CN112794912B - anti-IGF-1R antibody and application thereof - Google Patents

anti-IGF-1R antibody and application thereof Download PDF

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CN112794912B
CN112794912B CN202110402120.4A CN202110402120A CN112794912B CN 112794912 B CN112794912 B CN 112794912B CN 202110402120 A CN202110402120 A CN 202110402120A CN 112794912 B CN112794912 B CN 112794912B
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CN112794912A (en
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张鹏
郭树华
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Suzhou Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

The invention provides an antibody capable of binding IGF-1R, which consists of a light chain and a heavy chain, wherein the light chain and the heavy chain are selected from one of the combinations of SEQ ID NO 70 and SEQ ID NO 71, SEQ ID NO 72 and SEQ ID NO 73, SEQ ID NO 74 and SEQ ID NO 75, SEQ ID NO 76 and SEQ ID NO 77, SEQ ID NO 78 and SEQ ID NO 79, SEQ ID NO 80 and SEQ ID NO 81, SEQ ID NO 82 and SEQ ID NO 83, SEQ ID NO 84 and SEQ ID NO 85. The invention also provides a nucleic acid molecule for encoding the antibody, a vector containing the nucleic acid, a host cell transformed by the vector and application thereof.

Description

anti-IGF-1R antibody and application thereof
Technical Field
The invention relates to the technical field of biomedicine, in particular to an anti-IGF-1R antibody and application thereof.
Background
Thyroid-associated ophthalmopathy (TAO), also known as endocrine exophthalmos, infiltrative exophthalmos and thyroid eye disease, accounts for about 20% of orbital diseases. TAO is usually caused bilaterally, and also occurs asymmetrically or unilaterally. TAO associated with hyperthyroidism accounts for about 90%, and it may occur simultaneously with hyperthyroidism, or before or after hyperthyroidism, or in some cases, TAO may appear in hypothyroid patients. Thyroid-related eye diseases can cause eyeball herniation, eyelid contracture, extraocular muscle dysfunction, conjunctival congestion, periorbital edema and the like, and can lead to exposed keratitis, diplopia and compressive optic neuropathy in severe cases, and the latter can lead to blindness and seriously affect the quality of life of patients. Thyroid-associated eye diseases are site-specific autoimmune diseases mainly based on cellular immunity, which are triggered by common antigens expressed by thyroid epithelial cells, orbital preadipocytes and fibroblasts together. Inflammatory responses, orbital fibroblast proliferation and orbital adipocyte proliferation lead to exophthalmos, causing symptoms of thyroid-related eye disease.
The insulin-like growth factor 1 receptor (IGF-1R) (SEQ ID NO: 1) belongs to the tyrosine protein kinase receptor family, is a cell surface transmembrane protein, can be activated by IGF-1 and IGF-2 (both insulin growth factors), and the overexpression of the protein may be related to the onset of malignant tumors such as multiple sclerosis, Crohn's disease, pulmonary fibrosis and the like and autoimmune diseases. Antibodies against IGF-1R are detectable in most TAO patients, but are rarely found in normal humans. IGF-1R-associated IgG can activate IGF-1R-positive orbital fibroblasts from thyroid-associated eye disease patients, so that activation of Akt/FRAP/mTOR/P70s6k channels induces expression of interleukin-16 and factors (regulated activated normal T cell expressed and secreted factors) that regulate and activate normal T cell expression and secretion, promotes synthesis of T cell chemokines, causes inflammatory infiltration of T lymphocytes and production of hyaluronic acid, and indicates that IGF-1R may be involved in the development of TAO as a second antigen.
anti-IGF-1R antibodies (see patents WO2004087756, US20100158919, US 20140193404) reach major and all minor endpoints in clinical trials for treating thyroid eye disease, and can significantly improve symptoms of eyeball herniation. In addition to the above-mentioned antibodies, there is no other application of IGF-1R antibodies for treating thyroid eye diseases at home and abroad, and for example, the anti-IGF-1R antibodies in patents CN200880011970.4, CN200880114015.3, CN200780011979.0, CN200980137723.3, US20190040141, US20090175868 and US20060018910 are all used for treating malignant tumors. Therefore, in the field of thyroid-related eye diseases, it is necessary to develop novel therapeutic antibodies for IGF-1R for the treatment of the disease.
Terms and definitions
Before setting forth the context of the present invention, the terms used herein are defined as follows:
the term "antibody" refers to: a glycoprotein comprising a heavy chain (H) and a light chain (L) interconnected by a disulfide bond (S-S). Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of 3 domains, CH1, CH2, and CH 3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain CL. The light chains are classified into two types, a kappa-type light chain and a lambda-type light chain (for example, in the present invention, the light chain constant region Ck/lambda means that the light chain constant region is either a kappa-type light chain or a lambda-type light chain). The VH and VL regions can be further subdivided into hypervariable regions (being Complementarity Determining Regions (CDRs) interspersed with more conserved regions (being Framework Regions (FRs)). Each VH and VL consists of three CDRs and 4 FRs arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxy terminus.
The term "Fc domain" or "Fc region" is used herein to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. A native immunoglobulin "Fc domain" comprises two or three constant domains, namely a CH2 domain, a CH3 domain, and optionally a CH4 domain. For example, in natural antibodies, the immunoglobulin Fc domain comprises the second and third constant domains (CH 2 domain and CH3 domain) derived from the two heavy chains of IgG, IgA, and IgD class antibodies; or second, third and fourth constant domains (CH 2 domain, CH3 domain and CH4 domain) derived from the two heavy chains of antibodies of the IgM and IgE classes. The sequence of the Fc is derived from a sequence structure occurring in nature or a genetically engineered Fc sequence, such as an antibody-dependent cell-mediated cytotoxicity (ADCC) and/or a "LALA" mutation with reduced complement-dependent cytotoxicity (CDC), "PGLALA" mutation, "N297A" mutation, etc. (amino acid numbering is defined according to the rules of Kabat et al for encoding antibody amino acid Sequences, (Kabat et al, Sequences of Proteins of Immunological Interest, 4 th edition, U.S. Department of Health and Services, National Institutes of Health (1987)).
The term "CDR" refers to: antibody variable domains are mutated in sequence and form structurally defined loops ("hypervariable loops") and/or regions containing antigen-contacting residues ("antigen-contacting points"). The CDRs are primarily responsible for binding to an epitope of the antigen. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2 and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2 and LCDR 3. CDR partitioning according to the present invention is based on the Kabat amino acid sequence numbering system and CDR definition system (Kabat et al, Sequences of Proteins of Immunological Interest, 4 th edition, U.S. department of Health and Human Services, National Institutes of Health (1987)).
The term "expression vector" refers to: a vector containing a recombinant polynucleotide is a vector in which an expression element (e.g., a promoter, RBS, terminator, etc.) is added to the basic backbone of a cloning vector to allow expression of a desired gene. The expression vector contains sufficient cis-acting elements for expression; other elements for expression may be provided by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, including cosmids, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.
In the present invention, unless defined otherwise, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. Generally, nomenclature and techniques used in connection with, cell and tissue culture, molecular biology, and protein, oligo/polynucleotide chemistry and hybridization described herein are those well known and commonly used in the art. Standard techniques are used for recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to the manufacturer's instructions or as commonly done in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Sambrook et al, Molecular Cloning: a Laboratory Manual (2 nd edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1989)). In addition, exemplary techniques for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and patient treatment are also known in the art.
In this application, the use of "or" means "and/or" unless stated otherwise. In the case of multiple dependent claims, the use of "or" in the alternative merely refers to more than one of the foregoing independent or dependent claims.
As described herein, any concentration range, percentage range, ratio range, or integer range is to be understood as including the value of any integer within the range, and where appropriate including fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated.
Units, prefixes, and symbols are denoted in their international system of units (SI) recognized form. Numerical ranges include the numbers defining the range. The headings provided herein are not limitations of the various aspects of the disclosure which can be had by reference to the specification as a whole.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides an antibody binding IGF-1R and application thereof in preparing a medicine, wherein the antibody and the related medicine can be used for preventing or treating thyroid-related eye diseases.
In one aspect, the invention provides an antibody that binds IGF-1R.
The antibody consists of a light chain and a heavy chain.
The light chain complementarity determining region LCDR1 of the antibody is selected from one of amino acid sequences shown in SEQ ID NO. 22, SEQ ID NO. 25, SEQ ID NO. 28, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 40 and SEQ ID NO. 43, LCDR2 is selected from one of amino acid sequences shown in SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 29, SEQ ID NO. 32, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 41 and SEQ ID NO. 44, and LCDR3 is selected from one of amino acid sequences shown in SEQ ID NO. 24, SEQ ID NO. 27, SEQ ID NO. 30, SEQ ID NO. 33, SEQ ID NO. 36, SEQ ID NO. 39, SEQ ID NO. 42 and SEQ ID NO. 45; the heavy chain complementarity determining region HCDR1 of the antibody is selected from one of amino acid sequences shown in SEQ ID NO 46, SEQ ID NO 49, SEQ ID NO 52, SEQ ID NO 55, SEQ ID NO 58, SEQ ID NO 61, SEQ ID NO 64 and SEQ ID NO 67, HCDR2 is selected from one of amino acid sequences shown in SEQ ID NO 47, SEQ ID NO 50, SEQ ID NO 53, SEQ ID NO 56, SEQ ID NO 59, SEQ ID NO 62, SEQ ID NO 65 and SEQ ID NO 68, and HCDR3 is selected from one of amino acid sequences shown in SEQ ID NO 48, SEQ ID NO 51, SEQ ID NO 54, SEQ ID NO 57, SEQ ID NO 60, SEQ ID NO 63, SEQ ID NO 66 and SEQ ID NO 69.
The light chain variable region of the antibody is selected from one of amino acid sequences shown in SEQ ID NO 2, SEQ ID NO 4, SEQ ID NO 6, SEQ ID NO 8, SEQ ID NO 10, SEQ ID NO 12, SEQ ID NO 14 and SEQ ID NO 16, and the heavy chain variable region of the antibody is selected from one of amino acid sequences shown in SEQ ID NO 3, SEQ ID NO 5, SEQ ID NO 7, SEQ ID NO 9, SEQ ID NO 11, SEQ ID NO 13, SEQ ID NO 15 and SEQ ID NO 17.
The light chain and heavy chain variable regions of the antibody are selected from one of the combinations of SEQ ID NO 2 and 3, SEQ ID NO 4 and 5, SEQ ID NO 6 and 7, SEQ ID NO 8 and 9, SEQ ID NO 10 and 11, SEQ ID NO 12 and 13, SEQ ID NO 14 and 15, and SEQ ID NO 16 and 17.
The amino acid sequence of the light chain constant region of the antibody is shown in SEQ ID NO. 19.
The light chain of the antibody is formed by splicing the light chain variable region with the light chain constant region shown in SEQ ID NO. 19.
The amino acid sequence of the heavy chain constant region of the antibody is shown as SEQ ID NO:18, respectively.
The heavy chain of the antibody is formed by splicing a heavy chain variable region and a heavy chain constant region shown in SEQ ID NO. 18.
Specifically, the light chain and the heavy chain of the antibody are amino acid sequences shown as SEQ ID NO. 70 and SEQ ID NO. 71;
or, the amino acid sequences shown as SEQ ID NO 72 and SEQ ID NO 73;
or, the amino acid sequences shown as SEQ ID NO 74 and SEQ ID NO 75;
or, the amino acid sequences shown as SEQ ID NO 76 and SEQ ID NO 77;
or, the amino acid sequences shown as SEQ ID NO. 78 and SEQ ID NO. 79;
or, the amino acid sequences shown as SEQ ID NO 80 and SEQ ID NO 81;
or, the amino acid sequences shown as SEQ ID NO 82 and SEQ ID NO 83;
or, the amino acid sequences shown as SEQ ID NO 84 and SEQ ID NO 85.
Specifically, the light and heavy chains form a complete anti-IGF-1R antibody via interchain disulfide bonds.
In another aspect, the invention provides a biological molecule, vector or host cell comprising a nucleic acid molecule encoding an antibody according to any one of the preceding claims.
In a further aspect, the invention provides the use of an antibody and/or biological molecule, vector or host cell as described above that binds IGF-1R in the manufacture of a medicament for the treatment or co-treatment of an autoimmune disease.
The application includes but is not limited to the application of the antibody combining IGF-1R, the nucleotide sequence coding the antibody and the mutant thereof, the expression vector containing the nucleotide sequence and the host cell containing the vector in preparing the medicine for treating or assisting in treating autoimmune diseases.
Specifically, the antibody is separated and purified.
The nucleotide sequence, the expression vector and the host cell realize the application by expressing the antibody.
The antibody, the nucleotide sequence and the expression vector are directly added into a medicament to realize the application.
Wherein, the autoimmune disease includes but is not limited to diseases caused by thyroid gland dysfunction.
Further, the disease caused by the thyroid dysfunction is thyroid-associated ophthalmopathy.
Further, the thyroid-associated eye disease includes, but is not limited to: herniated eyes, eyelid recession, upper lid delayed, hypertrophy of the extraocular muscles, conjunctival congestion, edema of periorbital tissue, incomplete eyelid closure, photophobia, lacrimation, foreign body sensation, visual deterioration, or diplopia.
In yet another aspect, the invention provides methods of making the above-described antibodies that bind IGF-1R.
Specifically, the preparation method comprises the steps of constructing an expression vector by using the nucleotide sequence coding the antibody provided by any one of the technical schemes to transfect host cells, and obtaining the antibody binding IGF-1R through the expression of the host cells.
In yet another aspect, the present invention provides a pharmaceutical composition.
The pharmaceutical composition comprises the above antibody and/or biological molecule, vector or host cell that binds IGF-1R.
The pharmaceutical composition also comprises a pharmaceutically acceptable carrier and/or an auxiliary material.
Further, the pharmaceutically acceptable carriers and/or excipients include, but are not limited to: solubilizers, stabilizers, and excipients.
The administration modes of the pharmaceutical composition include but are not limited to: subcutaneous injection, intradermal injection, intramuscular injection, intravenous drip, eyelid injection.
The pharmaceutical composition can be applied to the prevention and/or treatment of thyroid-related eye diseases including, but not limited to, exophthalmos, eyelid retraction, upper eyelid retardation, extraocular muscle hypertrophy, conjunctival congestion, periorbital tissue edema, eyelid insufficiency, photophobia, lacrimation, foreign body sensation, visual deterioration, or diplopia.
Compared with the prior art, the invention has the following beneficial effects:
the IGF-1R-combined antibody provided by the invention can effectively inhibit the proliferation of MCF7 cells, can reduce the degree of extraocular muscle pathological changes of thyroid eye diseases of rats, and provides a new way for developing novel medicaments for treating thyroid-related eye diseases.
Drawings
FIG. 1 shows the results of measurement of the inhibition of MCF7 cell proliferation by PHP1003-1 antibody.
FIG. 2 shows the results of observation of the mouse model of hyperthyroidism and thyroid-associated eye disease after administering the test PHP1003-1 and the control for 4 weeks under the condition of staining the extraocular muscle tissue with a light microscope (400X).
Detailed Description
The present invention will be further illustrated in detail with reference to the following specific examples, which are not intended to limit the present invention but are merely illustrative thereof. The experimental methods used in the following examples are not specifically described, and the materials, reagents and the like used in the following examples are generally commercially available under the usual conditions without specific descriptions.
EXAMPLE 1 molecular screening for binding to IGF-1R proteins
Recombinant Human IGF-1R (Human IGF-1R, Peking Poissie Biotech Co., Ltd., cat. IGR-H5229) was used as an antigen to coat the high affinity microplate overnight at 4 ℃ in an amount of 50ng per well, and blocking was performed at 37 ℃ for 2 hours using 2% BSA (Beijing Solebao Tech Co., Ltd., cat. A8020). And (3) incubating the obtained phage library with human IGF-1R, eluting, amplifying, enriching phage with combined human IGF-1R, repeating for 3-4 times, selecting and amplifying clones of the finally obtained phage, and obtaining the clone with positive combination with human IGF-1R according to a phage ELISA detection method. The positive clones were sequenced to obtain molecules with the complete variable region sequences as shown in table 1 below.
TABLE 1 sequences of different clones
Clone number Light chain variable region sequences Column(s) of Light chain CDR sequences (LCDR 1, LCDR2, LCDR3) Variable region sequence of heavy chain Column(s) of Heavy chain CDR sequences (HCDR 1, HCDR2, HCDR3)
PHP1003-1 SEQ ID NO：2 SASSHWHSYMH(SEQ ID NO:22)、DTINLMT(SEQ ID NO: 23)、QQITGYPSVAE (SEQ ID NO:24) SEQ ID NO：3 GMHWG(SEQ ID NO:46)、YISSGSTDYNPSLKS(SEQ ID NO:47)、GSVEPYTH(SEQ ID NO:48)
PHP1003-2 SEQ ID NO：4 RASQDISNYVA(SEQ ID NO:25)、AASTLQS(SEQ ID NO: 26)、QKYNSDYST(SEQ ID NO:27) SEQ ID NO：5 NYWIG(SEQ ID NO:49)、IIYPDDSDTRYSPSFQG(SEQ ID NO:50)、SIVTGYYYYGLDV(SEQ ID NO:51)
PHP1003-3 SEQ ID NO：6 SGSSSNIGSNTVY(SEQ ID NO:28)、SHNQRPS(SEQ ID NO:29)、AAWDDSLNGGV(SEQ ID NO:30) SEQ ID NO：7 NAWMS(SEQ ID NO:52)、RIKSKTDGGTTDYAAPVKG(SEQ ID NO:53)、DPLLDY(SEQ ID NO:54)
PHP1003-4 SEQ ID NO：8 RASQGISISLA(SEQ ID NO:31)、AASTLQS(SEQ ID NO: 32)、QKYNSAPQT(SEQ ID NO:33) SEQ ID NO：9 NNYWS(SEQ ID NO:55)、YIYYSGSTNYNPSLKS(SEQ ID NO:56)、THPYGHFDF(SEQ ID NO:57)
PHP1003-5 SEQ ID NO：10 RASQGIRNDLG(SEQ ID NO:34)、AASSLQS(SEQ ID NO: 35)、LQDYNYPRT(SEQ ID NO:36) SEQ ID NO：11 DYDMS(SEQ ID NO:58)、GISASGGATFYADSVKG(SEQ ID NO:59)、HFSDTTYNYFDM(SEQ ID NO:60)
PHP1003-6 SEQ ID NO：12 RASQTICSNLA(SEQ ID NO:37)、GASTRAT(SEQ ID NO: 38)、QQYNDWPSYT(SEQ ID NO:39) SEQ ID NO：13 DYYLS(SEQ ID NO:61)、YISDSGTTIYYTDSVKG(SEQ ID NO:62)、GRWGLDY(SEQ ID NO:63)
PHP1003-7 SEQ ID NO：14 TGSYSNIGAGYDVH(SEQ ID NO:40)、GNSNRPS(SEQ ID NO:41)、QSYDSTLNARI(SEQ ID NO:42) SEQ ID NO：15 SFGMH(SEQ ID NO:64)、YISSGSTAIYYADTVKG(SEQ ID NO:65)、VYAMDY(SEQ ID NO:66)
PHP1003-8 SEQ ID NO：16 RASQGIRNYLA(SEQ ID NO:43)、AASSLQS(SEQ ID NO: 44)、LQHNTSPP(SEQ ID NO:45) SEQ ID NO：17 SYAMS(SEQ ID NO:67)、AISGSGGSTYYADSVKG(SEQ ID NO:68)、SYYDILTGYTH(SEQ ID NO:69)
Example 2 construction and expression of anti-IGF-1R antibodies
The light chain variable region and the light chain constant region (SEQ ID NO: 19) cloned in example 1 were directly spliced to form a light chain, and the heavy chain variable region and the heavy chain constant region (SEQ ID NO: 18) cloned in example 1 were directly spliced to form a heavy chain, specifically, as shown in Table 2 below, the light chain and the heavy chain of the antibody have the amino acid sequences shown in SEQ ID NO:70 and SEQ ID NO: 71;
or, the amino acid sequences shown as SEQ ID NO 72 and SEQ ID NO 73;
or, the amino acid sequences shown as SEQ ID NO 74 and SEQ ID NO 75;
or, the amino acid sequences shown as SEQ ID NO 76 and SEQ ID NO 77;
or, the amino acid sequences shown as SEQ ID NO. 78 and SEQ ID NO. 79;
or, the amino acid sequences shown as SEQ ID NO 80 and SEQ ID NO 81;
or, the amino acid sequences shown as SEQ ID NO 82 and SEQ ID NO 83;
or, the amino acid sequences shown as SEQ ID NO 84 and SEQ ID NO 85.
TABLE 2 light and heavy chain amino acid sequences
Numbering Amino acid sequence
SEQ ID NO:70 EIVLTQSPATLSLSPGERATLSCSASSHWHSYMHWYQQKPGQAPRLLIYDTINLMTGIPARFSGSRSGTDYTLTISSLEPEDA AVYYCQQITGYPSVAEFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:71 QVQLQESGPGLVKPPGTLSLTCALSGYSVTGMHWGWVRQPPGKGLEWIGYISSGSTDYNPSLKSRVTISSDTSKNQLSLKLSS VTAADTAVYYCARGSVEPYTHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:72 AIQLTQSPSSLSASVGDRVTITCRASQDISNYVAWYQQKPDKGPKLLIFAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQKYNSDYSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:73 QVQLVESGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADRSITTAYLQW SSLKASDTAMYYCAASIVTGYYYYGLDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:74 SYVLTQPPSASGAPGQRVTISCSGSSSNIGSNTVYWYQHLPGAAPRLLIYSHNQRPSGVPDRFSGSTSGTSASLAISGLQSDD EADYYCAAWDDSLNGGVFGGGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:75 QLQLQESGGGLVQPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDDSKNTLYL QMNSLKTEDTAVYYCTTDPLLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:76 AIRMTQSPSSLSASVGDRVTITCRASQGISISLAWYQQRPGKPPNLLIYAASTLQSGVPSRFSGRGSGTDFTLTISSLQPEDV ATYYCQKYNSAPQTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:77 QLQLQESGPGLVKPSETLSLTCTVSGGSISNNYWSWIRQPPGKEMEWIGYIYYSGSTNYNPSLKSRLSISVDSSKNLFSLRLN SVTAAGTAVYYCARTHPYGHFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:78 DIQMTQSPSSLPASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCLQDYNYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:79 QLQLQESGGGLVQPGGSLRLSCAAPGFTFSDYDMSWIRQAPGKGLEWVSGISASGGATFYADSVKGRFTISRDNSKNALSLQM NNLRADDAGIYYCARHFSDTTYNYFDMWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:80 ETTLTQSPATLSVSPGERATLSCRASQTICSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTPTISSLQSEDF AVYYCQQYNDWPSYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:81 QVQLQESGGGLVQPGGPLRLSCAASGFTFSDYYLSWIRQAPGKGLEYVSYISDSGTTIYYTDSVKGRFTIPRDNAKNSLHLQL NSLRAEDTAVYYCARGRWGLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:82 QSVLTQPPSVSGAPGQRVTLSCTGSYSNIGAGYDVHWYQKLPGVAPKLLIYGNSNRPSRIPDRFSGFKSGTSASLVITGLQAD DEADYYCQSYDSTLNARIFGGGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:83 QVQLQESGAGLVKPGGSRKLSCTASGFTFSSFGMHWFRQAPEKGLEWVAYISSGSTAIYYADTVKGRFTISRDNPKNTLFLQM TSLRSEDTAMYHCARVYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:84 AIQLTQSPSAMSASVRDRVTITCRASQGIRNYLAWSQEKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDF ATRYCLQHNTSPPFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:85 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAASYYDILTGYTHWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
For the amino acid sequences of the light and heavy chains, the genes were codon-optimized and routinely synthesized in human host cells and cloned into the vector pTT5 (ampicillin resistance) by 5 'EcoRI and 3' HindIII. Selecting clone for sequencing, selecting correctly sequenced thallus for conservation and enlarged culture, and using the enlarged thallus for extraction of plasmid. Similarly, the control antibody (light chain sequence SEQ ID NO:20, heavy chain sequence SEQ ID NO: 21) was subjected to gene synthesis and vector construction and plasmid preparation for transfection.
Cell transfection and protein isolation and purification of the extracted plasmid were performed as follows:
1. cell density was determined and viability should be greater than 95%, HEK293 cell density was adjusted to 3X 10 with (pre-warmed) HEK293 medium6cells/mL, gently shaken and aliquoted (transfection volume 90% of transfection system), and the shake flask is placed into a shaker until the cell volume does not exceed 1/3 of the shake flask specification.
2. Calculating the volume of the transfection buffer opti-MEM according to the volume of the transfected cells, which is 1/10 of the transfection system; calculating the amount of PEI as a transfection reagent, wherein the proportion of PEI is 3 mu L/mL of transfected cells; the total amount of transfected DNA was calculated in a ratio of 1. mu.g/mL of transfected cells.
The specific transfection procedure was as follows:
and (3) adding 10% MEM of a transfection system into 150 mL centrifuge tube, adding the plasmid, uniformly mixing, filtering, standing for 5 min, adding PEI into the DNA suspension, gently mixing (gently inverting and uniformly mixing for 2-3 times), and standing for 15-20 min. Then, the compound is gently added into the subpackaged cells, and the shake flask is gently shaken while the compound is added; the transfected cells were cultured in a shaker at 37 ℃. The anti-IGF-1R antibody in the supernatant transiently expressed by HEK293 cells is separated and purified by a conventional affinity purification method, and the brief steps are that a packed column is balanced by a binding buffer with 5-10 times volume, the supernatant sample is loaded, the binding buffer is used for eluting hybrid protein, and the protein is eluted.
Example 3 evaluation of biological Activity of anti-IGF-1R antibodies
The IGF-1R signaling pathway plays an important role in the proliferation, differentiation and metastasis processes of tumor cells. Activation of IGF-1R promotes proliferation of certain cells, such as MCF7 cells, while inhibition of IGF-1R activity inhibits proliferation of cells. For this purpose, the activity of the anti-IGF-1R antibody of the present invention can be evaluated by examining the cell proliferation status of MCF 7. The CCK8 method is used for detecting the inhibition efficiency of anti-IGF-1R antibody on MCF7 cell proliferation, and the brief steps are as follows:
1. the first day: MCF-7 cell plating at a density of 5X 103A hole;
2. the next day: after overnight culture of the cells, adding antibodies with different concentration gradients to incubate for 96 hours;
3. the sixth day: OD was measured after incubation for 4h with 10. mu.L of CCK8 solution per well450；
The proliferation of MCF7 cells is measured by adding purified chimeric antibodies with different concentrations, the proliferation inhibition results of different antibodies on MCF-7 are shown in the following table 3, wherein PHP1003-1 shows better inhibition effect on the proliferation of MCF7 (shown in figure 1), and the antibody on PHP1003-1 is further subjected to pharmacodynamic verification.
TABLE 3 inhibition of MCF-7 proliferation by different antibodies
Numbering IC50（μg/mL）
PHP1003-1 4.246
PHP1003-2 12.683
PHP1003-3 7.255
PHP1003-4 6.731
PHP1003-5 9.307
PHP1003-6 5.676
PHP1003-7 5.874
PHP1003-8 7.329
Example 4 efficacy of antibody PHP1003-1 and control antibody in animal model of hyperthyroidism
In this embodiment, a bovine thyroglobulin intraperitoneal injection is used to induce a rat hyperthyroidism and thyroid-associated eye disease model, and the effect of PHP1003-1 on rat thyroid-associated eye disease is observed, which includes the following steps:
(1) model group rats were molded by intraperitoneal injection of bovine thyroglobulin (sigma aldrich trade ltd, cat # 609310) at a dose of 150 μ g/rat every 2 weeks for 4 weeks.
(2) The test and control were administered separately and the groups of test animals are shown in Table 4 below.
Table 4 groups of test animals
Group of Factor of treatment Medicine Concentration of
Sham Group Injection of physiological saline - -
Vehicle Group Bovine thyroglobulin injection PBS -
L. Group Bovine thyroglobulin injection PHP1003-1 1 mg/kg
H. Group Bovine thyroglobulin injection PHP1003-1 10 mg/kg
P. Group Bovine thyroglobulin injection Control antibody 10 mg/kg
Group design: a normal control Group (Sham Group), a negative control Group (Vehicle Group), a test article treatment Group (L Group; H Group), and a control antibody Group (p. Group), in total 5 groups.
The specific dosing regimen was performed as in table 5 below.
TABLE 5 dosing regimens for different groups
Group of Factor of treatment Medicine Route of administration Concentration of Frequency of administration
Sham Group Injection of physiological saline - - - 1 times/w, total 4w
Vehicle Group Bovine thyroglobulin injection PBS Intramuscular injection - 1 times/w, total 4w
L. Group Bovine thyroglobulin injection PHP1003-1 1 mg/kg 1 times/w, total 4w
H. Group Bovine thyroglobulin injection PHP1003-1 10 mg/kg 1 times/w, total 4w
P. Group Bovine thyroglobulin injection Control antibody 10 mg/kg 1 times/w, total 4w
(3) Animals were euthanized 4 weeks after dosing and the material was taken. The rats were collected from the extraocular muscles after euthanasia, stained for tissue, and observed by collecting images under a light microscope.
(4) The results are shown in FIG. 2.
The Sham group showed homogeneous red staining of muscle fibers, regular alignment, abundant inter-myocapillary vessels, and normal muscle spacing. Various extraocular muscle lesions were seen in the Vehicle group, mainly including severe swelling, degeneration, necrosis, lysis of muscle fibers, narrowing or widening of the muscle space, and proliferation of fibrous connective tissue and blood vessels between muscles. Prompting the successful establishment of the thyroid eye disease model of the SD rat.
The lesions seen in the PHP1003-L group substantially covered all types of lesions in the Vehicle group, and the degree of myofiber necrosis and lysis was slightly less than that in the Vehicel group. The pathological changes of the PHP1003-H group are slight, the arrangement of muscle fibers is basically neat, and slight swelling or degeneration of part of the muscle fibers can be seen, which indicates that the PHP1003-H group medicaments have certain effect on treating the thyroid eye disease of SD rats. The dyeing result of the extraocular muscles of the P group shows that the swelling and hypertrophy of the extraocular muscles, the muscle fibrosis and the necrosis degree are reduced compared with those of the Vehicle group, and the results show that the PHP1003-H group and the P group can reduce the degree of the extraocular muscle pathological changes of the thyroid eye disease of the rats.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Sequence listing
<110> Suzhou pulekang pharmaceutical science and technology Co., Ltd
<120> anti-IGF-1R antibody and application thereof
<160> 85
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1337
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 1
Glu Ile Cys Gly Pro Gly Ile Asp Ile Arg Asn Asp Tyr Gln Gln Leu
1 5 10 15
Lys Arg Leu Glu Asn Cys Thr Val Ile Glu Gly Tyr Leu His Ile Leu
20 25 30
Leu Ile Ser Lys Ala Glu Asp Tyr Arg Ser Tyr Arg Phe Pro Lys Leu
35 40 45
Thr Val Ile Thr Glu Tyr Leu Leu Leu Phe Arg Val Ala Gly Leu Glu
50 55 60
Ser Leu Gly Asp Leu Phe Pro Asn Leu Thr Val Ile Arg Gly Trp Lys
65 70 75 80
Leu Phe Tyr Asn Tyr Ala Leu Val Ile Phe Glu Met Thr Asn Leu Lys
85 90 95
Asp Ile Gly Leu Tyr Asn Leu Arg Asn Ile Thr Arg Gly Ala Ile Arg
100 105 110
Ile Glu Lys Asn Ala Asp Leu Cys Tyr Leu Ser Thr Val Asp Trp Ser
115 120 125
Leu Ile Leu Asp Ala Val Ser Asn Asn Tyr Ile Val Gly Asn Lys Pro
130 135 140
Pro Lys Glu Cys Gly Asp Leu Cys Pro Gly Thr Met Glu Glu Lys Pro
145 150 155 160
Met Cys Glu Lys Thr Thr Ile Asn Asn Glu Tyr Asn Tyr Arg Cys Trp
165 170 175
Thr Thr Asn Arg Cys Gln Lys Met Cys Pro Ser Thr Cys Gly Lys Arg
180 185 190
Ala Cys Thr Glu Asn Asn Glu Cys Cys His Pro Glu Cys Leu Gly Ser
195 200 205
Cys Ser Ala Pro Asp Asn Asp Thr Ala Cys Val Ala Cys Arg His Tyr
210 215 220
Tyr Tyr Ala Gly Val Cys Val Pro Ala Cys Pro Pro Asn Thr Tyr Arg
225 230 235 240
Phe Glu Gly Trp Arg Cys Val Asp Arg Asp Phe Cys Ala Asn Ile Leu
245 250 255
Ser Ala Glu Ser Ser Asp Ser Glu Gly Phe Val Ile His Asp Gly Glu
260 265 270
Cys Met Gln Glu Cys Pro Ser Gly Phe Ile Arg Asn Gly Ser Gln Ser
275 280 285
Met Tyr Cys Ile Pro Cys Glu Gly Pro Cys Pro Lys Val Cys Glu Glu
290 295 300
Glu Lys Lys Thr Lys Thr Ile Asp Ser Val Thr Ser Ala Gln Met Leu
305 310 315 320
Gln Gly Cys Thr Ile Phe Lys Gly Asn Leu Leu Ile Asn Ile Arg Arg
325 330 335
Gly Asn Asn Ile Ala Ser Glu Leu Glu Asn Phe Met Gly Leu Ile Glu
340 345 350
Val Val Thr Gly Tyr Val Lys Ile Arg His Ser His Ala Leu Val Ser
355 360 365
Leu Ser Phe Leu Lys Asn Leu Arg Leu Ile Leu Gly Glu Glu Gln Leu
370 375 380
Glu Gly Asn Tyr Ser Phe Tyr Val Leu Asp Asn Gln Asn Leu Gln Gln
385 390 395 400
Leu Trp Asp Trp Asp His Arg Asn Leu Thr Ile Lys Ala Gly Lys Met
405 410 415
Tyr Phe Ala Phe Asn Pro Lys Leu Cys Val Ser Glu Ile Tyr Arg Met
420 425 430
Glu Glu Val Thr Gly Thr Lys Gly Arg Gln Ser Lys Gly Asp Ile Asn
435 440 445
Thr Arg Asn Asn Gly Glu Arg Ala Ser Cys Glu Ser Asp Val Leu His
450 455 460
Phe Thr Ser Thr Thr Thr Ser Lys Asn Arg Ile Ile Ile Thr Trp His
465 470 475 480
Arg Tyr Arg Pro Pro Asp Tyr Arg Asp Leu Ile Ser Phe Thr Val Tyr
485 490 495
Tyr Lys Glu Ala Pro Phe Lys Asn Val Thr Glu Tyr Asp Gly Gln Asp
500 505 510
Ala Cys Gly Ser Asn Ser Trp Asn Met Val Asp Val Asp Leu Pro Pro
515 520 525
Asn Lys Asp Val Glu Pro Gly Ile Leu Leu His Gly Leu Lys Pro Trp
530 535 540
Thr Gln Tyr Ala Val Tyr Val Lys Ala Val Thr Leu Thr Met Val Glu
545 550 555 560
Asn Asp His Ile Arg Gly Ala Lys Ser Glu Ile Leu Tyr Ile Arg Thr
565 570 575
Asn Ala Ser Val Pro Ser Ile Pro Leu Asp Val Leu Ser Ala Ser Asn
580 585 590
Ser Ser Ser Gln Leu Ile Val Lys Trp Asn Pro Pro Ser Leu Pro Asn
595 600 605
Gly Asn Leu Ser Tyr Tyr Ile Val Arg Trp Gln Arg Gln Pro Gln Asp
610 615 620
Gly Tyr Leu Tyr Arg His Asn Tyr Cys Ser Lys Asp Lys Ile Pro Ile
625 630 635 640
Arg Lys Tyr Ala Asp Gly Thr Ile Asp Ile Glu Glu Val Thr Glu Asn
645 650 655
Pro Lys Thr Glu Val Cys Gly Gly Glu Lys Gly Pro Cys Cys Ala Cys
660 665 670
Pro Lys Thr Glu Ala Glu Lys Gln Ala Glu Lys Glu Glu Ala Glu Tyr
675 680 685
Arg Lys Val Phe Glu Asn Phe Leu His Asn Ser Ile Phe Val Pro Arg
690 695 700
Pro Glu Arg Lys Arg Arg Asp Val Met Gln Val Ala Asn Thr Thr Met
705 710 715 720
Ser Ser Arg Ser Arg Asn Thr Thr Ala Ala Asp Thr Tyr Asn Ile Thr
725 730 735
Asp Pro Glu Glu Leu Glu Thr Glu Tyr Pro Phe Phe Glu Ser Arg Val
740 745 750
Asp Asn Lys Glu Arg Thr Val Ile Ser Asn Leu Arg Pro Phe Thr Leu
755 760 765
Tyr Arg Ile Asp Ile His Ser Cys Asn His Glu Ala Glu Lys Leu Gly
770 775 780
Cys Ser Ala Ser Asn Phe Val Phe Ala Arg Thr Met Pro Ala Glu Gly
785 790 795 800
Ala Asp Asp Ile Pro Gly Pro Val Thr Trp Glu Pro Arg Pro Glu Asn
805 810 815
Ser Ile Phe Leu Lys Trp Pro Glu Pro Glu Asn Pro Asn Gly Leu Ile
820 825 830
Leu Met Tyr Glu Ile Lys Tyr Gly Ser Gln Val Glu Asp Gln Arg Glu
835 840 845
Cys Val Ser Arg Gln Glu Tyr Arg Lys Tyr Gly Gly Ala Lys Leu Asn
850 855 860
Arg Leu Asn Pro Gly Asn Tyr Thr Ala Arg Ile Gln Ala Thr Ser Leu
865 870 875 880
Ser Gly Asn Gly Ser Trp Thr Asp Pro Val Phe Phe Tyr Val Gln Ala
885 890 895
Lys Thr Gly Tyr Glu Asn Phe Ile His Leu Ile Ile Ala Leu Pro Val
900 905 910
Ala Val Leu Leu Ile Val Gly Gly Leu Val Ile Met Leu Tyr Val Phe
915 920 925
His Arg Lys Arg Asn Asn Ser Arg Leu Gly Asn Gly Val Leu Tyr Ala
930 935 940
Ser Val Asn Pro Glu Tyr Phe Ser Ala Ala Asp Val Tyr Val Pro Asp
945 950 955 960
Glu Trp Glu Val Ala Arg Glu Lys Ile Thr Met Ser Arg Glu Leu Gly
965 970 975
Gln Gly Ser Phe Gly Met Val Tyr Glu Gly Val Ala Lys Gly Val Val
980 985 990
Lys Asp Glu Pro Glu Thr Arg Val Ala Ile Lys Thr Val Asn Glu Ala
995 1000 1005
Ala Ser Met Arg Glu Arg Ile Glu Phe Leu Asn Glu Ala Ser Val Met
1010 1015 1020
Lys Glu Phe Asn Cys His His Val Val Arg Leu Leu Gly Val Val Ser
1025 1030 1035 1040
Gln Gly Gln Pro Thr Leu Val Ile Met Glu Leu Met Thr Arg Gly Asp
1045 1050 1055
Leu Lys Ser Tyr Leu Arg Ser Leu Arg Pro Glu Met Glu Asn Asn Pro
1060 1065 1070
Val Leu Ala Pro Pro Ser Leu Ser Lys Met Ile Gln Met Ala Gly Glu
1075 1080 1085
Ile Ala Asp Gly Met Ala Tyr Leu Asn Ala Asn Lys Phe Val His Arg
1090 1095 1100
Asp Leu Ala Ala Arg Asn Cys Met Val Ala Glu Asp Phe Thr Val Lys
1105 1110 1115 1120
Ile Gly Asp Phe Gly Met Thr Arg Asp Ile Tyr Glu Thr Asp Tyr Tyr
1125 1130 1135
Arg Lys Gly Gly Lys Gly Leu Leu Pro Val Arg Trp Met Ser Pro Glu
1140 1145 1150
Ser Leu Lys Asp Gly Val Phe Thr Thr Tyr Ser Asp Val Trp Ser Phe
1155 1160 1165
Gly Val Val Leu Trp Glu Ile Ala Thr Leu Ala Glu Gln Pro Tyr Gln
1170 1175 1180
Gly Leu Ser Asn Glu Gln Val Leu Arg Phe Val Met Glu Gly Gly Leu
1185 1190 1195 1200
Leu Asp Lys Pro Asp Asn Cys Pro Asp Met Leu Phe Glu Leu Met Arg
1205 1210 1215
Met Cys Trp Gln Tyr Asn Pro Lys Met Arg Pro Ser Phe Leu Glu Ile
1220 1225 1230
Ile Ser Ser Ile Lys Glu Glu Met Glu Pro Gly Phe Arg Glu Val Ser
1235 1240 1245
Phe Tyr Tyr Ser Glu Glu Asn Lys Leu Pro Glu Pro Glu Glu Leu Asp
1250 1255 1260
Leu Glu Pro Glu Asn Met Glu Ser Val Pro Leu Asp Pro Ser Ala Ser
1265 1270 1275 1280
Ser Ser Ser Leu Pro Leu Pro Asp Arg His Ser Gly His Lys Ala Glu
1285 1290 1295
Asn Gly Pro Gly Pro Gly Val Leu Val Leu Arg Ala Ser Phe Asp Glu
1300 1305 1310
Arg Gln Pro Tyr Ala His Met Asn Gly Gly Arg Lys Asn Glu Arg Ala
1315 1320 1325
Leu Pro Leu Pro Gln Ser Ser Thr Cys
1330 1335
<210> 2
<211> 109
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser His Trp His Ser Tyr
20 25 30
Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Thr Ile Asn Leu Met Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Ala Ala Val Tyr Tyr Cys Gln Gln Ile Thr Gly Tyr Pro Ser
85 90 95
Val Ala Glu Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 3
<211> 115
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 3
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Pro Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Leu Ser Gly Tyr Ser Val Thr Gly Met
20 25 30
His Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
50 55 60
Arg Val Thr Ile Ser Ser Asp Thr Ser Lys Asn Gln Leu Ser Leu Lys
65 70 75 80
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Gly Ser Val Glu Pro Tyr Thr His Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 4
<211> 107
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 4
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Asp Lys Gly Pro Lys Leu Leu Ile
35 40 45
Phe Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Asp Tyr Ser
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 5
<211> 122
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 5
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Asn Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Arg Ser Ile Thr Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Ser Ile Val Thr Gly Tyr Tyr Tyr Tyr Gly Leu Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 6
<211> 110
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 6
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Tyr Trp Tyr Gln His Leu Pro Gly Ala Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser His Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Thr Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 7
<211> 117
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 7
Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Pro Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 8
<211> 107
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 8
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ile Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Pro Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Gln
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 9
<211> 117
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 9
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Asn
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Glu Met Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Val Asp Ser Ser Lys Asn Leu Phe Ser Leu
65 70 75 80
Arg Leu Asn Ser Val Thr Ala Ala Gly Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Thr His Pro Tyr Gly His Phe Asp Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 10
<211> 107
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 11
<211> 121
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 11
Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Ala Ser Gly Gly Ala Thr Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ala Leu Ser
65 70 75 80
Leu Gln Met Asn Asn Leu Arg Ala Asp Asp Ala Gly Ile Tyr Tyr Cys
85 90 95
Ala Arg His Phe Ser Asp Thr Thr Tyr Asn Tyr Phe Asp Met Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 12
<211> 108
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 12
Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Cys Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Pro Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asp Trp Pro Ser
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 116
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 13
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Leu Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Tyr Ile Ser Asp Ser Gly Thr Thr Ile Tyr Tyr Thr Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Pro Arg Asp Asn Ala Lys Asn Ser Leu His
65 70 75 80
Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Trp Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 14
<211> 111
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 14
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Leu Ser Cys Thr Gly Ser Tyr Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Lys Leu Pro Gly Val Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Arg Ile Pro Asp Arg Phe
50 55 60
Ser Gly Phe Lys Ser Gly Thr Ser Ala Ser Leu Val Ile Thr Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Thr
85 90 95
Leu Asn Ala Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 15
<211> 115
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 15
Gln Val Gln Leu Gln Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met His Trp Phe Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Ser Thr Ala Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr His Cys
85 90 95
Ala Arg Val Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser
115
<210> 16
<211> 106
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 16
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Ser Gln Glu Lys Pro Gly Lys Val Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Arg Tyr Cys Leu Gln His Asn Thr Ser Pro Pro
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 120
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Tyr Tyr Asp Ile Leu Thr Gly Tyr Thr His Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 18
<211> 330
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 18
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 19
<211> 107
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 19
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 20
<211> 215
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Lys Trp Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ser Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 21
<211> 448
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 21
Gln Val Glu Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Gln Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Trp Phe Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Glu Leu Gly Arg Arg Tyr Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Ser Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 22
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 22
Ser Ala Ser Ser His Trp His Ser Tyr Met His
1 5 10
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 23
Asp Thr Ile Asn Leu Met Thr
1 5
<210> 24
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 24
Gln Gln Ile Thr Gly Tyr Pro Ser Val Ala Glu
1 5 10
<210> 25
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 25
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Val Ala
1 5 10
<210> 26
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 26
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 27
<211> 9
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 27
Gln Lys Tyr Asn Ser Asp Tyr Ser Thr
1 5
<210> 28
<211> 13
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 28
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Tyr
1 5 10
<210> 29
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 29
Ser His Asn Gln Arg Pro Ser
1 5
<210> 30
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 30
Ala Ala Trp Asp Asp Ser Leu Asn Gly Gly Val
1 5 10
<210> 31
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 31
Arg Ala Ser Gln Gly Ile Ser Ile Ser Leu Ala
1 5 10
<210> 32
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 32
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 33
<211> 9
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 33
Gln Lys Tyr Asn Ser Ala Pro Gln Thr
1 5
<210> 34
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 34
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 35
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 35
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 36
Leu Gln Asp Tyr Asn Tyr Pro Arg Thr
1 5
<210> 37
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 37
Arg Ala Ser Gln Thr Ile Cys Ser Asn Leu Ala
1 5 10
<210> 38
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 38
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 39
<211> 10
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 39
Gln Gln Tyr Asn Asp Trp Pro Ser Tyr Thr
1 5 10
<210> 40
<211> 14
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 40
Thr Gly Ser Tyr Ser Asn Ile Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 41
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 41
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 42
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 42
Gln Ser Tyr Asp Ser Thr Leu Asn Ala Arg Ile
1 5 10
<210> 43
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 43
Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala
1 5 10
<210> 44
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 44
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 45
<211> 8
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 45
Leu Gln His Asn Thr Ser Pro Pro
1 5
<210> 46
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 46
Gly Met His Trp Gly
1 5
<210> 47
<211> 15
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 47
Tyr Ile Ser Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 48
<211> 8
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 48
Gly Ser Val Glu Pro Tyr Thr His
1 5
<210> 49
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 49
Asn Tyr Trp Ile Gly
1 5
<210> 50
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 50
Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
1 5 10 15
Gly
<210> 51
<211> 13
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 51
Ser Ile Val Thr Gly Tyr Tyr Tyr Tyr Gly Leu Asp Val
1 5 10
<210> 52
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 52
Asn Ala Trp Met Ser
1 5
<210> 53
<211> 19
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 53
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala Pro
1 5 10 15
Val Lys Gly
<210> 54
<211> 6
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 54
Asp Pro Leu Leu Asp Tyr
1 5
<210> 55
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 55
Asn Asn Tyr Trp Ser
1 5
<210> 56
<211> 16
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 56
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 57
<211> 9
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 57
Thr His Pro Tyr Gly His Phe Asp Phe
1 5
<210> 58
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 58
Asp Tyr Asp Met Ser
1 5
<210> 59
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 59
Gly Ile Ser Ala Ser Gly Gly Ala Thr Phe Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 60
<211> 12
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 60
His Phe Ser Asp Thr Thr Tyr Asn Tyr Phe Asp Met
1 5 10
<210> 61
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 61
Asp Tyr Tyr Leu Ser
1 5
<210> 62
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 62
Tyr Ile Ser Asp Ser Gly Thr Thr Ile Tyr Tyr Thr Asp Ser Val Lys
1 5 10 15
Gly
<210> 63
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 63
Gly Arg Trp Gly Leu Asp Tyr
1 5
<210> 64
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 64
Ser Phe Gly Met His
1 5
<210> 65
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 65
Tyr Ile Ser Ser Gly Ser Thr Ala Ile Tyr Tyr Ala Asp Thr Val Lys
1 5 10 15
Gly
<210> 66
<211> 6
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 66
Val Tyr Ala Met Asp Tyr
1 5
<210> 67
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 67
Ser Tyr Ala Met Ser
1 5
<210> 68
<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 68
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 69
<211> 11
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 69
Ser Tyr Tyr Asp Ile Leu Thr Gly Tyr Thr His
1 5 10
<210> 70
<211> 216
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 70
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser His Trp His Ser Tyr
20 25 30
Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Thr Ile Asn Leu Met Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Ala Ala Val Tyr Tyr Cys Gln Gln Ile Thr Gly Tyr Pro Ser
85 90 95
Val Ala Glu Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 71
<211> 445
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Pro Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Leu Ser Gly Tyr Ser Val Thr Gly Met
20 25 30
His Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
50 55 60
Arg Val Thr Ile Ser Ser Asp Thr Ser Lys Asn Gln Leu Ser Leu Lys
65 70 75 80
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Gly Ser Val Glu Pro Tyr Thr His Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 72
<211> 214
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 72
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Asp Lys Gly Pro Lys Leu Leu Ile
35 40 45
Phe Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Asp Tyr Ser
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 73
<211> 452
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 73
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Asn Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Arg Ser Ile Thr Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Ser Ile Val Thr Gly Tyr Tyr Tyr Tyr Gly Leu Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 74
<211> 217
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 74
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Tyr Trp Tyr Gln His Leu Pro Gly Ala Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser His Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Thr Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 75
<211> 447
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 75
Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Pro Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 76
<211> 214
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 76
Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ile Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Pro Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Gln
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 77
<211> 447
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 77
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Asn
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Glu Met Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Val Asp Ser Ser Lys Asn Leu Phe Ser Leu
65 70 75 80
Arg Leu Asn Ser Val Thr Ala Ala Gly Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Thr His Pro Tyr Gly His Phe Asp Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 78
<211> 214
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 78
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 79
<211> 451
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 79
Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Ala Ser Gly Gly Ala Thr Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ala Leu Ser
65 70 75 80
Leu Gln Met Asn Asn Leu Arg Ala Asp Asp Ala Gly Ile Tyr Tyr Cys
85 90 95
Ala Arg His Phe Ser Asp Thr Thr Tyr Asn Tyr Phe Asp Met Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 80
<211> 215
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 80
Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Cys Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Pro Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asp Trp Pro Ser
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 81
<211> 446
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 81
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Leu Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Tyr Ile Ser Asp Ser Gly Thr Thr Ile Tyr Tyr Thr Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Pro Arg Asp Asn Ala Lys Asn Ser Leu His
65 70 75 80
Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Trp Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 82
<211> 218
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 82
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Leu Ser Cys Thr Gly Ser Tyr Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Lys Leu Pro Gly Val Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Arg Ile Pro Asp Arg Phe
50 55 60
Ser Gly Phe Lys Ser Gly Thr Ser Ala Ser Leu Val Ile Thr Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Thr
85 90 95
Leu Asn Ala Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 83
<211> 445
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 83
Gln Val Gln Leu Gln Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met His Trp Phe Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Ser Thr Ala Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr His Cys
85 90 95
Ala Arg Val Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 84
<211> 213
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 84
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Ser Gln Glu Lys Pro Gly Lys Val Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Arg Tyr Cys Leu Gln His Asn Thr Ser Pro Pro
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 85
<211> 450
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 85
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Tyr Tyr Asp Ile Leu Thr Gly Tyr Thr His Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450

Claims (6)

1. An antibody that binds IGF-1R, wherein the amino acid sequences of the light chain complementarity determining regions LCDR1, LCDR2, LCDR3 and heavy chain complementarity determining regions HCDR1, HCDR2, HCDR3 of said antibody are one of the following combinations:
1) LCDR1 of the amino acid sequence shown in SEQ ID NO. 22, LCDR2 of the amino acid sequence shown in SEQ ID NO. 23, LCDR3 of the amino acid sequence shown in SEQ ID NO. 24, HCDR1 of the amino acid sequence shown in SEQ ID NO. 46, HCDR2 of the amino acid sequence shown in SEQ ID NO. 47, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 48; or
2) LCDR1 of the amino acid sequence shown in SEQ ID NO. 25, LCDR2 of the amino acid sequence shown in SEQ ID NO. 26, LCDR3 of the amino acid sequence shown in SEQ ID NO. 27, and HCDR1 of the amino acid sequence shown in SEQ ID NO. 49, HCDR2 of the amino acid sequence shown in SEQ ID NO. 50, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 51; or
3) LCDR1 of the amino acid sequence shown in SEQ ID NO. 28, LCDR2 of the amino acid sequence shown in SEQ ID NO. 29, LCDR3 of the amino acid sequence shown in SEQ ID NO. 30, HCDR1 of the amino acid sequence shown in SEQ ID NO. 52, HCDR2 of the amino acid sequence shown in SEQ ID NO. 53, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 54; or
4) LCDR1 of the amino acid sequence shown in SEQ ID NO. 31, LCDR2 of the amino acid sequence shown in SEQ ID NO. 32, LCDR3 of the amino acid sequence shown in SEQ ID NO. 33, HCDR1 of the amino acid sequence shown in SEQ ID NO. 55, HCDR2 of the amino acid sequence shown in SEQ ID NO. 56, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 57; or
5) LCDR1 of the amino acid sequence shown in SEQ ID NO. 34, LCDR2 of the amino acid sequence shown in SEQ ID NO. 35, LCDR3 of the amino acid sequence shown in SEQ ID NO. 36, HCDR1 of the amino acid sequence shown in SEQ ID NO. 58, HCDR2 of the amino acid sequence shown in SEQ ID NO. 59, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 60; or
6) LCDR1 of the amino acid sequence shown in SEQ ID NO. 37, LCDR2 of the amino acid sequence shown in SEQ ID NO. 38, LCDR3 of the amino acid sequence shown in SEQ ID NO. 39, and HCDR1 of the amino acid sequence shown in SEQ ID NO. 61, HCDR2 of the amino acid sequence shown in SEQ ID NO. 62, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 63; or
7) LCDR1 of the amino acid sequence shown in SEQ ID NO. 40, LCDR2 of the amino acid sequence shown in SEQ ID NO. 41, LCDR3 of the amino acid sequence shown in SEQ ID NO. 42, HCDR1 of the amino acid sequence shown in SEQ ID NO. 64, HCDR2 of the amino acid sequence shown in SEQ ID NO. 65, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 66; or
8) LCDR1 of the amino acid sequence shown in SEQ ID NO. 43, LCDR2 of the amino acid sequence shown in SEQ ID NO. 44, LCDR3 of the amino acid sequence shown in SEQ ID NO. 45, HCDR1 of the amino acid sequence shown in SEQ ID NO. 67, HCDR2 of the amino acid sequence shown in SEQ ID NO. 68, and HCDR3 of the amino acid sequence shown in SEQ ID NO. 69.
2. The antibody of claim 1, wherein the amino acid sequences of the light and heavy chain variable regions of the antibody are one of the combinations of SEQ ID NO 2 and 3, SEQ ID NO 4 and 5, SEQ ID NO 6 and 7, SEQ ID NO 8 and 9, SEQ ID NO 10 and 11, SEQ ID NO 12 and 13, SEQ ID NO 14 and 15, SEQ ID NO 16 and 17.
3. The antibody of claim 2, wherein the amino acid sequences of the light and heavy chains of said antibody are one of the combinations of SEQ ID NO 70 and 71, SEQ ID NO 72 and 73, SEQ ID NO 74 and 75, SEQ ID NO 76 and 77, SEQ ID NO 78 and 79, SEQ ID NO 80 and 81, SEQ ID NO 82 and 83, SEQ ID NO 84 and 85.
4. A vector or host cell comprising a nucleic acid molecule encoding the antibody of any one of claims 1 to 3.
5. Use of the antibody of claim 3 and/or the vector or host cell of claim 4 in the manufacture of a medicament for the treatment or co-treatment of an autoimmune disease, wherein the autoimmune disease is a disease caused by abnormal thyroid function; the disease caused by the thyroid dysfunction is thyroid-related ophthalmopathy; the amino acid sequences of the light chain and the heavy chain of the antibody are SEQ ID NO 70 and SEQ ID NO 71.
6. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 3 and/or a vector or host cell according to claim 4.
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PE20020801A1 (en) * 2001-01-05 2002-09-06 Pfizer ANTIBODIES AGAINST INSULIN-LIKE GROWTH FACTOR RECEPTOR
EP1613658B1 (en) * 2003-04-02 2012-03-14 F. Hoffmann-La Roche AG Antibodies against insulin-like growth factor i receptor and uses thereof
US20080226635A1 (en) * 2006-12-22 2008-09-18 Hans Koll Antibodies against insulin-like growth factor I receptor and uses thereof
US20090068110A1 (en) * 2006-12-22 2009-03-12 Genentech, Inc. Antibodies to insulin-like growth factor receptor
CN105315372A (en) * 2014-06-18 2016-02-10 中国人民解放军军事医学科学院基础医学研究所 Preparation and application of anti-insulin-like growth factor receptor (IGF-1R) human-sourced functional antibody LMAb1

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