR4/CD36-Fc	337.32	44.67	p＜0.05
				TLR2/Dectin-1-Fc	123.03	7.65	p＜0.05

These experiments demonstrate that the dimeric immunological fusion proteins described herein have the ability to attenuate sepsis cytokines and increase the survival of patients against sepsis. Can be used for treating acute organ inflammation injury.

Example 14 Effect of dimeric immune fusion proteins on Schistosoma infection and liver fibrosis caused by infection

Selecting Balb/c mice with the weight of 20-25 g. The schistosoma japonicum infectious oncomelania japonica is provided by the research institute for preventing and treating schistosomiasis in Jiangsu province. Experimental animals were randomly grouped into groups of 10 mice each, and each group was treated with healthy control (blank), infected control (model), and control IgG in combination with dimeric immune fusion protein. Except for the blank group, each mouse was infected with cercaria (30. + -.2) by the abdominal patch method. Administration was continued for 30 days starting at 42 days post infection. The administration amount of the dimeric immune fusion protein and the control IgG is 10mg/kg, the administration is carried out once in 3d, the animals are killed under the anesthesia of an inhalation isoflurane anesthesia machine after the last administration for 24 hours, blood samples are collected, and serum is separated for detection. After the mouse liver was removed, it was washed 2 times in pre-chilled saline to remove residual blood stains. Each liver was weighed and immediately cut into several parts, one part was fixed in 4% neutral paraformaldehyde solution for subsequent histopathological examination, and the other part was frozen with liquid nitrogen and stored in a-80 ℃ freezer for subsequent molecular biological examination.

Serum liver function indexes ALT and AST, serum hepatic fibrosis indexes Hyaluronic Acid (HA) and Laminin (LN) contents, and liver tissue oxidation damage indexes SOD, GSH-PX, GSH-R, MDA, GSH and hydroxyproline contents are detected according to the detection kit specification, and the results are shown in tables 41 to 49.

TABLE 41 liver function status of mice in each group

Group of	ALT level (U/L)	SD	p value
				Blank control	26.05	3.16
Model set	124.47	13.35
				Control IgG	126.48	7.09
TLR1-Fc	45.99	2.56	p＜0.05
				TLR2-Fc	41.33	5.82	p＜0.05
TLR4-Fc	22.31	2.20	p＜0.05
				TLR2/TLR4-Fc	33.67	2.27	p＜0.05
TLR4/TLR6-Fc	45.37	2.43	p＜0.05
				TLR4/MD-2-Fc	50.49	5.87	p＜0.05
TLR4/CD36-Fc	25.94	2.72	p＜0.05
				TLR2/Dectin-1-Fc	55.24	7.19	p＜0.05

TABLE 42 liver function status of mice in each group

Group of	AST level (U/L)	SD	p value
				Blank control	25.53	2.17
Model set	132.65	11.41
				Control IgG	121.00	6.43
TLR1-Fc	72.09	9.43	p＜0.05
				TLR2-Fc	46.35	3.45	p＜0.05
TLR4-Fc	47.52	5.05	p＜0.05
				TLR2/TLR4-Fc	69.30	7.45	p＜0.05
TLR4/TLR6-Fc	77.13	4.37	p＜0.05
				TLR4/MD-2-Fc	34.27	6.00	p＜0.05
TLR4/CD36-Fc	55.73	4.18	p＜0.05
				TLR2/Dectin-1-Fc	58.59	7.55	p＜0.05

TABLE 43 serum hyaluronic acid levels in groups of mice

TABLE 44 serum laminin levels in groups of mice

Group of	LN level (ng/ml)	SD	p value
				Blank control	30.83	3.82
Model set	150.79	21.06
				Control IgG	145.08	8.68
TLR1-Fc	51.71	6.02	p＜0.05
				TLR2-Fc	21.30	1.91	p＜0.05
TLR4-Fc	23.99	1.33	p＜0.05
				TLR2/TLR4-Fc	33.94	4.30	p＜0.05
TLR4/TLR6-Fc	39.10	2.24	p＜0.05
				TLR4/MD-2-Fc	56.23	8.17	p＜0.05
TLR4/CD36-Fc	34.24	2.74	p＜0.05
				TLR2/Dectin-1-Fc	31.47	2.02	p＜0.05

TABLE 45 hydroxyproline levels in the liver of groups of mice

TABLE 46 indexes of liver oxidative damage of mice in each group

TABLE 47 area ratio of worm egg granuloma in livers of mice in each group

Group of	Area ratio of granuloma%	SD	p value
				Blank control	0	0
Model set	65.18	7.35
				Control IgG	59.77	4.86
TLR1-Fc	11.51	0.69	p＜0.05
				TLR2-Fc	13.25	1.28	p＜0.05
TLR4-Fc	13.91	1.62	p＜0.05
				TLR2/TLR4-Fc	9.38	0.53	p＜0.05
TLR4/TLR6-Fc	17.66	1.55	p＜0.05
				TLR4/MD-2-Fc	15.04	1.95	p＜0.05
TLR4/CD36-Fc	13.85	1.22	p＜0.05
				TLR2/Dectin-1-Fc	6.21	0.52	p＜0.05

TABLE 48 TGF-beta-alpha expression levels in the liver of each group of mice

TABLE 49 expression levels of α SMA in the liver of each group of mice

Group of	Relative expression of TGF-beta%	SD	p value
				Blank control	1.65	0.19
Model set	99.47	9.40
				Control IgG	100	10.55
TLR1-Fc	13.54	1.34	p＜0.05
				TLR2-Fc	5.42	0.36	p＜0.05
TLR4-Fc	10.32	2.02	p＜0.05
				TLR2/TLR4-Fc	8.72	1.11	p＜0.05
TLR4/TLR6-Fc	2.94	0.32	p＜0.05
				TLR4/MD-2-Fc	16.22	2.22	p＜0.05
TLR4/CD36-Fc	19.99	1.06	p＜0.05
				TLR2/Dectin-1-Fc	19.05	1.16	p＜0.05

The experiments prove that the dimer immune fusion protein described by the invention has the effects of inhibiting the liver colonization of schistosome, reducing liver fibrosis and reducing organ inflammatory injury, and can be used as a product for resisting organ fibrosis.

Example 15 dimer immune fusion protein treatment model of endometrial injury in mice

(1) Construction of animal endometrium injury model (C57 mouse)

The method comprises the steps of dividing 8-week-old female mice into groups, constructing an endometrial injury model by a double (infection + mechanical) injury method, namely, after the mice are anesthetized, taking a longitudinal incision with the length of about 2cm in the middle of the abdomen and making an incision with the length of 0.5cm at 1/3 in the middle of the uterus, scratching the middle-upper uterine cavity by using an endometrial curette, stopping curettage when the curette is not pressed and the sense of the concavity and convexity of the uterus disappears and the sense of the four walls is coarse, reserving lipopolysaccharide cotton threads in the uterine cavity after curettage, suturing an abdominal incision, and taking out the lipopolysaccharide cotton threads after 48 hours.

After completion of modeling, a blank control group (sham group), a saline only injection (model) group, and a treatment group were set. Treatment groups were administered each 10mg/kg of a representative of the dimeric immune fusion protein of the invention per vein, once on 3 days, for a total of 3 times. Mice were mated with male mice 3 weeks after the mice were in estrus. Samples were taken 1 month later for HE staining and Masson staining for endometrial histology assessment, and mice were assessed 3 months later for pregnancy results. As a result: histological evaluation at 1 month post-surgery showed a significant reduction in the degree of fibrosis in the immune dimer-treated groups compared to the control groups (table 50); the number of exosome glands was higher than for each control group compared to each control group. Pregnancy results evaluation showed that the pregnancy rate was higher in the immune dimer-treated groups than in the control groups, and the results are shown in table 51.

TABLE 50 degree of endometrial fibrosis in groups of mice

Group of	Relative fiberization area%	SD	p value (vs control IgG)
				Blank control group	2.05	0.23
Model set	97.46	9.41
				Control IgG	100	10.58
TLR1-Fc	17.82	2.40	p＜0.05
				TLR2-Fc	24.29	1.56	p＜0.05
TLR4-Fc	40.77	2.89	p＜0.05
				TLR2/TLR4-Fc	22.39	2.31	p＜0.05
TLR4/TLR6-Fc	16.97	1.67	p＜0.05
				TLR4/MD-2-Fc	25.03	1.70	p＜0.05
TLR4/CD36-Fc	31.30	2.93	p＜0.05
				TLR2/Dectin-1-Fc	32.93	2.40	p＜0.05

TABLE 51 analysis of pregnancy results for groups of mice

Group of	Percentage of pregnancy	p value (vs control IgG)
			Blank control group	100
Model set	10
			Control IgG	20
Control IgG	70	p＜0.05
			TLR1-Fc	80	p＜0.05
TLR2-Fc	70	p＜0.05
			TLR4-Fc	80	p＜0.05
TLR2/TLR4-Fc	70	p＜0.05
			TLR4/TLR6-Fc	80	p＜0.05
TLR4/MD-2-Fc	80	p＜0.05
			TLR4/CD36-Fc	70	p＜0.05

These experiments prove that the dimer immune fusion protein described by the invention has the effects of inhibiting and reducing organ inflammatory injury and inhibiting chronic inflammation of organs, particularly endometritis and fibrosis, and can be used as a product for resisting organ fibrosis and improving the treatment of infertility diseases.

Example 16 therapeutic Effect of dimeric immune fusion proteins on spontaneous abortion model

CBA/J female mice and DBA/2J male mice are used for establishing a stress abortion model which is a classic maternal-fetal immune tolerance disorder research model, and establishing methods, experimental methods and observation time point equivalent documents (Blois S M, et al. Nature Medicine,2007,13(12): 1450-. Before the CBA/J female mice are caged, the CBA/J female mice are divided into a negative control group, a stress pressure group and a treatment group. The treatment groups were administered 10mg/kg of the dimeric immune fusion protein of the invention per vein, once in 3 days, for a total of 3 times. The cages were combined 3 days after the first administration. Mice were caged immediately after vaginal emboli were established and pregnant (effective n-10).

The experimental results show (table 52) that the abortion rate of the treatment group is significantly lower than that of the stress pressure abortion group, indicating that the dimeric immune fusion protein has good therapeutic effect.

TABLE 52 embryo uptake rate (abortion) analysis in groups of mice

Group of	Embryo absorption rate	SD	p value (specific stress + control IgG)
				Blank control group	7.86	6.80
Stress pressure set	48.04	5.48
				Control IgG	50.83	11.42
TLR1-Fc	19.76	7.36	p＜0.05
				TLR2-Fc	21.19	7.57	p＜0.05
TLR4-Fc	17.14	9.27	p＜0.05
				TLR2/TLR4-Fc	18.39	6.58	p＜0.05
TLR4/TLR6-Fc	22.86	8.41	p＜0.05
				TLR4/MD-2-Fc	21.01	8.76	p＜0.05
TLR4/CD36-Fc	16.25	8.12	p＜0.05
				TLR2/Dectin-1-Fc	16.07	8.25	p＜0.05

The mice in the control group, the stress pressure group and the treatment group were further isolated from the periaortic lymph nodes, and the levels of Foxp 3-positive T helper lymphocytes were measured. Isolating decidua tissue and detecting the level of TNF α in the tissue; the isolation and detection methods are described in the literature (Kim B J, et al.. Proceedings of National Academy of sciences,2015,112(5): 1559-.

TABLE 53 Foxp 3% expression analysis of groups of mice

TABLE 54 TNF α tissue expression analysis of each group

Group of	Relative TNF alpha expression%	SD	p-value (vs stress + control IgG)
				Blank control group	9.73	0.50
Stress pressure set	92.60	5.19
				Control IgG	100	5.56
TLR1-Fc	13.10	1.44	p＜0.05
				TLR2-Fc	15.50	1.83	p＜0.05
TLR4-Fc	18.91	2.45	p＜0.05
				TLR2/TLR4-Fc	11.20	0.77	p＜0.05
TLR4/TLR6-Fc	19.27	2.80	p＜0.05
				TLR4/MD-2-Fc	12.85	1.05	p＜0.05
TLR4/CD36-Fc	37.54	1.46	p＜0.05
				TLR2/Dectin-1-Fc	20.29	2.92	p＜0.05

These experiments prove that the dimer immune fusion protein described by the invention has the effects of inhibiting and reducing the abnormality of organ inflammatory factors, resisting abnormal immune disorder and improving the treatment of infertility diseases.

Example 17 therapeutic Effect of dimeric immune fusion proteins on lupus mouse models

Lupus nephritis is a representative immune system disease, the incidence rate is about 50/10 ten thousand, and the incidence rate in China is about 0.7 per thousand of the population. More than 90% lupus nephritis is seen in women, mainly young and middle-aged women, generally speaking, the kidney of patients under 30 years old has high incidence rate, about 70% of patients have kidney damage clinical manifestations with different degrees, proteinuria and microscopic hematuria with different degrees are common, cast urine and kidney function damage are often accompanied, and the normal life of the patients is seriously influenced.

The lupus mouse model is mainly generated by crossing NZB female mice and NZW male mice, and the first-generation hybrid (NZB multiplied by NZW) F1 can generate typical lupus symptoms including lupus nephritis, and is one of the currently accepted animal models for researching lupus nephritis. The model is established with reference to the non-patent document Brinks et al, Circ Res (2010)107: 1140-. Mice were then grouped into decidua NK cell-treated groups and control groups, each group n-10.

The administration dose of the dimeric immune fusion protein is 10mg/kg, and the injection is performed twice in tail vein every week and is performed continuously for ten weeks. Control group was injected with control IgG at the same dose as the treatment group.

The autoantibody level of each treatment group was detected at week 30, and the anti-dsDNA antibody and anti-histone antibody of each treatment group were significantly reduced compared to the control group, while the total IgG level was unchanged, confirming that the treatment had the effect of suppressing the production of the autoimmune antibody. As shown in tables 11-13.

Incidence of proteinuria was counted at 40 weeks, survival was counted at 50 weeks, mice were immediately histologically scored for death, surviving mice were identically sacrificed at 50 weeks, renal histology was scored for pathology, scoring method references [ Liu S, et al. clinical Immunology,2019,203:72-80 ]. As shown in tables 55-60, each treatment group was effective in reducing proteinuria levels, reducing kidney inflammation and pathological damage, and improving lupus mouse survival as compared to the control group.

TABLE 5530 weeks mice serum anti-dsDNA antibodies in each group

TABLE 5630 week groups of mice serum anti-histone antibodies

TABLE 5730 week groups of mice serum total IgG levels

TABLE 5840 week groups of mice incidence of proteinuria

Group of	Incidence of proteinuria%	p value
			Blank set (model set)	100
Control IgG	100
			TLR1-Fc	40	p＜0.05
TLR2-Fc	30	p＜0.05
			TLR4-Fc	30	p＜0.05
TLR2/TLR4-Fc	30	p＜0.05
			TLR4/TLR6-Fc	20	p＜0.05
TLR4/MD-2-Fc	30	p＜0.05
			TLR4/CD36-Fc	30	p＜0.05
TLR2/Dectin-1-Fc	30	p＜0.05

TABLE 5950 week survival rates of groups of mice

TABLE 60 survival rates of mice with various kidney pathology scores

Group of	Pathological scoring	SD	p value
				Blank set (model set)	3.20	0.26
Control IgG	3.30	0.26
				TLR1-Fc	0.85	0.47	p＜0.05
TLR2-Fc	0.80	0.35	p＜0.05
				TLR4-Fc	0.75	0.26	p＜0.05
TLR2/TLR4-Fc	1.05	0.44	p＜0.05
				TLR4/TLR6-Fc	1.10	0.70	p＜0.05
TLR4/MD-2-Fc	1.10	0.66	p＜0.05
				TLR4/CD36-Fc	0.80	0.35	p＜0.05
TLR2/Dectin-1-Fc	0.95	0.44	p＜0.05

In conclusion, in the lupus mouse model, the immune dimer fusion protein can reduce autoimmune antibodies, reduce pathological inflammatory exudation of organs, has good treatment effect on immune system diseases, and is beneficial to development of subsequent clinical tests.

The undescribed parts of the present invention are the same as or implemented using prior art. The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

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Phe Ala Trp Leu Pro Gln Leu Glu Tyr Phe Phe Leu Glu Tyr Asn Asn

275 280 285

Ile Gln His Leu Phe Ser His Ser Leu His Gly Leu Phe Asn Val Arg

290 295 300

Tyr Leu Asn Leu Lys Arg Ser Phe Thr Lys Gln Ser Ile Ser Leu Ala

305 310 315 320

Ser Leu Pro Lys Ile Asp Asp Phe Ser Phe Gln Trp Leu Lys Cys Leu

325 330 335

Glu His Leu Asn Met Glu Asp Asn Asp Ile Pro Gly Ile Lys Ser Asn

340 345 350

Met Phe Thr Gly Leu Ile Asn Leu Lys Tyr Leu Ser Leu Ser Asn Ser

355 360 365

Phe Thr Ser Leu Arg Thr Leu Thr Asn Glu Thr Phe Val Ser Leu Ala

370 375 380

His Ser Pro Leu His Ile Leu Asn Leu Thr Lys Asn Lys Ile Ser Lys

385 390 395 400

Ile Glu Ser Asp Ala Phe Ser Trp Leu Gly His Leu Glu Val Leu Asp

405 410 415

Leu Gly Leu Asn Glu Ile Gly Gln Glu Leu Thr Gly Gln Glu Trp Arg

420 425 430

Gly Leu Glu Asn Ile Phe Glu Ile Tyr Leu Ser Tyr Asn Lys Tyr Leu

435 440 445

Gln Leu Thr Arg Asn Ser Phe Ala Leu Val Pro Ser Leu Gln Arg Leu

450 455 460

Met Leu Arg Arg Val Ala Leu Lys Asn Val Asp Ser Ser Pro Ser Pro

465 470 475 480

Phe Gln Pro Leu Arg Asn Leu Thr Ile Leu Asp Leu Ser Asn Asn Asn

485 490 495

Ile Ala Asn Ile Asn Asp Asp Met Leu Glu Gly Leu Glu Lys Leu Glu

500 505 510

Ile Leu Asp Leu Gln His Asn Asn Leu Ala Arg Leu Trp Lys His Ala

515 520 525

Asn Pro Gly Gly Pro Ile Tyr Phe Leu Lys Gly Leu Ser His Leu His

530 535 540

Ile Leu Asn Leu Glu Ser Asn Gly Phe Asp Glu Ile Pro Val Glu Val

545 550 555 560

Phe Lys Asp Leu Phe Glu Leu Lys Ile Ile Asp Leu Gly Leu Asn Asn

565 570 575

Leu Asn Thr Leu Pro Ala Ser Val Phe Asn Asn Gln Val Ser Leu Lys

580 585 590

Ser Leu Asn Leu Gln Lys Asn Leu Ile Thr Ser Val Glu Lys Lys Val

595 600 605

Phe Gly Pro Ala Phe Arg Asn Leu Thr Glu Leu Asp Met Arg Phe Asn

610 615 620

Pro Phe Asp Cys Thr Cys Glu Ser Ile Ala Trp Phe Val Asn Trp Ile

625 630 635 640

Asn Glu Thr His Thr Asn Ile Pro Glu Leu Ser Ser His Tyr Leu Cys

645 650 655

Asn Thr Pro Pro His Tyr His Gly Phe Pro Val Arg Leu Phe Asp Thr

660 665 670

Ser Ser Cys Lys Asp Ser Ala Pro Phe Glu

675 680

<210> 4

<211> 605

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 4

Glu Pro Cys Val Glu Val Val Pro Asn Ile Thr Tyr Gln Cys Met Glu

1 5 10 15

Leu Asn Phe Tyr Lys Ile Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn

20 25 30

Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr Ser Phe

35 40 45

Phe Ser Phe Pro Glu Leu Gln Val Leu Asp Leu Ser Arg Cys Glu Ile

50 55 60

Gln Thr Ile Glu Asp Gly Ala Tyr Gln Ser Leu Ser His Leu Ser Thr

65 70 75 80

Leu Ile Leu Thr Gly Asn Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe

85 90 95

Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Ala Val Glu Thr Asn Leu

100 105 110

Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu

115 120 125

Leu Asn Val Ala His Asn Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr

130 135 140

Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys

145 150 155 160

Ile Gln Ser Ile Tyr Cys Thr Asp Leu Arg Val Leu His Gln Met Pro

165 170 175

Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile

180 185 190

Gln Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg

195 200 205

Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gln Gly Leu

210 215 220

Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu

225 230 235 240

Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn

245 250 255

Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp

260 265 270

Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser

275 280 285

Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe

290 295 300

Gly Trp Gln His Leu Glu Leu Val Asn Cys Lys Phe Gly Gln Phe Pro

305 310 315 320

Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys

325 330 335

Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu

340 345 350

Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser

355 360 365

Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly

370 375 380

Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu Glu His

385 390 395 400

Leu Asp Phe Gln His Ser Asn Leu Lys Gln Met Ser Glu Phe Ser Val

405 410 415

Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His

420 425 430

Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu

435 440 445

Val Leu Lys Met Ala Gly Asn Ser Phe Gln Glu Asn Phe Leu Pro Asp

450 455 460

Ile Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gln Cys

465 470 475 480

Gln Leu Glu Gln Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu

485 490 495

Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr Phe

500 505 510

Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu Asp Tyr Ser Leu Asn

515 520 525

His Ile Met Thr Ser Lys Lys Gln Glu Leu Gln His Phe Pro Ser Ser

530 535 540

Leu Ala Phe Leu Asn Leu Thr Gln Asn Asp Phe Ala Cys Thr Cys Glu

545 550 555 560

His Gln Ser Phe Leu Gln Trp Ile Lys Asp Gln Arg Gln Leu Leu Val

565 570 575

Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gln Gly Met

580 585 590

Pro Val Leu Ser Leu Asn Ile Thr Cys Gln Met Asn Lys

595 600 605

<210> 5

<211> 619

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 5

Ile Pro Ser Cys Ser Phe Asp Gly Arg Ile Ala Phe Tyr Arg Phe Cys

1 5 10 15

Asn Leu Thr Gln Val Pro Gln Val Leu Asn Thr Thr Glu Arg Leu Leu

20 25 30

Leu Ser Phe Asn Tyr Ile Arg Thr Val Thr Ala Ser Ser Phe Pro Phe

35 40 45

Leu Glu Gln Leu Gln Leu Leu Glu Leu Gly Ser Gln Tyr Thr Pro Leu

50 55 60

Thr Ile Asp Lys Glu Ala Phe Arg Asn Leu Pro Asn Leu Arg Ile Leu

65 70 75 80

Asp Leu Gly Ser Ser Lys Ile Tyr Phe Leu His Pro Asp Ala Phe Gln

85 90 95

Gly Leu Phe His Leu Phe Glu Leu Arg Leu Tyr Phe Cys Gly Leu Ser

100 105 110

Asp Ala Val Leu Lys Asp Gly Tyr Phe Arg Asn Leu Lys Ala Leu Thr

115 120 125

Arg Leu Asp Leu Ser Lys Asn Gln Ile Arg Ser Leu Tyr Leu His Pro

130 135 140

Ser Phe Gly Lys Leu Asn Ser Leu Lys Ser Ile Asp Phe Ser Ser Asn

145 150 155 160

Gln Ile Phe Leu Val Cys Glu His Glu Leu Glu Pro Leu Gln Gly Lys

165 170 175

Thr Leu Ser Phe Phe Ser Leu Ala Ala Asn Ser Leu Tyr Ser Arg Val

180 185 190

Ser Val Asp Trp Gly Lys Cys Met Asn Pro Phe Arg Asn Met Val Leu

195 200 205

Glu Ile Leu Asp Val Ser Gly Asn Gly Trp Thr Val Asp Ile Thr Gly

210 215 220

Asn Phe Ser Asn Ala Ile Ser Lys Ser Gln Ala Phe Ser Leu Ile Leu

225 230 235 240

Ala His His Ile Met Gly Ala Gly Phe Gly Phe His Asn Ile Lys Asp

245 250 255

Pro Asp Gln Asn Thr Phe Ala Gly Leu Ala Arg Ser Ser Val Arg His

260 265 270

Leu Asp Leu Ser His Gly Phe Val Phe Ser Leu Asn Ser Arg Val Phe

275 280 285

Glu Thr Leu Lys Asp Leu Lys Val Leu Asn Leu Ala Tyr Asn Lys Ile

290 295 300

Asn Lys Ile Ala Asp Glu Ala Phe Tyr Gly Leu Asp Asn Leu Gln Val

305 310 315 320

Leu Asn Leu Ser Tyr Asn Leu Leu Gly Glu Leu Tyr Ser Ser Asn Phe

325 330 335

Tyr Gly Leu Pro Lys Val Ala Tyr Ile Asp Leu Gln Lys Asn His Ile

340 345 350

Ala Ile Ile Gln Asp Gln Thr Phe Lys Phe Leu Glu Lys Leu Gln Thr

355 360 365

Leu Asp Leu Arg Asp Asn Ala Leu Thr Thr Ile His Phe Ile Pro Ser

370 375 380

Ile Pro Asp Ile Phe Leu Ser Gly Asn Lys Leu Val Thr Leu Pro Lys

385 390 395 400

Ile Asn Leu Thr Ala Asn Leu Ile His Leu Ser Glu Asn Arg Leu Glu

405 410 415

Asn Leu Asp Ile Leu Tyr Phe Leu Leu Arg Val Pro His Leu Gln Ile

420 425 430

Leu Ile Leu Asn Gln Asn Arg Phe Ser Ser Cys Ser Gly Asp Gln Thr

435 440 445

Pro Ser Glu Asn Pro Ser Leu Glu Gln Leu Phe Leu Gly Glu Asn Met

450 455 460

Leu Gln Leu Ala Trp Glu Thr Glu Leu Cys Trp Asp Val Phe Glu Gly

465 470 475 480

Leu Ser His Leu Gln Val Leu Tyr Leu Asn His Asn Tyr Leu Asn Ser

485 490 495

Leu Pro Pro Gly Val Phe Ser His Leu Thr Ala Leu Arg Gly Leu Ser

500 505 510

Leu Asn Ser Asn Arg Leu Thr Val Leu Ser His Asn Asp Leu Pro Ala

515 520 525

Asn Leu Glu Ile Leu Asp Ile Ser Arg Asn Gln Leu Leu Ala Pro Asn

530 535 540

Pro Asp Val Phe Val Ser Leu Ser Val Leu Asp Ile Thr His Asn Lys

545 550 555 560

Phe Ile Cys Glu Cys Glu Leu Ser Thr Phe Ile Asn Trp Leu Asn His

565 570 575

Thr Asn Val Thr Ile Ala Gly Pro Pro Ala Asp Ile Tyr Cys Val Tyr

580 585 590

Pro Asp Ser Phe Ser Gly Val Ser Leu Phe Ser Leu Ser Thr Glu Gly

595 600 605

Cys Asp Glu Glu Glu Val Leu Lys Ser Leu Lys

610 615

<210> 6

<211> 555

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 6

Asn Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gln Asn Tyr

20 25 30

Ile Ala Glu Leu Gln Val Ser Asp Met Ser Phe Leu Ser Glu Leu Thr

35 40 45

Val Leu Arg Leu Ser His Asn Arg Ile Gln Leu Leu Asp Leu Ser Val

50 55 60

Phe Lys Phe Asn Gln Asp Leu Glu Tyr Leu Asp Leu Ser His Asn Gln

65 70 75 80

Leu Gln Lys Ile Ser Cys His Pro Ile Val Ser Phe Arg His Leu Asp

85 90 95

Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Leu Ser Gln Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu Gln

115 120 125

Lys Leu Asp Leu Leu Pro Ile Ala His Leu His Leu Ser Tyr Ile Leu

130 135 140

Leu Asp Leu Arg Asn Tyr Tyr Ile Lys Glu Asn Glu Thr Glu Ser Leu

145 150 155 160

Gln Ile Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr Ser

165 170 175

Leu Phe Ala Ile Gln Val Asn Ile Ser Val Asn Thr Leu Gly Cys Leu

180 185 190

Gln Leu Thr Asn Ile Lys Leu Asn Asp Asp Asn Cys Gln Val Phe Ile

195 200 205

Lys Phe Leu Ser Glu Leu Thr Arg Gly Ser Thr Leu Leu Asn Phe Thr

210 215 220

Leu Asn His Ile Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe Gln

225 230 235 240

Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn Ile Tyr Asn Leu Thr

245 250 255

Ile Ile Glu Ser Ile Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr Thr

260 265 270

Leu Lys Ala Leu Thr Ile Glu His Ile Thr Asn Gln Val Phe Leu Phe

275 280 285

Ser Gln Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn Ile Met Met

290 295 300

Leu Thr Ile Ser Asp Thr Pro Phe Ile His Met Leu Cys Pro His Ala

305 310 315 320

Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gln Asn Val Phe Thr Asp

325 330 335

Ser Ile Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu Ile

340 345 350

Leu Gln Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met Thr

355 360 365

Lys Asp Met Pro Ser Leu Glu Ile Leu Asp Val Ser Trp Asn Ser Leu

370 375 380

Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser Ile Val

385 390 395 400

Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg Cys

405 410 415

Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys Ile Lys

420 425 430

Ser Val Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu Leu Asn

435 440 445

Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser

450 455 460

Ser Leu Ser Val Leu Ile Ile Asp His Asn Ser Val Ser His Pro Ser

465 470 475 480

Ala Asp Phe Phe Gln Ser Cys Gln Lys Met Arg Ser Ile Lys Ala Gly

485 490 495

Asp Asn Pro Phe Gln Cys Thr Cys Glu Leu Arg Glu Phe Val Lys Asn

500 505 510

Ile Asp Gln Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr

515 520 525

Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp Phe

530 535 540

His Met Ser Glu Leu Ser Cys Asn Ile Thr Leu

545 550 555

<210> 7

<211> 813

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 7

Ala Arg Trp Phe Pro Lys Thr Leu Pro Cys Asp Val Thr Leu Asp Val

1 5 10 15

Pro Lys Asn His Val Ile Val Asp Cys Thr Asp Lys His Leu Thr Glu

20 25 30

Ile Pro Gly Gly Ile Pro Thr Asn Thr Thr Asn Leu Thr Leu Thr Ile

35 40 45

Asn His Ile Pro Asp Ile Ser Pro Ala Ser Phe His Arg Leu Asp His

50 55 60

Leu Val Glu Ile Asp Phe Arg Cys Asn Cys Val Pro Ile Pro Leu Gly

65 70 75 80

Ser Lys Asn Asn Met Cys Ile Lys Arg Leu Gln Ile Lys Pro Arg Ser

85 90 95

Phe Ser Gly Leu Thr Tyr Leu Lys Ser Leu Tyr Leu Asp Gly Asn Gln

100 105 110

Leu Leu Glu Ile Pro Gln Gly Leu Pro Pro Ser Leu Gln Leu Leu Ser

115 120 125

Leu Glu Ala Asn Asn Ile Phe Ser Ile Arg Lys Glu Asn Leu Thr Glu

130 135 140

Leu Ala Asn Ile Glu Ile Leu Tyr Leu Gly Gln Asn Cys Tyr Tyr Arg

145 150 155 160

Asn Pro Cys Tyr Val Ser Tyr Ser Ile Glu Lys Asp Ala Phe Leu Asn

165 170 175

Leu Thr Lys Leu Lys Val Leu Ser Leu Lys Asp Asn Asn Val Thr Ala

180 185 190

Val Pro Thr Val Leu Pro Ser Thr Leu Thr Glu Leu Tyr Leu Tyr Asn

195 200 205

Asn Met Ile Ala Lys Ile Gln Glu Asp Asp Phe Asn Asn Leu Asn Gln

210 215 220

Leu Gln Ile Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Tyr Asn Ala

225 230 235 240

Pro Phe Pro Cys Ala Pro Cys Lys Asn Asn Ser Pro Leu Gln Ile Pro

245 250 255

Val Asn Ala Phe Asp Ala Leu Thr Glu Leu Lys Val Leu Arg Leu His

260 265 270

Ser Asn Ser Leu Gln His Val Pro Pro Arg Trp Phe Lys Asn Ile Asn

275 280 285

Lys Leu Gln Glu Leu Asp Leu Ser Gln Asn Phe Leu Ala Lys Glu Ile

290 295 300

Gly Asp Ala Lys Phe Leu His Phe Leu Pro Ser Leu Ile Gln Leu Asp

305 310 315 320

Leu Ser Phe Asn Phe Glu Leu Gln Val Tyr Arg Ala Ser Met Asn Leu

325 330 335

Ser Gln Ala Phe Ser Ser Leu Lys Ser Leu Lys Ile Leu Arg Ile Arg

340 345 350

Gly Tyr Val Phe Lys Glu Leu Lys Ser Phe Asn Leu Ser Pro Leu His

355 360 365

Asn Leu Gln Asn Leu Glu Val Leu Asp Leu Gly Thr Asn Phe Ile Lys

370 375 380

Ile Ala Asn Leu Ser Met Phe Lys Gln Phe Lys Arg Leu Lys Val Ile

385 390 395 400

Asp Leu Ser Val Asn Lys Ile Ser Pro Ser Gly Asp Ser Ser Glu Val

405 410 415

Gly Phe Cys Ser Asn Ala Arg Thr Ser Val Glu Ser Tyr Glu Pro Gln

420 425 430

Val Leu Glu Gln Leu His Tyr Phe Arg Tyr Asp Lys Tyr Ala Arg Ser

435 440 445

Cys Arg Phe Lys Asn Lys Glu Ala Ser Phe Met Ser Val Asn Glu Ser

450 455 460

Cys Tyr Lys Tyr Gly Gln Thr Leu Asp Leu Ser Lys Asn Ser Ile Phe

465 470 475 480

Phe Val Lys Ser Ser Asp Phe Gln His Leu Ser Phe Leu Lys Cys Leu

485 490 495

Asn Leu Ser Gly Asn Leu Ile Ser Gln Thr Leu Asn Gly Ser Glu Phe

500 505 510

Gln Pro Leu Ala Glu Leu Arg Tyr Leu Asp Phe Ser Asn Asn Arg Leu

515 520 525

Asp Leu Leu His Ser Thr Ala Phe Glu Glu Leu His Lys Leu Glu Val

530 535 540

Leu Asp Ile Ser Ser Asn Ser His Tyr Phe Gln Ser Glu Gly Ile Thr

545 550 555 560

His Met Leu Asn Phe Thr Lys Asn Leu Lys Val Leu Gln Lys Leu Met

565 570 575

Met Asn Asp Asn Asp Ile Ser Ser Ser Thr Ser Arg Thr Met Glu Ser

580 585 590

Glu Ser Leu Arg Thr Leu Glu Phe Arg Gly Asn His Leu Asp Val Leu

595 600 605

Trp Arg Glu Gly Asp Asn Arg Tyr Leu Gln Leu Phe Lys Asn Leu Leu

610 615 620

Lys Leu Glu Glu Leu Asp Ile Ser Lys Asn Ser Leu Ser Phe Leu Pro

625 630 635 640

Ser Gly Val Phe Asp Gly Met Pro Pro Asn Leu Lys Asn Leu Ser Leu

645 650 655

Ala Lys Asn Gly Leu Lys Ser Phe Ser Trp Lys Lys Leu Gln Cys Leu

660 665 670

Lys Asn Leu Glu Thr Leu Asp Leu Ser His Asn Gln Leu Thr Thr Val

675 680 685

Pro Glu Arg Leu Ser Asn Cys Ser Arg Ser Leu Lys Asn Leu Ile Leu

690 695 700

Lys Asn Asn Gln Ile Arg Ser Leu Thr Lys Tyr Phe Leu Gln Asp Ala

705 710 715 720

Phe Gln Leu Arg Tyr Leu Asp Leu Ser Ser Asn Lys Ile Gln Met Ile

725 730 735

Gln Lys Thr Ser Phe Pro Glu Asn Val Leu Asn Asn Leu Lys Met Leu

740 745 750

Leu Leu His His Asn Arg Phe Leu Cys Thr Cys Asp Ala Val Trp Phe

755 760 765

Val Trp Trp Val Asn His Thr Glu Val Thr Ile Pro Tyr Leu Ala Thr

770 775 780

Asp Val Thr Cys Val Gly Pro Gly Ala His Lys Gly Gln Ser Val Ile

785 790 795 800

Ser Leu Asp Leu Tyr Thr Cys Glu Leu Asp Leu Thr Asn

805 810

<210> 8

<211> 801

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 8

Glu Glu Asn Phe Ser Arg Ser Tyr Pro Cys Asp Glu Lys Lys Gln Asn

1 5 10 15

Asp Ser Val Ile Ala Glu Cys Ser Asn Arg Arg Leu Gln Glu Val Pro

20 25 30

Gln Thr Val Gly Lys Tyr Val Thr Glu Leu Asp Leu Ser Asp Asn Phe

35 40 45

Ile Thr His Ile Thr Asn Glu Ser Phe Gln Gly Leu Gln Asn Leu Thr

50 55 60

Lys Ile Asn Leu Asn His Asn Pro Asn Val Gln His Gln Asn Gly Asn

65 70 75 80

Pro Gly Ile Gln Ser Asn Gly Leu Asn Ile Thr Asp Gly Ala Phe Leu

85 90 95

Asn Leu Lys Asn Leu Arg Glu Leu Leu Leu Glu Asp Asn Gln Leu Pro

100 105 110

Gln Ile Pro Ser Gly Leu Pro Glu Ser Leu Thr Glu Leu Ser Leu Ile

115 120 125

Gln Asn Asn Ile Tyr Asn Ile Thr Lys Glu Gly Ile Ser Arg Leu Ile

130 135 140

Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn Cys Tyr Phe Asn Lys Val

145 150 155 160

Cys Glu Lys Thr Asn Ile Glu Asp Gly Val Phe Glu Thr Leu Thr Asn

165 170 175

Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu Ser His Val Pro Pro

180 185 190

Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu Ser Asn Thr Gln Ile

195 200 205

Lys Tyr Ile Ser Glu Glu Asp Phe Lys Gly Leu Ile Asn Leu Thr Leu

210 215 220

Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Phe Asn Ala Pro Phe Pro

225 230 235 240

Cys Val Pro Cys Asp Gly Gly Ala Ser Ile Asn Ile Asp Arg Phe Ala

245 250 255

Phe Gln Asn Leu Thr Gln Leu Arg Tyr Leu Asn Leu Ser Ser Thr Ser

260 265 270

Leu Arg Lys Ile Asn Ala Ala Trp Phe Lys Asn Met Pro His Leu Lys

275 280 285

Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly Glu Ile Ala Ser Gly

290 295 300

Ala Phe Leu Thr Met Leu Pro Arg Leu Glu Ile Leu Asp Leu Ser Phe

305 310 315 320

Asn Tyr Ile Lys Gly Ser Tyr Pro Gln His Ile Asn Ile Ser Arg Asn

325 330 335

Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His Leu Arg Gly Tyr Val

340 345 350

Phe Gln Glu Leu Arg Glu Asp Asp Phe Gln Pro Leu Met Gln Leu Pro

355 360 365

Asn Leu Ser Thr Ile Asn Leu Gly Ile Asn Phe Ile Lys Gln Ile Asp

370 375 380

Phe Lys Leu Phe Gln Asn Phe Ser Asn Leu Glu Ile Ile Tyr Leu Ser

385 390 395 400

Glu Asn Arg Ile Ser Pro Leu Val Lys Asp Thr Arg Gln Ser Tyr Ala

405 410 415

Asn Ser Ser Ser Phe Gln Arg His Ile Arg Lys Arg Arg Ser Thr Asp

420 425 430

Phe Glu Phe Asp Pro His Ser Asn Phe Tyr His Phe Thr Arg Pro Leu

435 440 445

Ile Lys Pro Gln Cys Ala Ala Tyr Gly Lys Ala Leu Asp Leu Ser Leu

450 455 460

Asn Ser Ile Phe Phe Ile Gly Pro Asn Gln Phe Glu Asn Leu Pro Asp

465 470 475 480

Ile Ala Cys Leu Asn Leu Ser Ala Asn Ser Asn Ala Gln Val Leu Ser

485 490 495

Gly Thr Glu Phe Ser Ala Ile Pro His Val Lys Tyr Leu Asp Leu Thr

500 505 510

Asn Asn Arg Leu Asp Phe Asp Asn Ala Ser Ala Leu Thr Glu Leu Ser

515 520 525

Asp Leu Glu Val Leu Asp Leu Ser Tyr Asn Ser His Tyr Phe Arg Ile

530 535 540

Ala Gly Val Thr His His Leu Glu Phe Ile Gln Asn Phe Thr Asn Leu

545 550 555 560

Lys Val Leu Asn Leu Ser His Asn Asn Ile Tyr Thr Leu Thr Asp Lys

565 570 575

Tyr Asn Leu Glu Ser Lys Ser Leu Val Glu Leu Val Phe Ser Gly Asn

580 585 590

Arg Leu Asp Ile Leu Trp Asn Asp Asp Asp Asn Arg Tyr Ile Ser Ile

595 600 605

Phe Lys Gly Leu Lys Asn Leu Thr Arg Leu Asp Leu Ser Leu Asn Arg

610 615 620

Leu Lys His Ile Pro Asn Glu Ala Phe Leu Asn Leu Pro Ala Ser Leu

625 630 635 640

Thr Glu Leu His Ile Asn Asp Asn Met Leu Lys Phe Phe Asn Trp Thr

645 650 655

Leu Leu Gln Gln Phe Pro Arg Leu Glu Leu Leu Asp Leu Arg Gly Asn

660 665 670

Lys Leu Leu Phe Leu Thr Asp Ser Leu Ser Asp Phe Thr Ser Ser Leu

675 680 685

Arg Thr Leu Leu Leu Ser His Asn Arg Ile Ser His Leu Pro Ser Gly

690 695 700

Phe Leu Ser Glu Val Ser Ser Leu Lys His Leu Asp Leu Ser Ser Asn

705 710 715 720

Leu Leu Lys Thr Ile Asn Lys Ser Ala Leu Glu Thr Lys Thr Thr Thr

725 730 735

Lys Leu Ser Met Leu Glu Leu His Gly Asn Pro Phe Glu Cys Thr Cys

740 745 750

Asp Ile Gly Asp Phe Arg Arg Trp Met Asp Glu His Leu Asn Val Lys

755 760 765

Ile Pro Arg Leu Val Asp Val Ile Cys Ala Ser Pro Gly Asp Gln Arg

770 775 780

Gly Lys Ser Ile Val Ser Leu Glu Leu Thr Thr Cys Val Ser Asp Val

785 790 795 800

Thr

<210> 9

<211> 793

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 9

Leu Gly Thr Leu Pro Ala Phe Leu Pro Cys Glu Leu Gln Pro His Gly

1 5 10 15

Leu Val Asn Cys Asn Trp Leu Phe Leu Lys Ser Val Pro His Phe Ser

20 25 30

Met Ala Ala Pro Arg Gly Asn Val Thr Ser Leu Ser Leu Ser Ser Asn

35 40 45

Arg Ile His His Leu His Asp Ser Asp Phe Ala His Leu Pro Ser Leu

50 55 60

Arg His Leu Asn Leu Lys Trp Asn Cys Pro Pro Val Gly Leu Ser Pro

65 70 75 80

Met His Phe Pro Cys His Met Thr Ile Glu Pro Ser Thr Phe Leu Ala

85 90 95

Val Pro Thr Leu Glu Glu Leu Asn Leu Ser Tyr Asn Asn Ile Met Thr

100 105 110

Val Pro Ala Leu Pro Lys Ser Leu Ile Ser Leu Ser Leu Ser His Thr

115 120 125

Asn Ile Leu Met Leu Asp Ser Ala Ser Leu Ala Gly Leu His Ala Leu

130 135 140

Arg Phe Leu Phe Met Asp Gly Asn Cys Tyr Tyr Lys Asn Pro Cys Arg

145 150 155 160

Gln Ala Leu Glu Val Ala Pro Gly Ala Leu Leu Gly Leu Gly Asn Leu

165 170 175

Thr His Leu Ser Leu Lys Tyr Asn Asn Leu Thr Val Val Pro Arg Asn

180 185 190

Leu Pro Ser Ser Leu Glu Tyr Leu Leu Leu Ser Tyr Asn Arg Ile Val

195 200 205

Lys Leu Ala Pro Glu Asp Leu Ala Asn Leu Thr Ala Leu Arg Val Leu

210 215 220

Asp Val Gly Gly Asn Cys Arg Arg Cys Asp His Ala Pro Asn Pro Cys

225 230 235 240

Met Glu Cys Pro Arg His Phe Pro Gln Leu His Pro Asp Thr Phe Ser

245 250 255

His Leu Ser Arg Leu Glu Gly Leu Val Leu Lys Asp Ser Ser Leu Ser

260 265 270

Trp Leu Asn Ala Ser Trp Phe Arg Gly Leu Gly Asn Leu Arg Val Leu

275 280 285

Asp Leu Ser Glu Asn Phe Leu Tyr Lys Cys Ile Thr Lys Thr Lys Ala

290 295 300

Phe Gln Gly Leu Thr Gln Leu Arg Lys Leu Asn Leu Ser Phe Asn Tyr

305 310 315 320

Gln Lys Arg Val Ser Phe Ala His Leu Ser Leu Ala Pro Ser Phe Gly

325 330 335

Ser Leu Val Ala Leu Lys Glu Leu Asp Met His Gly Ile Phe Phe Arg

340 345 350

Ser Leu Asp Glu Thr Thr Leu Arg Pro Leu Ala Arg Leu Pro Met Leu

355 360 365

Gln Thr Leu Arg Leu Gln Met Asn Phe Ile Asn Gln Ala Gln Leu Gly

370 375 380

Ile Phe Arg Ala Phe Pro Gly Leu Arg Tyr Val Asp Leu Ser Asp Asn

385 390 395 400

Arg Ile Ser Gly Ala Ser Glu Leu Thr Ala Thr Met Gly Glu Ala Asp

405 410 415

Gly Gly Glu Lys Val Trp Leu Gln Pro Gly Asp Leu Ala Pro Ala Pro

420 425 430

Val Asp Thr Pro Ser Ser Glu Asp Phe Arg Pro Asn Cys Ser Thr Leu

435 440 445

Asn Phe Thr Leu Asp Leu Ser Arg Asn Asn Leu Val Thr Val Gln Pro

450 455 460

Glu Met Phe Ala Gln Leu Ser His Leu Gln Cys Leu Arg Leu Ser His

465 470 475 480

Asn Cys Ile Ser Gln Ala Val Asn Gly Ser Gln Phe Leu Pro Leu Thr

485 490 495

Gly Leu Gln Val Leu Asp Leu Ser His Asn Lys Leu Asp Leu Tyr His

500 505 510

Glu His Ser Phe Thr Glu Leu Pro Arg Leu Glu Ala Leu Asp Leu Ser

515 520 525

Tyr Asn Ser Gln Pro Phe Gly Met Gln Gly Val Gly His Asn Phe Ser

530 535 540

Phe Val Ala His Leu Arg Thr Leu Arg His Leu Ser Leu Ala His Asn

545 550 555 560

Asn Ile His Ser Gln Val Ser Gln Gln Leu Cys Ser Thr Ser Leu Arg

565 570 575

Ala Leu Asp Phe Ser Gly Asn Ala Leu Gly His Met Trp Ala Glu Gly

580 585 590

Asp Leu Tyr Leu His Phe Phe Gln Gly Leu Ser Gly Leu Ile Trp Leu

595 600 605

Asp Leu Ser Gln Asn Arg Leu His Thr Leu Leu Pro Gln Thr Leu Arg

610 615 620

Asn Leu Pro Lys Ser Leu Gln Val Leu Arg Leu Arg Asp Asn Tyr Leu

625 630 635 640

Ala Phe Phe Lys Trp Trp Ser Leu His Phe Leu Pro Lys Leu Glu Val

645 650 655

Leu Asp Leu Ala Gly Asn Gln Leu Lys Ala Leu Thr Asn Gly Ser Leu

660 665 670

Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser Ile

675 680 685

Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg Glu

690 695 700

Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp Phe

705 710 715 720

Gly Pro Leu Ala Ser Ala Leu Gln Ile Leu Asp Val Ser Ala Asn Pro

725 730 735

Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu Val

740 745 750

Gln Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser Pro

755 760 765

Gly Gln Leu Gln Gly Leu Ser Ile Phe Ala Gln Asp Leu Arg Leu Cys

770 775 780

Leu Asp Glu Ala Leu Ser Trp Asp Cys

785 790

<210> 10

<211> 557

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 10

Asp Ala Pro Glu Leu Pro Glu Glu Arg Glu Leu Met Thr Asn Cys Ser

1 5 10 15

Asn Met Ser Leu Arg Lys Val Pro Ala Asp Leu Thr Pro Ala Thr Thr

20 25 30

Thr Leu Asp Leu Ser Tyr Asn Leu Leu Phe Gln Leu Gln Ser Ser Asp

35 40 45

Phe His Ser Val Ser Lys Leu Arg Val Leu Ile Leu Cys His Asn Arg

50 55 60

Ile Gln Gln Leu Asp Leu Lys Thr Phe Glu Phe Asn Lys Glu Leu Arg

65 70 75 80

Tyr Leu Asp Leu Ser Asn Asn Arg Leu Lys Ser Val Thr Trp Tyr Leu

85 90 95

Leu Ala Gly Leu Arg Tyr Leu Asp Leu Ser Phe Asn Asp Phe Asp Thr

100 105 110

Met Pro Ile Cys Glu Glu Ala Gly Asn Met Ser His Leu Glu Ile Leu

115 120 125

Gly Leu Ser Gly Ala Lys Ile Gln Lys Ser Asp Phe Gln Lys Ile Ala

130 135 140

His Leu His Leu Asn Thr Val Phe Leu Gly Phe Arg Thr Leu Pro His

145 150 155 160

Tyr Glu Glu Gly Ser Leu Pro Ile Leu Asn Thr Thr Lys Leu His Ile

165 170 175

Val Leu Pro Met Asp Thr Asn Phe Trp Val Leu Leu Arg Asp Gly Ile

180 185 190

Lys Thr Ser Lys Ile Leu Glu Met Thr Asn Ile Asp Gly Lys Ser Gln

195 200 205

Phe Val Ser Tyr Glu Met Gln Arg Asn Leu Ser Leu Glu Asn Ala Lys

210 215 220

Thr Ser Val Leu Leu Leu Asn Lys Val Asp Leu Leu Trp Asp Asp Leu

225 230 235 240

Phe Leu Ile Leu Gln Phe Val Trp His Thr Ser Val Glu His Phe Gln

245 250 255

Ile Arg Asn Val Thr Phe Gly Gly Lys Ala Tyr Leu Asp His Asn Ser

260 265 270

Phe Asp Tyr Ser Asn Thr Val Met Arg Thr Ile Lys Leu Glu His Val

275 280 285

His Phe Arg Val Phe Tyr Ile Gln Gln Asp Lys Ile Tyr Leu Leu Leu

290 295 300

Thr Lys Met Asp Ile Glu Asn Leu Thr Ile Ser Asn Ala Gln Met Pro

305 310 315 320

His Met Leu Phe Pro Asn Tyr Pro Thr Lys Phe Gln Tyr Leu Asn Phe

325 330 335

Ala Asn Asn Ile Leu Thr Asp Glu Leu Phe Lys Arg Thr Ile Gln Leu

340 345 350

Pro His Leu Lys Thr Leu Ile Leu Asn Gly Asn Lys Leu Glu Thr Leu

355 360 365

Ser Leu Val Ser Cys Phe Ala Asn Asn Thr Pro Leu Glu His Leu Asp

370 375 380

Leu Ser Gln Asn Leu Leu Gln His Lys Asn Asp Glu Asn Cys Ser Trp

385 390 395 400

Pro Glu Thr Val Val Asn Met Asn Leu Ser Tyr Asn Lys Leu Ser Asp

405 410 415

Ser Val Phe Arg Cys Leu Pro Lys Ser Ile Gln Ile Leu Asp Leu Asn

420 425 430

Asn Asn Gln Ile Gln Thr Val Pro Lys Glu Thr Ile His Leu Met Ala

435 440 445

Leu Arg Glu Leu Asn Ile Ala Phe Asn Phe Leu Thr Asp Leu Pro Gly

450 455 460

Cys Ser His Phe Ser Arg Leu Ser Val Leu Asn Ile Glu Met Asn Phe

465 470 475 480

Ile Leu Ser Pro Ser Leu Asp Phe Val Gln Ser Cys Gln Glu Val Lys

485 490 495

Thr Leu Asn Ala Gly Arg Asn Pro Phe Arg Cys Thr Cys Glu Leu Lys

500 505 510

Asn Phe Ile Gln Leu Glu Thr Tyr Ser Glu Val Met Met Val Gly Trp

515 520 525

Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg Gly Thr Arg

530 535 540

Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr

545 550 555

<210> 11

<211> 182

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 11

Thr Met Ala Ile Trp Arg Ser Asn Ser Gly Ser Asn Thr Leu Glu Asn

1 5 10 15

Gly Tyr Phe Leu Ser Arg Asn Lys Glu Asn His Ser Gln Pro Thr Gln

20 25 30

Ser Ser Leu Glu Asp Ser Val Thr Pro Thr Lys Ala Val Lys Thr Thr

35 40 45

Gly Val Leu Ser Ser Pro Cys Pro Pro Asn Trp Ile Ile Tyr Glu Lys

50 55 60

Ser Cys Tyr Leu Phe Ser Met Ser Leu Asn Ser Trp Asp Gly Ser Lys

65 70 75 80

Arg Gln Cys Trp Gln Leu Gly Ser Asn Leu Leu Lys Ile Asp Ser Ser

85 90 95

Asn Glu Leu Gly Phe Ile Val Lys Gln Val Ser Ser Gln Pro Asp Asn

100 105 110

Ser Phe Trp Ile Gly Leu Ser Arg Pro Gln Thr Glu Val Pro Trp Leu

115 120 125

Trp Glu Asp Gly Ser Thr Phe Ser Ser Asn Leu Phe Gln Ile Arg Thr

130 135 140

Thr Ala Thr Gln Glu Asn Pro Ser Pro Asn Cys Val Trp Ile His Val

145 150 155 160

Ser Val Ile Tyr Asp Gln Leu Cys Ser Val Pro Ser Tyr Ser Ile Cys

165 170 175

Glu Lys Lys Phe Ser Met

180

<210> 12

<211> 146

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 12

Leu Thr Cys Phe Ser Glu Gly Thr Lys Val Pro Ala Trp Gly Cys Cys

1 5 10 15

Pro Ala Ser Trp Lys Ser Phe Gly Ser Ser Cys Tyr Phe Ile Ser Ser

20 25 30

Glu Glu Lys Val Trp Ser Lys Ser Glu Gln Asn Cys Val Glu Met Gly

35 40 45

Ala His Leu Val Val Phe Asn Thr Glu Ala Glu Gln Asn Phe Ile Val

50 55 60

Gln Gln Leu Asn Glu Ser Phe Ser Tyr Phe Leu Gly Leu Ser Asp Pro

65 70 75 80

Gln Gly Asn Asn Asn Trp Gln Trp Ile Asp Lys Thr Pro Tyr Glu Lys

85 90 95

Asn Val Arg Phe Trp His Leu Gly Glu Pro Asn His Ser Ala Glu Gln

100 105 110

Cys Ala Ser Ile Val Phe Trp Lys Pro Thr Gly Trp Gly Trp Asn Asp

115 120 125

Val Ile Cys Glu Thr Arg Arg Asn Ser Ile Cys Glu Met Asn Lys Ile

130 135 140

Tyr Leu

145

<210> 13

<211> 146

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 13

Gly Ser Val Lys Asn Cys Cys Pro Leu Asn Trp Glu Tyr Phe Gln Ser

1 5 10 15

Ser Cys Tyr Phe Phe Ser Thr Asp Thr Ile Ser Trp Ala Leu Ser Leu

20 25 30

Lys Asn Cys Ser Ala Met Gly Ala His Leu Val Val Ile Asn Ser Gln

35 40 45

Glu Glu Gln Glu Phe Leu Ser Tyr Lys Lys Pro Lys Met Arg Glu Phe

50 55 60

Phe Ile Gly Leu Ser Asp Gln Val Val Glu Gly Gln Trp Gln Trp Val

65 70 75 80

Asp Gly Thr Pro Leu Thr Lys Ser Leu Ser Phe Trp Asp Val Gly Glu

85 90 95

Pro Asn Asn Ile Ala Thr Leu Glu Asp Cys Ala Thr Met Arg Asp Ser

100 105 110

Ser Asn Pro Arg Gln Asn Trp Asn Asp Val Thr Cys Phe Leu Asn Tyr

115 120 125

Phe Arg Ile Cys Glu Met Val Gly Ile Asn Pro Leu Asn Lys Gly Lys

130 135 140

Ser Leu

145

<210> 14

<211> 126

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 14

Gly His Lys Cys Ser Pro Cys Asp Thr Asn Trp Arg Tyr Tyr Gly Asp

1 5 10 15

Ser Cys Tyr Gly Phe Phe Arg His Asn Leu Thr Trp Glu Glu Ser Lys

20 25 30

Gln Tyr Cys Thr Asp Met Asn Ala Thr Leu Leu Lys Ile Asp Asn Arg

35 40 45

Asn Ile Val Glu Tyr Ile Lys Ala Arg Thr His Leu Ile Arg Trp Val

50 55 60

Gly Leu Ser Arg Gln Lys Ser Asn Glu Val Trp Lys Trp Glu Asp Gly

65 70 75 80

Ser Val Ile Ser Glu Asn Met Phe Glu Phe Leu Glu Asp Gly Lys Gly

85 90 95

Asn Met Asn Cys Ala Tyr Phe His Asn Gly Lys Met His Pro Thr Phe

100 105 110

Cys Glu Asn Lys His Tyr Leu Met Cys Glu Arg Lys Ala Gly

115 120 125

<210> 15

<211> 118

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 15

Val Cys Pro Lys Asp Trp Glu Phe Tyr Gln Ala Arg Cys Phe Phe Leu

1 5 10 15

Ser Thr Ser Glu Ser Ser Trp Asn Glu Ser Arg Asp Phe Cys Lys Gly

20 25 30

Lys Gly Ser Thr Leu Ala Ile Val Asn Thr Pro Glu Lys Leu Lys Phe

35 40 45

Leu Gln Asp Ile Thr Asp Ala Glu Lys Tyr Phe Ile Gly Leu Ile Tyr

50 55 60

His Arg Glu Glu Lys Arg Trp Arg Trp Ile Asn Asn Ser Val Phe Asn

65 70 75 80

Gly Asn Val Thr Asn Gln Asn Gln Asn Phe Asn Cys Ala Thr Ile Gly

85 90 95

Leu Thr Lys Thr Phe Asp Ala Ala Ser Cys Asp Ile Ser Tyr Arg Arg

100 105 110

Ile Cys Glu Lys Asn Ala

115

<210> 16

<211> 201

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 16

His Val Thr Leu Lys Ile Glu Met Lys Lys Met Asn Lys Leu Gln Asn

1 5 10 15

Ile Ser Glu Glu Leu Gln Arg Asn Ile Ser Leu Gln Leu Met Ser Asn

20 25 30

Met Asn Ile Ser Asn Lys Ile Arg Asn Leu Ser Thr Thr Leu Gln Thr

35 40 45

Ile Ala Thr Lys Leu Cys Arg Glu Leu Tyr Ser Lys Glu Gln Glu His

50 55 60

Lys Cys Lys Pro Cys Pro Arg Arg Trp Ile Trp His Lys Asp Ser Cys

65 70 75 80

Tyr Phe Leu Ser Asp Asp Val Gln Thr Trp Gln Glu Ser Lys Met Ala

85 90 95

Cys Ala Ala Gln Asn Ala Ser Leu Leu Lys Ile Asn Asn Lys Asn Ala

100 105 110

Leu Glu Phe Ile Lys Ser Gln Ser Arg Ser Tyr Asp Tyr Trp Leu Gly

115 120 125

Leu Ser Pro Glu Glu Asp Ser Thr Arg Gly Met Arg Val Asp Asn Ile

130 135 140

Ile Asn Ser Ser Ala Trp Val Ile Arg Asn Ala Pro Asp Leu Asn Asn

145 150 155 160

Met Tyr Cys Gly Tyr Ile Asn Arg Leu Tyr Val Gln Tyr Tyr His Cys

165 170 175

Thr Tyr Lys Lys Arg Met Ile Cys Glu Lys Met Ala Asn Pro Val Gln

180 185 190

Leu Gly Ser Thr Tyr Phe Arg Glu Ala

195 200

<210> 17

<211> 132

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 17

Cys Pro Lys Asn Trp Lys Ser Phe Ser Ser Asn Cys Tyr Phe Ile Ser

1 5 10 15

Thr Glu Ser Ala Ser Trp Gln Asp Ser Glu Lys Asp Cys Ala Arg Met

20 25 30

Glu Ala His Leu Leu Val Ile Asn Thr Gln Glu Glu Gln Asp Phe Ile

35 40 45

Phe Gln Asn Leu Gln Glu Glu Ser Ala Tyr Phe Val Gly Leu Ser Asp

50 55 60

Pro Glu Gly Gln Arg His Trp Gln Trp Val Asp Gln Thr Pro Tyr Asn

65 70 75 80

Glu Ser Ser Thr Phe Trp His Pro Arg Glu Pro Ser Asp Pro Asn Glu

85 90 95

Arg Cys Val Val Leu Asn Phe Arg Lys Ser Pro Lys Arg Trp Gly Trp

100 105 110

Asn Asp Val Asn Cys Leu Gly Pro Gln Arg Ser Val Cys Glu Met Met

115 120 125

Lys Ile His Leu

130

<210> 18

<211> 155

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 18

His Ala Lys Leu Lys Cys Ile Lys Glu Lys Ser Glu Leu Lys Ser Ala

1 5 10 15

Glu Gly Ser Thr Trp Asn Cys Cys Pro Ile Asp Trp Arg Ala Phe Gln

20 25 30

Ser Asn Cys Tyr Phe Pro Leu Thr Asp Asn Lys Thr Trp Ala Glu Ser

35 40 45

Glu Arg Asn Cys Ser Gly Met Gly Ala His Leu Met Thr Ile Ser Thr

50 55 60

Glu Ala Glu Gln Asn Phe Ile Ile Gln Phe Leu Asp Arg Arg Leu Ser

65 70 75 80

Tyr Phe Leu Gly Leu Arg Asp Glu Asn Ala Lys Gly Gln Trp Arg Trp

85 90 95

Val Asp Gln Thr Pro Phe Asn Pro Arg Arg Val Phe Trp His Lys Asn

100 105 110

Glu Pro Asp Asn Ser Gln Gly Glu Asn Cys Val Val Leu Val Tyr Asn

115 120 125

Gln Asp Lys Trp Ala Trp Asn Asp Val Pro Cys Asn Phe Glu Ala Ser

130 135 140

Arg Ile Cys Lys Ile Pro Gly Thr Thr Leu Asn

145 150 155

<210> 19

<211> 310

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 19

Glu Leu Asp Asp Glu Asp Phe Arg Cys Val Cys Asn Phe Ser Glu Pro

1 5 10 15

Gln Pro Asp Trp Ser Glu Ala Phe Gln Cys Val Ser Ala Val Glu Val

20 25 30

Glu Ile His Ala Gly Gly Leu Asn Leu Glu Pro Phe Leu Lys Arg Val

35 40 45

Asp Ala Asp Ala Asp Pro Arg Gln Tyr Ala Asp Thr Val Lys Ala Leu

50 55 60

Arg Val Arg Arg Leu Thr Val Gly Ala Ala Gln Val Pro Ala Gln Leu

65 70 75 80

Leu Val Gly Ala Leu Arg Val Leu Ala Tyr Ser Arg Leu Lys Glu Leu

85 90 95

Thr Leu Glu Asp Leu Lys Ile Thr Gly Thr Met Pro Pro Leu Pro Leu

100 105 110

Glu Ala Thr Gly Leu Ala Leu Ser Ser Leu Arg Leu Arg Asn Val Ser

115 120 125

Trp Ala Thr Gly Arg Ser Trp Leu Ala Glu Leu Gln Gln Trp Leu Lys

130 135 140

Pro Gly Leu Lys Val Leu Ser Ile Ala Gln Ala His Ser Pro Ala Phe

145 150 155 160

Ser Cys Glu Gln Val Arg Ala Phe Pro Ala Leu Thr Ser Leu Asp Leu

165 170 175

Ser Asp Asn Pro Gly Leu Gly Glu Arg Gly Leu Met Ala Ala Leu Cys

180 185 190

Pro His Lys Phe Pro Ala Ile Gln Asn Leu Ala Leu Arg Asn Thr Gly

195 200 205

Met Glu Thr Pro Thr Gly Val Cys Ala Ala Leu Ala Ala Ala Gly Val

210 215 220

Gln Pro His Ser Leu Asp Leu Ser His Asn Ser Leu Arg Ala Thr Val

225 230 235 240

Asn Pro Ser Ala Pro Arg Cys Met Trp Ser Ser Ala Leu Asn Ser Leu

245 250 255

Asn Leu Ser Phe Ala Gly Leu Glu Gln Val Pro Lys Gly Leu Pro Ala

260 265 270

Lys Leu Arg Val Leu Asp Leu Ser Cys Asn Arg Leu Asn Arg Ala Pro

275 280 285

Gln Pro Asp Glu Leu Pro Glu Val Asp Asn Leu Thr Leu Asp Gly Asn

290 295 300

Pro Phe Leu Val Pro Gly

305 310

<210> 20

<211> 144

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 20

Glu Ala Gln Lys Gln Tyr Trp Val Cys Asn Ser Ser Asp Ala Ser Ile

1 5 10 15

Ser Tyr Thr Tyr Cys Asp Lys Met Gln Tyr Pro Ile Ser Ile Asn Val

20 25 30

Asn Pro Cys Ile Glu Leu Lys Arg Ser Lys Gly Leu Leu His Ile Phe

35 40 45

Tyr Ile Pro Arg Arg Asp Leu Lys Gln Leu Tyr Phe Asn Leu Tyr Ile

50 55 60

Thr Val Asn Thr Met Asn Leu Pro Lys Arg Lys Glu Val Ile Cys Arg

65 70 75 80

Gly Ser Asp Asp Asp Tyr Ser Phe Cys Arg Ala Leu Lys Gly Glu Thr

85 90 95

Val Asn Thr Thr Ile Ser Phe Ser Phe Lys Gly Ile Lys Phe Ser Lys

100 105 110

Gly Lys Tyr Lys Cys Val Val Glu Ala Ile Ser Gly Ser Pro Glu Glu

115 120 125

Met Leu Phe Cys Leu Glu Phe Val Ile Leu His Gln Pro Asn Ser Asn

130 135 140

<210> 21

<211> 456

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 21

Ala Asn Pro Gly Leu Val Ala Arg Ile Thr Asp Lys Gly Leu Gln Tyr

1 5 10 15

Ala Ala Gln Glu Gly Leu Leu Ala Leu Gln Ser Glu Leu Leu Arg Ile

20 25 30

Thr Leu Pro Asp Phe Thr Gly Asp Leu Arg Ile Pro His Val Gly Arg

35 40 45

Gly Arg Tyr Glu Phe His Ser Leu Asn Ile His Ser Cys Glu Leu Leu

50 55 60

His Ser Ala Leu Arg Pro Val Pro Gly Gln Gly Leu Ser Leu Ser Ile

65 70 75 80

Ser Asp Ser Ser Ile Arg Val Gln Gly Arg Trp Lys Val Arg Lys Ser

85 90 95

Phe Phe Lys Leu Gln Gly Ser Phe Asp Val Ser Val Lys Gly Ile Ser

100 105 110

Ile Ser Val Asn Leu Leu Leu Gly Ser Glu Ser Ser Gly Arg Pro Thr

115 120 125

Val Thr Ala Ser Ser Cys Ser Ser Asp Ile Ala Asp Val Glu Val Asp

130 135 140

Met Ser Gly Asp Leu Gly Trp Leu Leu Asn Leu Phe His Asn Gln Ile

145 150 155 160

Glu Ser Lys Phe Gln Lys Val Leu Glu Ser Arg Ile Cys Glu Met Ile

165 170 175

Gln Lys Ser Val Ser Ser Asp Leu Gln Pro Tyr Leu Gln Thr Leu Pro

180 185 190

Val Thr Thr Glu Ile Asp Ser Phe Ala Asp Ile Asp Tyr Ser Leu Val

195 200 205

Glu Ala Pro Arg Ala Thr Ala Gln Met Leu Glu Val Met Phe Lys Gly

210 215 220

Glu Ile Phe His Arg Asn His Arg Ser Pro Val Thr Leu Leu Ala Ala

225 230 235 240

Val Met Ser Leu Pro Glu Glu His Asn Lys Met Val Tyr Phe Ala Ile

245 250 255

Ser Asp Tyr Val Phe Asn Thr Ala Ser Leu Val Tyr His Glu Glu Gly

260 265 270

Tyr Leu Asn Phe Ser Ile Thr Asp Asp Met Ile Pro Pro Asp Ser Asn

275 280 285

Ile Arg Leu Thr Thr Lys Ser Phe Arg Pro Phe Val Pro Arg Leu Ala

290 295 300

Arg Leu Tyr Pro Asn Met Asn Leu Glu Leu Gln Gly Ser Val Pro Ser

305 310 315 320

Ala Pro Leu Leu Asn Phe Ser Pro Gly Asn Leu Ser Val Asp Pro Tyr

325 330 335

Met Glu Ile Asp Ala Phe Val Leu Leu Pro Ser Ser Ser Lys Glu Pro

340 345 350

Val Phe Arg Leu Ser Val Ala Thr Asn Val Ser Ala Thr Leu Thr Phe

355 360 365

Asn Thr Ser Lys Ile Thr Gly Phe Leu Lys Pro Gly Lys Val Lys Val

370 375 380

Glu Leu Lys Glu Ser Lys Val Gly Leu Phe Asn Ala Glu Leu Leu Glu

385 390 395 400

Ala Leu Leu Asn Tyr Tyr Ile Leu Asn Thr Phe Tyr Pro Lys Phe Asn

405 410 415

Asp Lys Leu Ala Glu Gly Phe Pro Leu Pro Leu Leu Lys Arg Val Gln

420 425 430

Leu Tyr Asp Leu Gly Leu Gln Ile His Lys Asp Phe Leu Phe Leu Gly

435 440 445

Ala Asn Val Gln Tyr Met Arg Val

450 455

<210> 22

<211> 472

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 22

Met Gly Cys Asp Arg Asn Cys Gly Leu Ile Ala Gly Ala Val Ile Gly

1 5 10 15

Ala Val Leu Ala Val Phe Gly Gly Ile Leu Met Pro Val Gly Asp Leu

20 25 30

Leu Ile Gln Lys Thr Ile Lys Lys Gln Val Val Leu Glu Glu Gly Thr

35 40 45

Ile Ala Phe Lys Asn Trp Val Lys Thr Gly Thr Glu Val Tyr Arg Gln

50 55 60

Phe Trp Ile Phe Asp Val Gln Asn Pro Gln Glu Val Met Met Asn Ser

65 70 75 80

Ser Asn Ile Gln Val Lys Gln Arg Gly Pro Tyr Thr Tyr Arg Val Arg

85 90 95

Phe Leu Ala Lys Glu Asn Val Thr Gln Asp Ala Glu Asp Asn Thr Val

100 105 110

Ser Phe Leu Gln Pro Asn Gly Ala Ile Phe Glu Pro Ser Leu Ser Val

115 120 125

Gly Thr Glu Ala Asp Asn Phe Thr Val Leu Asn Leu Ala Val Ala Ala

130 135 140

Ala Ser His Ile Tyr Gln Asn Gln Phe Val Gln Met Ile Leu Asn Ser

145 150 155 160

Leu Ile Asn Lys Ser Lys Ser Ser Met Phe Gln Val Arg Thr Leu Arg

165 170 175

Glu Leu Leu Trp Gly Tyr Arg Asp Pro Phe Leu Ser Leu Val Pro Tyr

180 185 190

Pro Val Thr Thr Thr Val Gly Leu Phe Tyr Pro Tyr Asn Asn Thr Ala

195 200 205

Asp Gly Val Tyr Lys Val Phe Asn Gly Lys Asp Asn Ile Ser Lys Val

210 215 220

Ala Ile Ile Asp Thr Tyr Lys Gly Lys Arg Asn Leu Ser Tyr Trp Glu

225 230 235 240

Ser His Cys Asp Met Ile Asn Gly Thr Asp Ala Ala Ser Phe Pro Pro

245 250 255

Phe Val Glu Lys Ser Gln Val Leu Gln Phe Phe Ser Ser Asp Ile Cys

260 265 270

Arg Ser Ile Tyr Ala Val Phe Glu Ser Asp Val Asn Leu Lys Gly Ile

275 280 285

Pro Val Tyr Arg Phe Val Leu Pro Ser Lys Ala Phe Ala Ser Pro Val

290 295 300

Glu Asn Pro Asp Asn Tyr Cys Phe Cys Thr Glu Lys Ile Ile Ser Lys

305 310 315 320

Asn Cys Thr Ser Tyr Gly Val Leu Asp Ile Ser Lys Cys Lys Glu Gly

325 330 335

Arg Pro Val Tyr Ile Ser Leu Pro His Phe Leu Tyr Ala Ser Pro Asp

340 345 350

Val Ser Glu Pro Ile Asp Gly Leu Asn Pro Asn Glu Glu Glu His Arg

355 360 365

Thr Tyr Leu Asp Ile Glu Pro Ile Thr Gly Phe Thr Leu Gln Phe Ala

370 375 380

Lys Arg Leu Gln Val Asn Leu Leu Val Lys Pro Ser Glu Lys Ile Gln

385 390 395 400

Val Leu Lys Asn Leu Lys Arg Asn Tyr Ile Val Pro Ile Leu Trp Leu

405 410 415

Asn Glu Thr Gly Thr Ile Gly Asp Glu Lys Ala Asn Met Phe Arg Ser

420 425 430

Gln Val Thr Gly Lys Ile Asn Leu Leu Gly Leu Ile Glu Met Ile Leu

435 440 445

Leu Ser Val Gly Val Val Met Phe Val Ala Phe Met Ile Ser Tyr Cys

450 455 460

Ala Cys Arg Ser Lys Thr Ile Lys

465 470

<210> 23

<211> 232

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 23

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 25 30

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

35 40 45

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 55 60

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

65 70 75 80

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

85 90 95

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100 105 110

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

115 120 125

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

130 135 140

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

145 150 155 160

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

165 170 175

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

180 185 190

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

195 200 205

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

210 215 220

Ser Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 24

<211> 232

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 24

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 25 30

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

35 40 45

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 55 60

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

65 70 75 80

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

85 90 95

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100 105 110

Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

115 120 125

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

130 135 140

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

145 150 155 160

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

165 170 175

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

180 185 190

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

195 200 205

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

210 215 220

Ser Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 25

<211> 232

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 25

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 25 30

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

35 40 45

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 55 60

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

65 70 75 80

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

85 90 95

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100 105 110

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

115 120 125

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

130 135 140

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

145 150 155 160

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

165 170 175

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

180 185 190

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

195 200 205

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

210 215 220

Ser Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 26

<211> 232

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 26

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 25 30

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

35 40 45

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 55 60

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

65 70 75 80

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

85 90 95

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100 105 110

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

115 120 125

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

130 135 140

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

145 150 155 160

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

165 170 175

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

180 185 190

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

195 200 205

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

210 215 220

Ser Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 27

<211> 234

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 27

Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys

1 5 10 15

Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

20 25 30

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

35 40 45

Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp

50 55 60

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

65 70 75 80

Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

85 90 95

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

100 105 110

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

115 120 125

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu

130 135 140

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

145 150 155 160

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

165 170 175

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

180 185 190

Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

195 200 205

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

210 215 220

Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

225 230

<210> 28

<211> 234

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 28

Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys

1 5 10 15

Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

20 25 30

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

35 40 45

Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp

50 55 60

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

65 70 75 80

Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

85 90 95

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

100 105 110

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

115 120 125

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu

130 135 140

Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

145 150 155 160

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

165 170 175

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

180 185 190

Leu Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

195 200 205

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

210 215 220

Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

225 230

<210> 29

<211> 234

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 29

Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys

1 5 10 15

Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

20 25 30

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

35 40 45

Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp

50 55 60

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

65 70 75 80

Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

85 90 95

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

100 105 110

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

115 120 125

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu

130 135 140

Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr

145 150 155 160

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

165 170 175

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

180 185 190

Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

195 200 205

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

210 215 220

Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

225 230

<210> 30

<211> 683

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 30

Ser Glu Phe Leu Val Asp Arg Ser Lys Asn Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Ser Gln Lys Thr Thr Ile Leu Asn Ile Ser Gln Asn Tyr

20 25 30

Ile Ser Glu Leu Trp Thr Ser Asp Ile Leu Ser Leu Ser Lys Leu Arg

35 40 45

Ile Leu Ile Ile Ser His Asn Arg Ile Gln Tyr Leu Asp Ile Ser Val

50 55 60

Phe Lys Phe Asn Gln Glu Leu Glu Tyr Leu Asp Leu Ser His Asn Lys

65 70 75 80

Leu Val Lys Ile Ser Cys His Pro Thr Val Asn Leu Lys His Leu Asp

85 90 95

Leu Ser Phe Asn Ala Phe Asp Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Met Ser Gln Leu Lys Phe Leu Gly Leu Ser Thr Thr His Leu Glu

115 120 125

Lys Ser Ser Val Leu Pro Ile Ala His Leu Asn Ile Ser Lys Val Leu

130 135 140

Leu Val Leu Gly Glu Thr Tyr Gly Glu Lys Glu Asp Pro Glu Gly Leu

145 150 155 160

Gln Asp Phe Asn Thr Glu Ser Leu His Ile Val Phe Pro Thr Asn Lys

165 170 175

Glu Phe His Phe Ile Leu Asp Val Ser Val Lys Thr Val Ala Asn Leu

180 185 190

Glu Leu Ser Asn Ile Lys Cys Val Leu Glu Asp Asn Lys Cys Ser Tyr

195 200 205

Phe Leu Ser Ile Leu Ala Lys Leu Gln Thr Asn Pro Lys Leu Ser Asn

210 215 220

Leu Thr Leu Asn Asn Ile Glu Thr Thr Trp Asn Ser Phe Ile Arg Ile

225 230 235 240

Leu Gln Leu Val Trp His Thr Thr Val Trp Tyr Phe Ser Ile Ser Asn

245 250 255

Val Lys Leu Gln Gly Gln Leu Asp Phe Arg Asp Phe Asp Tyr Ser Gly

260 265 270

Thr Ser Leu Lys Ala Leu Ser Ile His Gln Val Val Ser Asp Val Phe

275 280 285

Gly Phe Pro Gln Ser Tyr Ile Tyr Glu Ile Phe Ser Asn Met Asn Ile

290 295 300

Lys Asn Phe Thr Val Ser Gly Thr Arg Met Val His Met Leu Cys Pro

305 310 315 320

Ser Lys Ile Ser Pro Phe Leu His Leu Asp Phe Ser Asn Asn Leu Leu

325 330 335

Thr Asp Thr Val Phe Glu Asn Cys Gly His Leu Thr Glu Leu Glu Thr

340 345 350

Leu Ile Leu Gln Met Asn Gln Leu Lys Glu Leu Ser Lys Ile Ala Glu

355 360 365

Met Thr Thr Gln Met Lys Ser Leu Gln Gln Leu Asp Ile Ser Gln Asn

370 375 380

Ser Val Ser Tyr Asp Glu Lys Lys Gly Asp Cys Ser Trp Thr Lys Ser

385 390 395 400

Leu Leu Ser Leu Asn Met Ser Ser Asn Ile Leu Thr Asp Thr Ile Phe

405 410 415

Arg Cys Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys

420 425 430

Ile Lys Ser Ile Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu

435 440 445

Leu Asn Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

450 455 460

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

465 470 475 480

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

485 490 495

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

500 505 510

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

515 520 525

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

530 535 540

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

545 550 555 560

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

565 570 575

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

580 585 590

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

595 600 605

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

610 615 620

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

625 630 635 640

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

645 650 655

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

660 665 670

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680

<210> 31

<211> 683

<212> PRT

<213> Artificial sequence (ARTIFICIAL SEQUENCE)

<400> 31

Ser Glu Phe Leu Val Asp Arg Ser Lys Asn Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Ser Gln Lys Thr Thr Ile Leu Asn Ile Ser Gln Asn Tyr

20 25 30

Ile Ser Glu Leu Trp Thr Ser Asp Ile Leu Ser Leu Ser Lys Leu Arg

35 40 45

Ile Leu Ile Ile Ser His Asn Arg Ile Gln Tyr Leu Asp Ile Ser Val

50 55 60

Phe Lys Phe Asn Gln Glu Leu Glu Tyr Leu Asp Leu Ser His Asn Lys

65 70 75 80

Leu Val Lys Ile Ser Cys His Pro Thr Val Asn Leu Lys His Leu Asp

85 90 95

Leu Ser Phe Asn Ala Phe Asp Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Met Ser Gln Leu Lys Phe Leu Gly Leu Ser Thr Thr His Leu Glu

115 120 125

Lys Ser Ser Val Leu Pro Ile Ala His Leu Asn Ile Ser Lys Val Leu

130 135 140

Leu Val Leu Gly Glu Thr Tyr Gly Glu Lys Glu Asp Pro Glu Gly Leu

145 150 155 160

Gln Asp Phe Asn Thr Glu Ser Leu His Ile Val Phe Pro Thr Asn Lys

165 170 175

Glu Phe His Phe Ile Leu Asp Val Ser Val Lys Thr Val Ala Asn Leu

180 185 190

Glu Leu Ser Asn Ile Lys Cys Val Leu Glu Asp Asn Lys Cys Ser Tyr

195 200 205

Phe Leu Ser Ile Leu Ala Lys Leu Gln Thr Asn Pro Lys Leu Ser Asn

210 215 220

Leu Thr Leu Asn Asn Ile Glu Thr Thr Trp Asn Ser Phe Ile Arg Ile

225 230 235 240

Leu Gln Leu Val Trp His Thr Thr Val Trp Tyr Phe Ser Ile Ser Asn

245 250 255

Val Lys Leu Gln Gly Gln Leu Asp Phe Arg Asp Phe Asp Tyr Ser Gly

260 265 270

Thr Ser Leu Lys Ala Leu Ser Ile His Gln Val Val Ser Asp Val Phe

275 280 285

Gly Phe Pro Gln Ser Tyr Ile Tyr Glu Ile Phe Ser Asn Met Asn Ile

290 295 300

Lys Asn Phe Thr Val Ser Gly Thr Arg Met Val His Met Leu Cys Pro

305 310 315 320

Ser Lys Ile Ser Pro Phe Leu His Leu Asp Phe Ser Asn Asn Leu Leu

325 330 335

Thr Asp Thr Val Phe Glu Asn Cys Gly His Leu Thr Glu Leu Glu Thr

340 345 350

Leu Ile Leu Gln Met Asn Gln Leu Lys Glu Leu Ser Lys Ile Ala Glu

355 360 365

Met Thr Thr Gln Met Lys Ser Leu Gln Gln Leu Asp Ile Ser Gln Asn

370 375 380

Ser Val Ser Tyr Asp Glu Lys Lys Gly Asp Cys Ser Trp Thr Lys Ser

385 390 395 400

Leu Leu Ser Leu Asn Met Ser Ser Asn Ile Leu Thr Asp Thr Ile Phe

405 410 415

Arg Cys Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys

420 425 430

Ile Lys Ser Ile Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu

435 440 445

Leu Asn Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

450 455 460

Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro

465 470 475 480

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

485 490 495

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

500 505 510

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

515 520 525

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

530 535 540

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

545 550 555 560

Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

565 570 575

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

580 585 590

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

595 600 605

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

610 615 620

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

625 630 635 640

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

645 650 655

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

660 665 670

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680

<210> 32

<211> 712

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 32

Ser Leu Ser Cys Asp Arg Asn Gly Ile Cys Lys Gly Ser Ser Gly Ser

1 5 10 15

Leu Asn Ser Ile Pro Ser Gly Leu Thr Glu Ala Val Lys Ser Leu Asp

20 25 30

Leu Ser Asn Asn Arg Ile Thr Tyr Ile Ser Asn Ser Asp Leu Gln Arg

35 40 45

Cys Val Asn Leu Gln Ala Leu Val Leu Thr Ser Asn Gly Ile Asn Thr

50 55 60

Ile Glu Glu Asp Ser Phe Ser Ser Leu Gly Ser Leu Glu His Leu Asp

65 70 75 80

Leu Ser Tyr Asn Tyr Leu Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro

85 90 95

Leu Ser Ser Leu Thr Phe Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr

100 105 110

Leu Gly Glu Thr Ser Leu Phe Ser His Leu Thr Lys Leu Gln Ile Leu

115 120 125

Arg Val Gly Asn Met Asp Thr Phe Thr Lys Ile Gln Arg Lys Asp Phe

130 135 140

Ala Gly Leu Thr Phe Leu Glu Glu Leu Glu Ile Asp Ala Ser Asp Leu

145 150 155 160

Gln Ser Tyr Glu Pro Lys Ser Leu Lys Ser Ile Gln Asn Val Ser His

165 170 175

Leu Ile Leu His Met Lys Gln His Ile Leu Leu Leu Glu Ile Phe Val

180 185 190

Asp Val Thr Ser Ser Val Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu

195 200 205

Asp Thr Phe His Phe Ser Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu

210 215 220

Ile Lys Lys Phe Thr Phe Arg Asn Val Lys Ile Thr Asp Glu Ser Leu

225 230 235 240

Phe Gln Val Met Lys Leu Leu Asn Gln Ile Ser Gly Leu Leu Glu Leu

245 250 255

Glu Phe Asp Asp Cys Thr Leu Asn Gly Val Gly Asn Phe Arg Ala Ser

260 265 270

Asp Asn Asp Arg Val Ile Asp Pro Gly Lys Val Glu Thr Leu Thr Ile

275 280 285

Arg Arg Leu His Ile Pro Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr

290 295 300

Leu Tyr Ser Leu Thr Glu Arg Val Lys Arg Ile Thr Val Glu Asn Ser

305 310 315 320

Lys Val Phe Leu Val Pro Cys Leu Leu Ser Gln His Leu Lys Ser Leu

325 330 335

Glu Tyr Leu Asp Leu Ser Glu Asn Leu Met Val Glu Glu Tyr Leu Lys

340 345 350

Asn Ser Ala Cys Glu Asp Ala Trp Pro Ser Leu Gln Thr Leu Ile Leu

355 360 365

Arg Gln Asn His Leu Ala Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu

370 375 380

Thr Leu Lys Asn Leu Thr Asn Ile Asp Ile Ser Lys Asn Ser Phe His

385 390 395 400

Ser Met Pro Glu Thr Cys Gln Trp Pro Glu Lys Met Lys Tyr Leu Asn

405 410 415

Leu Ser Ser Thr Arg Ile His Ser Val Thr Gly Cys Ile Pro Lys Thr

420 425 430

Leu Glu Ile Leu Asp Val Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu

435 440 445

Asn Leu Pro Gln Leu Lys Glu Leu Tyr Ile Ser Arg Asn Lys Leu Met

450 455 460

Thr Leu Pro Asp Ala Ser Leu Leu Pro Met Leu Leu Val Leu Lys Ile

465 470 475 480

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

485 490 495

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

500 505 510

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

515 520 525

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

530 535 540

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

545 550 555 560

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

565 570 575

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

580 585 590

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

595 600 605

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

610 615 620

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

625 630 635 640

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

645 650 655

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

660 665 670

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

675 680 685

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

690 695 700

Ser Leu Ser Leu Ser Pro Gly Lys

705 710

<210> 33

<211> 712

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 33

Ser Leu Ser Cys Asp Arg Asn Gly Ile Cys Lys Gly Ser Ser Gly Ser

1 5 10 15

Leu Asn Ser Ile Pro Ser Gly Leu Thr Glu Ala Val Lys Ser Leu Asp

20 25 30

Leu Ser Asn Asn Arg Ile Thr Tyr Ile Ser Asn Ser Asp Leu Gln Arg

35 40 45

Cys Val Asn Leu Gln Ala Leu Val Leu Thr Ser Asn Gly Ile Asn Thr

50 55 60

Ile Glu Glu Asp Ser Phe Ser Ser Leu Gly Ser Leu Glu His Leu Asp

65 70 75 80

Leu Ser Tyr Asn Tyr Leu Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro

85 90 95

Leu Ser Ser Leu Thr Phe Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr

100 105 110

Leu Gly Glu Thr Ser Leu Phe Ser His Leu Thr Lys Leu Gln Ile Leu

115 120 125

Arg Val Gly Asn Met Asp Thr Phe Thr Lys Ile Gln Arg Lys Asp Phe

130 135 140

Ala Gly Leu Thr Phe Leu Glu Glu Leu Glu Ile Asp Ala Ser Asp Leu

145 150 155 160

Gln Ser Tyr Glu Pro Lys Ser Leu Lys Ser Ile Gln Asn Val Ser His

165 170 175

Leu Ile Leu His Met Lys Gln His Ile Leu Leu Leu Glu Ile Phe Val

180 185 190

Asp Val Thr Ser Ser Val Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu

195 200 205

Asp Thr Phe His Phe Ser Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu

210 215 220

Ile Lys Lys Phe Thr Phe Arg Asn Val Lys Ile Thr Asp Glu Ser Leu

225 230 235 240

Phe Gln Val Met Lys Leu Leu Asn Gln Ile Ser Gly Leu Leu Glu Leu

245 250 255

Glu Phe Asp Asp Cys Thr Leu Asn Gly Val Gly Asn Phe Arg Ala Ser

260 265 270

Asp Asn Asp Arg Val Ile Asp Pro Gly Lys Val Glu Thr Leu Thr Ile

275 280 285

Arg Arg Leu His Ile Pro Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr

290 295 300

Leu Tyr Ser Leu Thr Glu Arg Val Lys Arg Ile Thr Val Glu Asn Ser

305 310 315 320

Lys Val Phe Leu Val Pro Cys Leu Leu Ser Gln His Leu Lys Ser Leu

325 330 335

Glu Tyr Leu Asp Leu Ser Glu Asn Leu Met Val Glu Glu Tyr Leu Lys

340 345 350

Asn Ser Ala Cys Glu Asp Ala Trp Pro Ser Leu Gln Thr Leu Ile Leu

355 360 365

Arg Gln Asn His Leu Ala Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu

370 375 380

Thr Leu Lys Asn Leu Thr Asn Ile Asp Ile Ser Lys Asn Ser Phe His

385 390 395 400

Ser Met Pro Glu Thr Cys Gln Trp Pro Glu Lys Met Lys Tyr Leu Asn

405 410 415

Leu Ser Ser Thr Arg Ile His Ser Val Thr Gly Cys Ile Pro Lys Thr

420 425 430

Leu Glu Ile Leu Asp Val Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu

435 440 445

Asn Leu Pro Gln Leu Lys Glu Leu Tyr Ile Ser Arg Asn Lys Leu Met

450 455 460

Thr Leu Pro Asp Ala Ser Leu Leu Pro Met Leu Leu Val Leu Lys Ile

465 470 475 480

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

485 490 495

Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

500 505 510

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

515 520 525

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

530 535 540

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

545 550 555 560

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

565 570 575

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

580 585 590

Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

595 600 605

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

610 615 620

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

625 630 635 640

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

645 650 655

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

660 665 670

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

675 680 685

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

690 695 700

Ser Leu Ser Leu Ser Pro Gly Lys

705 710

<210> 34

<211> 837

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 34

Glu Pro Cys Val Glu Val Val Pro Asn Ile Thr Tyr Gln Cys Met Glu

1 5 10 15

Leu Asn Phe Tyr Lys Ile Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn

20 25 30

Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr Ser Phe

35 40 45

Phe Ser Phe Pro Glu Leu Gln Val Leu Asp Leu Ser Arg Cys Glu Ile

50 55 60

Gln Thr Ile Glu Asp Gly Ala Tyr Gln Ser Leu Ser His Leu Ser Thr

65 70 75 80

Leu Ile Leu Thr Gly Asn Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe

85 90 95

Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Ala Val Glu Thr Asn Leu

100 105 110

Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu

115 120 125

Leu Asn Val Ala His Asn Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr

130 135 140

Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys

145 150 155 160

Ile Gln Ser Ile Tyr Cys Thr Asp Leu Arg Val Leu His Gln Met Pro

165 170 175

Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile

180 185 190

Gln Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg

195 200 205

Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gln Gly Leu

210 215 220

Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu

225 230 235 240

Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn

245 250 255

Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp

260 265 270

Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser

275 280 285

Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe

290 295 300

Gly Trp Gln His Leu Glu Leu Val Asn Cys Lys Phe Gly Gln Phe Pro

305 310 315 320

Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys

325 330 335

Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu

340 345 350

Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser

355 360 365

Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly

370 375 380

Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu Glu His

385 390 395 400

Leu Asp Phe Gln His Ser Asn Leu Lys Gln Met Ser Glu Phe Ser Val

405 410 415

Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His

420 425 430

Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu

435 440 445

Val Leu Lys Met Ala Gly Asn Ser Phe Gln Glu Asn Phe Leu Pro Asp

450 455 460

Ile Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gln Cys

465 470 475 480

Gln Leu Glu Gln Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu

485 490 495

Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr Phe

500 505 510

Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu Asp Tyr Ser Leu Asn

515 520 525

His Ile Met Thr Ser Lys Lys Gln Glu Leu Gln His Phe Pro Ser Ser

530 535 540

Leu Ala Phe Leu Asn Leu Thr Gln Asn Asp Phe Ala Cys Thr Cys Glu

545 550 555 560

His Gln Ser Phe Leu Gln Trp Ile Lys Asp Gln Arg Gln Leu Leu Val

565 570 575

Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gln Gly Met

580 585 590

Pro Val Leu Ser Leu Asn Ile Thr Cys Gln Met Asn Lys Glu Pro Lys

595 600 605

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

610 615 620

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

625 630 635 640

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

645 650 655

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

660 665 670

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

675 680 685

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

690 695 700

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

705 710 715 720

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

725 730 735

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

740 745 750

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

755 760 765

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

770 775 780

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

785 790 795 800

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

805 810 815

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

820 825 830

Leu Ser Pro Gly Lys

835

<210> 35

<211> 837

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 35

Glu Pro Cys Val Glu Val Val Pro Asn Ile Thr Tyr Gln Cys Met Glu

1 5 10 15

Leu Asn Phe Tyr Lys Ile Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn

20 25 30

Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr Ser Phe

35 40 45

Phe Ser Phe Pro Glu Leu Gln Val Leu Asp Leu Ser Arg Cys Glu Ile

50 55 60

Gln Thr Ile Glu Asp Gly Ala Tyr Gln Ser Leu Ser His Leu Ser Thr

65 70 75 80

Leu Ile Leu Thr Gly Asn Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe

85 90 95

Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Ala Val Glu Thr Asn Leu

100 105 110

Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu

115 120 125

Leu Asn Val Ala His Asn Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr

130 135 140

Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys

145 150 155 160

Ile Gln Ser Ile Tyr Cys Thr Asp Leu Arg Val Leu His Gln Met Pro

165 170 175

Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile

180 185 190

Gln Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg

195 200 205

Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gln Gly Leu

210 215 220

Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu

225 230 235 240

Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn

245 250 255

Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp

260 265 270

Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser

275 280 285

Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe

290 295 300

Gly Trp Gln His Leu Glu Leu Val Asn Cys Lys Phe Gly Gln Phe Pro

305 310 315 320

Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys

325 330 335

Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu

340 345 350

Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser

355 360 365

Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly

370 375 380

Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu Glu His

385 390 395 400

Leu Asp Phe Gln His Ser Asn Leu Lys Gln Met Ser Glu Phe Ser Val

405 410 415

Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His

420 425 430

Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu

435 440 445

Val Leu Lys Met Ala Gly Asn Ser Phe Gln Glu Asn Phe Leu Pro Asp

450 455 460

Ile Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gln Cys

465 470 475 480

Gln Leu Glu Gln Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu

485 490 495

Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr Phe

500 505 510

Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu Asp Tyr Ser Leu Asn

515 520 525

His Ile Met Thr Ser Lys Lys Gln Glu Leu Gln His Phe Pro Ser Ser

530 535 540

Leu Ala Phe Leu Asn Leu Thr Gln Asn Asp Phe Ala Cys Thr Cys Glu

545 550 555 560

His Gln Ser Phe Leu Gln Trp Ile Lys Asp Gln Arg Gln Leu Leu Val

565 570 575

Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gln Gly Met

580 585 590

Pro Val Leu Ser Leu Asn Ile Thr Cys Gln Met Asn Lys Glu Pro Lys

595 600 605

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

610 615 620

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

625 630 635 640

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

645 650 655

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

660 665 670

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

675 680 685

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

690 695 700

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala

705 710 715 720

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

725 730 735

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

740 745 750

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

755 760 765

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

770 775 780

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

785 790 795 800

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

805 810 815

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

820 825 830

Leu Ser Pro Gly Lys

835

<210> 36

<211> 787

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 36

Asn Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gln Asn Tyr

20 25 30

Ile Ala Glu Leu Gln Val Ser Asp Met Ser Phe Leu Ser Glu Leu Thr

35 40 45

Val Leu Arg Leu Ser His Asn Arg Ile Gln Leu Leu Asp Leu Ser Val

50 55 60

Phe Lys Phe Asn Gln Asp Leu Glu Tyr Leu Asp Leu Ser His Asn Gln

65 70 75 80

Leu Gln Lys Ile Ser Cys His Pro Ile Val Ser Phe Arg His Leu Asp

85 90 95

Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Leu Ser Gln Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu Gln

115 120 125

Lys Leu Asp Leu Leu Pro Ile Ala His Leu His Leu Ser Tyr Ile Leu

130 135 140

Leu Asp Leu Arg Asn Tyr Tyr Ile Lys Glu Asn Glu Thr Glu Ser Leu

145 150 155 160

Gln Ile Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr Ser

165 170 175

Leu Phe Ala Ile Gln Val Asn Ile Ser Val Asn Thr Leu Gly Cys Leu

180 185 190

Gln Leu Thr Asn Ile Lys Leu Asn Asp Asp Asn Cys Gln Val Phe Ile

195 200 205

Lys Phe Leu Ser Glu Leu Thr Arg Gly Ser Thr Leu Leu Asn Phe Thr

210 215 220

Leu Asn His Ile Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe Gln

225 230 235 240

Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn Ile Tyr Asn Leu Thr

245 250 255

Ile Ile Glu Ser Ile Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr Thr

260 265 270

Leu Lys Ala Leu Thr Ile Glu His Ile Thr Asn Gln Val Phe Leu Phe

275 280 285

Ser Gln Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn Ile Met Met

290 295 300

Leu Thr Ile Ser Asp Thr Pro Phe Ile His Met Leu Cys Pro His Ala

305 310 315 320

Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gln Asn Val Phe Thr Asp

325 330 335

Ser Ile Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu Ile

340 345 350

Leu Gln Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met Thr

355 360 365

Lys Asp Met Pro Ser Leu Glu Ile Leu Asp Val Ser Trp Asn Ser Leu

370 375 380

Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser Ile Val

385 390 395 400

Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg Cys

405 410 415

Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys Ile Lys

420 425 430

Ser Val Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu Leu Asn

435 440 445

Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser

450 455 460

Ser Leu Ser Val Leu Ile Ile Asp His Asn Ser Val Ser His Pro Ser

465 470 475 480

Ala Asp Phe Phe Gln Ser Cys Gln Lys Met Arg Ser Ile Lys Ala Gly

485 490 495

Asp Asn Pro Phe Gln Cys Thr Cys Glu Leu Arg Glu Phe Val Lys Asn

500 505 510

Ile Asp Gln Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr

515 520 525

Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp Phe

530 535 540

His Met Ser Glu Leu Ser Cys Asn Ile Thr Leu Glu Pro Lys Ser Cys

545 550 555 560

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

565 570 575

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

580 585 590

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

595 600 605

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

610 615 620

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

625 630 635 640

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

645 650 655

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

660 665 670

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

675 680 685

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

690 695 700

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

705 710 715 720

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

725 730 735

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

740 745 750

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

755 760 765

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

770 775 780

Pro Gly Lys

785

<210> 37

<211> 787

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 37

Asn Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gln Asn Tyr

20 25 30

Ile Ala Glu Leu Gln Val Ser Asp Met Ser Phe Leu Ser Glu Leu Thr

35 40 45

Val Leu Arg Leu Ser His Asn Arg Ile Gln Leu Leu Asp Leu Ser Val

50 55 60

Phe Lys Phe Asn Gln Asp Leu Glu Tyr Leu Asp Leu Ser His Asn Gln

65 70 75 80

Leu Gln Lys Ile Ser Cys His Pro Ile Val Ser Phe Arg His Leu Asp

85 90 95

Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Leu Ser Gln Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu Gln

115 120 125

Lys Leu Asp Leu Leu Pro Ile Ala His Leu His Leu Ser Tyr Ile Leu

130 135 140

Leu Asp Leu Arg Asn Tyr Tyr Ile Lys Glu Asn Glu Thr Glu Ser Leu

145 150 155 160

Gln Ile Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr Ser

165 170 175

Leu Phe Ala Ile Gln Val Asn Ile Ser Val Asn Thr Leu Gly Cys Leu

180 185 190

Gln Leu Thr Asn Ile Lys Leu Asn Asp Asp Asn Cys Gln Val Phe Ile

195 200 205

Lys Phe Leu Ser Glu Leu Thr Arg Gly Ser Thr Leu Leu Asn Phe Thr

210 215 220

Leu Asn His Ile Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe Gln

225 230 235 240

Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn Ile Tyr Asn Leu Thr

245 250 255

Ile Ile Glu Ser Ile Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr Thr

260 265 270

Leu Lys Ala Leu Thr Ile Glu His Ile Thr Asn Gln Val Phe Leu Phe

275 280 285

Ser Gln Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn Ile Met Met

290 295 300

Leu Thr Ile Ser Asp Thr Pro Phe Ile His Met Leu Cys Pro His Ala

305 310 315 320

Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gln Asn Val Phe Thr Asp

325 330 335

Ser Ile Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu Ile

340 345 350

Leu Gln Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met Thr

355 360 365

Lys Asp Met Pro Ser Leu Glu Ile Leu Asp Val Ser Trp Asn Ser Leu

370 375 380

Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser Ile Val

385 390 395 400

Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg Cys

405 410 415

Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys Ile Lys

420 425 430

Ser Val Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu Leu Asn

435 440 445

Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser

450 455 460

Ser Leu Ser Val Leu Ile Ile Asp His Asn Ser Val Ser His Pro Ser

465 470 475 480

Ala Asp Phe Phe Gln Ser Cys Gln Lys Met Arg Ser Ile Lys Ala Gly

485 490 495

Asp Asn Pro Phe Gln Cys Thr Cys Glu Leu Arg Glu Phe Val Lys Asn

500 505 510

Ile Asp Gln Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr

515 520 525

Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp Phe

530 535 540

His Met Ser Glu Leu Ser Cys Asn Ile Thr Leu Glu Pro Lys Ser Cys

545 550 555 560

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

565 570 575

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

580 585 590

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

595 600 605

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

610 615 620

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

625 630 635 640

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

645 650 655

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile

660 665 670

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

675 680 685

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

690 695 700

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

705 710 715 720

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

725 730 735

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

740 745 750

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

755 760 765

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

770 775 780

Pro Gly Lys

785

<210> 38

<211> 683

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 38

Ser Glu Phe Leu Val Asp Arg Ser Lys Asn Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Ser Gln Lys Thr Thr Ile Leu Asn Ile Ser Gln Asn Tyr

20 25 30

Ile Ser Glu Leu Trp Thr Ser Asp Ile Leu Ser Leu Ser Lys Leu Arg

35 40 45

Ile Leu Ile Ile Ser His Asn Arg Ile Gln Tyr Leu Asp Ile Ser Val

50 55 60

Phe Lys Phe Asn Gln Glu Leu Glu Tyr Leu Asp Leu Ser His Asn Lys

65 70 75 80

Leu Val Lys Ile Ser Cys His Pro Thr Val Asn Leu Lys His Leu Asp

85 90 95

Leu Ser Phe Asn Ala Phe Asp Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Met Ser Gln Leu Lys Phe Leu Gly Leu Ser Thr Thr His Leu Glu

115 120 125

Lys Ser Ser Val Leu Pro Ile Ala His Leu Asn Ile Ser Lys Val Leu

130 135 140

Leu Val Leu Gly Glu Thr Tyr Gly Glu Lys Glu Asp Pro Glu Gly Leu

145 150 155 160

Gln Asp Phe Asn Thr Glu Ser Leu His Ile Val Phe Pro Thr Asn Lys

165 170 175

Glu Phe His Phe Ile Leu Asp Val Ser Val Lys Thr Val Ala Asn Leu

180 185 190

Glu Leu Ser Asn Ile Lys Cys Val Leu Glu Asp Asn Lys Cys Ser Tyr

195 200 205

Phe Leu Ser Ile Leu Ala Lys Leu Gln Thr Asn Pro Lys Leu Ser Asn

210 215 220

Leu Thr Leu Asn Asn Ile Glu Thr Thr Trp Asn Ser Phe Ile Arg Ile

225 230 235 240

Leu Gln Leu Val Trp His Thr Thr Val Trp Tyr Phe Ser Ile Ser Asn

245 250 255

Val Lys Leu Gln Gly Gln Leu Asp Phe Arg Asp Phe Asp Tyr Ser Gly

260 265 270

Thr Ser Leu Lys Ala Leu Ser Ile His Gln Val Val Ser Asp Val Phe

275 280 285

Gly Phe Pro Gln Ser Tyr Ile Tyr Glu Ile Phe Ser Asn Met Asn Ile

290 295 300

Lys Asn Phe Thr Val Ser Gly Thr Arg Met Val His Met Leu Cys Pro

305 310 315 320

Ser Lys Ile Ser Pro Phe Leu His Leu Asp Phe Ser Asn Asn Leu Leu

325 330 335

Thr Asp Thr Val Phe Glu Asn Cys Gly His Leu Thr Glu Leu Glu Thr

340 345 350

Leu Ile Leu Gln Met Asn Gln Leu Lys Glu Leu Ser Lys Ile Ala Glu

355 360 365

Met Thr Thr Gln Met Lys Ser Leu Gln Gln Leu Asp Ile Ser Gln Asn

370 375 380

Ser Val Ser Tyr Asp Glu Lys Lys Gly Asp Cys Ser Trp Thr Lys Ser

385 390 395 400

Leu Leu Ser Leu Asn Met Ser Ser Asn Ile Leu Thr Asp Thr Ile Phe

405 410 415

Arg Cys Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys

420 425 430

Ile Lys Ser Ile Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu

435 440 445

Leu Asn Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

450 455 460

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

465 470 475 480

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

485 490 495

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

500 505 510

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

515 520 525

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

530 535 540

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

545 550 555 560

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

565 570 575

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

580 585 590

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

595 600 605

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

610 615 620

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

625 630 635 640

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

645 650 655

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

660 665 670

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680

<210> 39

<211> 712

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 39

Ser Leu Ser Cys Asp Arg Asn Gly Ile Cys Lys Gly Ser Ser Gly Ser

1 5 10 15

Leu Asn Ser Ile Pro Ser Gly Leu Thr Glu Ala Val Lys Ser Leu Asp

20 25 30

Leu Ser Asn Asn Arg Ile Thr Tyr Ile Ser Asn Ser Asp Leu Gln Arg

35 40 45

Cys Val Asn Leu Gln Ala Leu Val Leu Thr Ser Asn Gly Ile Asn Thr

50 55 60

Ile Glu Glu Asp Ser Phe Ser Ser Leu Gly Ser Leu Glu His Leu Asp

65 70 75 80

Leu Ser Tyr Asn Tyr Leu Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro

85 90 95

Leu Ser Ser Leu Thr Phe Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr

100 105 110

Leu Gly Glu Thr Ser Leu Phe Ser His Leu Thr Lys Leu Gln Ile Leu

115 120 125

Arg Val Gly Asn Met Asp Thr Phe Thr Lys Ile Gln Arg Lys Asp Phe

130 135 140

Ala Gly Leu Thr Phe Leu Glu Glu Leu Glu Ile Asp Ala Ser Asp Leu

145 150 155 160

Gln Ser Tyr Glu Pro Lys Ser Leu Lys Ser Ile Gln Asn Val Ser His

165 170 175

Leu Ile Leu His Met Lys Gln His Ile Leu Leu Leu Glu Ile Phe Val

180 185 190

Asp Val Thr Ser Ser Val Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu

195 200 205

Asp Thr Phe His Phe Ser Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu

210 215 220

Ile Lys Lys Phe Thr Phe Arg Asn Val Lys Ile Thr Asp Glu Ser Leu

225 230 235 240

Phe Gln Val Met Lys Leu Leu Asn Gln Ile Ser Gly Leu Leu Glu Leu

245 250 255

Glu Phe Asp Asp Cys Thr Leu Asn Gly Val Gly Asn Phe Arg Ala Ser

260 265 270

Asp Asn Asp Arg Val Ile Asp Pro Gly Lys Val Glu Thr Leu Thr Ile

275 280 285

Arg Arg Leu His Ile Pro Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr

290 295 300

Leu Tyr Ser Leu Thr Glu Arg Val Lys Arg Ile Thr Val Glu Asn Ser

305 310 315 320

Lys Val Phe Leu Val Pro Cys Leu Leu Ser Gln His Leu Lys Ser Leu

325 330 335

Glu Tyr Leu Asp Leu Ser Glu Asn Leu Met Val Glu Glu Tyr Leu Lys

340 345 350

Asn Ser Ala Cys Glu Asp Ala Trp Pro Ser Leu Gln Thr Leu Ile Leu

355 360 365

Arg Gln Asn His Leu Ala Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu

370 375 380

Thr Leu Lys Asn Leu Thr Asn Ile Asp Ile Ser Lys Asn Ser Phe His

385 390 395 400

Ser Met Pro Glu Thr Cys Gln Trp Pro Glu Lys Met Lys Tyr Leu Asn

405 410 415

Leu Ser Ser Thr Arg Ile His Ser Val Thr Gly Cys Ile Pro Lys Thr

420 425 430

Leu Glu Ile Leu Asp Val Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu

435 440 445

Asn Leu Pro Gln Leu Lys Glu Leu Tyr Ile Ser Arg Asn Lys Leu Met

450 455 460

Thr Leu Pro Asp Ala Ser Leu Leu Pro Met Leu Leu Val Leu Lys Ile

465 470 475 480

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

485 490 495

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

500 505 510

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

515 520 525

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

530 535 540

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

545 550 555 560

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

565 570 575

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

580 585 590

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

595 600 605

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

610 615 620

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

625 630 635 640

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

645 650 655

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

660 665 670

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

675 680 685

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

690 695 700

Ser Leu Ser Leu Ser Pro Gly Lys

705 710

<210> 40

<211> 787

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 40

Asn Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu Ile His Val Pro

1 5 10 15

Lys Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gln Asn Tyr

20 25 30

Ile Ala Glu Leu Gln Val Ser Asp Met Ser Phe Leu Ser Glu Leu Thr

35 40 45

Val Leu Arg Leu Ser His Asn Arg Ile Gln Leu Leu Asp Leu Ser Val

50 55 60

Phe Lys Phe Asn Gln Asp Leu Glu Tyr Leu Asp Leu Ser His Asn Gln

65 70 75 80

Leu Gln Lys Ile Ser Cys His Pro Ile Val Ser Phe Arg His Leu Asp

85 90 95

Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro Ile Cys Lys Glu Phe Gly

100 105 110

Asn Leu Ser Gln Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu Gln

115 120 125

Lys Leu Asp Leu Leu Pro Ile Ala His Leu His Leu Ser Tyr Ile Leu

130 135 140

Leu Asp Leu Arg Asn Tyr Tyr Ile Lys Glu Asn Glu Thr Glu Ser Leu

145 150 155 160

Gln Ile Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr Ser

165 170 175

Leu Phe Ala Ile Gln Val Asn Ile Ser Val Asn Thr Leu Gly Cys Leu

180 185 190

Gln Leu Thr Asn Ile Lys Leu Asn Asp Asp Asn Cys Gln Val Phe Ile

195 200 205

Lys Phe Leu Ser Glu Leu Thr Arg Gly Ser Thr Leu Leu Asn Phe Thr

210 215 220

Leu Asn His Ile Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe Gln

225 230 235 240

Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn Ile Tyr Asn Leu Thr

245 250 255

Ile Ile Glu Ser Ile Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr Thr

260 265 270

Leu Lys Ala Leu Thr Ile Glu His Ile Thr Asn Gln Val Phe Leu Phe

275 280 285

Ser Gln Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn Ile Met Met

290 295 300

Leu Thr Ile Ser Asp Thr Pro Phe Ile His Met Leu Cys Pro His Ala

305 310 315 320

Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gln Asn Val Phe Thr Asp

325 330 335

Ser Ile Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu Ile

340 345 350

Leu Gln Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met Thr

355 360 365

Lys Asp Met Pro Ser Leu Glu Ile Leu Asp Val Ser Trp Asn Ser Leu

370 375 380

Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser Ile Val

385 390 395 400

Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg Cys

405 410 415

Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn Lys Ile Lys

420 425 430

Ser Val Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln Glu Leu Asn

435 440 445

Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser

450 455 460

Ser Leu Ser Val Leu Ile Ile Asp His Asn Ser Val Ser His Pro Ser

465 470 475 480

Ala Asp Phe Phe Gln Ser Cys Gln Lys Met Arg Ser Ile Lys Ala Gly

485 490 495

Asp Asn Pro Phe Gln Cys Thr Cys Glu Leu Arg Glu Phe Val Lys Asn

500 505 510

Ile Asp Gln Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr

515 520 525

Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp Phe

530 535 540

His Met Ser Glu Leu Ser Cys Asn Ile Thr Leu Glu Pro Lys Ser Cys

545 550 555 560

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

565 570 575

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

580 585 590

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

595 600 605

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

610 615 620

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

625 630 635 640

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

645 650 655

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

660 665 670

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

675 680 685

Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

690 695 700

Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

705 710 715 720

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

725 730 735

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val

740 745 750

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

755 760 765

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

770 775 780

Pro Gly Lys

785

<210> 41

<211> 837

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 41

Glu Pro Cys Val Glu Val Val Pro Asn Ile Thr Tyr Gln Cys Met Glu

1 5 10 15

Leu Asn Phe Tyr Lys Ile Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn

20 25 30

Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr Ser Phe

35 40 45

Phe Ser Phe Pro Glu Leu Gln Val Leu Asp Leu Ser Arg Cys Glu Ile

50 55 60

Gln Thr Ile Glu Asp Gly Ala Tyr Gln Ser Leu Ser His Leu Ser Thr

65 70 75 80

Leu Ile Leu Thr Gly Asn Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe

85 90 95

Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Ala Val Glu Thr Asn Leu

100 105 110

Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu

115 120 125

Leu Asn Val Ala His Asn Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr

130 135 140

Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys

145 150 155 160

Ile Gln Ser Ile Tyr Cys Thr Asp Leu Arg Val Leu His Gln Met Pro

165 170 175

Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile

180 185 190

Gln Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg

195 200 205

Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gln Gly Leu

210 215 220

Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu

225 230 235 240

Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn

245 250 255

Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp

260 265 270

Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser

275 280 285

Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe

290 295 300

Gly Trp Gln His Leu Glu Leu Val Asn Cys Lys Phe Gly Gln Phe Pro

305 310 315 320

Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys

325 330 335

Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu

340 345 350

Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser

355 360 365

Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly

370 375 380

Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu Glu His

385 390 395 400

Leu Asp Phe Gln His Ser Asn Leu Lys Gln Met Ser Glu Phe Ser Val

405 410 415

Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His

420 425 430

Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu

435 440 445

Val Leu Lys Met Ala Gly Asn Ser Phe Gln Glu Asn Phe Leu Pro Asp

450 455 460

Ile Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gln Cys

465 470 475 480

Gln Leu Glu Gln Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu

485 490 495

Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr Phe

500 505 510

Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu Asp Tyr Ser Leu Asn

515 520 525

His Ile Met Thr Ser Lys Lys Gln Glu Leu Gln His Phe Pro Ser Ser

530 535 540

Leu Ala Phe Leu Asn Leu Thr Gln Asn Asp Phe Ala Cys Thr Cys Glu

545 550 555 560

His Gln Ser Phe Leu Gln Trp Ile Lys Asp Gln Arg Gln Leu Leu Val

565 570 575

Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gln Gly Met

580 585 590

Pro Val Leu Ser Leu Asn Ile Thr Cys Gln Met Asn Lys Glu Pro Lys

595 600 605

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

610 615 620

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

625 630 635 640

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

645 650 655

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

660 665 670

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

675 680 685

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

690 695 700

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

705 710 715 720

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

725 730 735

Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln

740 745 750

Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

755 760 765

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

770 775 780

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

785 790 795 800

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

805 810 815

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

820 825 830

Leu Ser Pro Gly Lys

835

<210> 42

<211> 742

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 42

Glu Leu Thr Val Leu Arg Leu Ser His Asn Arg Ile Gln Leu Leu Asp

1 5 10 15

Leu Ser Val Phe Lys Phe Asn Gln Asp Leu Glu Tyr Leu Asp Leu Ser

20 25 30

His Asn Gln Leu Gln Lys Ile Ser Cys His Pro Ile Val Ser Phe Arg

35 40 45

His Leu Asp Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro Ile Cys Lys

50 55 60

Glu Phe Gly Asn Leu Ser Gln Leu Asn Phe Leu Gly Leu Ser Ala Met

65 70 75 80

Lys Leu Gln Lys Leu Asp Leu Leu Pro Ile Ala His Leu His Leu Ser

85 90 95

Tyr Ile Leu Leu Asp Leu Arg Asn Tyr Tyr Ile Lys Glu Asn Glu Thr

100 105 110

Glu Ser Leu Gln Ile Leu Asn Ala Lys Thr Leu His Leu Val Phe His

115 120 125

Pro Thr Ser Leu Phe Ala Ile Gln Val Asn Ile Ser Val Asn Thr Leu

130 135 140

Gly Cys Leu Gln Leu Thr Asn Ile Lys Leu Asn Asp Asp Asn Cys Gln

145 150 155 160

Val Phe Ile Lys Phe Leu Ser Glu Leu Thr Arg Gly Ser Thr Leu Leu

165 170 175

Asn Phe Thr Leu Asn His Ile Glu Thr Thr Trp Lys Cys Leu Val Arg

180 185 190

Val Phe Gln Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn Ile Tyr

195 200 205

Asn Leu Thr Ile Ile Glu Ser Ile Arg Glu Glu Asp Phe Thr Tyr Ser

210 215 220

Lys Thr Thr Leu Lys Ala Leu Thr Ile Glu His Ile Thr Asn Gln Val

225 230 235 240

Phe Leu Phe Ser Gln Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn

245 250 255

Ile Met Met Leu Thr Ile Ser Asp Thr Pro Phe Ile His Met Leu Cys

260 265 270

Pro His Ala Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gln Asn Val

275 280 285

Phe Thr Asp Ser Ile Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu

290 295 300

Thr Leu Ile Leu Gln Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly

305 310 315 320

Leu Met Thr Lys Asp Met Pro Ser Leu Glu Ile Leu Asp Val Ser Trp

325 330 335

Asn Ser Leu Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu

340 345 350

Ser Ile Val Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val

355 360 365

Phe Arg Cys Leu Pro Pro Arg Ile Lys Val Leu Asp Leu His Ser Asn

370 375 380

Lys Ile Lys Ser Val Pro Lys Gln Val Val Lys Leu Glu Ala Leu Gln

385 390 395 400

Glu Leu Asn Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly

405 410 415

Ser Phe Ser Ser Leu Ser Val Leu Ile Ile Asp His Asn Ser Val Ser

420 425 430

His Pro Ser Ala Asp Phe Phe Gln Ser Cys Gln Lys Met Arg Ser Ile

435 440 445

Lys Ala Gly Asp Asn Pro Phe Gln Cys Thr Cys Glu Leu Arg Glu Phe

450 455 460

Val Lys Asn Ile Asp Gln Val Ser Ser Glu Val Leu Glu Gly Trp Pro

465 470 475 480

Asp Ser Tyr Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu

485 490 495

Lys Asp Phe His Met Ser Glu Leu Ser Cys Asn Ile Thr Leu Glu Pro

500 505 510

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

515 520 525

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

530 535 540

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

545 550 555 560

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

565 570 575

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

580 585 590

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

595 600 605

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

610 615 620

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

625 630 635 640

Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn

645 650 655

Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

660 665 670

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

675 680 685

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

690 695 700

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

705 710 715 720

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

725 730 735

Ser Leu Ser Pro Gly Lys

740

<210> 43

<211> 688

<212> PRT

<213> Artificial sequence (ARTIFICIAL SEQUENCE)

<400> 43

Ala Asn Pro Gly Leu Val Ala Arg Ile Thr Asp Lys Gly Leu Gln Tyr

1 5 10 15

Ala Ala Gln Glu Gly Leu Leu Ala Leu Gln Ser Glu Leu Leu Arg Ile

20 25 30

Thr Leu Pro Asp Phe Thr Gly Asp Leu Arg Ile Pro His Val Gly Arg

35 40 45

Gly Arg Tyr Glu Phe His Ser Leu Asn Ile His Ser Cys Glu Leu Leu

50 55 60

His Ser Ala Leu Arg Pro Val Pro Gly Gln Gly Leu Ser Leu Ser Ile

65 70 75 80

Ser Asp Ser Ser Ile Arg Val Gln Gly Arg Trp Lys Val Arg Lys Ser

85 90 95

Phe Phe Lys Leu Gln Gly Ser Phe Asp Val Ser Val Lys Gly Ile Ser

100 105 110

Ile Ser Val Asn Leu Leu Leu Gly Ser Glu Ser Ser Gly Arg Pro Thr

115 120 125

Val Thr Ala Ser Ser Cys Ser Ser Asp Ile Ala Asp Val Glu Val Asp

130 135 140

Met Ser Gly Asp Leu Gly Trp Leu Leu Asn Leu Phe His Asn Gln Ile

145 150 155 160

Glu Ser Lys Phe Gln Lys Val Leu Glu Ser Arg Ile Cys Glu Met Ile

165 170 175

Gln Lys Ser Val Ser Ser Asp Leu Gln Pro Tyr Leu Gln Thr Leu Pro

180 185 190

Val Thr Thr Glu Ile Asp Ser Phe Ala Asp Ile Asp Tyr Ser Leu Val

195 200 205

Glu Ala Pro Arg Ala Thr Ala Gln Met Leu Glu Val Met Phe Lys Gly

210 215 220

Glu Ile Phe His Arg Asn His Arg Ser Pro Val Thr Leu Leu Ala Ala

225 230 235 240

Val Met Ser Leu Pro Glu Glu His Asn Lys Met Val Tyr Phe Ala Ile

245 250 255

Ser Asp Tyr Val Phe Asn Thr Ala Ser Leu Val Tyr His Glu Glu Gly

260 265 270

Tyr Leu Asn Phe Ser Ile Thr Asp Asp Met Ile Pro Pro Asp Ser Asn

275 280 285

Ile Arg Leu Thr Thr Lys Ser Phe Arg Pro Phe Val Pro Arg Leu Ala

290 295 300

Arg Leu Tyr Pro Asn Met Asn Leu Glu Leu Gln Gly Ser Val Pro Ser

305 310 315 320

Ala Pro Leu Leu Asn Phe Ser Pro Gly Asn Leu Ser Val Asp Pro Tyr

325 330 335

Met Glu Ile Asp Ala Phe Val Leu Leu Pro Ser Ser Ser Lys Glu Pro

340 345 350

Val Phe Arg Leu Ser Val Ala Thr Asn Val Ser Ala Thr Leu Thr Phe

355 360 365

Asn Thr Ser Lys Ile Thr Gly Phe Leu Lys Pro Gly Lys Val Lys Val

370 375 380

Glu Leu Lys Glu Ser Lys Val Gly Leu Phe Asn Ala Glu Leu Leu Glu

385 390 395 400

Ala Leu Leu Asn Tyr Tyr Ile Leu Asn Thr Phe Tyr Pro Lys Phe Asn

405 410 415

Asp Lys Leu Ala Glu Gly Phe Pro Leu Pro Leu Leu Lys Arg Val Gln

420 425 430

Leu Tyr Asp Leu Gly Leu Gln Ile His Lys Asp Phe Leu Phe Leu Gly

435 440 445

Ala Asn Val Gln Tyr Met Arg Val Glu Pro Lys Ser Cys Asp Lys Thr

450 455 460

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

465 470 475 480

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

485 490 495

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

500 505 510

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

515 520 525

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

530 535 540

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

545 550 555 560

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

565 570 575

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu

580 585 590

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys

595 600 605

Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

610 615 620

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

625 630 635 640

Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser

645 650 655

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

660 665 670

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680 685

<210> 44

<211> 542

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 44

Glu Leu Asp Asp Glu Asp Phe Arg Cys Val Cys Asn Phe Ser Glu Pro

1 5 10 15

Gln Pro Asp Trp Ser Glu Ala Phe Gln Cys Val Ser Ala Val Glu Val

20 25 30

Glu Ile His Ala Gly Gly Leu Asn Leu Glu Pro Phe Leu Lys Arg Val

35 40 45

Asp Ala Asp Ala Asp Pro Arg Gln Tyr Ala Asp Thr Val Lys Ala Leu

50 55 60

Arg Val Arg Arg Leu Thr Val Gly Ala Ala Gln Val Pro Ala Gln Leu

65 70 75 80

Leu Val Gly Ala Leu Arg Val Leu Ala Tyr Ser Arg Leu Lys Glu Leu

85 90 95

Thr Leu Glu Asp Leu Lys Ile Thr Gly Thr Met Pro Pro Leu Pro Leu

100 105 110

Glu Ala Thr Gly Leu Ala Leu Ser Ser Leu Arg Leu Arg Asn Val Ser

115 120 125

Trp Ala Thr Gly Arg Ser Trp Leu Ala Glu Leu Gln Gln Trp Leu Lys

130 135 140

Pro Gly Leu Lys Val Leu Ser Ile Ala Gln Ala His Ser Pro Ala Phe

145 150 155 160

Ser Cys Glu Gln Val Arg Ala Phe Pro Ala Leu Thr Ser Leu Asp Leu

165 170 175

Ser Asp Asn Pro Gly Leu Gly Glu Arg Gly Leu Met Ala Ala Leu Cys

180 185 190

Pro His Lys Phe Pro Ala Ile Gln Asn Leu Ala Leu Arg Asn Thr Gly

195 200 205

Met Glu Thr Pro Thr Gly Val Cys Ala Ala Leu Ala Ala Ala Gly Val

210 215 220

Gln Pro His Ser Leu Asp Leu Ser His Asn Ser Leu Arg Ala Thr Val

225 230 235 240

Asn Pro Ser Ala Pro Arg Cys Met Trp Ser Ser Ala Leu Asn Ser Leu

245 250 255

Asn Leu Ser Phe Ala Gly Leu Glu Gln Val Pro Lys Gly Leu Pro Ala

260 265 270

Lys Leu Arg Val Leu Asp Leu Ser Cys Asn Arg Leu Asn Arg Ala Pro

275 280 285

Gln Pro Asp Glu Leu Pro Glu Val Asp Asn Leu Thr Leu Asp Gly Asn

290 295 300

Pro Phe Leu Val Pro Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr

305 310 315 320

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

325 330 335

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

340 345 350

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

355 360 365

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

370 375 380

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

385 390 395 400

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

405 410 415

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

420 425 430

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro

435 440 445

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val

450 455 460

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

465 470 475 480

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

485 490 495

Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

500 505 510

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

515 520 525

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

530 535 540

<210> 45

<211> 376

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 45

Glu Ala Gln Lys Gln Tyr Trp Val Cys Asn Ser Ser Asp Ala Ser Ile

1 5 10 15

Ser Tyr Thr Tyr Cys Asp Lys Met Gln Tyr Pro Ile Ser Ile Asn Val

20 25 30

Asn Pro Cys Ile Glu Leu Lys Arg Ser Lys Gly Leu Leu His Ile Phe

35 40 45

Tyr Ile Pro Arg Arg Asp Leu Lys Gln Leu Tyr Phe Asn Leu Tyr Ile

50 55 60

Thr Val Asn Thr Met Asn Leu Pro Lys Arg Lys Glu Val Ile Cys Arg

65 70 75 80

Gly Ser Asp Asp Asp Tyr Ser Phe Cys Arg Ala Leu Lys Gly Glu Thr

85 90 95

Val Asn Thr Thr Ile Ser Phe Ser Phe Lys Gly Ile Lys Phe Ser Lys

100 105 110

Gly Lys Tyr Lys Cys Val Val Glu Ala Ile Ser Gly Ser Pro Glu Glu

115 120 125

Met Leu Phe Cys Leu Glu Phe Val Ile Leu His Gln Pro Asn Ser Asn

130 135 140

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

145 150 155 160

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

165 170 175

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

180 185 190

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

195 200 205

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

210 215 220

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

225 230 235 240

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

245 250 255

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

260 265 270

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

275 280 285

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

290 295 300

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

305 310 315 320

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

325 330 335

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

340 345 350

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

355 360 365

Ser Leu Ser Leu Ser Pro Gly Lys

370 375

<210> 46

<211> 542

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 46

Glu Leu Asp Asp Glu Asp Phe Arg Cys Val Cys Asn Phe Ser Glu Pro

1 5 10 15

Gln Pro Asp Trp Ser Glu Ala Phe Gln Cys Val Ser Ala Val Glu Val

20 25 30

Glu Ile His Ala Gly Gly Leu Asn Leu Glu Pro Phe Leu Lys Arg Val

35 40 45

Asp Ala Asp Ala Asp Pro Arg Gln Tyr Ala Asp Thr Val Lys Ala Leu

50 55 60

Arg Val Arg Arg Leu Thr Val Gly Ala Ala Gln Val Pro Ala Gln Leu

65 70 75 80

Leu Val Gly Ala Leu Arg Val Leu Ala Tyr Ser Arg Leu Lys Glu Leu

85 90 95

Thr Leu Glu Asp Leu Lys Ile Thr Gly Thr Met Pro Pro Leu Pro Leu

100 105 110

Glu Ala Thr Gly Leu Ala Leu Ser Ser Leu Arg Leu Arg Asn Val Ser

115 120 125

Trp Ala Thr Gly Arg Ser Trp Leu Ala Glu Leu Gln Gln Trp Leu Lys

130 135 140

Pro Gly Leu Lys Val Leu Ser Ile Ala Gln Ala His Ser Pro Ala Phe

145 150 155 160

Ser Cys Glu Gln Val Arg Ala Phe Pro Ala Leu Thr Ser Leu Asp Leu

165 170 175

Ser Asp Asn Pro Gly Leu Gly Glu Arg Gly Leu Met Ala Ala Leu Cys

180 185 190

Pro His Lys Phe Pro Ala Ile Gln Asn Leu Ala Leu Arg Asn Thr Gly

195 200 205

Met Glu Thr Pro Thr Gly Val Cys Ala Ala Leu Ala Ala Ala Gly Val

210 215 220

Gln Pro His Ser Leu Asp Leu Ser His Asn Ser Leu Arg Ala Thr Val

225 230 235 240

Asn Pro Ser Ala Pro Arg Cys Met Trp Ser Ser Ala Leu Asn Ser Leu

245 250 255

Asn Leu Ser Phe Ala Gly Leu Glu Gln Val Pro Lys Gly Leu Pro Ala

260 265 270

Lys Leu Arg Val Leu Asp Leu Ser Cys Asn Arg Leu Asn Arg Ala Pro

275 280 285

Gln Pro Asp Glu Leu Pro Glu Val Asp Asn Leu Thr Leu Asp Gly Asn

290 295 300

Pro Phe Leu Val Pro Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr

305 310 315 320

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

325 330 335

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

340 345 350

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

355 360 365

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

370 375 380

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

385 390 395 400

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

405 410 415

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

420 425 430

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

435 440 445

Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val

450 455 460

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

465 470 475 480

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

485 490 495

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

500 505 510

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

515 520 525

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

530 535 540

<210> 47

<211> 704

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 47

Met Gly Cys Asp Arg Asn Cys Gly Leu Ile Ala Gly Ala Val Ile Gly

1 5 10 15

Ala Val Leu Ala Val Phe Gly Gly Ile Leu Met Pro Val Gly Asp Leu

20 25 30

Leu Ile Gln Lys Thr Ile Lys Lys Gln Val Val Leu Glu Glu Gly Thr

35 40 45

Ile Ala Phe Lys Asn Trp Val Lys Thr Gly Thr Glu Val Tyr Arg Gln

50 55 60

Phe Trp Ile Phe Asp Val Gln Asn Pro Gln Glu Val Met Met Asn Ser

65 70 75 80

Ser Asn Ile Gln Val Lys Gln Arg Gly Pro Tyr Thr Tyr Arg Val Arg

85 90 95

Phe Leu Ala Lys Glu Asn Val Thr Gln Asp Ala Glu Asp Asn Thr Val

100 105 110

Ser Phe Leu Gln Pro Asn Gly Ala Ile Phe Glu Pro Ser Leu Ser Val

115 120 125

Gly Thr Glu Ala Asp Asn Phe Thr Val Leu Asn Leu Ala Val Ala Ala

130 135 140

Ala Ser His Ile Tyr Gln Asn Gln Phe Val Gln Met Ile Leu Asn Ser

145 150 155 160

Leu Ile Asn Lys Ser Lys Ser Ser Met Phe Gln Val Arg Thr Leu Arg

165 170 175

Glu Leu Leu Trp Gly Tyr Arg Asp Pro Phe Leu Ser Leu Val Pro Tyr

180 185 190

Pro Val Thr Thr Thr Val Gly Leu Phe Tyr Pro Tyr Asn Asn Thr Ala

195 200 205

Asp Gly Val Tyr Lys Val Phe Asn Gly Lys Asp Asn Ile Ser Lys Val

210 215 220

Ala Ile Ile Asp Thr Tyr Lys Gly Lys Arg Asn Leu Ser Tyr Trp Glu

225 230 235 240

Ser His Cys Asp Met Ile Asn Gly Thr Asp Ala Ala Ser Phe Pro Pro

245 250 255

Phe Val Glu Lys Ser Gln Val Leu Gln Phe Phe Ser Ser Asp Ile Cys

260 265 270

Arg Ser Ile Tyr Ala Val Phe Glu Ser Asp Val Asn Leu Lys Gly Ile

275 280 285

Pro Val Tyr Arg Phe Val Leu Pro Ser Lys Ala Phe Ala Ser Pro Val

290 295 300

Glu Asn Pro Asp Asn Tyr Cys Phe Cys Thr Glu Lys Ile Ile Ser Lys

305 310 315 320

Asn Cys Thr Ser Tyr Gly Val Leu Asp Ile Ser Lys Cys Lys Glu Gly

325 330 335

Arg Pro Val Tyr Ile Ser Leu Pro His Phe Leu Tyr Ala Ser Pro Asp

340 345 350

Val Ser Glu Pro Ile Asp Gly Leu Asn Pro Asn Glu Glu Glu His Arg

355 360 365

Thr Tyr Leu Asp Ile Glu Pro Ile Thr Gly Phe Thr Leu Gln Phe Ala

370 375 380

Lys Arg Leu Gln Val Asn Leu Leu Val Lys Pro Ser Glu Lys Ile Gln

385 390 395 400

Val Leu Lys Asn Leu Lys Arg Asn Tyr Ile Val Pro Ile Leu Trp Leu

405 410 415

Asn Glu Thr Gly Thr Ile Gly Asp Glu Lys Ala Asn Met Phe Arg Ser

420 425 430

Gln Val Thr Gly Lys Ile Asn Leu Leu Gly Leu Ile Glu Met Ile Leu

435 440 445

Leu Ser Val Gly Val Val Met Phe Val Ala Phe Met Ile Ser Tyr Cys

450 455 460

Ala Cys Arg Ser Lys Thr Ile Lys Glu Pro Lys Ser Cys Asp Lys Thr

465 470 475 480

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

485 490 495

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

500 505 510

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

515 520 525

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

530 535 540

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

545 550 555 560

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

565 570 575

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

580 585 590

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu

595 600 605

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys

610 615 620

Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

625 630 635 640

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

645 650 655

Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser

660 665 670

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

675 680 685

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

690 695 700

<210> 48

<211> 414

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 48

Thr Met Ala Ile Trp Arg Ser Asn Ser Gly Ser Asn Thr Leu Glu Asn

1 5 10 15

Gly Tyr Phe Leu Ser Arg Asn Lys Glu Asn His Ser Gln Pro Thr Gln

20 25 30

Ser Ser Leu Glu Asp Ser Val Thr Pro Thr Lys Ala Val Lys Thr Thr

35 40 45

Gly Val Leu Ser Ser Pro Cys Pro Pro Asn Trp Ile Ile Tyr Glu Lys

50 55 60

Ser Cys Tyr Leu Phe Ser Met Ser Leu Asn Ser Trp Asp Gly Ser Lys

65 70 75 80

Arg Gln Cys Trp Gln Leu Gly Ser Asn Leu Leu Lys Ile Asp Ser Ser

85 90 95

Asn Glu Leu Gly Phe Ile Val Lys Gln Val Ser Ser Gln Pro Asp Asn

100 105 110

Ser Phe Trp Ile Gly Leu Ser Arg Pro Gln Thr Glu Val Pro Trp Leu

115 120 125

Trp Glu Asp Gly Ser Thr Phe Ser Ser Asn Leu Phe Gln Ile Arg Thr

130 135 140

Thr Ala Thr Gln Glu Asn Pro Ser Pro Asn Cys Val Trp Ile His Val

145 150 155 160

Ser Val Ile Tyr Asp Gln Leu Cys Ser Val Pro Ser Tyr Ser Ile Cys

165 170 175

Glu Lys Lys Phe Ser Met Glu Pro Lys Ser Cys Asp Lys Thr His Thr

180 185 190

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

195 200 205

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

210 215 220

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

225 230 235 240

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

245 250 255

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

260 265 270

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

275 280 285

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

290 295 300

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

305 310 315 320

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

325 330 335

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

340 345 350

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

355 360 365

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

370 375 380

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

385 390 395 400

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

405 410

<210> 49

<211> 378

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 49

Leu Thr Cys Phe Ser Glu Gly Thr Lys Val Pro Ala Trp Gly Cys Cys

1 5 10 15

Pro Ala Ser Trp Lys Ser Phe Gly Ser Ser Cys Tyr Phe Ile Ser Ser

20 25 30

Glu Glu Lys Val Trp Ser Lys Ser Glu Gln Asn Cys Val Glu Met Gly

35 40 45

Ala His Leu Val Val Phe Asn Thr Glu Ala Glu Gln Asn Phe Ile Val

50 55 60

Gln Gln Leu Asn Glu Ser Phe Ser Tyr Phe Leu Gly Leu Ser Asp Pro

65 70 75 80

Gln Gly Asn Asn Asn Trp Gln Trp Ile Asp Lys Thr Pro Tyr Glu Lys

85 90 95

Asn Val Arg Phe Trp His Leu Gly Glu Pro Asn His Ser Ala Glu Gln

100 105 110

Cys Ala Ser Ile Val Phe Trp Lys Pro Thr Gly Trp Gly Trp Asn Asp

115 120 125

Val Ile Cys Glu Thr Arg Arg Asn Ser Ile Cys Glu Met Asn Lys Ile

130 135 140

Tyr Leu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

145 150 155 160

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

165 170 175

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

180 185 190

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

195 200 205

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

210 215 220

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

225 230 235 240

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

245 250 255

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

260 265 270

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

275 280 285

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

290 295 300

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

305 310 315 320

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

325 330 335

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

340 345 350

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

355 360 365

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

370 375

<210> 50

<211> 414

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 50

Thr Met Ala Ile Trp Arg Ser Asn Ser Gly Ser Asn Thr Leu Glu Asn

1 5 10 15

Gly Tyr Phe Leu Ser Arg Asn Lys Glu Asn His Ser Gln Pro Thr Gln

20 25 30

Ser Ser Leu Glu Asp Ser Val Thr Pro Thr Lys Ala Val Lys Thr Thr

35 40 45

Gly Val Leu Ser Ser Pro Cys Pro Pro Asn Trp Ile Ile Tyr Glu Lys

50 55 60

Ser Cys Tyr Leu Phe Ser Met Ser Leu Asn Ser Trp Asp Gly Ser Lys

65 70 75 80

Arg Gln Cys Trp Gln Leu Gly Ser Asn Leu Leu Lys Ile Asp Ser Ser

85 90 95

Asn Glu Leu Gly Phe Ile Val Lys Gln Val Ser Ser Gln Pro Asp Asn

100 105 110

Ser Phe Trp Ile Gly Leu Ser Arg Pro Gln Thr Glu Val Pro Trp Leu

115 120 125

Trp Glu Asp Gly Ser Thr Phe Ser Ser Asn Leu Phe Gln Ile Arg Thr

130 135 140

Thr Ala Thr Gln Glu Asn Pro Ser Pro Asn Cys Val Trp Ile His Val

145 150 155 160

Ser Val Ile Tyr Asp Gln Leu Cys Ser Val Pro Ser Tyr Ser Ile Cys

165 170 175

Glu Lys Lys Phe Ser Met Glu Pro Lys Ser Cys Asp Lys Thr His Thr

180 185 190

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

195 200 205

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

210 215 220

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

225 230 235 240

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

245 250 255

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

260 265 270

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

275 280 285

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

290 295 300

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

305 310 315 320

Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val

325 330 335

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

340 345 350

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

355 360 365

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

370 375 380

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

385 390 395 400

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

405 410

<210> 51

<211> 378

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 51

Gly Ser Val Lys Asn Cys Cys Pro Leu Asn Trp Glu Tyr Phe Gln Ser

1 5 10 15

Ser Cys Tyr Phe Phe Ser Thr Asp Thr Ile Ser Trp Ala Leu Ser Leu

20 25 30

Lys Asn Cys Ser Ala Met Gly Ala His Leu Val Val Ile Asn Ser Gln

35 40 45

Glu Glu Gln Glu Phe Leu Ser Tyr Lys Lys Pro Lys Met Arg Glu Phe

50 55 60

Phe Ile Gly Leu Ser Asp Gln Val Val Glu Gly Gln Trp Gln Trp Val

65 70 75 80

Asp Gly Thr Pro Leu Thr Lys Ser Leu Ser Phe Trp Asp Val Gly Glu

85 90 95

Pro Asn Asn Ile Ala Thr Leu Glu Asp Cys Ala Thr Met Arg Asp Ser

100 105 110

Ser Asn Pro Arg Gln Asn Trp Asn Asp Val Thr Cys Phe Leu Asn Tyr

115 120 125

Phe Arg Ile Cys Glu Met Val Gly Ile Asn Pro Leu Asn Lys Gly Lys

130 135 140

Ser Leu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

145 150 155 160

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

165 170 175

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

180 185 190

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

195 200 205

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

210 215 220

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

225 230 235 240

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

245 250 255

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

260 265 270

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

275 280 285

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

290 295 300

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

305 310 315 320

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

325 330 335

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

340 345 350

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

355 360 365

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

370 375

<210> 52

<211> 378

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 52

Leu Thr Cys Phe Ser Glu Gly Thr Lys Val Pro Ala Trp Gly Cys Cys

1 5 10 15

Pro Ala Ser Trp Lys Ser Phe Gly Ser Ser Cys Tyr Phe Ile Ser Ser

20 25 30

Glu Glu Lys Val Trp Ser Lys Ser Glu Gln Asn Cys Val Glu Met Gly

35 40 45

Ala His Leu Val Val Phe Asn Thr Glu Ala Glu Gln Asn Phe Ile Val

50 55 60

Gln Gln Leu Asn Glu Ser Phe Ser Tyr Phe Leu Gly Leu Ser Asp Pro

65 70 75 80

Gln Gly Asn Asn Asn Trp Gln Trp Ile Asp Lys Thr Pro Tyr Glu Lys

85 90 95

Asn Val Arg Phe Trp His Leu Gly Glu Pro Asn His Ser Ala Glu Gln

100 105 110

Cys Ala Ser Ile Val Phe Trp Lys Pro Thr Gly Trp Gly Trp Asn Asp

115 120 125

Val Ile Cys Glu Thr Arg Arg Asn Ser Ile Cys Glu Met Asn Lys Ile

130 135 140

Tyr Leu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

145 150 155 160

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

165 170 175

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

180 185 190

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

195 200 205

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

210 215 220

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

225 230 235 240

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

245 250 255

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

260 265 270

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu

275 280 285

Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr

290 295 300

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

305 310 315 320

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

325 330 335

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

340 345 350

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

355 360 365

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

370 375

<210> 53

<211> 358

<212> PRT

<213> Artificial sequence (ARTIFICIAL SEQUENCE)

<400> 53

Gly His Lys Cys Ser Pro Cys Asp Thr Asn Trp Arg Tyr Tyr Gly Asp

1 5 10 15

Ser Cys Tyr Gly Phe Phe Arg His Asn Leu Thr Trp Glu Glu Ser Lys

20 25 30

Gln Tyr Cys Thr Asp Met Asn Ala Thr Leu Leu Lys Ile Asp Asn Arg

35 40 45

Asn Ile Val Glu Tyr Ile Lys Ala Arg Thr His Leu Ile Arg Trp Val

50 55 60

Gly Leu Ser Arg Gln Lys Ser Asn Glu Val Trp Lys Trp Glu Asp Gly

65 70 75 80

Ser Val Ile Ser Glu Asn Met Phe Glu Phe Leu Glu Asp Gly Lys Gly

85 90 95

Asn Met Asn Cys Ala Tyr Phe His Asn Gly Lys Met His Pro Thr Phe

100 105 110

Cys Glu Asn Lys His Tyr Leu Met Cys Glu Arg Lys Ala Gly Glu Pro

115 120 125

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

130 135 140

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

145 150 155 160

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

165 170 175

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

180 185 190

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

195 200 205

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

210 215 220

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

225 230 235 240

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

245 250 255

Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

260 265 270

Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile

275 280 285

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

290 295 300

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys

305 310 315 320

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

325 330 335

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

340 345 350

Ser Leu Ser Pro Gly Lys

355

<210> 54

<211> 350

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 54

Val Cys Pro Lys Asp Trp Glu Phe Tyr Gln Ala Arg Cys Phe Phe Leu

1 5 10 15

Ser Thr Ser Glu Ser Ser Trp Asn Glu Ser Arg Asp Phe Cys Lys Gly

20 25 30

Lys Gly Ser Thr Leu Ala Ile Val Asn Thr Pro Glu Lys Leu Lys Phe

35 40 45

Leu Gln Asp Ile Thr Asp Ala Glu Lys Tyr Phe Ile Gly Leu Ile Tyr

50 55 60

His Arg Glu Glu Lys Arg Trp Arg Trp Ile Asn Asn Ser Val Phe Asn

65 70 75 80

Gly Asn Val Thr Asn Gln Asn Gln Asn Phe Asn Cys Ala Thr Ile Gly

85 90 95

Leu Thr Lys Thr Phe Asp Ala Ala Ser Cys Asp Ile Ser Tyr Arg Arg

100 105 110

Ile Cys Glu Lys Asn Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr

115 120 125

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

130 135 140

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

145 150 155 160

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

165 170 175

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

180 185 190

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

195 200 205

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

210 215 220

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

225 230 235 240

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro

245 250 255

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val

260 265 270

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

275 280 285

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

290 295 300

Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

305 310 315 320

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

325 330 335

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

340 345 350

<210> 55

<211> 433

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 55

His Val Thr Leu Lys Ile Glu Met Lys Lys Met Asn Lys Leu Gln Asn

1 5 10 15

Ile Ser Glu Glu Leu Gln Arg Asn Ile Ser Leu Gln Leu Met Ser Asn

20 25 30

Met Asn Ile Ser Asn Lys Ile Arg Asn Leu Ser Thr Thr Leu Gln Thr

35 40 45

Ile Ala Thr Lys Leu Cys Arg Glu Leu Tyr Ser Lys Glu Gln Glu His

50 55 60

Lys Cys Lys Pro Cys Pro Arg Arg Trp Ile Trp His Lys Asp Ser Cys

65 70 75 80

Tyr Phe Leu Ser Asp Asp Val Gln Thr Trp Gln Glu Ser Lys Met Ala

85 90 95

Cys Ala Ala Gln Asn Ala Ser Leu Leu Lys Ile Asn Asn Lys Asn Ala

100 105 110

Leu Glu Phe Ile Lys Ser Gln Ser Arg Ser Tyr Asp Tyr Trp Leu Gly

115 120 125

Leu Ser Pro Glu Glu Asp Ser Thr Arg Gly Met Arg Val Asp Asn Ile

130 135 140

Ile Asn Ser Ser Ala Trp Val Ile Arg Asn Ala Pro Asp Leu Asn Asn

145 150 155 160

Met Tyr Cys Gly Tyr Ile Asn Arg Leu Tyr Val Gln Tyr Tyr His Cys

165 170 175

Thr Tyr Lys Lys Arg Met Ile Cys Glu Lys Met Ala Asn Pro Val Gln

180 185 190

Leu Gly Ser Thr Tyr Phe Arg Glu Ala Glu Pro Lys Ser Cys Asp Lys

195 200 205

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

210 215 220

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

225 230 235 240

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

245 250 255

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

260 265 270

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

275 280 285

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

290 295 300

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

305 310 315 320

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr

325 330 335

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser

340 345 350

Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

355 360 365

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

370 375 380

Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys

385 390 395 400

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

405 410 415

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

420 425 430

Lys

<210> 56

<211> 364

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 56

Cys Pro Lys Asn Trp Lys Ser Phe Ser Ser Asn Cys Tyr Phe Ile Ser

1 5 10 15

Thr Glu Ser Ala Ser Trp Gln Asp Ser Glu Lys Asp Cys Ala Arg Met

20 25 30

Glu Ala His Leu Leu Val Ile Asn Thr Gln Glu Glu Gln Asp Phe Ile

35 40 45

Phe Gln Asn Leu Gln Glu Glu Ser Ala Tyr Phe Val Gly Leu Ser Asp

50 55 60

Pro Glu Gly Gln Arg His Trp Gln Trp Val Asp Gln Thr Pro Tyr Asn

65 70 75 80

Glu Ser Ser Thr Phe Trp His Pro Arg Glu Pro Ser Asp Pro Asn Glu

85 90 95

Arg Cys Val Val Leu Asn Phe Arg Lys Ser Pro Lys Arg Trp Gly Trp

100 105 110

Asn Asp Val Asn Cys Leu Gly Pro Gln Arg Ser Val Cys Glu Met Met

115 120 125

Lys Ile His Leu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro

130 135 140

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

145 150 155 160

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

165 170 175

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

180 185 190

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

195 200 205

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

210 215 220

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

225 230 235 240

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

245 250 255

Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg

260 265 270

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly

275 280 285

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

290 295 300

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

305 310 315 320

Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

325 330 335

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

340 345 350

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

355 360

<210> 57

<211> 387

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 57

His Ala Lys Leu Lys Cys Ile Lys Glu Lys Ser Glu Leu Lys Ser Ala

1 5 10 15

Glu Gly Ser Thr Trp Asn Cys Cys Pro Ile Asp Trp Arg Ala Phe Gln

20 25 30

Ser Asn Cys Tyr Phe Pro Leu Thr Asp Asn Lys Thr Trp Ala Glu Ser

35 40 45

Glu Arg Asn Cys Ser Gly Met Gly Ala His Leu Met Thr Ile Ser Thr

50 55 60

Glu Ala Glu Gln Asn Phe Ile Ile Gln Phe Leu Asp Arg Arg Leu Ser

65 70 75 80

Tyr Phe Leu Gly Leu Arg Asp Glu Asn Ala Lys Gly Gln Trp Arg Trp

85 90 95

Val Asp Gln Thr Pro Phe Asn Pro Arg Arg Val Phe Trp His Lys Asn

100 105 110

Glu Pro Asp Asn Ser Gln Gly Glu Asn Cys Val Val Leu Val Tyr Asn

115 120 125

Gln Asp Lys Trp Ala Trp Asn Asp Val Pro Cys Asn Phe Glu Ala Ser

130 135 140

Arg Ile Cys Lys Ile Pro Gly Thr Thr Leu Asn Glu Pro Lys Ser Cys

145 150 155 160

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

165 170 175

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

180 185 190

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

195 200 205

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

210 215 220

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

225 230 235 240

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

245 250 255

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

260 265 270

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

275 280 285

Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

290 295 300

Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

305 310 315 320

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

325 330 335

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val

340 345 350

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

355 360 365

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

370 375 380

Pro Gly Lys

385

<210> 58

<211> 416

<212> PRT

<213> Artificial sequence (Artificial sequence)

<400> 58

Thr Met Ala Ile Trp Arg Ser Asn Ser Gly Ser Asn Thr Leu Glu Asn

1 5 10 15

Gly Tyr Phe Leu Ser Arg Asn Lys Glu Asn His Ser Gln Pro Thr Gln

20 25 30

Ser Ser Leu Glu Asp Ser Val Thr Pro Thr Lys Ala Val Lys Thr Thr

35 40 45

Gly Val Leu Ser Ser Pro Cys Pro Pro Asn Trp Ile Ile Tyr Glu Lys

50 55 60

Ser Cys Tyr Leu Phe Ser Met Ser Leu Asn Ser Trp Asp Gly Ser Lys

65 70 75 80

Arg Gln Cys Trp Gln Leu Gly Ser Asn Leu Leu Lys Ile Asp Ser Ser

85 90 95

Asn Glu Leu Gly Phe Ile Val Lys Gln Val Ser Ser Gln Pro Asp Asn

100 105 110

Ser Phe Trp Ile Gly Leu Ser Arg Pro Gln Thr Glu Val Pro Trp Leu

115 120 125

Trp Glu Asp Gly Ser Thr Phe Ser Ser Asn Leu Phe Gln Ile Arg Thr

130 135 140

Thr Ala Thr Gln Glu Asn Pro Ser Pro Asn Cys Val Trp Ile His Val

145 150 155 160

Ser Val Ile Tyr Asp Gln Leu Cys Ser Val Pro Ser Tyr Ser Ile Cys

165 170 175

Glu Lys Lys Phe Ser Met Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

180 185 190

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

195 200 205

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

210 215 220

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

225 230 235 240

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

245 250 255

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

260 265 270

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

275 280 285

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

290 295 300

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

305 310 315 320

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

325 330 335

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

340 345 350

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

355 360 365

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

370 375 380

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

385 390 395 400

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

405 410 415

Claims

1. A dimeric immunological fusion protein comprising a first polypeptide chain and a second polypeptide chain which dimerize, said first polypeptide chain having the general structural formula Z1-Z2, said second polypeptide chain having the general structural formula Y1-Y2,

wherein Z1 and Y1 are both extracellular domains of pattern recognition receptors or functional variants thereof, and Z2 and Y2 are both dimerization domains or functional variants thereof;

when Z1 and Y1 are derived identically, the sequences of the Z1-Z2 and Y1-Y2 polypeptide chains are each selected from any one of:

(1) when Z1 and Y1 are both TLR1 extracellular domains, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown as SEQ ID NO:30,

(2) when Z1 and Y1 are both functional variants of the extracellular domain of TLR1, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown in SEQ ID NO:31,

(3) when Z1 and Y1 are both TLR2 extracellular domains, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown as SEQ ID NO:32,

(4) when Z1 and Y1 are both functional variants of the extracellular domain of TLR2, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown in SEQ ID NO:33,

(5) when Z1 and Y1 are both the extracellular domains of TLR4, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown in SEQ ID NO:34,

(6) when Z1 and Y1 are both functional variants of the extracellular domain of TLR4, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown in SEQ ID NO:35,

(7) when Z1 and Y1 are both TLR6 extracellular domains, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown as SEQ ID NO:36,

(8) when Z1 and Y1 are both functional variants of the extracellular domain of TLR6, the sequences of the Z1-Z2 polypeptide chain and the Y1-Y2 polypeptide chain are shown in SEQ ID NO:37, respectively;

when Z1 and Y1 are of different origin, the sequences of the Z1-Z2 and Y1-Y2 polypeptide chains are selected from any one of the following groups:

(1) the sequence of the polypeptide chain of Z1-Z2 is shown as SEQ ID NO.38, the sequence of the polypeptide chain of Y1-Y2 is shown as SEQ ID NO.39,

(2) the sequence of the polypeptide chain of Z1-Z2 is shown as SEQ ID NO.39, the sequence of the polypeptide chain of Y1-Y2 is shown as SEQ ID NO.41 or SEQ ID NO.50,

(3) the sequence of the polypeptide chain of Z1-Z2 is shown as SEQ ID NO.41, and the sequence of the polypeptide chain of Y1-Y2 is shown as SEQ ID NO.40, SEQ ID NO.45 or SEQ ID NO. 47.

2. A pharmaceutical composition comprising the dimeric immunological fusion protein of claim 1, further comprising a pharmaceutically acceptable pharmaceutical carrier.

3. Use of a dimeric electrofusion protein according to claim 1 in the preparation of a medicament for the treatment of inflammation, infectious disease or autoimmunity.

4. Use of the dimeric immunoaffinity protein of claim 1 in the preparation of a reagent or kit for the diagnosis of inflammation, infectious disease or autoimmune disease.

5. Use according to claim 3 or 4, characterized in that:

wherein the inflammation comprises sepsis, acute lung injury, inflammatory injury of the liver, or endometrial injury;

the infectious diseases comprise bacterial, fungal, viral or parasitic infectious diseases;

the autoimmune disease includes systemic lupus erythematosus or immune infertility.