CN101330925A - Therapeutic methods for inhibiting tumor growth with D114 antagonists - Google Patents

Therapeutic methods for inhibiting tumor growth with D114 antagonists Download PDF

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CN101330925A
CN101330925A CNA2006800473723A CN200680047372A CN101330925A CN 101330925 A CN101330925 A CN 101330925A CN A2006800473723 A CNA2006800473723 A CN A2006800473723A CN 200680047372 A CN200680047372 A CN 200680047372A CN 101330925 A CN101330925 A CN 101330925A
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I·诺格拉
G·瑟斯顿
N·盖尔
E·史密斯
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Regeneron Pharmaceuticals Inc
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Regeneron Pharmaceuticals Inc
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Abstract

A therapeutic method for inhibiting tumor development or growth, comprising administering an agent capable of inhibiting human delta-like ligand 4 (DII4) activity to a subject in need thereof. In one embodiment, the agent is an anti-DII4 antibody or antibody fragment capable of inhibiting the binding of DII4 to a Notch receptor. In another embodiment, the agent is a fusion protein comprising the extracellular domain of DII4 or a fragment or variant thereof, fused to a multimerizing component such as an Fc domain. The method of the invention is useful for inhibiting tumor growth, particularly in tumors which are not responsive to other therapeutic agents.

Description

Therapeutic Method with the D114 antagonist for inhibiting growth of tumor
Background of invention
Invention field
[0002] the present invention relates to method with δ sample part 4 (D114) antagonist for inhibiting growth of tumor.The D114 antagonist especially can be used for treating the tumor growth in the unresponsive tumor of other antitumor agent.
Description of related art
[0003] the Notch signal pathway is the alternative system of iuntercellular that various eukaryotes use in many bioprocesss such as differentiation, hypertrophy and homoiostasis.δ sample 4 (D114) or δ sample part 4 (D114) (to call " D114 " in the following text) are the members of δ family of Notch part, and it demonstrates high selectivity by blood vessel endothelium and expresses (Shutter etc., (2000) Genes Develop.14:1313-1318).D114 is a kind of part of Notch receptor, comprises Notch1 and Notch4.The nucleic acid of people and mice D114 and aminoacid sequence are respectively shown in SEQ ID NO:1-2 and SEQ IDNO:3-4.D114 mice (Duarte etc., (2004) Genes ﹠amp of gene target have been produced; Dev.18:doi:10.1101/gad.1239004; Krebs etc., (2004) Genes﹠amp; Dev.18:doi:10.1101/gad.1239204:Gale etc., (2004) Proc NatlAcad Sci USA 101:15949-15954).
Summary of the invention
[0004] experiment of hereinafter describing shows that the D114 antagonist is effectively in suppressing tumor growth, especially in to other anti-tumor therapeutic agent such as the insensitive tumor of VEGF (VEGF) antagonist.
[0005] on the one hand, the present invention is characterised in that the D114 antagonist that can suppress D114.In one embodiment, the D114 antagonist is a specificity in conjunction with D114 and blocking-up D114 and Notch receptor for example bonded antibody of Notch1 or antibody fragment.In another embodiment, D114 antagonist of the present invention is to comprise D114 extracellular domain or its segmental fusion rotein that merges with the multimerization composition.
[0006] antibody or the antibody fragment that is used for the inventive method can be polyclonal or monoclonal, and can be humanized, chimeric or people fully.Preferably this antibody is people's monoclonal antibody or monoclonal antibody fragment fully.Antibody fragment can be for example single-chain antibody, Fab or F (ab ') 2
[0007] when the D114 antagonist is fusion rotein, the extracellular domain of D114 or its fragment or modified fragment and multimerization composition merge.The multimerization composition is preferably immunoglobulin domain, as the Fc functional domain, for example, people Fc (SEQ ID NO:20).Fusion rotein randomly can comprise signal sequence, and it can be that cell is born, reorganization or synthetic.
[0008] in second aspect, the pharmaceutical composition that is used to suppress angiogenic growth or development that is characterized as of the present invention comprises and can suppress the active therapeutic agent of D114 and pharmaceutically suitable carrier.In one embodiment, therapeutic agent is the antibody or the antibody fragment of blocking-up D114 and Notch receptors bind.Preferably, the D114 antagonist is for suppressing fully human antibodies or its fragment of D114 and Notch1 receptors bind.In another embodiment, therapeutic agent is can be in conjunction with the modified D114 albumen of its Notch receptor, but this combination does not cause the activation of receptor.
[0009] in the third aspect, the method that is characterized as the disease of treatment D114 mediation of the present invention comprises using and can suppress the therapeutic agent that D114 is active or express.The disease of D114 mediation is a kind of disease that needs to suppress angiogenic growth or development.D114 antagonist of the present invention can be particularly useful for treating to the unresponsive tumor of other therapeutic agent or to other therapeutic agent and be lower than best responsive tumor.The generation and the oxygen of D114 antagonist function blood vessel capable of blocking are delivered to tumor.In specific embodiment, antagonist is anti-D114 antibody or antibody fragment or fusion rotein.Anti-D114 antibody or antibody fragment preferably suppress combining of D114 and Notch1 receptor.Fusion rotein of the present invention comprises reservation and Notch receptor binding capacity and lacks the natural extracellular region that D114 strides film district and cytoplasmic tail.In one embodiment, D114 antagonist of the present invention is used in treatment with treatment using the insensitive tumor of VEGF antagonist for treating.
[0010] in others, feature of the present invention is to suppress the active therapeutic agent of δ sample part 4 (D114) suppresses tumor development or growth for the patient of this treatment of needs purposes.In one embodiment, therapeutic agent is antibody or antibody fragment, or is polyclone or for monoclonal.When therapeutic agent is antibody or antibody fragment, can be humanized, chimeric or fully human antibodies or antibody fragment.In some embodiments, antibody fragment is single-chain antibody, Fab or F (ab ') 2In one embodiment, the D114 antagonist is the D114 fragment that merges with the multimerization composition.On the one hand, of the present invention being characterized as can be suppressed the active therapeutic agent of D114 as defined above as first therapeutic agent, with the purposes of another kind of therapeutic agent in the medicine of preparation inhibition tumor development or growth, described another kind of therapeutic agent is VEGF (VEGF) inhibitor.Preferably, the VEGF inhibitor is VEGF antibody or VEGF agent for capturing.When the VEGF inhibitor was the VEGF agent for capturing, therapeutic agent was the albumen with the aminoacid sequence shown in SEQ ID NO:19.
[0011] other purpose and advantage will become clear after reading detailed explanation.
Summary of drawings
[0012] Fig. 1 shows that the D114-Fc of C6 tumor cell crosses expression and causes the C6 tumor to diminish.
[0013] Fig. 2 D114-Fc of showing the whole body administration is efficiently with respect to the VEGF antagonist of receptor type in reducing the HT1080 tumor.Left side: when tumor is implanted, bestow D114-Fc or VEGF agent for capturing albumen, gathered tumor at the 25th day; Right side: bestowed D114-Fc or VEGF agent for capturing (Trap) albumen in back 15 days in implantation, gathered tumor at the 25th day.
[0014] Fig. 3 shows that the D114-Fc albumen of purification or polyclone D114 antibody suppress the HT1080 tumor growth.
[0015] Fig. 4 is presented at surface plasmon resonance (BiaCore
Figure A20068004737200051
) in the test, at the inhibition of the polyclonal antibody of D114 to D114 and Notch1 receptors bind.
Describe in detail
[0016] before describing method of the present invention, is to be understood that the present invention is not limited to institute and retouches The ad hoc approach of stating and experiment condition are because these methods and condition can change. Also should manage Separate term used herein just in order to describe specific embodiment, rather than in order to limit, Because scope of the present invention will only be subjected to the restriction of appended claims.
[0017] employed such as specification and appended claims, singulative " a kind of (a, An) " and " should (the) " comprise the plural number that refers to, unless clearly rule are arranged in the context in addition Fixed. Thereby, for example " a kind of method " comprise described type herein one or more methods, And/or step, they are to ability after the content of reading content of the present invention and the like Field technique personnel understand.
[0018] unless otherwise defined, all industry and scientific terminology and institute of the present invention herein The implication that the those of ordinary skill in genus field is understood usually is identical. Although any and description herein Similar or equivalent method and material all can be used for enforcement of the present invention or test, but the application Preferred method and material have been described.
Definition
[0019] term " D114 is correlated with " or " the D114 mediation " illness or disease refer to be subjected to The active directly or indirectly illness of impact of regulating of D114. More specifically, D114 shows and blood The pipe advolution is relevant. Therefore, in one embodiment, can treat by the inventive method The D114 associated conditions be a kind of angiogenic growth or development that need to suppress or reduce the D114 mediation Or ripe for example for suppressing the illness of tumor development.
[0020] term " inhibitor " or " antagonist " refer to that delay or prevention chemistry or physiology are anti-The material that should or respond. Can be direct, for example pass through to suppress receptor activation with blocking antibody, Or indirectly, by the expression of disturbing encoding D 114 genes, the D114 activity of inhibition. Often The inhibitor of seeing comprises but is not limited to spreading out of antisense molecule, antibody, soluble recepter and they Biological and in conjunction with its Notch acceptor but can not be by this modified in conjunction with activation signal The D114 part.
[0021] " neutralization " or " blocking-up " antibody is used to refer in conjunction with D114 and causes D114 to give birth to The antibody of the inhibition of thing activity. The bioactive inhibition of this D114 can be given birth to by measuring D114 One or more indicants of thing activity are estimated. The bioactive indicant of this class D114 can lead to Crossing in detecting in the external or body of some standards known in the art one or more detects to comment Valency (referring to the following examples). Preferably, antagonist is by suppressing D114 in conjunction with Notch During coming, acceptor such as Notch1 estimate with the ability of D114 activity.
General description
[0022] δ sample/Notch signal pathway is necessary to setting up organized and fractionated vascular system between period of expansion.Various δ samples/Notch gene comprises the targeting disappearance of D114, can cause mice death owing to serious vascular defects during fetal development.Utilize microarray analysis, we find that in mice xenotransplantation tumor model δ sample part 4 (D114) are the genes that a kind of VEGF-regulates.In addition, in this class tumor model, also find, express with D114 in the adjacent normal skin and compare that D114 expresses significantly higher in tumor vessel.In order to probe into the effect of D114/Notch signal in the blocking-up tumor, carry out xenotransplantation research in mice, wherein solubility D114-Fc molecule is expressed by crossing of retrovirus-mediated method in the tumor cell and is locally discharged or adopt adenovirus method or discharge by injection purifying protein whole body.The method of all release D114-Fc all causes tumor growth to reduce compared with the control.In addition, the tumor vessel comparison of D114-Fc treatment is according to having more many, and formation has the meticulous network of intensive blood vessel development, but this class blood vessel comparison is poor according to the effectiveness of the blood vessel of tumor.As array and Taqman TMAnalyze indicatedly, this class effect and Notch signal reduce relevant.Adopt and to be injected into the intravital polyclonal antibody solution of mice capapie and also to observe similar effect tumor growth.Find that also this class polyclonal antibody solution suppresses combining of D114 and Notch1 receptor.In addition, also find D114-Fc than the VEGF blocker (" VEGF agent for capturing ", United States Patent (USP) 7,070,959) of receptor type reduce aspect some growth of tumor more effective.These discoveries show that D114 plays a crucial role in tumor growth, and support D114 to be used for the development of angiogenesis inhibitor treatment as target.
The D114 antagonist
[0023] the D114 antagonist comprises and can block D114 and bonded D114 of Notch receptor (as Notch1) and segmental antibody thereof, fusion rotein, described fusion rotein comprises the D114 extracellular domain that merges with the multimerization composition or its fragment and peptide and peptibodies (referring to for example, U.S. Patent Publication 2003/0229023 Oliner etc.).
[0024] D114 antibody.Term used herein " immunoglobulin or antibody " refers to that mammal comprises the peptide that the people is many, and it comprises specificity combination and the antigenic immunoglobulin gene of identification or its segmental framework region, and for the present invention, it is D114 albumen or its part.If desired antibody or antibody sample albumen will use as mammalian therapeutic agents, the immunoglobulin land should be by the derivation of corresponding mammalian immune globulin.Use if this molecule is intended for use nontherapeutic agent, as diagnosis and ELISA, then the immunoglobulin land can be by people or non-human mammal such as mice derivation.Human immunoglobulin gene or genetic fragment comprise κ, λ, alpha, gamma, δ, ε and μ constant region, and all immune globulin variable region genes.Light chain is categorized as κ or λ.Heavy chain is categorized as γ, μ, and α, δ or ε, it defines immunoglobulin class, IgG, IgM, IgA, IgD and IgE successively respectively.At each IgG apoplexy due to endogenous wind, there is various homotypes (IgG for example 1, IgG 2, IgG 3, IgG 4) and their abnormal shape.
[0025] immunoglobulin of exemplary human IgG (antibody) construction unit comprises the tetramer.Each tetramer comprises that two identical polypeptide chains are right, and each polypeptide chain is to having a light chain (about 25kD) and a heavy chain (about 50-70kD).The terminal about 100-110 of definition of the N-of every chain or the variable region of amino acids more, mainly responsible antigen recognition.Term " variable light chain " (V L) and variable heavy chain (V H) refer to this class light chain and heavy chain respectively.
[0026] antibody exists with intact immunoglobulin form, or exists with the pieces of passing through various peptide enzymic digestions generations of many abundant signs.For example, the antibody under the disulfide bond of pepsin digestion in hinge region produces F (ab) ' 2, the dimer of a kind of Fab, itself are by disulfide bond and V H-C HThe light chain that connects.F (ab) ' 2Under the condition of gentleness, can be reduced so that the disulfide bonds in the hinge region, thereby with F (ab) ' 2Dimer is converted into Fab ' monomer.Fab ' monomer is the Fab with part hinge region basically.Although various antibody fragments define according to the digestion of complete antibody, the technical staff more is ready the from the beginning chemosynthesis or adopt recombinant DNA method synthetic of this fragment.Therefore, term antibody used herein, also comprise antibody fragment by the modified generation of whole antibody, or the antibody fragment of employing recombinant DNA method de novo synthesis (for example, the single variable domain of strand Fv (scFv) (Dabs)) or adopt to show storehouse such as phage escherichia coli or yeast show the antibody fragment identified in the storehouse (referring to, for example, (1990) Nature 348:552-554 such as McCafferty).
[0027] method for preparing antibody is known in the art.Referring to, for example, Kohler ﹠amp; Milstein (1975) Nature 256:495-497; Harlow ﹠amp; Lane (1988) Antibodies:a Laboratory Manual, Cold Spring Harbor Lab., ColdSpring Harbor, NY).From inhuman organism such as mice, rat, rabbit, the isolated antibody of milch cow, can make its similar people by chimeric or humanization.
[0028] " humanization " of inhuman (for example, Mus) antibody or chimeric form for by the immunoglobulin that contains the required minmal sequence of conjugated antigen, immunoglobulin chain or its fragment of non-human immunoglobulin derivation (as Fv, Fab, Fab ', F (ab ') 2Or the antibody sequence of other conjugated antigen).They and mice or other non-human antibody have same or analogous binding specificity and affinity, and it provides and makes up initiation material chimeric or humanized antibody.Chimeric antibody is the antibody that its light chain and heavy chain gene have typically been made up by the immunoglobulin gene fragment that belongs to different plant species by genetic engineering.For example, be derived from variable (V) fragment of the gene of mouse monoclonal antibody can constant (C) fragment with the people such as IgG1 be connected with IgG4.The hybrid protein of therefore typical chimeric antibody for constituting by C in the V in the mouse antibodies or antigen binding domain territory and the people's antibody or effector functions territory.The complementary determining region (CDR district) (being called the donor immunity globulin) that humanized antibody has the variable region framework residue (being called receptor antibody) that is derived from people's antibody basically and is derived from mouse antibodies basically.Referring to, Queen etc., Proc.Natl.Acad Sci.USA86:10029-10033 (1989) and WO 90/07861, U.S. patent 5,693,762,5,693,761,5,585,089,5,530,101 and 5,225,539.Constant region is if exist, also basically or fully from the human normal immunoglobulin.People's variable domain is selected from people's antibody usually, and its framework sequence demonstrates and obtain the sequence homogeneity of the Mus variable region functional domain height of CDR.Heavy chain and variable region of light chain framework residue can be derived from identical or different human antibody sequence.Human antibody sequence can be that natural human antibody sequence maybe can be the consensus sequence of some people's antibody.Referring to WO92/22653.May influence to the CDR structure and/or to antigen is bonded based on it, select to be derived from some aminoacid of people variable region framework residue in order to displacement.This research that may influence is to be undertaken by simulation, the aminoacids characteristic of check specific site or the displacement of empirical observation specific amino acids or the effect of sudden change.For example, aminoacid is not simultaneously between Mus variable region framework residue and the people variable region framework residue through selecting, usually people's framework amino acid will be by the equivalent framework amino acid displacement from mouse antibodies, and condition is a rational expectation aminoacid: (1) non-covalent direct conjugated antigen; (2) with CDR district adjacency; (3) otherwise with the CDR district (for example about 6
Figure A20068004737200091
The CDR district within) interact, or (4) participate in V L-V HThe interface.Other is used for metathetical candidate is for the rare receptor people framework amino acid of human normal immunoglobulin on this position.This amino acid can be by from the equivalent position of mice donor antibody or from the amino acid replacement of more typical human normal immunoglobulin's equivalent position.Other is used for metathetical candidate is for the rare receptor people framework amino acid of human normal immunoglobulin on this position.The variable region framework of humanized immunoglobulin usually show with people variable region framework sequence at least 85% sequence homogeneity or with the concordance of such sequence.
[0029] method of generation people antibody comprises, for example, and VelocImmune TM(RegeneronPharmaceuticals), XenoMouse TMTechnology (Abgenix), " minilocus " method and phage display.VelocImmune TMTechnology (US 6,596,541) comprises that generation has the method for the fully human antibodies of high specific to selected antigen.This technology relates to having and comprises the generation that operability is connected to the genomic transgenic mice of people's heavy chain in endogenous mice constant region site and variable region of light chain, makes mice response antigenic stimulus produce the antibody that comprises people variable region and mice constant region.Encode the DNA of variable region of the heavy chain of this antibody and light chain through separating and operability is connected to the DNA of coding people's heavy chain and constant region of light chain.In the cell that can express fully human antibodies, express described DNA then.In specific embodiment, cell is a Chinese hamster ovary celI.
[0030] XenoMouse TMTechnology (Green etc. (1994) Nature Genetics7:13-21) produces to have simultaneously and is derived from heavy chain and the people variable region in κ light chain site and the mice of constant region.In other method, other people used ' minilocus " method, wherein by comprise each gene that is derived from the Ig site simulate exogenous Ig site (referring to, for example, US5,545,807).It is separated that the DNA operability of coding people's heavy chain and constant region of light chain is connected or does not connect the encode DNA ground of variable region.
[0031] or, phage display or relevant display technique can be used for identifying antibody, the antibody fragment of specificity in conjunction with D114, as (heteromeric) Fab fragment of variable domain and heteropleural.(for example referring to U.S. Patent Publication 2003/0229023).
[0032] screen analysis of preferred immunoglobulin (antibody) and selection can be undertaken by the whole bag of tricks known in the art.For example, can be undertaken by using method or phage display at the Preliminary screening of the existence of the monoclonal antibody of D114 for specificity based on ELISA.Preferably carry out the screening of second road to identify and to select required monoclonal antibody.Second road screens available any suitable method known in the art to carry out.A kind of preferable methods is called " BiosensorModification-Assisted Profiling " (" BiaMAP ") and is described in U.S. Patent Application Publication 2004/101920.BiaMAP can discern the hybridoma clone who produces the monoclonal antibody with desirable characteristics rapidly.More specifically, based on antibody: the evaluation of AI is categorized as monoclonal antibody the relevant group of epi-position of different in kind.Perhaps, based on ELISA type, pearl type or Biacore
Figure A20068004737200101
The competition analysis of type can be used for identifying in conjunction with right, and described combination is in conjunction with different D114 epi-position and therefore may be with the high-affinity binding partner of cooperating.
[0033] The D114 fusion roteinWhen the D114 antagonist is fusion rotein, the multimerization composition can be selected from (i) immunoglobulin domain, the multimerization composition that (ii) blocks, (iii) length is about 500 the amino acid whose aminoacid sequences of 1-, randomly comprise at least one cysteine residues, (iv) leucine zipper, (v) helical ring motif and (vi) coiled coil motif.In preferred embodiments, the multimerization composition is preferably immunoglobulin domain, is preferably the Fc functional domain, for example, and people Fc (SEQ ID NO:20).Fusion rotein can randomly comprise signal sequence, and it can comprise cells involved direct secretion polypeptide known to the skilled or proteinic any sequence, comprises natural or synthetic sequence.Usually, signal sequence is positioned at the beginning or the amino terminal of fusion rotein of the present invention.The sort signal sequence can be that cell is born, reorganization or synthetic.The composition of fusion rotein of the present invention can directly connect mutually or connect by one or more intervening sequences.In an embodiment preferred, these compositions directly merge mutually.In another embodiment preferred, these compositions are connected with the nucleotide sequence of 1-200 amino acid whose spacer of coding.Any spacer known in the art all can be used to connect protein component.The spacer sequence also can comprise the sequence that is used to increase expressing fusion protein, restriction site is provided and allows the composition functional domain to form best three grades and quarternary structure and/or increase composition and its acceptor interaction.In one embodiment, fusion rotein of the present invention comprises the one or more peptide sequences between one or more compositions (between 1-25 aminoacid).
[0034] extracellular domain of D114 is made of the concatermer of δ/Serrate/Lag-2 (DSL) functional domain and eight epidermal growth factors (EGF) sample repetitive.Usually, the EGF functional domain is considered to appear at about 218-251 (functional domain 1), 252-282 (functional domain 2), 284-322 (functional domain 3), 324-360 (functional domain 4), and the position of 362-400 (functional domain 5), the DSL functional domain appears at the position of about 173-217, and the terminal functional domain of N-appears at the position of the 27-172 of about hD114 (SEQ ID NO:2).In specific embodiment, can suppress the active hD114 antagonist of D114 and be the about aminoacid 27 that comprises SEQ ID NO:2 that merges with hFc (the SEQ ID NO:20) DSL-hFc (SEQ ID NO:21) to about 172, N-end functional domain-DSL-hFc (SEQ ID NO:22) of the about 27-217 that comprises SEQ ID NO:2 that merges with hFc, the EGF functional domain 1-5-hFc that comprises about 218-400 (SEQ ID NO:23) with the hFc fusion, the EGF functional domain 1-4-hFc that comprises about 218-360 (SEQ ID NO:24) with the hFc fusion, the EGF functional domain 1-3-hFc that comprises about 218-322 (SEQ ID NO:25) with the hFc fusion, the EGF functional domain 1-2-hFc that comprises about 218-282 (SEQ ID NO:26) that merges with hFc, or between the functional domain composition, randomly comprise its variant of connexon.The composition of fusion rotein can also be that various configurations are arranged keeping when it serves as the D114 performance.
Medication
[0035] the invention provides Therapeutic Method, comprise the therapeutic agent of the present invention of using effective dose to the patient.Preferably, therapeutic agent is purified (for example, being substantially free of the material that limits its effect or produce undesirable side effect) basically.The patient is preferably animal, for example, and milch cow, pig, horse, chicken, cat, Canis familiaris L. etc., and be preferably mammal, most preferably be the people.
[0036] various drug-supplying systems are known and can be used for using therapeutic agent of the present invention, for example the encapsulation of liposome form, microgranule, microcapsule, the reconstitution cell that can express chemical compound, receptor-mediated endocytosis (referring to, for example, Wu and Wu, 1987, J.Biol.Chem.262:4429-4432), as the structure of the nucleic acid of a retroviral part or other carrier etc.The method of introducing can include but not limited under intradermal, intramuscular, intraperitoneal, intravenous, the epidermis through intestinal or parenteral, intranasal, epidural and oral approach.Chemical compound can pass through any administration easily, for example by infusion or inject fast, absorb (for example, oral mucosa, rectum and intestinal mucosa etc.) by epithelium or cutaneomucosal theca interna, and can be with other bioactivator administration.Use can be whole body or partial.In addition, it may be desirable that pharmaceutical composition of the present invention is introduced the central nervous system by any suitable approach, and described approach comprises in the ventricle and intrathecal injection; Injection becomes more convenient by the ventricle inner catheter in the ventricle, for example connects reservoir, as the Ommaya reservoir.Also can adopt pulmonary administration, for example, by utilizing inhaler or aerosol apparatus and the preparation administration that contains propellant.
[0037] in specific embodiment, it may be desirable that pharmaceutical composition of the present invention is locally applied to need the position of treatment; For example, this can realize by following manner without limitation: pass through local infusion at the surgery intra-operative, and local application, for example, by injection, by conduit, or by implanting, described implant is porous, atresia or gelatinous material, comprise film, as the sialastic film, fiber, or commercial Graftskin.
[0038] in another embodiment, activating agent can be sent (referring to Langer (1990) Science 249:1527-1533) with the form of vesicle (vesicle), particularly liposome.In another embodiment, activating agent can be sent with the form of controlled release system.In one embodiment, can use pump (above) referring to Langer (1990).In another embodiment, can use polymeric material (referring to (1989) J.Neurosurg.71:105 such as Howard).In another embodiment, activating agent wherein of the present invention is the nucleic acid of encoding proteins, but uses in the nucleic acid body promoting the expression of its encoded protein, and the part by it being configured to suitable nucleic acid expression vector is also used it it is become in the cell, for example by utilize retroviral vector (referring to, for example, United States Patent (USP) 4,980,286), or by direct injection, or by utilizing microparticle bombardment (for example, particle gun; Biolistic, Dupont), or with lipid or cell surface receptor or transfection agents coating, or by to enter the form that nuclear homeobox sample peptide is connected and it used with notifying (referring to for example, Joliot etc., 1991, Proc.Natl.Acad.Sci.USA 88:1864-1868).As selection, can nucleic acid be introduced in the cell and incorporate host cell DNA into by homologous recombination and be used for expressing.
Pharmaceutical composition
[0039] the present invention also provides pharmaceutical composition.This compositions comprises the activating agent and the pharmaceutically suitable carrier for the treatment of effective dose.Term " pharmaceutically useful " refer to through the approval of federation or administrative organization of state government or be listed on American Pharmacopeia or other pharmacopeia of generally acknowledging for animal especially human.Term " load agent " refers to diluent, adjuvant, excipient or the carrier with the therapeutic agent administration.The medicinal load agent of this class can be a sterile liquid, and Ru Shui and oil comprise oil, animal, plant or synthetic oil of originating, as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods.Suitable pharmaceutical excipient comprises starch, glucose, lactose, sucrose, gelatin, ale, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, Pulvis Talci, sodium chloride, defatted milk powder, glycerol, propylene, ethylene glycol, water, ethanol etc.If desired, compositions can also contain a spot of wetting agent or emulsifying agent or pH buffer agent.This based composition can be taked forms such as solution, suspension, Emulsion, tablet, pill, capsule, powder, slow releasing preparation.Compositions can be mixed with suppository with the binding agent of routine and load agent such as triglyceride.Oral formulations can comprise mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate of the load agent of standard such as pharmaceutical grade etc.The case description of appropriate drug load agent is in E.W.Martin " Remington ' s Pharmaceutical Sciences ".
[0040] in preferred embodiments, compositions is mixed with the pharmaceutical composition that is suitable for being administered intravenously in the people according to a conventional method.In case of necessity, compositions can comprise that also solubilizing agent and local anesthetic such as lignocaine are to ease pain in the injection site.Want in compositions under the situation of infusion administration, it can save sterile pharmaceutical grade water or brinish infusion bottle are housed.Under the situation of compositions drug administration by injection, can provide the sterile water for injection of an ampoule or saline so that each composition can mix before administration.
[0041] activating agent of the present invention can neutrality or the form preparation of salt.Officinal salt comprises the salt that forms with free amine group, as the salt that is obtained by hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid etc.And the salt that forms with free carboxyl group, as the salt that obtains by sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, hydrated ferric oxide., 2-aminopropane., triethylamine, 2-ethylaminoethanol, histidine, procaine etc.
[0042] activating agent of the present invention effective amount in the disease of treatment D114 mediation can be determined by the clinical technology of standard based on the application's explanation.In addition, in vitro tests can randomly be used to help to determine best dosage range.The exact dose that is used for preparation also will depend on the order of severity of route of administration and disease, and decide according to doctor's judgement and each patient's situation.But, the suitable dosage range of intravenously administrable is generally about 0.5 to the 20 milligram reactive compound of per kilogram of body weight.Intranasal administration appropriate dosage scope is generally about 0.01pg/kg body weight to the 1mg/kg body weight.Effective dose can be by extrapolating from dose-response curve external or that animal model test system obtains.
Therapeutic alliance
[0043] in many embodiments, D114 of the present invention can or treat use in conjunction with one or more additional compounds.For example, but multiple fusion rotein or anti-D114 antibody co-administered or with together with one or more treatment chemical compound administrations.In preferred embodiments, D114 inhibitor of the present invention and VEGF antagonist are as VEGF antibody or the administration together of VEGF agent for capturing.The preferred implementation of VEGF agent for capturing (according to the description among the WO 00/75319) is VEGFR1R2-Fc Δ Cl (a).
[0044] term used herein " cytotoxic agent " material that refers to suppress or stop the function of cell and/or cause cytoclasis.This term is meant and comprises radiosiotope (I for example 131, I 125, Y 90And Re 186), enzyme activity toxin or its fragment of chemotherapeutics and toxin such as antibacterial, mycete, plant or animal origin.
[0045] therapeutic alliance comprises the administration of the single medicine dosage preparaton that contains D114 antagonist of the present invention and one or more VEGF antagonisies; And D114 antagonist and one or more other therapeutic agents are with its independently administration of drug dose preparaton separately.For example, D114 antagonist and cytotoxic agent, chemotherapeutics or growth inhibitor can the single dose compositions such as the co-formulated agent be applied to the patient together, perhaps every kind of therapeutic agent independently the dosage preparaton use.Using under the situation of dosage preparaton independently fusion rotein of the present invention and one or more other therapeutic agents administration simultaneously or in the i.e. administration in turn of the time administration that staggers.
[0046] " chemotherapeutics " is for being used for the treatment of the chemical compound of cancer.The example of chemotherapeutics comprises that alkylating agent replaces group and cyclophosphamide (CYTOXAN as plug
Figure A20068004737200151
); Alkyl sulfonates such as busulfan, an improsulfan and piposulfan; Aziridine such as benzodopa, carboquone, meturedopa and uredopa; Ethylenimine class (ethylenimines) and methylmelamine class (methylamelamines) comprise altretamine, tretamine, triethylenephosphoramide (trietylenephosphoramide), triethylene thiophosphoramide and trimethylolomelamine; Nitrogen mustards such as chlorambucil, chlornaphazine, chloro phosphamide, estramustine, ifosfamide, chlormethine, nitromin hydrochloride, melphalan, novoembichin, phenesterin, prednimustine, trofosfamide, uracil mustard; Nitro ureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, Ranimustine; As aclacinomysins, D actinomycin D, authramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carabicin, carminomycin, carzinophillin, chromomycin, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-nor-leucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, Mycophenolic Acid, nogalamycin, Olivomycin, peplomycin, potfiromycin, puromycin, triferricdoxorubicin, rodorubicin, rufocromomycin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; Antimetabolite such as methotrexate and 5-fluorouracil (5-FU); Folacin such as front three folic acid, methotrexate, Pteropterin, trimetrexate; Purine analogue such as fludarabine, 6-mercaptopurine, ITG, thioguanine; Pyrimidine analogue such as ancitabine, azacitidine, 6-azauridine carmofur, carmofur, cytosine arabinoside, two deoxidation urea glycosides (dideoxyuridine), doxifluridine, enocitabine, floxuridine; Androgen such as calusterone, Masterone, epitiostanol, mepitiostane, testolactone; Antiadrenergic drug class such as aminoglutethimide, mitotane, trilostane; Folic acid supplement such as frolinic acid; Aceglatone; Aldophosphamide; Amino-laevulic acid; Amsacrine; Bestrabucil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diaziquone; Elfornithine; Elliptinium acetate; Etoglucid; Ganite (Fujisawa).; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; C-283; Pentostatin; Phenamet; Pirarubicin; Podophyllinic acid; 2-ethyl hydrazides; Procarbazine; PSK
Figure A20068004737200161
Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2 ', 2 " RA3s; Urethanes; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Cytosine arabinoside (" Ara-C "); Cyclophosphamide; Plug is for group; Taxanes, for example paclitaxel (TAXOL , Bristol-Myers Squibb Oncology, Princeton, N.J.) and Docetaxel (TAXOTERE
Figure A20068004737200163
Aventis Antony, France); Chlorambucil; Gemcitabine; The 6-thioguanine; Mercaptopurine; Methotrexate; Platinum analogs such as cisplatin and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Ametycin; Mitoxantrone; Vincristine; Vinorelbine; Nvelbine; Novantrone; Teniposide; Daunorubicin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase enzyme inhibitor RFS 2000; Er Fujiajiniaoansuan (DMFO); Tretinoin; Esperamicins; Capecitabine; And the officinal salt of above-mentioned any medicine, acid or derivant.Also comprising in this definition works regulates or inhibition active antihormone agent of tumor such as estrogen antagonist, for example comprise tamoxifen, raloxifene, 4 (5)-imidazoles that suppress aromatase, the 4-hydroxy-tamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); And androgen antagonist such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; And the officinal salt of above-mentioned any medicine, acid or derivant.
[0047] " growth inhibitor " refers to when using in this article external or suppress the chemical compound or the compositions of cell, especially growth of cancer cells in vivo.The example of growth inhibitor comprises the therapeutic agent (in the position of non-S phase) of blocking-up cell cycle progress, as induces G1 to stop the therapeutic agent that stops mutually with M-.Typical M-phase blocker comprises vincamine (vincristine and vinblastine), TAXOL
Figure A20068004737200164
And topo II inhibitor such as doxorubicin, epirubicin, daunorubicin, etoposide and bleomycin.Those therapeutic agents that stop G1 also surplus enter S and stop mutually, for example DNA alkylating agent such as tamoxifen, prednisone, dacarbazine, chlormethine, cisplatin, methotrexate, 5-fluorouracil and cytosine arabinoside.
Embodiment
[0048] providing following examples is for providing open completely and explanation with regard to how to prepare and use method and composition of the present invention for those of ordinary skills, and be not intended to limit the inventor it not being invented the scope of considering.Guaranteed the correctness of used numeral (for example, measuring temperature etc.) hardy, but some experimental erroies of existence and deviation should be described.Except as otherwise noted, umber is parts by weight, and molecular weight is a mean molecule quantity, and temperature is degree centigrade, and pressure is atmospheric pressure or near atmospheric pressure.
Embodiment 1: targeting D114 gene in mice.
[0049] Gene targeting.Use Velocigene TMTechnology (Valenzuela etc. (2003) Nat.Biotechnol.21:652-9) produces the disappearance and the exchange of accurate D114 coding region, from beginning to contain b-tilactase indicator and neomycin selection box (selection cassette) to termination codon (being equivalent to comprise the 8.1kB district of all coding exons and insertion intron) extension.Briefly, the bacterial artificial chromosome (BAC) of the flanking sequence that contains 8.1kb D114 coding region and 140Kb (being derived from the clone 475d4 in the 129/SvJ BAC storehouse that is obtained by the Incyte genome) is modified to produce the targeting vector of BAC type, then with its linearize and as targeting vector with the D114 gene in displacement F1H4 (C57BL/6:129 cenospecies) mouse embryonic stem (ES) cell.Adopt natural allelic loss (LONA) analytic process to identify the embryonic stem cell of correct targeting (Valenzuela etc. (2003) above).Use two chimeric male mices of independently correct targeting ES system's generation, it is the complete transmitter of the sperm of ES-generation.It is female to produce F1 mice or embryo then chimera to be bred into C57BL/6 and/or ICR, by LONA analytic process and beta galactosidase tissue chemical analysis method it is carried out gene type assay.Both are identical by the mice performance that ES system obtains, and merging (pooled) data of being cloned by both are used for statistics.
[0050] The result.Targeting D114 gene causes embryonic death phenomenon and serious vascular defects in mice, even also (referring to (2004) Proc Natl Acad Sci USA 101:15949-15954 such as Gale) can occur in the mice of single allele targeting.
[0051] Tumor is implanted.With the chimeric mice flank of the subcutaneous implantation D114 of Lewis lung cancer cell (ATCC), gather after 16 days, be cut into 80 microns sections, and according to describing CD31/PECAM or beta galactosidase dyeing (Holash etc. (2002) Proc Natl.Acad.Sci.USA 99:11393-8).
[0052] PECAM and reporter molecule dyeing.The embryo that integral body is loaded and be derived from the embryo and the tissue slice of adult, method according to the aforementioned CD31/PECAM of being used for dyes to define blood vessel endothelium, and the method dyeing that is used for beta galactosidase is so that D114 indicator product video picture (Gale etc. (2004) PNAS 101:15949-54).
Embodiment 2.D114-Fc makes up and mice xenotransplantation research.
[0053] D114-Fc (TM) makes up.Structure has the nucleotide sequence of 2297 nucleotide, and its extracellular domain corresponding to people D114 (SEQ ID NO:1) does not contain and strides film (TM) functional domain contains people Fc functional domain.This amino acid sequence coded has proteic 765 aminoacid of D114 (SEQID NO:18), and molecular weight is about 85kDa.
[0054] Fig. 1 shows that the D114-Fc of C6 tumor cell crosses to express and causes the C6 tumor (meansigma methods ± SD) that diminishes.
[0055] Tumor cell is crossed the retrovirus engineering of expressing D114-Fc.Make C6 rat glioma tumor cell (ATCC) retroviral infection to cross expression green fluorescent protein (GFP) and solubility D114-Fc; The cell of infecing GFP is used alone as contrast.Cell is carried out the FACS branch be selected to twice of GFP fluorescence.
[0056] The D114-Fc that retrovirus discharges.With the C6 cell of GFP or D114-Fc retrovirus engineering with 10 6The right rib of male SCID/CB17 mice (8-10wk is big) of light is shaved in the subcutaneous implantation of individual cell/mice.
[0057] Gross tumor volume is measured:After tumor becomes obviously, write down per dimensional measurement (size=(length x width of once using vernier in three days 2/ 2).One puts to death animal, just obtains stripped measurement and utilizes the formula length with vernier) volume calculated.
[0058] Tumor histology.After tumor cell is implanted 12 to 16 days, gather tumor and processing to organize or expression analysis.Tumor is cut into 80 μ m section, dyes with antibody and to CD31/Pecam-1, carry out the DAB-peroxidase reaction, and redye with pyronin Y.Utilize NIH Image 1.62 analysis programmes to carry out the vascular morphology determination and analysis.
[0059] Northern trace and real-time-PCR.(LifeTechnologies, Grand Island NY) prepare total RNA by tumor tissues to use Trizol reagent.Isolation of RNA on 1.2% agarose gel (10mg) changes on the nylon membrane and by UV is crosslinked and fixes.After prehybridization, add the D114 or glyceraldehyde-3-phosphate dehydrogenase (the GAPDH)-specific probe of 32P labelling, and filtrate is spent the night 42 ℃ of hybridization.Carry out strictness washing (with 0.2 X SSPE buffer washed twice, at every turn carrying out 30 minutes after the once washing 0.5 X SSPE buffer) with standard scheme at 55 ℃.After being exposed to the X-ray film 48h that has intensifying screen (intensifying screens), obtain autoradiogram.In addition, use Taqman
Figure A20068004737200191
(AppliedBiosystems, Foster City, California) PCR in real time chemistry and detection system are analyzed tissue specific expression in the reaction that separates, described system have primer to D114, notch receptor 1 and 4 and notch downstream targeting, Hes1, Hey2, HeyL and the special label probe of Nrarp.Acquisition reaches the necessary number of cycles of cDNA amplification threshold value (or CT value), in being standardized as operation reference (housekeeping reference) (GAPDH) (=2-DCT).Result standard is turned to baseline, the vehicle contrast of experiment, obtain relative mRNA abundance change (=2DDCT) and with the meansigma methods ± s.e.m. of at least 4 sample triplicates that separate represent (Livak and Schmittgen (2001) Methods.Dec; 25 (4): 402-8).
[0060] D114, HeyL Nrarp and Hes1 are carried out quantitative RT-PCR analysis.Carry out RT-PCR according to description and analyze (Livak etc. (2001) Methods 24:402-8).The result recently represents with target RNA amount and contrast RNA (GAPDH) amount, wherein said amount uses following Auele Specific Primer and probe to obtain on Applied Biosystems7900HT according to describing (Daly etc., (2004) Genes Dev.18:1060-71): D114 primer: D114-1574F (SEQ ID NO:9) and D114-1644R (SEQ ID NO:10) and D114 probe: D114-1594T (SEQ ID NO:11); HeyL primer: mHeyL-135F (SEQ ID NO:12) and mHeyL-216R (SEQ ID NO:13) and HeyLProbe:mHeyL-154T (SEQ IDNO:14); MNrarp-373T:(SEQ ID NO:17) and mHes1 (IDMm00468601 m1 Nrarp primer: mNrarp-350F (SEQ ID NO:15) and mNrarp-418R (SEQID NO:16) and Nrarp probe:, Hes1) (ABI, Assay on demand services).CDNA obtains from C6-D114-Fc and C6-D114 tumor.
[0061] Analyzed in vitro measures whether the excretory D114-Fc of expression activates in the C6 cell Notch signal among the HUVEC.With 4 * 10 5The HUVEC cell is tiled on the 60mm plate subsequently several days and obtains～50% confluent culture.Second day, with 8 * 10 5The C6 cell is layered on the upper strata of HUVECs.After 24 hours common cultivation, cell breakage is gone in the Tri reagent of 1ml and to prepare total RNA according to preceding method.End user's specificity Hes1, HeyL and Nrarp probe are with Taqman Analytic sample.
The effect of embodiment 3.D114-Fc whole body administration.
[0062] D114-Fc albumen.With the plasmid transfection of above-mentioned encoding D 114-Fc cDNA construct in Chinese hamster ovary celI, and with secreted protein purification from supernatant.With the D114-Fc protein purification and be used under the percutaneous mice that injection (10mg/kg, 3x weekly) treatment has tumor.
[0063] The result.Experimentize, wherein the HT1080 tumor was implanted mice as stated above at the 0th day.The 0th day or the 15th day (with 100mm 3Size), with the D114-Fc albumen (10mg/kg, 3x weekly) of purification or reference protein treatment mice.With the dosage of VEGF antagonist (VEGF agent for capturing, SEQ ID NO:19) with 25mg/kg, inferior on every Wendesdays other group of treatment.The result as shown in Figure 2.In the tumor of the 0th day begin treatment (left side), VEGF antagonist and D114-Fc can both effectively control tumor growth.Be of a size of 100mm 3Tumor in (the right), D114-Fc also controls tumor growth effectively, and is in fact more effective than VEGF antagonist.
[0064] Cyclicity D114-Fc and hFc's is quantitativeBy the elisa assay method blood serum sample that obtains from the mice that tumor is arranged of GFP or D114-Fc treatment is analyzed.Carry out ELISA by covering plate with hFc as trapping antibody, with 0.2%I-blocking solution (Tropix) blocking-up, and the hFc of use and peroxidase conjugated is as report antibody.The hFc and the D114-Fc albumen of purification are included in the standard curve.
[0065] The VEGF-inhibitor for treating.With VEGF agent for capturing (R1R2) (RegeneronPharmaceuticals) (SEQ ID NO:19) or placebo (5%v/v PBS/ glycerol) with per three days one time subcutaneous administration of the dosage of 25mg/kg in mice with 100mm3 tumor, finish up to research.
[0066] The adenovirus of D114-Fc is sent.Other experimental applications adenovirus systemic delivery D114-Fc that does not provide.C6, HT1080 or the subcutaneous implantation of MMT tumor cell are shaved the right rib of male SCID/CB17 mice (8-10wk is big) of light.After 24 hours, with 1x10 9Gland-the hFc of pfu or gland D114-Fc are injected in the jugular vein of mice.Observe and the similar result of usefulness D114-Fc albumen whole body therapeutic with gland-D114-Fc.
The polyclonal antibody of embodiment 4.D114-Fc is to the effect of HT1080 tumor.
[0067] experimentizes, wherein the HT1080 tumor is implanted mice as stated above the 0th day the time.When tumor reaches 100mm 3The time (greatly about 15 days), with D114-Fc separately (25mg/kg), control antibodies (rabbit Ig) or remove (depleted) in conjunction with the anti-D114 polyclonal antibody of people Fc time treatment mice (10mg/kg) on every Wendesdays.The result shows the tumor size ± S.D. (Fig. 3) in each treatment group.D114 antibody antagonism HT1080 tumor growth is efficiently, has the viewed similar effectiveness to D114-Fc.These results show that the agent of D114 specific inhibition is the effective antitumour agent.
[0068] carries out surface plasmon resonance (BiaCore
Figure A20068004737200211
) analyze to confirm D114 antibody capable blocking-up D114 and Notch receptors bind.Notch1 covered on fragment (chip) surface and with rabbit polyclonal anti-D114 antibody (as mentioned above) incubation of D114-Fc with incremental change.Result among Fig. 4 shows that the D114 antibody of incremental change increases ground blocking-up D114-Fc and combines (the non-specific rabbit polyclonal antibody of contrast=D114-Fc+) with Notch1.
Sequence table
<110>Regeneron?Pharmaceuticals，Inc
＜120〉method for the treatment of with the D114 antagonist for inhibiting growth of tumor
<130>2071A-WO
<140>PCT/US2006/047848
<141>2006-12-15
<150>60/751,176
<151>2005-12-16
<150>60/771,276
<151>2006-02-08
<150>60/788,456
<151>2006-03-31
<150>60/830,543
<151>2006-07-12
<160>26
<170>FastSEQ?for?Windows?Version?4.0
<210>1
<211>2058
<212>DNA
＜213〉homo sapiens
<400>1
atggcggcag?cgtcccggag?cgcctctggc?tgggcgctac?tgctgctggt?ggcactttgg?60
cagcagcgcg?cggccggctc?cggcgtcttc?cagctgcagc?tgcaggagtt?catcaacgag?120
cgcggcgtac?tggccagtgg?gcggccttgc?gagcccggct?gccggacttt?cttccgcgtc?180
tgccttaagc?acttccaggc?ggtcgtctcg?cccggaccct?gcaccttcgg?gaccgtctcc?240
acgccggtat?tgggcaccaa?ctccttcgct?gtccgggacg?acagtagcgg?cggggggcgc?300
aaccctctcc?aactgccctt?caatttcacc?tggccgggta?ccttctcgct?catcatcgaa?360
gcttggcacg?cgccaggaga?cgacctgcgg?ccagaggcct?tgccaccaga?tgcactcatc?420
agcaagatcg?ccatccaggg?ctccctagct?gtgggtcaga?actggttatt?ggatgagcaa?480
accagcaccc?tcacaaggct?gcgctactct?taccgggtca?tctgcagtga?caactactat?540
ggagacaact?gctcccgcct?gtgcaagaag?cgcaatgacc?acttcggcca?ctatgtgtgc?600
cagccagatg?gcaacttgtc?ctgcctgccc?ggttggactg?gggaatattg?ccaacagcct?660
atctgtcttt?cgggctgtca?tgaacagaat?ggctactgca?gcaagccagc?agagtgcctc?720
tgccgcccag?gctggcaggg?ccggctgtgt?aacgaatgca?tcccccacaa?tggctgtcgc?780
cacggcacct?gcagcactcc?ctggcaatgt?acttgtgatg?agggctgggg?aggcctgttt?840
tgtgaccaag?atctcaacta?ctgcacccac?cactccccat?gcaagaatgg?ggcaacgtgc?900
tccaacagtg?ggcagcgaag?ctacacctgc?acctgtcgcc?caggctacac?tggtgtggac?960
tgtgagctgg?agctcagcga?gtgtgacagc?aacccctgtc?gcaatggagg?cagctgtaag?1020
gaccaggagg?atggctacca?ctgcctgtgt?cctccgggct?actatggcct?gcattgtgaa?1080
cacagcacct?tgagctgcgc?cgactccccc?tgcttcaatg?ggggctcctg?ccgggagcgc?1140
aaccaggggg?ccaactatgc?ttgtgaatgt?ccccccaact?tcaccggctc?caactgcgag?1200
aagaaagtgg?acaggtgcac?cagcaacccc?tgtgccaacg?ggggacagtg?cctgaaccga?1260
ggtccaagcc?gcatgtgccg?ctgccgtcct?ggattcacgg?gcacctactg?tgaactccac?1320
gtcagcgact?gtgcccgtaa?cccttgcgcc?cacggtggca?cttgccatga?cctggagaat?1380
gggctcatgt?gcacctgccc?tgccggcttc?tctggccgac?gctgtgaggt?gcggacatcc?1440
atcgatgcct?gtgcctcgag?tccctgcttc?aacagggcca?cctgctacac?cgacctctcc?1500
acagacacct?ttgtgtgcaa?ctgcccttat?ggctttgtgg?gcagccgctg?cgagttcccc?1560
gtgggcttgc?cgcccagctt?cccctgggtg?gccgtctcgc?tgggtgtggg?gctggcagtg?1620
ctgctggtac?tgctgggcat?ggtggcagtg?gctgtgcggc?agctgcggct?tcgacggccg?1680
gacgacggca?gcagggaagc?catgaacaac?ttgtcggact?tccagaagga?caacctgatt?1740
cctgccgccc?agcttaaaaa?cacaaaccag?aagaaggagc?tggaagtgga?ctgtggcctg?1800
gacaagtcca?actgtggcaa?acagcaaaac?cacacattgg?actataatct?ggccccaggg?1860
cccctggggc?gggggaccat?gccaggaaag?tttccccaca?gtgacaagag?cttaggagag?1920
aaggcgccac?tgcggttaca?cagtgaaaag?ccagagtgtc?ggatatcagc?gatatgctcc?1980
cccagggact?ccatgtacca?gtctgtgtgt?ttgatatcag?aggagaggaa?tgaatgtgtc?2040
attgccacgg?aggtataa 2058
<210>2
<211>685
<212>PRT
＜213〉homo sapiens
<400>2
Met?Ala?Ala?Ala?Ser?Arg?Ser?Ala?Ser?Gly?Trp?Ala?Leu?Leu?Leu?Leu
1 5 10 15
Val?Ala?Leu?Trp?Gln?Gln?Arg?Ala?Ala?Gly?Ser?Gly?Val?Phe?Gln?Leu
20 25 30
Gln?Leu?Gln?Glu?Phe?Ile?Asn?Glu?Arg?Gly?Val?Leu?Ala?Ser?Gly?Arg
35 40 45
Pro?Cys?Glu?Pro?Gly?Cys?Arg?Thr?Phe?Phe?Arg?Val?Cys?Leu?Lys?His
50 55 60
Phe?Gln?Ala?Val?Val?Ser?Pro?Gly?Pro?Cys?Thr?Phe?Gly?Thr?Val?Ser
65 70 75 80
Thr?Pro?Val?Leu?Gly?Thr?Asn?Ser?Phe?Ala?Val?Arg?Asp?Asp?Ser?Ser
85 90 95
Gly?Gly?Gly?Arg?Asn?Pro?Leu?Gln?Leu?Pro?Phe?Asn?Phe?Thr?Trp?Pro
100 105 110
Gly?Thr?Phe?Ser?Leu?Ile?Ile?Glu?Ala?Trp?His?Ala?Pro?Gly?Asp?Asp
115 120 125
Leu?Arg?Pro?Glu?Ala?Leu?Pro?Pro?Asp?Ala?Leu?Ile?Ser?Lys?Ile?Ala
130 135 140
Ile?Gln?Gly?Ser?Leu?Ala?Val?Gly?Gln?Asn?Trp?Leu?Leu?Asp?Glu?Gln
145 150 155 160
Thr?Ser?Thr?Leu?Thr?Arg?Leu?Arg?Tyr?Ser?Tyr?Arg?Val?Ile?Cys?Ser
165 170 175
Asp?Asn?Tyr?Tyr?Gly?Asp?Asn?Cys?Ser?Arg?Leu?Cys?Lys?Lys?Arg?Asn
180 185 190
Asp?His?Phe?Gly?His?Tyr?Val?Cys?Gln?Pro?Asp?Gly?Asn?Leu?Ser?Cys
195 200 205
Leu?Pro?Gly?Trp?Thr?Gly?Glu?Tyr?Cys?Gln?Gln?Pro?Ile?Cys?Leu?Ser
210 215 220
Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys?Ser?Lys?Pro?Ala?Glu?Cys?Leu
225 230 235 240
Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu?Cys?Asn?Glu?Cys?Ile?Pro?His
245 250 255
Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser?Thr?Pro?Trp?Gln?Cys?Thr?Cys
260 265 270
Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys?Asp?Gln?Asp?Leu?Asn?Tyr?Cys
275 280 285
Thr?His?His?Ser?Pro?Cys?Lys?Asn?Gly?Ala?Thr?Cys?Ser?Asn?Ser?Gly
290 295 300
Gln?Arg?Ser?Tyr?Thr?Cys?Thr?Cys?Arg?Pro?Gly?Tyr?Thr?Gly?Val?Asp
305 310 315 320
Cys?Glu?Leu?Glu?Leu?Ser?Glu?Cys?Asp?Ser?Asn?Pro?Cys?Arg?Asn?Gly
325 330 335
Gly?Ser?Cys?Lys?Asp?Gln?Glu?Asp?Gly?Tyr?His?Cys?Leu?Cys?Pro?Pro
340 345 350
Gly?Tyr?Tyr?Gly?Leu?His?Cys?Glu?His?Ser?Thr?Leu?Ser?Cys?Ala?Asp
355 360 365
Ser?Pro?Cys?Phe?Asn?Gly?Gly?Ser?Cys?Arg?Glu?Arg?Asn?Gln?Gly?Ala
370 375 380
Asn?Tyr?Ala?Cys?Glu?Cys?Pro?Pro?Asn?Phe?Thr?Gly?Ser?Asn?Cys?Glu
385 390 395 400
Lys?Lys?Val?Asp?Arg?Cys?Thr?Ser?Asn?Pro?Cys?Ala?Asn?Gly?Gly?Gln
405 410 415
Cys?Leu?Asn?Arg?Gly?Pro?Ser?Arg?Met?Cys?Arg?Cys?Arg?Pro?Gly?Phe
420 425 430
Thr?Gly?Thr?Tyr?Cys?Glu?Leu?His?Val?Ser?Asp?Cys?Ala?Arg?Asn?Pro
435 440 445
Cys?Ala?His?Gly?Gly?Thr?Cys?His?Asp?Leu?Glu?Asn?Gly?Leu?Met?Cys
450 455 460
Thr?Cys?Pro?Ala?Gly?Phe?Ser?Gly?Arg?Arg?Cys?Glu?Val?Arg?Thr?Ser
465 470 475 480
Ile?Asp?Ala?Cys?Ala?Ser?Ser?Pro?Cys?Phe?Asn?Arg?Ala?Thr?Cys?Tyr
485 490 495
Thr?Asp?Leu?Ser?Thr?Asp?Thr?Phe?Val?Cys?Asn?Cys?Pro?Tyr?Gly?Phe
500 505 510
Val?Gly?Ser?Arg?Cys?Glu?Phe?Pro?Val?Gly?Leu?Pro?Pro?Ser?Phe?Pro
515 520 525
Trp?Val?Ala?Val?Ser?Leu?Gly?Val?Gly?Leu?Ala?Val?Leu?Leu?Val?Leu
530 535 540
Leu?Gly?Met?Val?Ala?Val?Ala?Val?Arg?Gln?Leu?Arg?Leu?Arg?Arg?Pro
545 550 555 560
Asp?Asp?Gly?Ser?Arg?Glu?Ala?Met?Asn?Asn?Leu?Ser?Asp?Phe?Gln?Lys
565 570 575
Asp?Asn?Leu?Ile?Pro?Ala?Ala?Gln?Leu?Lys?Asn?Thr?Asn?Gln?Lys?Lys
580 585 590
Glu?Leu?Glu?Val?Asp?Cys?Gly?Leu?Asp?Lys?Ser?Asn?Cys?Gly?Lys?Gln
595 600 605
Gln?Asn?His?Thr?Leu?Asp?Tyr?Asn?Leu?Ala?Pro?Gly?Pro?Leu?Gly?Arg
610 615 620
Gly?Thr?Met?Pro?Gly?Lys?Phe?Pro?His?Ser?Asp?Lys?Ser?Leu?Gly?Glu
625 630 635 640
Lys?Ala?Pro?Leu?Arg?Leu?His?Ser?Glu?Lys?Pro?Glu?Cys?Arg?Ile?Ser
645 650 655
Ala?Ile?Cys?Ser?Pro?Arg?Asp?Ser?Met?Tyr?Gln?Ser?Val?Cys?Leu?Ile
660 665 670
Ser?Glu?Glu?Arg?Asn?Glu?Cys?Val?Ile?Ala?Thr?Glu?Val
675 680 685
<210>3
<211>3427
<212>DNA
＜213〉homo sapiens
<400>3
ctcgcaggct?aggaacccga?ggccaagagc?tgcagccaaa?gtcacttggg?tgcagtgtac?60
tccctcacta?gcccgctcga?gaccctagga?tttgctccag?gacacgtact?tagagcagcc?120
accgcccagt?cgccctcacc?tggattacct?accgaggcat?cgagcagcgg?agtttttgag?180
aaggcgacaa?gggagcagcg?tcccgagggg?aatcagcttt?tcaggaactc?ggctggcaga?240
cgggacttgc?gggagagcga?catccctaac?aagcagattc?ggagtcccgg?agtggagagg?300
acaccccaag?ggatgacgcc?tgcgtcccgg?agcgcctgtc?gctgggcgct?actgctgctg?360
gcggtactgt?ggccgcagca?gcgcgctgcg?ggctccggca?tcttccagct?gcggctgcag?420
gagttcgtca?accagcgcgg?tatgctggcc?aatgggcagt?cctgcgaacc?gggctgccgg?480
actttcttcc?gcatttgcct?taagcacttc?caggcaacct?tctccgaggg?accctgcacc?540
tttggcaatg?tctccacgcc?ggtattgggc?accaactcct?tcgtcgtcag?ggacaagaat?600
agcggcagtg?gtcgcaaccc?tctgcagttg?cccttcaatt?tcacctggcc?gggaaccttc?660
tcactcaaca?tccaagcttg?gcacacaccg?ggagacgacc?tgcggccaga?gacttcgcca?720
ggaaactctc?tcatcagcca?aatcatcatc?caaggctctc?ttgctgtggg?taagatttgg?780
cgaacagacg?agcaaaatga?caccctcacc?agactgagct?actcttaccg?ggtcatctgc?840
agtgacaact?actatggaga?gagctgttct?cgcctatgca?agaagcgcga?tgaccacttc?900
ggacattatg?agtgccagcc?agatggcagc?ctgtcctgcc?tgccgggctg?gactgggaag?960
tactgtgacc?agcctatatg?tctttctggc?tgtcatgagc?agaatggtta?ctgcagcaag?1020
ccagatgagt?gcatctgccg?tccaggttgg?cagggtcgcc?tgtgcaatga?atgtatcccc?1080
cacaatggct?gtcgtcatgg?cacctgcagc?atcccctggc?agtgtgcctg?cgatgaggga?1140
tggggaggtc?tgttttgtga?ccaagatctc?aactactgta?ctcaccactc?tccgtgcaag?1200
aatggatcaa?cgtgttccaa?cagtgggcca?aagggttata?cctgcacctg?tctcccaggc?1260
tacactggtg?agcactgtga?gctgggactc?agcaagtgtg?ccagcaaccc?ctgtcgaaat?1320
ggtggcagct?gtaaggacca?ggagaatagc?taccactgcc?tgtgtccccc?aggctactat?1380
ggccagcact?gtgagcatag?taccttgacc?tgtgcggact?caccctgctt?caatgggggc?1440
tcttgccggg?agcgcaacca?ggggtccagt?tatgcctgcg?aatgcccccc?caactttacc?1500
ggctctaact?gtgagaagaa?agtagacagg?tgtaccagca?acccgtgtgc?caatggaggc?1560
cagtgcctga?acagaggtcc?aagccgaacc?tgccgctgcc?ggcctggatt?cacaggcacc?1620
cactgtgaac?tgcacatcag?cgattgtgcc?cgaagtccct?gtgcccacgg?gggcacttgc?1680
cacgatctgg?agaatgggcc?tgtgtgcacc?tgccccgctg?gcttctctgg?caggcgctgc?1740
gaggtgcgga?taacccacga?tgcctgtgcc?tccggaccct?gcttcaatgg?ggccacctgc?1800
tacactggcc?tctccccaaa?caacttcgtc?tgcaactgtc?cttatggctt?tgtgggcagc?1860
cgctgcgagt?ttcccgtggg?cttgccaccc?agcttcccct?gggtagctgt?ctcgctgggc?1920
gtggggctag?tggtactgct?ggtgctgctg?gtcatggtgg?tagtggctgt?gcggcagctg?1980
cggcttcgga?ggcccgatga?cgagagcagg?gaagccatga?acaatctgtc?agacttccag?2040
aaggacaacc?taatccctgc?cgcccagctc?aaaaacacaa?accagaagaa?ggagctggaa?2100
gtggactgtg?gtctggacaa?gtccaattgt?ggcaaactgc?agaaccacac?attggactac?2160
aatctagccc?cgggactcct?aggacggggc?agcatgcctg?ggaagtatcc?tcacagtgac?2220
aagagcttag?gagagaaggt?gccacttcgg?ttacacagtg?agaagccaga?gtgtcgaata?2280
tcagccattt?gctctcccag?ggactctatg?taccaatcag?tgtgtttgat?atcagaagag?2340
aggaacgagt?gtgtgattgc?cacagaggta?taaggcagga?gcctactcag?acacccagct?2400
ccggcccagc?agctgggcct?tccttctgca?ttgtttacat?tgcatcctgt?atgggacatc?2460
tttagtatgc?acagtgctgc?tctgcggagg?aggagggaat?ggcatgaact?gaacagactg?2520
tgaacccgcc?aagagttgca?ccggctctgc?acacctccag?gagtctgcct?ggcttcagat?2580
gggcagcccc?gccaagggaa?cagagttgag?gagttagagg?agcatcagtt?gagctgatat?2640
ctaaggtgcc?tctcgaactt?ggacttgctc?tgccaacagt?ggtcatcatg?gagctcttga?2700
ctgttctcca?gagagtggca?gtggccctag?tgggtcttgg?cgctgctgta?gctcctgtgg?2760
gcatctgtat?ttccaaagtg?cctttgccca?gactccatcc?tcacagctgg?gcccaaatga?2820
gaaagcagag?aggaggcttg?caaaggatag?gcctcccgca?ggcagaacag?ccttggagtt?2880
tggcattaag?caggagctac?tctgcaggtg?aggaaagccc?gaggagggga?cacgtgtgac?2940
tcctgcctcc?aaccccagca?ggtggggtgc?cacctgcagc?ctctaggcaa?gagttggtcc?3000
ttcccctggt?cctggtgcct?ctgggctcat?gtgaacagat?gggcttaggg?cacgcccctt?3060
ttgccagcca?ggggtacagg?cctcactggg?gagctcaggg?ccttcatgct?aaactcccaa?3120
taagggagat?ggggggaagg?gggctgtggc?ctaggccctt?ccctccctca?cacccatttt?3180
tgggcccttg?agcctgggct?ccaccagtgc?ccactgttgc?cccgagacca?accttgaagc?3240
cgattttcaa?aaatcaataa?tatgaggttt?tgttttgtag?tttattttgg?aatctagtat?3300
tttgataatt?taagaatcag?aagcactggc?ctttctacat?tttataacat?tattttgtat?3360
ataatgtgta?tttataatat?gaaacagatg?tgtacataaa?aaaaaaaaaa?aaaaaaaaaa?3420
aaaaaaa 3427
<210>4
<211>686
<212>PRT
＜213〉homo sapiens
<400>4
Met?Thr?Pro?Ala?Ser?Arg?Ser?Ala?Cys?Arg?Trp?Ala?Leu?Leu?Leu?Leu
1 5 10 15
Ala?Val?Leu?Trp?Pro?Gln?Gln?Arg?Ala?Ala?Gly?Ser?Gly?Ile?Phe?Gln
20 25 30
Leu?Arg?Leu?Gln?Glu?Phe?Val?Asn?Gln?Arg?Gly?Met?Leu?Ala?Asn?Gly
35 40 45
Gln?Ser?Cys?Glu?Pro?Gly?Cys?Arg?Thr?Phe?Phe?Arg?Ile?Cys?Leu?Lys
50 55 60
His?Phe?Gln?Ala?Thr?Phe?Ser?Glu?Gly?Pro?Cys?Thr?Phe?Gly?Asn?Val
65 70 75 80
Ser?Thr?Pro?Val?Leu?Gly?Thr?Asn?Ser?Phe?Val?Val?Arg?Asp?Lys?Asn
85 90 95
Ser?Gly?Ser?Gly?Arg?Asn?Pro?Leu?Gln?Leu?Pro?Phe?Asn?Phe?Thr?Trp
100 105 110
Pro?Gly?Thr?Phe?Ser?Leu?Asn?Ile?Gln?Ala?Trp?His?Thr?Pro?Gly?Asp
115 120 125
Asp?Leu?Arg?Pro?Glu?Thr?Ser?Pro?Gly?Asn?Ser?Leu?Ile?Ser?Gln?Ile
130 135 140
Ile?Ile?Gln?Gly?Ser?Leu?Ala?Val?Gly?Lys?Ile?Trp?Arg?Thr?Asp?Glu
145 150 155 160
Gln?Asn?Asp?Thr?Leu?Thr?Arg?Leu?Ser?Tyr?Ser?Tyr?Arg?Val?Ile?Cys
165 170 175
Ser?Asp?Asn?Tyr?Tyr?Gly?Glu?Ser?Cys?Ser?Arg?Leu?Cys?Lys?Lys?Arg
180 185 190
Asp?Asp?His?Phe?Gly?His?Tyr?Glu?Cys?Gln?Pro?Asp?Gly?Ser?Leu?Ser
195 200 205
Cys?Leu?Pro?Gly?Trp?Thr?Gly?Lys?Tyr?Cys?Asp?Gln?Pro?Ile?Cys?Leu
210 215 220
Ser?Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys?Ser?Lys?Pro?Asp?Glu?Cys
225 230 235 240
Ile?Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu?Cys?Asn?Glu?Cys?Ile?Pro
245 250 255
His?Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser?Ile?Pro?Trp?Gln?Cys?Ala
260 265 270
Cys?Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys?Asp?Gln?Asp?Leu?Asn?Tyr
275 280 285
Cys?Thr?His?His?Ser?Pro?Cys?Lys?Asn?Gly?Ser?Thr?Cys?Ser?Asn?Ser
290 295 300
Gly?Pro?Lys?Gly?Tyr?Thr?Cys?Thr?Cys?Leu?Pro?Gly?Tyr?Thr?Gly?Glu
305 310 315 320
His?Cys?Glu?Leu?Gly?Leu?Ser?Lys?Cys?Ala?Ser?Asn?Pro?Cys?Arg?Asn
325 330 335
Gly?Gly?Ser?Cys?Lys?Asp?Gln?Glu?Asn?Ser?Tyr?His?Cys?Leu?Cys?Pro
340 345 350
Pro?Gly?Tyr?Tyr?Gly?Gln?His?Cys?Glu?His?Ser?Thr?Leu?Thr?Cys?Ala
355 360 365
Asp?Ser?Pro?Cys?Phe?Asn?Gly?Gly?Ser?Cys?Arg?Glu?Arg?Asn?Gln?Gly
370 375 380
Ser?Ser?Tyr?Ala?Cys?Glu?Cys?Pro?Pro?Asn?Phe?Thr?Gly?Ser?Asn?Cys
385 390 395 400
Glu?Lys?Lys?Val?Asp?Arg?Cys?Thr?Ser?Asn?Pro?Cys?Ala?Asn?Gly?Gly
405 410 415
Gln?Cys?Leu?Asn?Arg?Gly?Pro?Ser?Arg?Thr?Cys?Arg?Cys?Arg?Pro?Gly
420 425 430
Phe?Thr?Gly?Thr?His?Cys?Glu?Leu?His?Ile?Ser?Asp?Cys?Ala?Arg?Ser
435 440 445
Pro?Cys?Ala?His?Gly?Gly?Thr?Cys?His?Asp?Leu?Glu?Asn?Gly?Pro?Val
450 455 460
Cys?Thr?Cys?Pro?Ala?Gly?Phe?Ser?Gly?Arg?Arg?Cys?Glu?Val?Arg?Ile
465 470 475 480
Thr?His?Asp?Ala?Cys?Ala?Ser?Gly?Pro?Cys?Phe?Asn?Gly?Ala?Thr?Cys
485 490 495
Tyr?Thr?Gly?Leu?Ser?Pro?Asn?Asn?Phe?Val?Cys?Asn?Cys?Pro?Tyr?Gly
500 505 510
Phe?Val?Gly?Ser?Arg?Cys?Glu?Phe?Pro?Val?Gly?Leu?Pro?Pro?Ser?Phe
515 520 525
Pro?Trp?Val?Ala?Val?Ser?Leu?Gly?Val?Gly?Leu?Val?Val?Leu?Leu?Val
530 535 540
Leu?Leu?Val?Met?Val?Val?Val?Ala?Val?Arg?Gln?Leu?Arg?Leu?Arg?Arg
545 550 555 560
Pro?Asp?Asp?Glu?Ser?Arg?Glu?Ala?Met?Asn?Asn?Leu?Ser?Asp?Phe?Gln
565 570 575
Lys?Asp?Asn?Leu?Ile?Pro?Ala?Ala?Gln?Leu?Lys?Asn?Thr?Asn?Gln?Lys
580 585 590
Lys?Glu?Leu?Glu?Val?Asp?Cys?Gly?Leu?Asp?Lys?Ser?Asn?Cys?Gly?Lys
595 600 605
Leu?Gln?Asn?His?Thr?Leu?Asp?Tyr?Asn?Leu?Ala?Pro?Gly?Leu?Leu?Gly
610 615 620
Arg?Gly?Ser?Met?Pro?Gly?Lys?Tyr?Pro?His?Ser?Asp?Lys?Ser?Leu?Gly
625 630 635 640
Glu?Lys?Val?Pro?Leu?Arg?Leu?His?Ser?Glu?Lys?Pro?Glu?Cys?Arg?Ile
645 650 655
Ser?Ala?Ile?Cys?Ser?Pro?Arg?Asp?Ser?Met?Tyr?Gln?Ser?Val?Cys?Leu
660 665 670
Ile?Ser?Glu?Glu?Arg?Asn?Glu?Cys?Val?Ile?Ala?Thr?Glu?Val
675 680 685
<210>5
<211>9312
<212>DNA
＜213〉homo sapiens
<400>5
atgccgccgc?tcctggcgcc?cctgctctgc?ctggcgctgc?tgcccgcgct?cgccgcacga?60
ggcccgcgat?gctcccagcc?cggtgagacc?tgcctgaatg?gcgggaagtg?tgaagcggcc?120
aatggcacgg?aggcctgcgt?ctgtggcggg?gccttcgtgg?gcccgcgatg?ccaggacccc?180
aacccgtgcc?tcagcacccc?ctgcaagaac?gccgggacat?gccacgtggt?ggaccgcaga?240
ggcgtggcag?actatgcctg?cagctgtgcc?ctgggcttct?ctgggcccct?ctgcctgaca?300
cccctggaca?atgcctgcct?caccaacccc?tgccgcaacg?ggggcacctg?cgacctgctc?360
acgctgacgg?agtacaagtg?ccgctgcccg?cccggctggt?cagggaaatc?gtgccagcag?420
gctgacccgt?gcgcctccaa?cccctgcgcc?aacggtggcc?agtgcctgcc?cttcgaggcc?480
tcctacatct?gccactgccc?acccagcttc?catggcccca?cctgccggca?ggatgtcaac?540
gagtgtggcc?agaagcccgg?gctttgccgc?cacggaggca?cctgccacaa?cgaggtcggc?600
tcctaccgct?gcgtctgccg?cgccacccac?actggcccca?actgcgagcg?gccctacgtg?660
ccctgcagcc?cctcgccctg?ccagaacggg?ggcacctgcc?gccccacggg?cgacgtcacc?720
cacgagtgtg?cctgcctgcc?aggcttcacc?ggccagaact?gtgaggaaaa?tatcgacgat?780
tgtccaggaa?acaactgcaa?gaacgggggt?gcctgtgtgg?acggcgtgaa?cacctacaac?840
tgccgctgcc?cgccagagtg?gacaggtcag?tactgtaccg?aggatgtgga?cgagtgccag?900
ctgatgccaa?atgcctgcca?gaacggcggg?acctgccaca?acacccacgg?tggctacaac?960
tgcgtgtgtg?tcaacggctg?gactggtgag?gactgcagcg?agaacattga?tgactgtgcc?1020
agcgccgcct?gcttccacgg?cgccacctgc?catgaccgtg?tggcctcctt?ctactgcgag?1080
tgtccccatg?gccgcacagg?tctgctgtgc?cacctcaacg?acgcatgcat?cagcaacccc?1140
tgtaacgagg?gctccaactg?cgacaccaac?cctgtcaatg?gcaaggccat?ctgcacctgc?1200
ccctcggggt?acacgggccc?ggcctgcagc?caggacgtgg?atgagtgctc?gctgggtgcc?1260
aacccctgcg?agcatgcggg?caagtgcatc?aacacgctgg?gctccttcga?gtgccagtgt?1320
ctgcagggct?acacgggccc?ccgatgcgag?atcgacgtca?acgagtgcgt?ctcgaacccg?1380
tgccagaacg?acgccacctg?cctggaccag?attggggagt?tccagtgcat?ctgcatgccc?1440
ggctacgagg?gtgtgcactg?cgaggtcaac?acagacgagt?gtgccagcag?cccctgcctg?1500
cacaatggcc?gctgcctgga?caagatcaat?gagttccagt?gcgagtgccc?cacgggcttc?1560
actgggcatc?tgtgccagta?cgatgtggac?gagtgtgcca?gcaccccctg?caagaatggt?1620
gccaagtgcc?tggacggacc?caacacttac?acctgtgtgt?gcacggaagg?gtacacgggg?1680
acgcactgcg?aggtggacat?cgatgagtgc?gaccccgacc?cctgccacta?cggctcctgc?1740
aaggacggcg?tcgccacctt?cacctgcctc?tgccgcccag?gctacacggg?ccaccactgc?1800
gagaccaaca?tcaacgagtg?ctccagccag?ccctgccgcc?acgggggcac?ctgccaggac?1860
cgcgacaacg?cctacctctg?cttctgcctg?aaggggacca?caggacccaa?ctgcgagatc?1920
aacctggatg?actgtgccag?cagcccctgc?gactcgggca?cctgtctgga?caagatcgat?1980
ggctacgagt?gtgcctgtga?gccgggctac?acagggagca?tgtgtaacat?caacatcgat?2040
gagtgtgcgg?gcaacccctg?ccacaacggg?ggcacctgcg?aggacggcat?caatggcttc?2100
acctgccgct?gccccgaggg?ctaccacgac?cccacctgcc?tgtctgaggt?caatgagtgc?2160
aacagcaacc?cctgcgtcca?cggggcctgc?cgggacagcc?tcaacgggta?caagtgcgac?2220
tgtgaccctg?ggtggagtgg?gaccaactgt?gacatcaaca?acaatgagtg?tgaatccaac?2280
ccttgtgtca?acggcggcac?ctgcaaagac?atgaccagtg?gctacgtgtg?cacctgccgg?2340
gagggcttca?gcggtcccaa?ctgccagacc?aacatcaacg?agtgtgcgtc?caacccatgt?2400
ctgaaccagg?gcacgtgtat?tgacgacgtt?gccgggtaca?agtgcaactg?cctgctgccc?2460
tacacaggtg?ccacgtgtga?ggtggtgctg?gccccgtgtg?cccccagccc?ctgcagaaac?2520
ggcggggagt?gcaggcaatc?cgaggactat?gagagcttct?cctgtgtctg?ccccacgggc?2580
tggcaagcag?ggcagacctg?tgaggtcgac?atcaacgagt?gcgttctgag?cccgtgccgg?2640
cacggcgcat?cctgccagaa?cacccacggc?ggctaccgct?gccactgcca?ggccggctac?2700
agtgggcgca?actgcgagac?cgacatcgac?gactgccggc?ccaacccgtg?tcacaacggg?2760
ggctcctgca?cagacggcat?caacacggcc?ttctgcgact?gcctgcccgg?cttccggggc?2820
actttctgtg?aggaggacat?caacgagtgt?gccagtgacc?cctgccgcaa?cggggccaac?2880
tgcacggact?gcgtggacag?ctacacgtgc?acctgccccg?caggcttcag?cgggatccac?2940
tgtgagaaca?acacgcctga?ctgcacagag?agctcctgct?tcaacggtgg?cacctgcgtg?3000
gacggcatca?actcgttcac?ctgcctgtgt?ccacccggct?tcacgggcag?ctactgccag?3060
cacgatgtca?atgagtgcga?ctcacagccc?tgcctgcatg?gcggcacctg?tcaggacggc?3120
tgcggctcct?acaggtgcac?ctgcccccag?ggctacactg?gccccaactg?ccagaacctt?3180
gtgcactggt?gtgactcctc?gccctgcaag?aacggcggca?aatgctggca?gacccacacc?3240
cagtaccgct?gcgagtgccc?cagcggctgg?accggccttt?actgcgacgt?gcccagcgtg?3300
tcctgtgagg?tggctgcgca?gcgacaaggt?gttgacgttg?cccgcctgtg?ccagcatgga?3360
gggctctgtg?tggacgcggg?caacacgcac?cactgccgct?gccaggcggg?ctacacaggc?3420
agctactgtg?aggacctggt?ggacgagtgc?tcacccagcc?cctgccagaa?cggggccacc?3480
tgcacggact?acctgggcgg?ctactcctgc?aagtgcgtgg?ccggctacca?cggggtgaac?3540
tgctctgagg?agatcgacga?gtgcctctcc?cacccctgcc?agaacggggg?cacctgcctc?3600
gacctcccca?acacctacaa?gtgctcctgc?ccacggggca?ctcagggtgt?gcactgtgag?3660
atcaacgtgg?acgactgcaa?tccccccgtt?gaccccgtgt?cccggagccc?caagtgcttt?3720
aacaacggca?cctgcgtgga?ccaggtgggc?ggctacagct?gcacctgccc?gccgggcttc?3780
gtgggtgagc?gctgtgaggg?ggatgtcaac?gagtgcctgt?ccaatccctg?cgacgcccgt?3840
ggcacccaga?actgcgtgca?gcgcgtcaat?gacttccact?gcgagtgccg?tgctggtcac?3900
accgggcgcc?gctgcgagtc?cgtcatcaat?ggctgcaaag?gcaagccctg?caagaatggg?3960
ggcacctgcg?ccgtggcctc?caacaccgcc?cgcgggttca?tctgcaagtg?ccctgcgggc?4020
ttcgagggcg?ccacgtgtga?gaatgacgct?cgtacctgcg?gcagcctgcg?ctgcctcaac?4080
ggcggcacat?gcatctccgg?cccgcgcagc?cccacctgcc?tgtgcctggg?ccccttcacg?4140
ggccccgaat?gccagttccc?ggccagcagc?ccctgcctgg?gcggcaaccc?ctgctacaac?4200
caggggacct?gtgagcccac?atccgagagc?cccttctacc?gttgcctgtg?ccccgccaaa?4260
ttcaacgggc?tcttgtgcca?catcctggac?tacagcttcg?ggggtggggc?cgggcgcgac?4320
atccccccgc?cgctgatcga?ggaggcgtgc?gagctgcccg?agtgccagga?ggacgcgggc?4380
aacaaggtct?gcagcctgca?gtgcaacaac?cacgcgtgcg?gctgggacgg?cggtgactgc?4440
tccctcaact?tcaatgaccc?ctggaagaac?tgcacgcagt?ctctgcagtg?ctggaagtac?4500
ttcagtgacg?gccactgtga?cagccagtgc?aactcagccg?gctgcctctt?cgacggcttt?4560
gactgccagc?gtgcggaagg?ccagtgcaac?cccctgtacg?accagtactg?caaggaccac?4620
ttcagcgacg?ggcactgcga?ccagggctgc?aacagcgcgg?agtgcgagtg?ggacgggctg?4680
gactgtgcgg?agcatgtacc?cgagaggctg?gcggccggca?cgctggtggt?ggtggtgctg?4740
atgccgccgg?agcagctgcg?caacagctcc?ttccacttcc?tgcgggagct?cagccgcgtg?4800
ctgcacacca?acgtggtctt?caagcgtgac?gcacacggcc?agcagatgat?cttcccctac?4860
tacggccgcg?aggaggagct?gcgcaagcac?cccatcaagc?gtgccgccga?gggctgggcc?4920
gcacctgacg?ccctgctggg?ccaggtgaag?gcctcgctgc?tccctggtgg?cagcgagggt?4980
gggcggcggc?ggagggagct?ggaccccatg?gacgtccgcg?gctccatcgt?ctacctggag?5040
attgacaacc?ggcagtgtgt?gcaggcctcc?tcgcagtgct?tccagagtgc?caccgacgtg?5100
gccgcattcc?tgggagcgct?cgcctcgctg?ggcagcctca?acatccccta?caagatcgag?5160
gccgtgcaga?gtgagaccgt?ggagccgccc?ccgccggcgc?agctgcactt?catgtacgtg?5220
gcggcggccg?cctttgtgct?tctgttcttc?gtgggctgcg?gggtgctgct?gtcccgcaag?5280
cgccggcggc?agcatggcca?gctctggttc?cctgagggct?tcaaagtgtc?tgaggccagc?5340
aagaagaagc?ggcgggagcc?cctcggcgag?gactccgtgg?gcctcaagcc?cctgaagaac?5400
gcttcagacg?gtgccctcat?ggacgacaac?cagaatgagt?ggggggacga?ggacctggag?5460
accaagaagt?tccggttcga?ggagcccgtg?gttctgcctg?acctggacga?ccagacagac?5520
caccggcagt?ggactcagca?gcacctggat?gccgctgacc?tgcgcatgtc?tgccatggcc?5580
cccacaccgc?cccagggtga?ggttgacgcc?gactgcatgg?acgtcaatgt?ccgcgggcct?5640
gatggcttca?ccccgctcat?gatcgcctcc?tgcagcgggg?gcggcctgga?gacgggcaac?5700
agcgaggaag?aggaggacgc?gccggccgtc?atctccgact?tcatctacca?gggcgccagc?5760
ctgcacaacc?agacagaccg?cacgggcgag?accgccttgc?acctggccgc?ccgctactca?5820
cgctctgatg?ccgecaagcg?cctgctggag?gccagcgcag?atgccaacat?ccaggacaac?5880
atgggccgca?ccccgctgca?tgcggctgtg?tctgccgacg?cacaaggtgt?cttccagatc?5940
ctgatccgga?accgagccac?agacctggat?gcccgcatgc?atgatggcac?gacgccactg?6000
atcctggctg?cccgcctggc?cgtggagggc?atgctggagg?acctcatcaa?ctcacacgcc?6060
gacgtcaacg?ccgtagatga?cctgggcaag?tccgccctgc?actgggccgc?cgccgtgaac?6120
aatgtggatg?ccgcagttgt?gctcctgaag?aacggggcta?acaaagatat?gcagaacaac?6180
agggaggaga?cacccctgtt?tctggccgcc?cgggagggca?gctacgagac?cgccaaggtg?6240
ctgctggacc?actttgccaa?ccgggacatc?acggatcata?tggaccgcct?gccgcgcgac?6300
atcgcacagg?agcgcatgca?tcacgacatc?gtgaggctgc?tggacgagta?caacctggtg?6360
cgcagcccgc?agctgcacgg?agccccgctg?gggggcacgc?ccaccctgtc?gcccccgctc?6420
tgctcgccca?acggctacct?gggcagcctc?aagcccggcg?tgcagggcaa?gaaggtccgc?6480
aagcccagca?gcaaaggcct?ggcctgtgga?agcaaggagg?ccaaggacct?caaggcacgg?6540
aggaagaagt?cccaggacgg?caagggctgc?ctgctggaca?gctccggcat?gctctcgccc?6600
gtggactccc?tggagtcacc?ccatggctac?ctgtcagacg?tggcctcgcc?gccactgctg?6660
ccctccccgt?tccagcagtc?tccgtccgtg?cccctcaacc?acctgcctgg?gatgcccgac?6720
acccacctgg?gcatcgggca?cctgaacgtg?gcggccaagc?ccgagatggc?ggcgctgggt?6780
gggggcggcc?ggctggcctt?tgagactggc?ccacctcgtc?tctcccacct?gcctgtggcc?6840
tctggcacca?gcaccgtcct?gggctccagc?agcggagggg?ccctgaattt?cactgtgggc?6900
gggtccacca?gtttgaatgg?tcaatgcgag?tggctgtccc?ggctgcagag?cggcatggtg?6960
ccgaaccaat?acaaccctct?gcgggggagt?gtggcaccag?gccccctgag?cacacaggcc?7020
ccctccctgc?agcatggcat?ggtaggcccg?ctgcacagta?gccttgctgc?cagcgccctg?7080
tcccagatga?tgagctacca?gggcctgccc?agcacccggc?tggccaccca?gcctcacctg?7140
gtgcagaccc?agcaggtgca?gccacaaaac?ttacagatgc?agcagcagaa?cctgcagcca?7200
gcaaacatcc?agcagcagca?aagcctgcag?ccgccaccac?caccaccaca?gccgcacctt?7260
ggcgtgagct?cagcagccag?cggccacctg?ggccggagct?tcctgagtgg?agagccgagc?7320
caggcagacg?tgcagccact?gggccccagc?agcctggcgg?tgcacactat?tctgccccag?7380
gagagccccg?ccctgcccac?gtcgctgcca?tcctcgctgg?tcccacccgt?gaccgcagcc?7440
cagttcctga?cgcccccctc?gcagcacagc?tactcctcgc?ctgtggacaa?cacccccagc?7500
caccagctac?aggtgcctga?gcaccccttc?ctcaccccgt?cccctgagtc?ccctgaccag?7560
tggtccagct?cgtccccgca?ttccaacgtc?tccgactggt?ccgagggcgt?ctccagccct?7620
cccaccagca?tgcagtccca?gatcgcccgc?attccggagg?ccttcaagta?aacggcgcgc?7680
cccacgagac?cccggcttcc?tttcccaagc?cttcgggcgt?ctgtgtgcgc?tctgtggatg?7740
ccagggccga?ccagaggagc?ctttttaaaa?cacatgtttt?tatacaaaat?aagaacgagg?7800
attttaattt?tttttagtat?ttatttatgt?acttttattt?tacacagaaa?cactgccttt?7860
ttatttatat?gtactgtttt?atctggcccc?aggtagaaac?ttttatctat?tctgagaaaa?7920
caagcaagtt?ctgagagcca?gggttttcct?acgtaggatg?aaaagattct?tctgtgttta?7980
taaaatataa?acaaagattc?atgatttata?aatgccattt?atttattgat?tccttttttc?8040
aaaatccaaa?aagaaatgat?gttggagaag?ggaagttgaa?cgagcatagt?ccaaaaagct?8100
cctggggcgt?ccaggccgcg?ccctttcccc?gacgcccacc?caaccccaag?ccagcccggc?8160
cgctccacca?gcatcacctg?cctgttagga?gaagctgcat?ccagaggcaa?acggaggcaa?8220
agctggctca?ccttccgcac?gcggattaat?ttgcatctga?aataggaaac?aagtgaaagc?8280
atatgggtta?gatgttgcca?tgtgttttag?atggtttctt?gcaagcatgc?ttgtgaaaat?8340
gtgttctcgg?agtgtgtatg?ccaagagtgc?acccatggta?ccaatcatga?atctttgttt?8400
caggttcagt?attatgtagt?tgttcgttgg?ttatacaagt?tcttggtccc?tccagaacca?8460
ccccggcccc?ctgcccgttc?ttgaaatgta?ggcatcatgc?atgtcaaaca?tgagatgtgt?8520
ggactgtggc?acttgcctgg?gtcacacacg?gaggcatcct?acccttttct?ggggaaagac?8580
actgcctggg?ctgaccccgg?tggcggcccc?agcacctcag?cctgcacagt?gtcccccagg?8640
ttccgaagaa?gatgctccag?caacacagcc?tgggccccag?ctcgcgggac?ccgacccccc?8700
gtgggctccc?gtgttttgta?ggagacttgc?cagagccggg?cacattgagc?tgtgcaacgc?8760
cgtgggctgc?gtcctttggt?cctgtccccg?cagccctggc?agggggcatg?cggtcgggca?8820
ggggctggag?ggaggcgggg?gctgcccttg?ggccacccct?cctagtttgg?gaggagcaga?8880
tttttgcaat?accaagtata?gcctatggca?gaaaaaatgt?ctgtaaatat?gtttttaaag?8940
gtggattttg?tttaaaaaat?cttaatgaat?gagtctgttg?tgtgtcatgc?cagtgaggga?9000
cgtcagactt?ggctcagctc?ggggagcctt?agccgcccat?gcactgggga?cgctccgctg?9060
ccgtgccgcc?tgcactcctc?agggcagcct?cccccggctc?tacgggggcc?gcgtggtgcc?9120
atccccaggg?ggcatgacca?gatgcgtccc?aagatgttga?tttttactgt?gttttataaa?9180
atagagtgta?gtttacagaa?aaagacttta?aaagtgatct?acatgaggaa?ctgtagatga?9240
tgtatttttt?tcatcttttt?tgttaactga?tttgcaataa?aaatgatact?gatggtgaaa?9300
aaaaaaaaaa?aa 9312
<210>6
<211>2556
<212>PRT
＜213〉homo sapiens
<400>6
Met?Pro?Pro?Leu?Leu?Ala?Pro?Leu?Leu?Cys?Leu?Ala?Leu?Leu?Pro?Ala
1 5 10 15
Leu?Ala?Ala?Arg?Gly?Pro?Arg?Cys?Ser?Gln?Pro?Gly?Glu?Thr?Cys?Leu
20 25 30
Asn?Gly?Gly?Lys?Cys?Glu?Ala?Ala?Asn?Gly?Thr?Glu?Ala?Cys?Val?Cys
35 40 45
Gly?Gly?Ala?Phe?Val?Gly?Pro?Arg?Cys?Gln?Asp?Pro?Asn?Pro?Cys?Leu
50 55 60
Ser?Thr?Pro?Cys?Lys?Asn?Ala?Gly?Thr?Cys?His?Val?Val?Asp?Arg?Arg
65 70 75 80
Gly?Val?Ala?Asp?Tyr?Ala?Cys?Ser?Cys?Ala?Leu?Gly?Phe?Ser?Gly?Pro
85 90 95
Leu?Cys?Leu?Thr?Pro?Leu?Asp?Asn?Ala?Cys?Leu?Thr?Asn?Pro?Cys?Arg
100 105 110
Asn?Gly?Gly?Thr?Cys?Asp?Leu?Leu?Thr?Leu?Thr?Glu?Tyr?Lys?Cys?Arg
115 120 125
Cys?Pro?Pro?Gly?Trp?Ser?Gly?Lys?Ser?Cys?Gln?Gln?Ala?Asp?Pro?Cys
130 135 140
Ala?Ser?Asn?Pro?Cys?Ala?Asn?Gly?Gly?Gln?Cys?Leu?Pro?Phe?Glu?Ala
145 150 155 160
Ser?Tyr?Ile?Cys?His?Cys?Pro?Pro?Ser?Phe?His?Gly?Pro?Thr?Cys?Arg
165 170 175
Gln?Asp?Val?Asn?Glu?Cys?Gly?Gln?Lys?Pro?Gly?Leu?Cys?Arg?His?Gly
180 185 190
Gly?Thr?Cys?His?Asn?Glu?Val?Gly?Ser?Tyr?Arg?Cys?Val?Cys?Arg?Ala
195 200 205
Thr?His?Thr?Gly?Pro?Asn?Cys?Glu?Arg?Pro?Tyr?Val?Pro?Cys?Ser?Pro
210 215 220
Ser?Pro?Cys?Gln?Asn?Gly?Gly?Thr?Cys?Arg?Pro?Thr?Gly?Asp?Val?Thr
225 230 235 240
His?Glu?Cys?Ala?Cys?Leu?Pro?Gly?Phe?Thr?Gly?Gln?Asn?Cys?Glu?Glu
245 250 255
Asn?Ile?Asp?Asp?Cys?Pro?Gly?Asn?Asn?Cys?Lys?Asn?Gly?Gly?Ala?Cys
260 265 270
Val?Asp?Gly?Val?Asn?Thr?Tyr?Asn?Cys?Arg?Cys?Pro?Pro?Glu?Trp?Thr
275 280 285
Gly?Gln?Tyr?Cys?Thr?Glu?Asp?Val?Asp?Glu?Cys?Gln?Leu?Met?Pro?Asn
290 295 300
Ala?Cys?Gln?Asn?Gly?Gly?Thr?Cys?His?Asn?Thr?His?Gly?Gly?Tyr?Asn
305 310 315 320
Cys?Val?Cys?Val?Asn?Gly?Trp?Thr?Gly?Glu?Asp?Cys?Ser?Glu?Asn?Ile
325 330 335
Asp?Asp?Cys?Ala?Ser?Ala?Ala?Cys?Phe?His?Gly?Ala?Thr?Cys?His?Asp
340 345 350
Arg?Val?Ala?Ser?Phe?Tyr?Cys?Glu?Cys?Pro?His?Gly?Arg?Thr?Gly?Leu
355 360 365
Leu?Cys?His?Leu?Asn?Asp?Ala?Cys?Ile?Ser?Asn?Pro?Cys?Asn?Glu?Gly
370 375 380
Ser?Asn?Cys?Asp?Thr?Asn?Pro?Val?Asn?Gly?Lys?Ala?Ile?Cys?Thr?Cys
385 390 395 400
Pro?Ser?Gly?Tyr?Thr?Gly?Pro?Ala?Cys?Ser?Gln?Asp?Val?Asp?Glu?Cys
405 410 415
Ser?Leu?Gly?Ala?Asn?Pro?Cys?Glu?His?Ala?Gly?Lys?Cys?Ile?Asn?Thr
420 425 430
Leu?Gly?Ser?Phe?Glu?Cys?Gln?Cys?Leu?Gln?Gly?Tyr?Thr?Gly?Pro?Arg
435 440 445
Cys?Glu?Ile?Asp?Val?Asn?Glu?Cys?Val?Ser?Asn?Pro?Cys?Gln?Asn?Asp
450 455 460
Ala?Thr?Cys?Leu?Asp?Gln?Ile?Gly?Glu?Phe?Gln?Cys?Ile?Cys?Met?Pro
465 470 475 480
Gly?Tyr?Glu?Gly?Val?His?Cys?Glu?Val?Asn?Thr?Asp?Glu?Cys?Ala?Ser
485 490 495
Ser?Pro?Cys?Leu?His?Asn?Gly?Arg?Cys?Leu?Asp?Lys?Ile?Asn?Glu?Phe
500 505 510
Gln?Cys?Glu?Cys?Pro?Thr?Gly?Phe?Thr?Gly?His?Leu?Cys?Gln?Tyr?Asp
515 520 525
Val?Asp?Glu?Cys?Ala?Ser?Thr?Pro?Cys?Lys?Asn?Gly?Ala?Lys?Cys?Leu
530 535 540
Asp?Gly?Pro?Asn?Thr?Tyr?Thr?Cys?Val?Cys?Thr?Glu?Gly?Tyr?Thr?Gly
545 550 555 560
Thr?His?Cys?Glu?Val?Asp?Ile?Asp?Glu?Cys?Asp?Pro?Asp?Pro?Cys?His
565 570 575
Tyr?Gly?Ser?Cys?Lys?Asp?Gly?Val?Ala?Thr?Phe?Thr?Cys?Leu?Cys?Arg
580 585 590
Pro?Gly?Tyr?Thr?Gly?His?His?Cys?Glu?Thr?Asn?Ile?Asn?Glu?Cys?Ser
595 600 605
Ser?Gln?Pro?Cys?Arg?His?Gly?Gly?Thr?Cys?Gln?Asp?Arg?Asp?Asn?Ala
610 615 620
Tyr?Leu?Cys?Phe?Cys?Leu?Lys?Gly?Thr?Thr?Gly?Pro?Asn?Cys?Glu?Ile
625 630 635 640
Asn?Leu?Asp?Asp?Cys?Ala?Ser?Ser?Pro?Cys?Asp?Ser?Gly?Thr?Cys?Leu
645 650 655
Asp?Lys?Ile?Asp?Gly?Tyr?Glu?Cys?Ala?Cys?Glu?Pro?Gly?Tyr?Thr?Gly
660 665 670
Ser?Met?Cys?Asn?Ile?Asn?Ile?Asp?Glu?Cys?Ala?Gly?Asn?Pro?Cys?His
675 680 685
Asn?Gly?Gly?Thr?Cys?Glu?Asp?GlyIle?Asn?Gly?Phe?Thr?Cys?Arg?Cys
690 695 700
Pro?Glu?Gly?Tyr?His?Asp?Pro?Thr?Cys?Leu?Ser?Glu?Val?Asn?Glu?Cys
705 710 715 720
Asn?Ser?Asn?Pro?Cys?Val?His?Gly?Ala?Cys?Arg?Asp?Ser?Leu?Asn?Gly
725 730 735
Tyr?Lys?Cys?Asp?Cys?Asp?Pro?Gly?Trp?Ser?Gly?Thr?Asn?Cys?Asp?Ile
740 745 750
Asn?Asn?Asn?Glu?Cys?Glu?Ser?Asn?Pro?Cys?Val?Asn?Gly?Gly?Thr?Cys
755 760 765
Lys?Asp?Met?Thr?Ser?Gly?Tyr?Val?Cys?Thr?Cys?Arg?Glu?Gly?Phe?Ser
770 775 780
Gly?Pro?Asn?Cys?Gln?Thr?Asn?Ile?Asn?Glu?Cys?Ala?Ser?Asn?Pro?Cys
785 790 795 800
Leu?Asn?Gln?Gly?Thr?Cys?Ile?Asp?Asp?Val?Ala?Gly?Tyr?Lys?Cys?Asn
805 810 815
Cys?Leu?Leu?Pro?Tyr?Thr?Gly?Ala?Thr?Cys?Glu?Val?Val?Leu?Ala?Pro
820 825 830
Cys?Ala?Pro?Ser?Pro?Cys?Arg?Asn?Gly?Gly?Glu?Cys?Arg?Gln?Ser?Glu
835 840 845
Asp?Tyr?Glu?Ser?Phe?Ser?Cys?Val?Cys?Pro?Thr?Gly?Trp?Gln?Ala?Gly
850 855 860
Gln?Thr?Cys?Glu?Val?Asp?Ile?Asn?Glu?Cys?Val?Leu?Ser?Pro?Cys?Arg
865 870 875 880
His?Gly?Ala?Ser?Cys?Gln?Asn?Thr?His?Gly?Gly?Tyr?Arg?Cys?His?Cys
885 890 895
Gln?Ala?Gly?Tyr?Ser?Gly?Arg?Asn?Cys?Glu?Thr?Asp?Ile?Asp?Asp?Cys
900 905 910
Arg?Pro?Asn?Pro?Cys?His?Asn?Gly?Gly?Ser?Cys?Thr?Asp?Gly?Ile?Asn
915 920 925
Thr?Ala?Phe?Cys?Asp?Cys?Leu?Pro?Gly?Phe?Arg?Gly?Thr?Phe?Cys?Glu
930 935 940
Glu?Asp?Ile?Asn?Glu?Cys?Ala?Ser?Asp?Pro?Cys?Arg?Asn?Gly?Ala?Asn
945 950 955 960
Cys?Thr?Asp?Cys?Val?Asp?Ser?Tyr?Thr?Cys?Thr?Cys?Pro?Ala?Gly?Phe
965 970 975
Ser?Gly?Ile?His?Cys?Glu?Asn?Asn?Thr?Pro?Asp?Cys?Thr?Glu?Ser?Ser
980 985 990
Cys?Phe?Asn?Gly?Gly?Thr?Cys?Val?Asp?Gly?Ile?Asn?Ser?Phe?Thr?Cys
995 1000 1005
Leu?Cys?Pro?Pro?Gly?Phe?Thr?Gly?Ser?Tyr?Cys?Gln?His?Asp?Val?Asn
1010 1015 1020
Glu?Cys?Asp?Ser?Gln?Pro?Cys?Leu?His?Gly?Gly?Thr?Cys?Gln?Asp?Gly
1025 1030 1035 1040
Cys?Gly?Ser?Tyr?Arg?Cys?Thr?Cys?Pro?Gln?Gly?Tyr?Thr?Gly?Pro?Asn
1045 1050 1055
Cys?Gln?Asn?Leu?Val?His?Trp?Cys?Asp?Ser?Ser?Pro?Cys?Lys?Asn?Gly
1060 1065 1070
Gly?Lys?Cys?Trp?Gln?Thr?His?Thr?Gln?Tyr?Arg?Cys?Glu?Cys?Pro?Ser
1075 1080 1085
Gly?Trp?Thr?Gly?Leu?Tyr?Cys?Asp?Val?Pro?Ser?Val?Ser?Cys?Glu?Val
1090 1095 1100
Ala?Ala?Gln?Arg?Gln?Gly?Val?Asp?Val?Ala?Arg?Leu?Cys?Gln?His?Gly
1105 1110 1115 1120
Gly?Leu?Cys?Val?Asp?Ala?Gly?Asn?Thr?His?His?Cys?Arg?Cys?Gln?Ala
1125 1130 1135
Gly?Tyr?Thr?Gly?Ser?Tyr?Cys?Glu?Asp?Leu?Val?Asp?Glu?Cys?Ser?Pro
1140 1145 1150
Ser?Pro?Cys?Gln?Asn?Gly?Ala?Thr?Cys?Thr?Asp?Tyr?Leu?Gly?Gly?Tyr
1155 1160 1165
Ser?Cys?Lys?Cys?Val?Ala?Gly?Tyr?His?Gly?Val?Asn?Cys?Ser?Glu?Glu
1170 1175 1180
Ile?Asp?Glu?Cys?Leu?Ser?His?Pro?Cys?Gln?Asn?Gly?Gly?Thr?Cys?Leu
1185 1190 1195 1200
Asp?Leu?Pro?Asn?Thr?Tyr?Lys?Cys?Ser?Cys?Pro?Arg?Gly?Thr?Gln?Gly
1205 1210 1215
Val?His?Cys?Glu?Ile?Asn?Val?Asp?Asp?Cys?Asn?Pro?Pro?Val?Asp?Pro
1220 1225 1230
Val?Ser?Arg?Ser?Pro?Lys?Cys?Phe?Asn?Asn?Gly?Thr?Cys?Val?Asp?Gln
1235 1240 1245
Val?Gly?Gly?Tyr?Ser?Cys?Thr?Cys?Pro?Pro?Gly?Phe?Val?Gly?Glu?Arg
1250 1255 1260
Cys?Glu?Gly?Asp?Val?Asn?Glu?Cys?Leu?Ser?Asn?Pro?Cys?Asp?Ala?Arg
1265 1270 1275 1280
Gly?Thr?Gln?Asn?Cys?Val?Gln?Arg?Val?Asn?Asp?Phe?His?Cys?Glu?Cys
1285 1290 1295
Arg?Ala?Gly?His?Thr?Gly?Arg?Arg?Cys?Glu?Ser?Val?Ile?Asn?Gly?Cys
1300 1305 1310
Lys?Gly?Lys?Pro?Cys?Lys?Asn?Gly?Gly?Thr?Cys?Ala?Val?Ala?Ser?Asn
1315 1320 1325
Thr?Ala?Arg?Gly?Phe?Ile?Cys?Lys?Cys?Pro?Ala?Gly?Phe?Glu?Gly?Ala
1330 1335 1340
Thr?Cys?Glu?Asn?Asp?Ala?Arg?Thr?Cys?Gly?Ser?Leu?Arg?Cys?Leu?Asn
1345 1350 1355 1360
Gly?Gly?Thr?Cys?Ile?Ser?Gly?Pro?Arg?Ser?Pro?Thr?Cys?Leu?Cys?Leu
1365 1370 1375
Gly?Pro?Phe?Thr?Gly?Pro?Glu?Cys?Gln?Phe?Pro?Ala?Ser?Ser?Pro?Cys
1380 1385 1390
Leu?Gly?Gly?Asn?Pro?Cys?Tyr?Asn?Gln?Gly?Thr?Cys?Glu?Pro?Thr?Ser
1395 1400 1405
Glu?Ser?Pro?Phe?Tyr?Arg?Cys?Leu?Cys?Pro?Ala?Lys?Phe?Asn?Gly?Leu
1410 1415 1420
Leu?Cys?HisIle?Leu?Asp?Tyr?Ser?Phe?Gly?Gly?Gly?Ala?Gly?Arg?Asp
1425 1430 1435 1440
Ile?Pro?Pro?Pro?Leu?Ile?Glu?Glu?Ala?Cys?Glu?Leu?Pro?Glu?Cys?Gln
1445 1450 1455
Glu?Asp?Ala?Gly?Asn?Lys?Val?Cys?Ser?Leu?Gln?Cys?Asn?Asn?His?Ala
1460 1465 1470
Cys?Gly?Trp?Asp?Gly?Gly?Asp?Cys?Ser?Leu?Asn?Phe?Asn?Asp?Pro?Trp
1475 1480 1485
Lys?Asn?Cys?Thr?Gln?Ser?Leu?Gln?Cys?Trp?Lys?Tyr?Phe?Ser?Asp?Gly
1490 1495 1500
His?Cys?Asp?Ser?Gln?Cys?Asn?Ser?Ala?Gly?Cys?Leu?Phe?Asp?Gly?Phe
1505 1510 1515 1520
Asp?Cys?Gln?Arg?Ala?Glu?Gly?Gln?Cys?Asn?Pro?Leu?Tyr?Asp?Gln?Tyr
1525 1530 1535
Cys?Lys?Asp?His?Phe?Ser?Asp?Gly?His?Cys?Asp?Gln?Gly?Cys?Asn?Ser
1540 1545 1550
Ala?Glu?Cys?Glu?Trp?Asp?Gly?Leu?Asp?Cys?Ala?Glu?His?Val?Pro?Glu
1555 1560 1565
Arg?Leu?Ala?Ala?Gly?Thr?Leu?Val?Val?Val?Val?Leu?Met?Pro?Pro?Glu
1570 1575 1580
Gln?Leu?Arg?Asn?Ser?Ser?Phe?His?Phe?Leu?Arg?Glu?Leu?Ser?Arg?Val
1585 1590 1595 1600
Leu?His?Thr?Asn?Val?Val?Phe?Lys?Arg?Asp?Ala?His?Gly?Gln?Gln?Met
1605 1610 1615
Ile?Phe?Pro?Tyr?Tyr?Gly?Arg?Glu?Glu?Glu?Leu?Arg?Lys?His?Pro?Ile
1620 1625 1630
Lys?Arg?Ala?Ala?Glu?Gly?Trp?Ala?Ala?Pro?Asp?Ala?Leu?Leu?Gly?Gln
1635 1640 1645
Val?Lys?Ala?Ser?Leu?Leu?Pro?Gly?Gly?Ser?Glu?Gly?Gly?Arg?Arg?Arg
1650 1655 1660
Arg?Glu?Leu?Asp?Pro?Met?Asp?ValArg?GlySer?Ile?Val?Tyr?Leu?Glu
1665 1670 1675 1680
Ile?Asp?Asn?Arg?Gln?Cys?Val?Gln?Ala?Ser?Ser?Gln?Cys?Phe?Gln?Ser
1685 1690 1695
Ala?Thr?Asp?Val?Ala?Ala?Phe?Leu?Gly?Ala?Leu?Ala?Ser?Leu?Gly?Ser
1700 1705 1710
Leu?Asn?Ile?Pro?Tyr?Lys?Ile?Glu?Ala?Val?Gln?Ser?Glu?Thr?Val?Glu
1715 1720 1725
Pro?Pro?Pro?Pro?Ala?Gln?Leu?His?Phe?Met?Tyr?Val?Ala?Ala?Ala?Ala
1730 1735 1740
Phe?Val?Leu?Leu?Phe?Phe?Val?Gly?Cys?Gly?Val?Leu?Leu?Ser?Arg?Lys
1745 1750 1755 1760
Arg?Arg?Arg?Gln?His?Gly?Gln?Leu?Trp?Phe?Pro?Glu?Gly?Phe?Lys?Val
1765 1770 1775
Ser?Glu?Ala?Ser?Lys?Lys?Lys?Arg?Arg?Glu?Pro?Leu?Gly?Glu?Asp?Ser
1780 1785 1790
Val?Gly?Leu?Lys?Pro?Leu?Lys?Asn?Ala?Ser?Asp?Gly?Ala?Leu?Met?Asp
1795 1800 1805
Asp?Asn?Gln?Asn?Glu?Trp?Gly?Asp?Glu?Asp?Leu?Glu?Thr?Lys?Lys?Phe
1810 1815 1820
Arg?Phe?Glu?Glu?Pro?Val?Val?Leu?Pro?Asp?Leu?Asp?Asp?Gln?Thr?Asp
1825 1830 1835 1840
His?Arg?Gln?Trp?Thr?Gln?Gln?His?Leu?Asp?Ala?Ala?Asp?Leu?Arg?Met
1845 1850 1855
Ser?Ala?Met?Ala?Pro?Thr?Pro?Pro?Gln?Gly?Glu?Val?Asp?Ala?Asp?Cys
1860 1865 1870
Met?Asp?Val?Asn?Val?Arg?Gly?Pro?Asp?Gly?Phe?Thr?Pro?Leu?Met?Ile
1875 1880 1885
Ala?Ser?Cys?Ser?Gly?Gly?Gly?Leu?Glu?Thr?Gly?Asn?Ser?Glu?Glu?Glu
1890 1895 1900
Glu?Asp?Ala?Pro?Ala?Val?Ile?Ser?Asp?Phe?Ile?Tyr?Gln?Gly?Ala?Ser
1905 1910 1915 1920
Leu?His?Asn?Gln?Thr?Asp?Arg?Thr?Gly?Glu?Thr?Ala?Leu?His?Leu?Ala
1925 1930 1935
Ala?Arg?Tyr?Ser?Arg?Ser?Asp?Ala?Ala?Lys?Arg?Leu?Leu?Glu?Ala?Ser
1940 1945 1950
Ala?Asp?Ala?Asn?Ile?Gln?Asp?Asn?Met?Gly?Arg?Thr?Pro?Leu?His?Ala
1955 1960 1965
Ala?Val?Ser?Ala?Asp?Ala?Gln?Gly?Val?Phe?Gln?Ile?Leu?Ile?Arg?Asn
1970 1975 1980
Arg?Ala?Thr?Asp?Leu?Asp?Ala?Arg?Met?His?Asp?Gly?Thr?Thr?Pro?Leu
1985 1990 1995 2000
Ile?Leu?Ala?Ala?Arg?Leu?Ala?Val?Glu?Gly?Met?Leu?Glu?Asp?Leu?Ile
2005 2010 2015
Asn?Ser?His?Ala?Asp?Val?Asn?Ala?Val?Asp?Asp?Leu?Gly?Lys?Ser?Ala
2020 2025 2030
Leu?His?Trp?Ala?Ala?Ala?Val?Asn?Asn?Val?Asp?Ala?Ala?Val?Val?Leu
2035 2040 2045
Leu?Lys?Asn?Gly?Ala?Asn?Lys?Asp?Met?Gln?Asn?Asn?Arg?Glu?Glu?Thr
2050 2055 2060
Pro?Leu?Phe?Leu?Ala?Ala?Arg?Glu?Gly?Ser?Tyr?Glu?Thr?Ala?Lys?Val
2065 2070 2075 2080
Leu?Leu?Asp?His?Phe?Ala?Asn?Arg?Asp?Ile?Thr?Asp?His?Met?Asp?Arg
2085 2090 2095
Leu?Pro?Arg?Asp?Ile?Ala?Gln?Glu?Arg?Met?His?His?Asp?Ile?Val?Arg
2100 2105 2110
Leu?Leu?Asp?Glu?Tyr?Asn?Leu?Val?Arg?Ser?Pro?Gln?Leu?His?Gly?Ala
2115 2120 2125
Pro?Leu?Gly?Gly?Thr?Pro?Thr?Leu?Ser?Pro?Pro?Leu?Cys?Ser?Pro?Asn
2130 2135 2140
Gly?Tyr?Leu?Gly?Ser?Leu?Lys?Pro?Gly?Val?Gln?Gly?Lys?Lys?Val?Arg
2145 2150 2155 2160
Lys?Pro?Ser?Ser?Lys?Gly?Leu?Ala?Cys?Gly?Ser?Lys?Glu?Ala?Lys?Asp
2165 2170 2175
Leu?Lys?Ala?Arg?Arg?Lys?Lys?Ser?Gln?Asp?Gly?Lys?Gly?Cys?Leu?Leu
2180 2185 2190
Asp?Ser?Ser?Gly?Met?Leu?Ser?Pro?Val?Asp?Ser?Leu?Glu?Ser?Pro?His
2195 2200 2205
Gly?Tyr?Leu?Ser?Asp?Val?Ala?Ser?Pro?Pro?Leu?Leu?Pro?Ser?Pro?Phe
2210 2215 2220
Gln?Gln?Ser?Pro?Ser?Val?Pro?Leu?Asn?His?Leu?Pro?Gly?Met?Pro?Asp
2225 2230 2235 2240
Thr?His?Leu?Gly?Ile?Gly?His?Leu?Asn?Val?Ala?Ala?Lys?Pro?Glu?Met
2245 2250 2255
Ala?Ala?Leu?Gly?Gly?Gly?Gly?Arg?Leu?Ala?Phe?Glu?Thr?Gly?Pro?Pro
2260 2265 2270
Arg?Leu?Ser?His?Leu?Pro?Val?Ala?Ser?Gly?Thr?Ser?Thr?Val?Leu?Gly
2275 2280 2285
Ser?Ser?Ser?Gly?Gly?Ala?Leu?Asn?Phe?Thr?Val?Gly?Gly?Ser?Thr?Ser
2290 2295 2300
Leu?Asn?Gly?Gln?Cys?Glu?Trp?Leu?Ser?Arg?Leu?Gln?Ser?Gly?Met?Val
2305 2310 2315 2320
Pro?Asn?Gln?Tyr?Asn?Pro?Leu?Arg?Gly?Ser?Val?Ala?Pro?Gly?Pro?Leu
2325 2330 2335
Ser?Thr?Gln?Ala?Pro?Ser?Leu?Gln?His?Gly?Met?Val?Gly?Pro?Leu?His
2340 2345 2350
Ser?Ser?Leu?Ala?Ala?Ser?Ala?Leu?Ser?Gln?Met?Met?Ser?Tyr?Gln?Gly
2355 2360 2365
Leu?Pro?Ser?Thr?Arg?Leu?Ala?Thr?Gln?Pro?His?Leu?Val?Gln?Thr?Gln
2370 2375 2380
Gln?Val?Gln?Pro?Gln?Asn?Leu?Gln?Met?Gln?Gln?Gln?Asn?Leu?Gln?Pro
2385 2390 2395 2400
Ala?Asn?Ile?Gln?Gln?Gln?Gln?Ser?Leu?Gln?Pro?Pro?Pro?Pro?Pro?Pro
2405 2410 2415
Gln?Pro?His?Leu?Gly?Val?Ser?Ser?Ala?Ala?Ser?Gly?His?Leu?Gly?Arg
2420 2425 2430
Ser?Phe?Leu?Ser?Gly?Glu?Pro?Ser?Gln?Ala?Asp?Val?Gln?Pro?Leu?Gly
2435 2440 2445
Pro?Ser?Ser?Leu?Ala?Val?His?Thr?Ile?Leu?Pro?Gln?Glu?Ser?Pro?Ala
2450 2455 2460
Leu?Pro?Thr?Ser?Leu?Pro?Ser?Ser?Leu?Val?Pro?Pro?Val?Thr?Ala?Ala
2465 2470 2475 2480
Gln?Phe?Leu?Thr?Pro?Pro?Ser?Gln?His?Ser?Tyr?Ser?Ser?Pro?Val?Asp
2485 2490 2495
Asn?Thr?Pro?Ser?His?Gln?Leu?Gln?Val?Pro?Glu?His?Pro?Phe?Leu?Thr
2500 2505 2510
Pro?Ser?Pro?Glu?Ser?Pro?Asp?Gln?Trp?Ser?Ser?Ser?Ser?Pro?His?Ser
2515 2520 2525
Asn?Val?Ser?Asp?Trp?Ser?Glu?Gly?Val?Ser?Ser?Pro?Pro?Thr?Ser?Met
2530 2535 2540
Gln?Ser?Gln?Ile?Ala?Arg?Ile?Pro?Glu?Ala?Phe?Lys
2545 2550 2555
<210>7
<211>6009
<212>DNA
＜213〉homo sapiens
<400>7
atgcagcccc?cttcactgct?gctgctgctg?ctgctgctgc?tgctatgtgt?ctcagtggtc?60
agacccagag?ggctgctgtg?tgggagtttc?ccagaaccct?gtgccaatgg?aggcacctgc?120
ctgagcctgt?ctctgggaca?agggacctgc?cagtgtgccc?ctggcttcct?gggtgagacg?180
tgccagtttc?ctgacccctg?ccagaacgcc?cagctctgcc?aaaatggagg?cagctgccaa?240
gccctgcttc?ccgctcccct?agggctcccc?agctctccct?ctccattgac?acccagcttc?300
ttgtgcactt?gcctccctgg?cttcactggt?gagagatgcc?aggccaagct?tgaagaccct?360
tgtcctccct?ccttctgttc?caaaaggggc?cgctgccaca?tccaggcctc?gggccgccca?420
cagtgctcct?gcatgcctgg?atggacaggt?gagcagtgcc?agcttcggga?cttctgttca?480
gccaacccat?gtgttaatgg?aggggtgtgt?ctggccacgt?acccccagat?ccagtgccac?540
tgcccaccgg?gcttcgaggg?ccatgcctgt?gaacgtgatg?tcaacgagtg?cttccaggac?600
ccaggaccct?gccccaaagg?cacctcctgc?cataacaccc?tgggctcctt?ccagtgcctc?660
tgccctgtgg?ggcaggaggg?tccacgttgt?gagctgcggg?caggaccctg?ccctcctagg?720
ggctgttcga?atgggggcac?ctgccagctg?atgccagaga?aagactccac?ctttcacctc?780
tgcctctgtc?ccccaggttt?cataggcccg?ggctgtgagg?tgaatccaga?caactgtgtc?840
agccaccaat?gtcagaatgg?gggcacttgc?caggatgggc?tggacaccta?cacctgcctc?900
tgcccagaaa?cctggacagg?ctgggactgc?tccgaagatg?tggatgagtg?tgaggcccag?960
ggtccccctc?actgcagaaa?cgggggcacc?tgccagaact?ctgctggtag?ctttcactgc?1020
gtgtgtgtga?gtggctgggg?gggcacaagc?tgtgaggaga?acctggatga?ctgtattgct?1080
gccacctgtg?ccccgggatc?cacctgcatt?gaccgggtgg?gctctttctc?ctgcctctgc?1140
ccacctggac?gcacaggact?cctgtgccac?ttggaagaca?tgtgtctgag?ccagccgtgc?1200
catggggatg?cccaatgcag?caccaacccc?ctcacaggct?ccacactctg?cctgtgtcag?1260
cctggctatt?cggggcccac?ctgccaccag?gacctggacg?agtgtctgat?ggcccagcaa?1320
ggcccaagtc?cctgtgaaca?tggcggttcc?tgcctcaaca?ctcctggctc?cttcaactgc?1380
ctctgtccac?ctggctacac?aggctcccgt?tgtgaggctg?atcacaatga?gtgcctctcc?1440
cagccctgcc?acccaggaag?cacctgtctg?gacctacttg?ccaccttcca?ctgcctctgc?1500
ccgccaggct?tagaagggca?gctctgtgag?gtggagacca?acgagtgtgc?ctcagctccc?1560
tgcctgaacc?acgcggattg?ccatgacctg?ctcaacggct?tccagtgcat?ctgcctgcct?1620
ggattctccg?gcacccgatg?tgaggaggat?atcgatgagt?gcagaagctc?tccctgtgcc?1680
aatggtgggc?agtgccagga?ccagcctgga?gccttccact?gcaagtgtct?cccaggcttt?1740
gaagggccac?gctgtcaaac?agaggtggat?gagtgcctga?gtgacccatg?tcccgttgga?1800
gccagctgcc?ttgatcttcc?aggagccttc?ttttgcctct?gcccctctgg?tttcacaggc?1860
cagctctgtg?aggttcccct?gtgtgctccc?aacctgtgcc?agcccaagca?gatatgtaag?1920
gaccagaaag?acaaggccaa?ctgcctctgt?cctgatggaa?gccctggctg?tgccccacct?1980
gaggacaact?gcacctgcca?ccacgggcac?tgccagagat?cctcatgtgt?gtgtgacgtg?2040
ggttggacgg?ggccagagtg?tgaggcagag?ctagggggct?gcatctctgc?accctgtgcc?2100
catgggggga?cctgctaccc?ccagccctct?ggctacaact?gcacctgccc?tacaggctac?2160
acaggaccca?cctgtagtga?ggagatgaca?gcttgtcact?cagggccatg?tctcaatggc?2220
ggctcctgca?accctagccc?tggaggctac?tactgcacct?gccctccaag?ccacacaggg?2280
ccccagtgcc?aaaccagcac?tgactactgt?gtgtctgccc?cgtgcttcaa?tgggggtacc?2340
tgtgtgaaca?ggcctggcac?cttctcctgc?ctctgtgcca?tgggctteca?gggcccgcgc?2400
tgtgagggaa?agctccgccc?cagctgtgca?gacagcccct?gtaggaatag?ggcaacctgc?2460
caggacagcc?ctcagggtcc?ccgctgcctc?tgccccactg?gctacaccgg?aggcagctgc?2520
cagactctga?tggacttatg?tgcccagaag?ccctgcccac?gcaattccca?ctgcctccag?2580
actgggccct?ccttccactg?cttgtgcctc?cagggatgga?ccgggcctct?ctgcaacctt?2640
ccactgtcct?cctgccagaa?ggctgcactg?agccaaggca?tagacgtctc?ttccctttgc?2700
cacaatggag?gcctctgtgt?cgacagcggc?ccctcctatt?tctgccactg?cccccctgga?2760
ttccaaggca?gcctgtgcca?ggatcacgtg?aacccatgtg?agtccaggcc?ttgccagaac?2820
ggggccacct?gcatggccca?gcccagtggg?tatctctgcc?agtgtgcccc?aggctacgat?2880
ggacagaact?gctcaaagga?actcgatgct?tgtcagtccc?aaccctgtca?caaccatgga?2940
acctgtactc?ccaaacctgg?aggcttccac?tgtgcctgcc?ctccaggctt?tgtggggcta?3000
cgctgtgagg?gagacgtgga?cgagtgtctg?gaccagccct?gccaccccac?aggcactgca?3060
gcctgccact?ctctggccaa?tgccttctac?tgccagtgtc?tgcctggaca?cacaggccag?3120
tggtgtgagg?tggagataga?cccctgccac?agccaaccct?gctttcatgg?agggacctgt?3180
gaggccacag?caggatcacc?cctgggtttc?atctgccact?gccccaaggg?ttttgaaggc?3240
cccacctgca?gccacagggc?cccttcctgc?ggcttccatc?actgccacca?cggaggcctg?3300
tgtctgccct?cccctaagcc?aggcttccca?ccacgctgtg?cctgcctcag?tggctatggg?3360
ggtcctgact?gcctgacccc?accagctcct?aaaggctgtg?gccctccctc?cccatgccta?3420
tacaatggca?gctgctcaga?gaccacgggc?ttggggggcc?caggctttcg?atgctcctgc?3480
cctcacagct?ctccagggcc?ccggtgtcag?aaacccggag?ccaaggggtg?tgagggcaga?3540
agtggagatg?gggcctgcga?tgctggctgc?agtggcccgg?gaggaaactg?ggatggaggg?3600
gactgctctc?tgggagtccc?agacccctgg?aagggctgcc?cctcccactc?tcggtgctgg?3660
cttctcttcc?gggacgggca?gtgccaccca?cagtgtgact?ctgaagagtg?tctgtttgat?3720
ggctacgact?gtgagacccc?tccagcctgc?actccagcct?atgaccagta?ctgccatgat?3780
cacttccaca?acgggcactg?tgagaaaggc?tgcaacactg?cagagtgtgg?ctgggatgga?3840
ggtgactgca?ggcctgaaga?tggggaccca?gagtgggggc?cctccctggc?cctgctggtg?3900
gtactgagcc?ccccagccct?agaccagcag?ctgtttgccc?tggcccgggt?gctgtccctg?3960
actctgaggg?taggactctg?ggtaaggaag?gatcgtgatg?gcagggacat?ggtgtacccc?4020
tatcctgggg?cccgggctga?agaaaagcta?ggaggaactc?gggaccccac?ctatcaggag?4080
agagcagccc?ctcaaacaca?gcccctgggc?aaggagaccg?actccctcag?tgctgggttt?4140
gtggtggtca?tgggtgtgga?tttgtcccgc?tgtggccctg?accacccggc?atcccgctgt?4200
ccctgggacc?ctgggcttct?actccgcttc?cttgctgcga?tggctgcagt?gggagccctg?4260
gagcccctgc?tgcctggacc?actgctggct?gtccaccctc?atgcagggac?cgcaccccct?4320
gccaaccagc?ttccctggcc?tgtgctgtgc?tccccagtgg?ccggggtgat?tctcctggcc?4380
ctaggggctc?ttctcgtcct?ccagctcatc?cggcgtcgac?gccgagagca?tggagctctc?4440
tggctgcccc?ctggtttcac?tcgacggcct?cggactcagt?cagctcccca?ccgacgccgg?4500
cccccactag?gcgaggacag?cattggtctc?aaggcactga?agccaaaggc?agaagttgat?4560
gaggatggag?ttgtgatgtg?ctcaggccct?gaggagggag?aggaggtggg?ccaggctgaa?4620
gaaacaggcc?caccctccac?gtgccagctc?tggtctctga?gtggtggctg?tggggcgctc?4680
cctcaggcag?ccatgctaac?tcctccccag?gaatctgaga?tggaagcccc?tgacctggac?4740
acccgtggac?ctgatggggt?gacacccctg?atgtcagcag?tttgctgtgg?ggaagtacag?4800
tccgggacct?tccaaggggc?atggttggga?tgtcctgagc?cctgggaacc?tctgctggat?4860
ggaggggcct?gtccccaggc?tcacaccgtg?ggcactgggg?agacccccct?gcacctggct?4920
gcccgattct?cccggccaac?cgctgcccgc?cgcctccttg?aggctggagc?caaccccaac?4980
cagccagacc?gggcagggcg?cacacccctt?catgctgctg?tggctgctga?tgctcgggag?5040
gtctgccagc?ttctgctccg?tagcagacaa?actgcagtgg?acgctcgcac?agaggacggg?5100
accacaccct?tgatgctggc?tgccaggctg?gcggtggaag?acctggttga?agaactgatt?5160
gcagcccaag?cagacgtggg?ggccagagat?aaatggggga?aaactgcgct?gcactgggct?5220
gctgccgtga?acaacgcccg?agccgcccgc?tcgcttctcc?aggccggagc?cgataaagat?5280
gcccaggaca?acagggagca?gacgccgcta?ttcctggcgg?cgcgggaagg?agcggtggaa?5340
gtagcccagc?tactgctggg?gctgggggca?gcccgagagc?tgcgggacca?ggctgggcta?5400
gcgccggcgg?acgtcgctca?ccaacgtaac?cactgggatc?tgctgacgct?gctggaaggg?5460
gctgggccac?cagaggcccg?tcacaaagcc?acgccgggcc?gcgaggctgg?gcccttcccg?5520
cgcgcacgga?cggtgtcagt?aagcgtgccc?ccgcatgggg?gcggggctct?gccgcgctgc?5580
cggacgctgt?cagccggagc?aggccctcgt?gggggcggag?cttgtctgca?ggctcggact?5640
tggtccgtag?acttggctgc?gcgggggggc?ggggcctatt?ctcattgccg?gagcctctcg?5700
ggagtaggag?caggaggagg?cccgacccct?cgcggccgta?ggttttctgc?aggcatgcgc?5760
gggcctcggc?ccaaccctgc?gataatgcga?ggaagatacg?gagtggctgc?cgggcgcgga?5820
ggcagggtct?caacggatga?ctggccctgt?gattgggtgg?ccctgggagc?ttgcggttct?5880
gcctccaaca?ttccgatccc?gcctccttgc?cttactccgt?ccccggagcg?gggatcacct?5940
caacttgact?gtggtccccc?agccctccaa?gaaatgccca?taaaccaagg?aggagagggt?6000
aaaaaatag 6009
<210>8
<211>2003
<212>PRT
＜213〉homo sapiens
<400>8
Met?Gln?Pro?Pro?Ser?Leu?Leu?Leu?Leu?Leu?Leu?Leu?Leu?Leu?Leu?Leu
1 5 10 15
Cys?Val?Ser?Val?Val?Arg?Pro?Arg?Gly?Leu?Leu?Cys?Gly?Ser?Phe?Pro
20 25 30
Glu?Pro?Cys?Ala?Asn?Gly?Gly?Thr?Cys?Leu?Ser?Leu?Ser?Leu?Gly?Gln
35 40 45
Gly?Thr?Cys?Gln?Cys?Ala?Pro?Gly?Phe?Leu?Gly?Glu?Thr?Cys?Gln?Phe
50 55 60
Pro?Asp?Pro?Cys?Gln?Asn?Ala?Gln?Leu?Cys?Gln?Asn?Gly?Gly?Ser?Cys
65 70 75 80
Gln?Ala?Leu?Leu?Pro?Ala?Pro?Leu?Gly?Leu?Pro?Ser?Ser?Pro?Ser?Pro
85 90 95
Leu?Thr?Pro?Ser?Phe?Leu?Cys?Thr?Cys?Leu?Pro?Gly?Phe?Thr?Gly?Glu
100 105 110
Arg?Cys?Gln?Ala?Lys?Leu?Glu?Asp?Pro?Cys?Pro?Pro?Ser?Phe?Cys?Ser
115 120 125
Lys?Arg?Gly?Arg?Cys?His?Ile?Gln?Ala?Ser?Gly?Arg?Pro?Gln?Cys?Ser
130 135 140
Cys?Met?Pro?Gly?Trp?Thr?Gly?Glu?Gln?Cys?Gln?Leu?Arg?Asp?Phe?Cys
145 150 155 160
Ser?Ala?Asn?Pro?Cys?Val?Asn?Gly?Gly?Val?Cys?Leu?Ala?Thr?Tyr?Pro
165 170 175
Gln?Ile?Gln?Cys?His?Cys?Pro?Pro?Gly?Phe?Glu?Gly?His?Ala?Cys?Glu
180 185 190
Arg?Asp?Val?Asn?Glu?Cys?Phe?Gln?Asp?Pro?Gly?Pro?Cys?Pro?Lys?Gly
195 200 205
Thr?Ser?Cys?His?Asn?Thr?Leu?Gly?Ser?Phe?Gln?Cys?Leu?Cys?Pro?Val
210 215 220
Gly?Gln?Glu?Gly?Pro?Arg?Cys?Glu?Leu?Arg?Ala?Gly?Pro?Cys?Pro?Pro
225 230 235 240
Arg?Gly?Cys?Ser?Asn?Gly?Gly?Thr?Cys?Gln?Leu?Met?Pro?Glu?Lys?Asp
245 250 255
Ser?Thr?Phe?His?Leu?Cys?Leu?Cys?Pro?Pro?Gly?Phe?Ile?Gly?Pro?Asp
260 265 270
Cys?Glu?Val?Asn?Pro?Asp?Asn?Cys?Val?Ser?His?Gln?Cys?Gln?Asn?Gly
275 280 285
Gly?Thr?Cys?Gln?Asp?Gly?Leu?Asp?Thr?Tyr?Thr?Cys?Leu?Cys?Pro?Glu
290 295 300
Thr?Trp?Thr?Gly?Trp?Asp?Cys?Ser?Glu?Asp?Val?Asp?Glu?Cys?Glu?Thr
305 310 315 320
Gln?Gly?Pro?Pro?His?Cys?Arg?Asn?Gly?Gly?Thr?Cys?Gln?Asn?Ser?Ala
325 330 335
Gly?Ser?Phe?His?Cys?Val?Cys?Val?Ser?Gly?Trp?Gly?Gly?Thr?Ser?Cys
340 345 350
Glu?Glu?Asn?Leu?Asp?Asp?Cys?Ile?Ala?Ala?Thr?Cys?Ala?Pro?Gly?Ser
355 360 365
Thr?Cys?Ile?Asp?Arg?Val?Gly?Ser?Phe?Ser?Cys?Leu?Cys?Pro?Pro?Gly
370 375 380
Arg?Thr?Gly?Leu?Leu?Cys?His?Leu?Glu?Asp?Met?Cys?Leu?Ser?Gln?Pro
385 390 395 400
Cys?His?Gly?Asp?Ala?Gln?Cys?Ser?Thr?Asn?Pro?Leu?Thr?Gly?Ser?Thr
405 410 415
Leu?Cys?Leu?Cys?Gln?Pro?Gly?Tyr?Ser?Gly?Pro?Thr?Cys?His?Gln?Asp
420 425 430
Leu?Asp?Glu?Cys?Leu?Met?Ala?Gln?Gln?Gly?Pro?Ser?Pro?Cys?Glu?His
435 440 445
Gly?Gly?Ser?Cys?Leu?Asn?Thr?Pro?Gly?Ser?Phe?Asn?Cys?Leu?Cys?Pro
450 455 460
Pro?Gly?Tyr?Thr?Gly?Ser?Arg?Cys?Glu?Ala?Asp?His?Asn?Glu?Cys?Leu
465 470 475 480
Ser?Gln?Pro?Cys?His?Pro?Gly?SerThr?Cys?Leu?Asp?Leu?Leu?Ala?Thr
485 490 495
Phe?His?Cys?Leu?Cys?Pro?Pro?Gly?Leu?Glu?Gly?Gln?Leu?Cys?Glu?Val
500 505 510
Glu?Thr?Asn?Glu?Cys?Ala?Ser?Ala?Pro?Cys?Leu?Asn?His?Ala?Asp?Cys
515 520 525
His?Asp?Leu?Leu?Asn?Gly?Phe?Gln?Cys?Ile?Cys?Leu?Pro?Gly?Phe?Ser
530 535 540
Gly?Thr?Arg?Cys?Glu?Glu?Asp?Ile?Asp?Glu?Cys?Arg?Ser?Ser?Pro?Cys
545 550 555 560
Ala?Asn?Gly?Gly?Gln?Cys?Gln?Asp?Gln?Pro?Gly?Ala?Phe?His?Cys?Lys
565 570 575
Cys?Leu?Pro?Gly?Phe?Glu?Gly?Pro?Arg?Cys?Gln?Thr?Glu?Val?Asp?Glu
580 585 590
Cys?Leu?Ser?Asp?Pro?Cys?Pro?Val?Gly?Ala?Ser?Cys?Leu?Asp?Leu?Pro
595 600 605
Gly?Ala?Phe?Phe?Cys?Leu?Cys?Pro?Ser?Gly?Phe?Thr?Gly?Gln?Leu?Cys
610 615 620
Glu?Val?Pro?Leu?Cys?Ala?Pro?Asn?Leu?Cys?Gln?Pro?Lys?Gln?Ile?Cys
625 630 635 640
Lys?Asp?Gln?Lys?Asp?Lys?Ala?Asn?Cys?Leu?Cys?Pro?Asp?Gly?Ser?Pro
645 650 655
Gly?Cys?Ala?Pro?Pro?Glu?Asp?Asn?Cys?Thr?Cys?His?His?Gly?His?Cys
660 665 670
Gln?Arg?Ser?Ser?Cys?Val?Cys?Asp?Val?Gly?Trp?Thr?Gly?Pro?Glu?Cys
675 680 685
Glu?Ala?Glu?Leu?Gly?Gly?Cys?Ile?Ser?Ala?Pro?Cys?Ala?His?Gly?Gly
690 695 700
Thr?Cys?Tyr?Pro?Gln?Pro?Ser?Gly?Tyr?Asn?Cys?Thr?Cys?Pro?Thr?Gly
705 710 715 720
Tyr?Thr?Gly?Pro?Thr?Cys?Ser?Glu?Glu?Met?Thr?Ala?Cys?His?Ser?Gly
725 730 735
Pro?Cys?Leu?Asn?Gly?Gly?Ser?Cys?Asn?Pro?Ser?Pro?Gly?Gly?Tyr?Tyr
740 745 750
Cys?Thr?Cys?Pro?Pro?Ser?His?Thr?Gly?Pro?Gln?Cys?Gln?Thr?Ser?Thr
755 760 765
Asp?Tyr?Cys?Val?Ser?Ala?Pro?Cys?Phe?Asn?Gly?Gly?Thr?Cys?Val?Asn
770 775 780
Arg?Pro?Gly?Thr?Phe?Ser?Cys?Leu?Cys?Ala?Met?Gly?Phe?Gln?Gly?Pro
785 790 795 800
Arg?Cys?Glu?Gly?Lys?Leu?Arg?Pro?Ser?Cys?Ala?Asp?Ser?Pro?Cys?Arg
805 810 815
Asn?Arg?Ala?Thr?Cys?Gln?Asp?Ser?Pro?Gln?Gly?Pro?Arg?Cys?Leu?Cys
820 825 830
Pro?Thr?Gly?Tyr?Thr?Gly?Gly?Ser?Cys?Gln?Thr?Leu?Met?Asp?Leu?Cys
835 840 845
Ala?Gln?Lys?Pro?Cys?Pro?Arg?Asn?Ser?His?Cys?Leu?Gln?Thr?Gly?Pro
850 855 860
Ser?Phe?His?Cys?Leu?Cys?Leu?Gln?Gly?Trp?Thr?Gly?Pro?Leu?Cys?Asn
865 870 875 880
Leu?Pro?Leu?Ser?Ser?Cys?Gln?Lys?Ala?Ala?Leu?Ser?Gln?Gly?Ile?Asp
885 890 895
Val?Ser?Ser?Leu?Cys?His?Asn?Gly?Gly?Leu?Cys?Val?Asp?Ser?Gly?Pro
900 905 910
Ser?Tyr?Phe?Cys?His?Cys?Pro?Pro?Gly?Phe?Gln?Gly?Ser?Leu?Cys?Gln
915 920 925
Asp?His?Val?Asn?Pro?Cys?Glu?Ser?Arg?Pro?Cys?Gln?Asn?Gly?Ala?Thr
930 935 940
Cys?Met?Ala?Gln?Pro?Ser?Gly?Tyr?Leu?Cys?Gln?Cys?Ala?Pro?Gly?Tyr
945 950 955 960
Asp?Gly?Gln?Asn?Cys?Ser?Lys?Glu?Leu?Asp?Ala?Cys?Gln?Ser?Gln?Pro
965 970 975
Cys?His?Asn?His?Gly?Thr?Cys?Thr?Pro?Lys?Pro?Gly?Gly?Phe?His?Cys
980 985 990
Ala?Cys?Pro?Pro?Gly?Phe?Val?Gly?Leu?Arg?Cys?Glu?Gly?Asp?Val?Asp
995 1000 1005
Glu?Cys?Leu?Asp?Gln?Pro?Cys?His?Pro?Thr?Gly?Thr?Ala?Ala?Cys?His
1010 1015 1020
Ser?Leu?Ala?Asn?Ala?Phe?Tyr?Cys?Gln?Cys?Leu?Pro?Gly?His?Thr?Gly
1025 1030 1035 1040
Gln?Trp?Cys?Glu?Val?Glu?Ile?Asp?Pro?Cys?His?Ser?Gln?Pro?Cys?Phe
1045 1050 1055
His?Gly?Gly?Thr?Cys?Glu?Ala?Thr?Ala?Gly?Ser?Pro?Leu?Gly?Phe?Ile
1060 1065 1070
Cys?His?Cys?Pro?Lys?Gly?Phe?Glu?Gly?Pro?Thr?Cys?Ser?His?Arg?Ala
1075 1080 1085
Pro?Ser?Cys?Gly?Phe?His?His?Cys?His?His?Gly?Gly?Leu?Cys?Leu?Pro
1090 1095 1100
Ser?Pro?Lys?Pro?Gly?Phe?Pro?Pro?Arg?Cys?Ala?Cys?Leu?Ser?Gly?Tyr
1105 1110 1115 1120
Gly?Gly?Pro?Asp?Cys?Leu?Thr?Pro?Pro?Ala?Pro?Lys?Gly?Cys?Gly?Pro
1125 1130 1135
Pro?Ser?Pro?Cys?Leu?Tyr?Asn?Gly?Ser?Cys?Ser?Glu?Thr?Thr?Gly?Leu
1140 1145 1150
Gly?Gly?Pro?Gly?Phe?Arg?Cys?Ser?Cys?Pro?His?Ser?Ser?Pro?Gly?Pro
1155 1160 1165
Arg?Cys?Gln?Lys?Pro?Gly?Ala?Lys?Gly?Cys?Glu?Gly?Arg?Ser?Gly?Asp
1170 1175 1180
Gly?Ala?Cys?Asp?Ala?Gly?Cys?Ser?Gly?Pro?Gly?Gly?Asn?Trp?Asp?Gly
1185 1190 1195 1200
Gly?Asp?Cys?Ser?Leu?Gly?Val?Pro?Asp?Pro?Trp?Lys?Gly?Cys?Pro?Ser
1205 1210 1215
His?Ser?Arg?Cys?Trp?Leu?Leu?Phe?Arg?Asp?Gly?Gln?Cys?His?Pro?Gln
1220 1225 1230
Cys?Asp?Ser?Glu?Glu?Cys?Leu?Phe?Asp?Gly?Tyr?Asp?Cys?Glu?Thr?Pro
1235 1240 1245
Pro?Ala?Cys?Thr?Pro?Ala?Tyr?Asp?Gln?Tyr?Cys?His?Asp?His?Phe?His
1250 1255 1260
Asn?Gly?His?Cys?Glu?Lys?Gly?Cys?Asn?Thr?Ala?Glu?Cys?Gly?Trp?Asp
1265 1270 1275 1280
Gly?Gly?Asp?Cys?Arg?Pro?Glu?Asp?Gly?Asp?Pro?Glu?Trp?Gly?Pro?Ser
1285 1290 1295
Leu?Ala?Leu?Leu?Val?Val?Leu?Ser?Pro?Pro?Ala?Leu?Asp?Gln?Gln?Leu
1300 1305 1310
Phe?Ala?Leu?Ala?Arg?Val?Leu?Ser?Leu?Thr?Leu?Arg?Val?Gly?Leu?Trp
1315 1320 1325
Val?Arg?Lys?Asp?Arg?Asp?Gly?Arg?Asp?Met?Val?Tyr?Pro?Tyr?Pro?Gly
1330 1335 1340
Ala?Arg?Ala?Glu?Glu?Lys?Leu?Gly?Gly?Thr?Arg?Asp?Pro?Thr?Tyr?Gln
1345 1350 1355 1360
Glu?Arg?Ala?Ala?Pro?Gln?Thr?Gln?Pro?Leu?Gly?Lys?Glu?Thr?Asp?Ser
1365 1370 1375
Leu?Ser?Ala?Gly?Phe?Val?Val?Val?Met?Gly?Val?Asp?Leu?Ser?Arg?Cys
1380 1385 1390
Gly?Pro?Asp?His?Pro?Ala?Ser?Arg?Cys?Pro?Trp?Asp?Pro?Gly?Leu?Leu
1395 1400 1405
Leu?Arg?Phe?Leu?Ala?Ala?Met?Ala?Ala?Val?Gly?Ala?Leu?Glu?Pro?Leu
1410 1415 1420
Leu?Pro?Gly?Pro?Leu?Leu?Ala?Val?His?Pro?His?Ala?Gly?Thr?Ala?Pro
1425 1430 1435 1440
Pro?Ala?Asn?Gln?Leu?Pro?Trp?Pro?Val?Leu?Cys?Ser?Pro?Val?Ala?Gly
1445 1450 1455
Val?Ile?Leu?Leu?Ala?Leu?Gly?Ala?Leu?Leu?Val?Leu?Gln?Leu?Ile?Arg
1460 1465 1470
Arg?Arg?Arg?Arg?Glu?His?Gly?Ala?Leu?Trp?Leu?Pro?Pro?Gly?Phe?Thr
1475 1480 1485
Arg?Arg?Pro?Arg?Thr?Gln?Ser?Ala?Pro?His?Arg?Arg?Arg?Pro?Pro?Leu
1490 1495 1500
Gly?Glu?Asp?Ser?Ile?Gly?Leu?Lys?Ala?Leu?Lys?Pro?Lys?Ala?Glu?Val
1505 1510 1515 1520
Asp?Glu?Asp?Gly?Val?Val?Met?Cys?Ser?Gly?Pro?Glu?Glu?Gly?Glu?Glu
1525 1530 1535
Val?Gly?Gln?Ala?Glu?Glu?Thr?Gly?Pro?Pro?Ser?Thr?Cys?Gln?Leu?Trp
1540 1545 1550
Ser?Leu?Ser?Gly?Gly?Cys?Gly?Ala?Leu?Pro?Gln?Ala?Ala?Met?Leu?Thr
1555 1560 1565
Pro?Pro?Gln?Glu?Ser?Glu?Met?Glu?Ala?Pro?Asp?Leu?Asp?Thr?Arg?Gly
1570 1575 1580
Pro?Asp?Gly?Val?Thr?Pro?Leu?Met?Ser?Ala?Val?Cys?Cys?Gly?Glu?Val
1585 1590 1595 1600
Gln?Ser?Gly?Thr?Phe?Gln?Gly?Ala?Trp?Leu?Gly?Cys?Pro?Glu?Pro?Trp
1605 1610 1615
Glu?Pro?Leu?Leu?Asp?Gly?Gly?Ala?Cys?Pro?Gln?Ala?His?Thr?Val?Gly
1620 1625 1630
Thr?Gly?Glu?Thr?Pro?Leu?His?Leu?Ala?Ala?Arg?Phe?Ser?Arg?Pro?Thr
1635 1640 1645
Ala?Ala?Arg?Arg?Leu?Leu?Glu?Ala?Gly?Ala?Asn?Pro?Asn?Gln?Pro?Asp
1650 1655 1660
Arg?Ala?Gly?Arg?Thr?Pro?Leu?His?Ala?Ala?Val?Ala?Ala?Asp?Ala?Arg
1665 1670 1675 1680
Glu?Val?Cys?Gln?Leu?Leu?Leu?Arg?Ser?Arg?Gln?Thr?Ala?Val?Asp?Ala
1685 1690 1695
Arg?Thr?Glu?Asp?Gly?Thr?Thr?Pro?Leu?Met?Leu?Ala?Ala?Arg?Leu?Ala
1700 1705 1710
Val?Glu?Asp?Leu?Val?Glu?Glu?Leu?Ile?Ala?Ala?Gln?Ala?Asp?Val?Gly
1715 1720 1725
Ala?Arg?Asp?Lys?Trp?Gly?Lys?Thr?Ala?Leu?His?Trp?Ala?Ala?Ala?Val
1730 1735 1740
Asn?Asn?Ala?Arg?Ala?Ala?Arg?Ser?Leu?Leu?Gln?Ala?Gly?Ala?Asp?Lys
1745 1750 1755 1760
Asp?Ala?Gln?Asp?Asn?Arg?Glu?Gln?Thr?Pro?Leu?Phe?Leu?Ala?Ala?Arg
1765 1770 1775
Glu?Gly?Ala?Val?Glu?Val?Ala?Gln?Leu?Leu?Leu?Gly?Leu?Gly?Ala?Ala
1780 1785 1790
Arg?Glu?Leu?Arg?Asp?Gln?Ala?Gly?Leu?Ala?Pro?Ala?Asp?Val?Ala?His
1795 1800 1805
Gln?Arg?Asn?His?Trp?Asp?Leu?Leu?Thr?Leu?Leu?Glu?Gly?Ala?Gly?Pro
1810 1815 1820
Pro?Glu?Ala?Arg?His?Lys?Ala?Thr?Pro?Gly?Arg?Glu?Ala?Gly?Pro?Phe
1825 1830 1835 1840
Pro?Arg?Ala?Arg?Thr?Val?Ser?Val?Ser?Val?Pro?Pro?His?Gly?Gly?Gly
1845 1850 1855
Ala?Leu?Pro?Arg?Cys?Arg?Thr?Leu?Ser?Ala?Gly?Ala?Gly?Pro?Arg?Gly
1860 1865 1870
Gly?Gly?Ala?Cys?Leu?Gln?Ala?Arg?Thr?Trp?Ser?Val?Asp?Leu?Ala?Ala
1875 1880 1885
Arg?Gly?Gly?Gly?Ala?Tyr?Ser?His?Cys?Arg?Ser?Leu?Ser?Gly?Val?Gly
1890 1895 1900
Ala?Gly?Gly?Gly?Pro?Thr?Pro?Arg?Gly?Arg?Arg?Phe?Ser?Ala?Gly?Met
1905 1910 1915 1920
Arg?Gly?Pro?Arg?Pro?Asn?Pro?Ala?Ile?Met?Arg?Gly?Arg?Tyr?Gly?Val
1925 1930 1935
Ala?Ala?Gly?Arg?Gly?Gly?Arg?Val?Ser?Thr?Asp?Asp?Trp?Pro?Cys?Asp
1940 1945 1950
Trp?Val?Ala?Leu?Gly?Ala?Cys?Gly?Ser?Ala?Ser?Asn?Ile?Pro?Ile?Pro
1955 1960 1965
Pro?Pro?Cys?Leu?Thr?Pro?Ser?Pro?Glu?Arg?Gly?Ser?Pro?Gln?Leu?Asp
1970 1975 1980
Cys?Gly?Pro?Pro?Ala?Leu?Gln?Glu?Met?Pro?Ile?Asn?Gln?Gly?Gly?Glu
1985 1990 1995 2000
Gly?Lys?Lys
<210>9
<211>19
<212>DNA
＜213〉mice
<400>9
gaggtccaag?ccgaacctg 19
<210>10
<211>21
<212>DNA
＜213〉mice
<400>10
atcgctgatg?tgcagttcac?a 21
<210>11
<211>20
<212>DNA
＜213〉mice
<400>11
cgctgccggc?ctggattcac 20
<210>12
<211>18
<212>DNA
＜213〉mice
<400>12
gatgcaagcc?cggaagaa 18
<210>13
<211>22
<212>DNA
＜213〉mice
<400>13
tcgcaattca?gaaaggctac?tg 22
<210>14
<211>17
<212>DNA
＜213〉mice
<400>14
cgcagaggga?tcataga 17
<210>15
<211>19
<212>DNA
＜213〉mice
<400>15
ctacacatcg?ccgctttcg 19
<210>16
<211>18
<212>DNA
＜213〉mice
<400>16
cgcgtacttg?gccttggt 18
<210>17
<211>15
<212>DNA
＜213〉mice
<400>17
ccaccaggac?atcgt 15
<210>18
<211>530
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>18
Met?Thr?Pro?Ala?Ser?Arg?Ser?Ala?Cys?Arg?Trp?Ala?Leu?Leu?Leu?Leu
1 5 10 15
Ala?Val?Leu?Trp?Pro?Gln?Gln?Arg?Ala?Ala?Gly?Ser?Gly?Ile?Phe?Gln
20 25 30
Leu?Arg?Leu?Gln?Glu?Phe?Val?Asn?Gln?Arg?Gly?Met?Leu?Ala?Asn?Gly
35 40 45
Gln?Ser?Cys?Glu?Pro?Gly?Cys?Arg?Thr?Phe?Phe?Arg?Ile?Cys?Leu?Lys
50 55 60
His?Phe?Gln?Ala?Thr?Phe?Ser?Glu?Gly?Pro?Cys?Thr?Phe?Gly?Asn?Val
65 70 75 80
Ser?Thr?Pro?Val?Leu?Gly?Thr?Asn?Ser?Phe?Val?Val?Arg?Asp?Lys?Asn
85 90 95
Ser?Gly?Ser?Gly?Arg?Asn?Pro?Leu?Gln?Leu?Pro?Phe?Asn?Phe?Thr?Trp
100 105 110
Pro?Gly?Thr?Phe?Ser?Leu?Asn?Ile?Gln?Ala?Trp?His?Thr?Pro?Gly?Asp
115 120 125
Asp?Leu?Arg?Pro?Glu?Thr?Ser?Pro?Gly?Asn?Ser?Leu?Ile?Ser?Gln?Ile
130 135 140
Ile?Ile?Gln?Gly?Ser?Leu?Ala?Val?Gly?Lys?Ile?Trp?Arg?Thr?Asp?Glu
145 150 155 160
Gln?Asn?Asp?Thr?Leu?Thr?Arg?Leu?Ser?Tyr?Ser?Tyr?Arg?Val?Ile?Cys
165 170 175
Ser?Asp?Asn?Tyr?Tyr?Gly?Glu?Ser?Cys?Ser?Arg?Leu?Cys?Lys?Lys?Arg
180 185 190
Asp?Asp?His?Phe?Gly?His?Tyr?Glu?Cys?Gln?Pro?Asp?Gly?Ser?Leu?Ser
195 200 205
Cys?Leu?Pro?Gly?Trp?Thr?Gly?Lys?Tyr?Cys?Asp?Gln?Pro?Ile?Cys?Leu
210 215 220
Ser?Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys?Ser?Lys?Pro?Asp?Glu?Cys
225 230 235 240
Ile?Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu?Cys?Asn?Glu?Cys?Ile?Pro
245 250 255
His?Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser?Ile?Pro?Trp?Gln?Cys?Ala
260 265 270
Cys?Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys?Asp?Gln?Asp?Leu?Asn?Tyr
275 280 285
Cys?Thr?His?His?Ser?Pro?Cys?Lys?Asn?Gly?Ser?Thr?Cys?Ser?Asn?Ser
290 295 300
Gly?Pro?Lys?Gly?Tyr?Thr?Cys?Thr?Cys?Leu?Pro?Gly?Tyr?Thr?Gly?Glu
305 310 315 320
His?Cys?Glu?Leu?Gly?Leu?Ser?Lys?Cys?Ala?Ser?Asn?Pro?Cys?Arg?Asn
325 330 335
Gly?Gly?Ser?Cys?Lys?Asp?Gln?Glu?Asn?Ser?Tyr?His?Cys?Leu?Cys?Pro
340 345 350
Pro?Gly?Tyr?Tyr?Gly?Gln?His?Cys?Glu?His?Ser?Thr?Leu?Thr?Cys?Ala
355 360 365
Asp?Ser?Pro?Cys?Phe?Asn?Gly?Gly?Ser?Cys?Arg?Glu?Arg?Asn?Gln?Gly
370 375 380
Ser?Ser?Tyr?Ala?Cys?Glu?Cys?Pro?Pro?Asn?Phe?Thr?Gly?Ser?Asn?Cys
385 390 395 400
Glu?Lys?Lys?Val?Asp?Arg?Cys?Thr?Ser?Asn?Pro?Cys?Ala?Asn?Gly?Gly
405 410 415
Gln?Cys?Leu?Asn?Arg?Gly?Pro?Ser?Arg?Thr?Cys?Arg?Cys?Arg?Pro?Gly
420 425 430
Phe?Thr?Gly?Thr?His?Cys?Glu?Leu?His?Ile?Ser?Asp?Cys?Ala?Arg?Ser
435 440 445
Pro?Cys?Ala?His?Gly?Gly?Thr?Cys?His?Asp?Leu?Glu?Asn?Gly?Pro?Val
450 455 460
Cys?Thr?Cys?Pro?Ala?Gly?Phe?Ser?Gly?Arg?Arg?Cys?Glu?Val?Arg?Ile
465 470 475 480
Thr?His?Asp?Ala?Cys?Ala?Ser?Gly?Pro?Cys?Phe?Asn?Gly?Ala?Thr?Cys
485 490 495
Tyr?Thr?Gly?Leu?Ser?Pro?Asn?Asn?Phe?Val?Cys?Asn?Cys?Pro?Tyr?Gly
500 505 510
Phe?Val?Gly?Ser?Arg?Cys?Glu?Phe?Pro?Val?Gly?Leu?Pro?Pro?Ser?Phe
515 520 525
Pro?Trp
530
<210>19
<211>458
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>19
Met?Val?Ser?Tyr?Trp?Asp?Thr?Gly?Val?Leu?Leu?Cys?Ala?Leu?Leu?Ser
1 5 10 15
Cys?Leu?Leu?Leu?Thr?Gly?Ser?Ser?Ser?Gly?Ser?Asp?Thr?Gly?Arg?Pro
20 25 30
Phe?Val?Glu?Met?Tyr?Ser?Glu?Ile?Pro?Glu?Ile?Ile?His?Met?Thr?Glu
35 40 45
Gly?Arg?Glu?Leu?Val?Ile?Pro?Cys?Arg?Val?Thr?Ser?Pro?Asn?Ile?Thr
50 55 60
Val?Thr?Leu?Lys?Lys?Phe?Pro?Leu?Asp?Thr?Leu?Ile?Pro?Asp?Gly?Lys
65 70 75 80
Arg?Ile?Ile?Trp?Asp?Ser?Arg?Lys?Gly?Phe?Ile?Ile?Ser?Asn?Ala?Thr
85 90 95
Tyr?Lys?Glu?Ile?Gly?Leu?Leu?Thr?Cys?Glu?Ala?Thr?Val?Asn?Gly?His
100 105 110
Leu?Tyr?Lys?Thr?Asn?Tyr?Leu?Thr?His?Arg?Gln?Thr?Asn?Thr?Ile?Ile
115 120 125
Asp?Val?Val?Leu?Ser?Pro?Ser?His?Gly?Ile?Glu?Leu?Ser?Val?Gly?Glu
130 135 140
Lys?Leu?Val?Leu?Asn?Cys?Thr?Ala?Arg?Thr?Glu?Leu?Asn?Val?Gly?Ile
145 150 155 160
Asp?Phe?Asn?Trp?Glu?Tyr?Pro?Ser?Ser?Lys?His?Gln?His?Lys?Lys?Leu
165 170 175
Val?Asn?Arg?Asp?Leu?Lys?Thr?Gln?Ser?Gly?Ser?Glu?Met?Lys?Lys?Phe
180 185 190
Leu?Ser?Thr?Leu?Thr?Ile?Asp?Gly?Val?Thr?Arg?Ser?Asp?Gln?Gly?Leu
195 200 205
Tyr?Thr?Cys?Ala?Ala?Ser?Ser?Gly?Leu?Met?Thr?Lys?Lys?Asn?Ser?Thr
210 215 220
Phe?Val?Arg?Val?His?Glu?Lys?Asp?Lys?Thr?His?Thr?Cys?Pro?Pro?Cys
225 230 235 240
Pro?Ala?Pro?Glu?Leu?Leu?Gly?Gly?Pro?Ser?Val?Phe?Leu?Phe?Pro?Pro
245 250 255
Lys?Pro?Lys?Asp?Thr?Leu?Met?Ile?Ser?Arg?Thr?Pro?Glu?Val?Thr?Cys
260 265 270
Val?Val?Val?Asp?Val?Ser?His?Glu?Asp?Pro?Glu?Val?Lys?Phe?Asn?Trp
275 280 285
Tyr?Val?Asp?Gly?Val?Glu?Val?His?Asn?Ala?Lys?Thr?Lys?Pro?Arg?Glu
290 295 300
Glu?Gln?Tyr?Asn?Ser?Thr?Tyr?Arg?Val?Val?Ser?Val?Leu?Thr?Val?Leu
305 310 315 320
His?Gln?Asp?Trp?Leu?Asn?Gly?Lys?Glu?Tyr?Lys?Cys?Lys?Val?Ser?Asn
325 330 335
Lys?Ala?Leu?Pro?Ala?Pro?Ile?Glu?Lys?Thr?Ile?Ser?Lys?Ala?Lys?Gly
340 345 350
Gln?Pro?Arg?Glu?Pro?Gln?Val?Tyr?Thr?Leu?Pro?Pro?Ser?Arg?Asp?Glu
355 360 365
Leu?Thr?Lys?Asn?Gln?Val?Ser?Leu?Thr?Cys?Leu?Val?Lys?Gly?Phe?Tyr
370 375 380
Pro?Ser?AspIle?Ala?Val?Glu?Trp?Glu?Ser?Asn?Gly?Gln?Pro?Glu?Asn
385 390 395 400
Asn?Tyr?Lys?Thr?Thr?Pro?Pro?Val?Leu?Asp?Ser?Asp?Gly?Ser?Phe?Phe
405 410 415
Leu?Tyr?Ser?Lys?Leu?Thr?Val?Asp?Lys?Ser?Arg?Trp?Gln?Gln?Gly?Asn
420 425 430
Val?Phe?Ser?Cys?Ser?Val?Met?His?Glu?Ala?Leu?His?Asn?His?Tyr?Thr
435 440 445
Gln?Lys?Ser?Leu?Ser?Leu?Ser?Pro?Gly?Lys
450 455
<210>20
<211>227
<212>PRT
＜213〉homo sapiens s
<400>20
Asp?Lys?Thr?His?Thr?Cys?Pro?Pro?Cys?Pro?Ala?Pro?Glu?Leu?Leu?Gly
1 5 10 15
Gly?Pro?Ser?Val?Phe?Leu?Phe?Pro?Pro?Lys?Pro?Lys?Asp?Thr?Leu?Met
20 25 30
Ile?Ser?Arg?Thr?Pro?Glu?Val?Thr?Cys?Val?Val?Val?Asp?Val?Ser?His
35 40 45
Glu?Asp?Pro?Glu?Val?Lys?Phe?Asn?Trp?Tyr?Val?Asp?Gly?Val?Glu?Val
50 55 60
His?Asn?Ala?Lys?Thr?Lys?Pro?Arg?Glu?Glu?Gln?Tyr?Asn?Ser?Thr?Tyr
65 70 75 80
Arg?Val?Val?Ser?Val?Leu?Thr?Val?Leu?His?Gln?Asp?Trp?Leu?Asn?Gly
85 90 95
Lys?Glu?Tyr?Lys?Cys?Lys?Val?Ser?Asn?Lys?Ala?Leu?Pro?Ala?Pro?Ile
100 105 110
Glu?Lys?Thr?Ile?Ser?Lys?Ala?Lys?Gly?Gln?Pro?Arg?Glu?Pro?Gln?Val
115 120 125
Tyr?Thr?Leu?Pro?Pro?Ser?Arg?Asp?Glu?Leu?Thr?Lys?Asn?Gln?Val?Ser
130 135 140
Leu?Thr?Cys?Leu?Val?Lys?Gly?Phe?Tyr?Pro?Ser?Asp?Ile?Ala?Val?Glu
145 150 155 160
Trp?Glu?Ser?Asn?Gly?Gln?Pro?Glu?Asn?Asn?Tyr?Lys?Thr?Thr?Pro?Pro
165 170 175
Val?Leu?Asp?Ser?Asp?Gly?Ser?Phe?Phe?Leu?Tyr?Ser?Lys?Leu?Thr?Val
180 185 190
Asp?Lys?Ser?Arg?Trp?Gln?Gln?Gly?Asn?Val?Phe?Ser?Cys?Ser?Val?Met
195 200 205
His?Glu?Ala?Leu?His?Asn?His?Tyr?Thr?Gln?Lys?Ser?Leu?Ser?Leu?Ser
210 215 220
Pro?Gly?Lys
225
<210>21
<211>272
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>21
Val?Ile?Cys?Ser?Asp?Asn?Tyr?Tyr?Gly?Asp?Asn?Cys?Ser?Arg?Leu?Cys
1 5 10 15
Lys?Lys?Arg?Asn?Asp?His?Phe?Gly?His?Tyr?Val?Cys?Gln?Pro?Asp?Gly
20 25 30
Asn?Leu?Ser?Cys?Leu?Pro?Gly?Trp?Thr?Gly?Glu?Tyr?Cys?Asp?Lys?Thr
35 40 45
His?Thr?Cys?Pro?Pro?Cys?Pro?Ala?Pro?Glu?Leu?Leu?Gly?Gly?Pro?Ser
50 55 60
Val?Phe?Leu?Phe?Pro?Pro?Lys?Pro?Lys?Asp?Thr?Leu?Met?Ile?Ser?Arg
65 70 75 80
Thr?Pro?Glu?Val?Thr?Cys?Val?Val?Val?Asp?Val?Ser?His?Glu?Asp?Pro
85 90 95
Glu?Val?Lys?Phe?Asn?Trp?Tyr?Val?Asp?Gly?Val?Glu?Val?His?Asn?Ala
100 105 110
Lys?Thr?Lys?Pro?Arg?Glu?Glu?Gln?Tyr?Asn?Ser?Thr?Tyr?Arg?Val?Val
115 120 125
Ser?Val?Leu?Thr?Val?Leu?His?Gln?Asp?Trp?Leu?Asn?Gly?Lys?Glu?Tyr
130 135 140
Lys?Cys?Lys?Val?Ser?Asn?Lys?Ala?Leu?Pro?Ala?Pro?Ile?Glu?Lys?Thr
145 150 155 160
Ile?Ser?Lys?Ala?Lys?Gly?Gln?Pro?Arg?Glu?Pro?Gln?Val?Tyr?Thr?Leu
165 170 175
Pro?Pro?Ser?Arg?Asp?Glu?Leu?Thr?Lys?Asn?Gln?Val?Ser?Leu?Thr?Cys
180 185 190
Leu?Val?Lys?Gly?Phe?Tyr?Pro?Ser?Asp?Ile?Ala?Val?Glu?Trp?Glu?Ser
195 200 205
Asn?Gly?Gln?Pro?GluAsn?Asn?Tyr?Lys?Thr?Thr?Pro?Pro?Val?Leu?Asp
210 215 220
Ser?Asp?Gly?SerPhe?Phe?Leu?Tyr?Ser?Lys?Leu?Thr?Val?Asp?Lys?Ser
225 230 235 240
Arg?Trp?Gln?Gln?Gly?Asn?Val?Phe?Ser?Cys?Ser?Val?Met?His?Glu?Ala
245 250 255
Leu?His?Asn?His?Tyr?Thr?Gln?Lys?Ser?Leu?Ser?Leu?Ser?Pro?Gly?Lys
260 265 270
<210>22
<211>418
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>22
Ser?Gly?Val?Phe?Gln?Leu?Gln?Leu?Gln?Glu?Phe?Ile?Asn?Glu?Arg?Gly
1 5 10 15
Val?Leu?Ala?Ser?Gly?Arg?Pro?Cys?Glu?Pro?Gly?Cys?Arg?Thr?Phe?Phe
20 25 30
Arg?Val?Cys?Leu?Lys?His?Phe?Gln?Ala?Val?Val?Ser?Pro?Gly?Pro?Cys
35 40 45
Thr?Phe?Gly?Thr?Val?Ser?Thr?Pro?Val?Leu?Gly?Thr?Asn?Ser?Phe?Ala
50 55 60
Val?Arg?Asp?Asp?Ser?Ser?Gly?Gly?Gly?Arg?Asn?Pro?Leu?Gln?Leu?Pro
65 70 75 80
Phe?Asn?Phe?Thr?Trp?Pro?Gly?Thr?Phe?Ser?Leu?Ile?Ile?Glu?Ala?Trp
85 90 95
His?Ala?Pro?Gly?Asp?Asp?Leu?Arg?Pro?Glu?Ala?Leu?Pro?Pro?Asp?Ala
100 105 110
Leu?Ile?Ser?Lys?Ile?Ala?Ile?Gln?Gly?Ser?Leu?Ala?Val?Gly?Gln?Asn
115 120 125
Trp?Leu?Leu?Asp?Glu?Gln?Thr?Ser?Thr?Leu?Thr?Arg?Leu?Arg?Tyr?Ser
130 135 140
Tyr?Arg?Val?Ile?Cys?Ser?Asp?Asn?Tyr?Tyr?Gly?Asp?Asn?Cys?Ser?Arg
145 150 155 160
Leu?Cys?Lys?Lys?Arg?Asn?Asp?His?Phe?Gly?His?Tyr?Val?Cys?Gln?Pro
165 170 175
Asp?Gly?Asn?Leu?Ser?Cys?Leu?Pro?Gly?Trp?Thr?Gly?Glu?Tyr?Cys?Asp
180 185 190
Lys?Thr?His?Thr?Cys?Pro?Pro?Cys?Pro?Ala?Pro?Glu?Leu?Leu?Gly?Gly
195 200 205
Pro?Ser?Val?Phe?Leu?Phe?Pro?Pro?Lys?Pro?Lys?Asp?Thr?Leu?Met?Ile
210 215 220
Ser?Arg?Thr?Pro?Glu?Val?Thr?Cys?Val?Val?Val?Asp?Val?Ser?His?Glu
225 230 235 240
Asp?Pro?Glu?Val?Lys?Phe?Asn?Trp?Tyr?Val?Asp?Gly?Val?Glu?Val?His
245 250 255
Asn?Ala?Lys?Thr?Lys?Pro?Arg?Glu?Glu?Gln?Tyr?Asn?Ser?Thr?Tyr?Arg
260 265 270
Val?Val?Ser?Val?Leu?Thr?Val?Leu?His?Gln?Asp?Trp?Leu?Asn?Gly?Lys
275 280 285
Glu?Tyr?Lys?Cys?Lys?Val?Ser?Asn?Lys?Ala?Leu?Pro?Ala?Pro?Ile?Glu
290 295 300
Lys?Thr?Ile?Ser?Lys?Ala?Lys?Gly?Gln?Pro?Arg?Glu?Pro?Gln?Val?Tyr
305 310 315 320
Thr?Leu?Pro?Pro?Ser?Arg?Asp?Glu?Leu?Thr?Lys?Asn?Gln?Val Ser?Leu
325 330 335
Thr?Cys?Leu?Val?Lys?Gly?Phe?Tyr?Pro?Ser?Asp?Ile?Ala?Val?Glu?Trp
340 345 350
Glu?Ser?Asn?Gly?Gln?Pro?Glu?Asn?Asn?Tyr?Lys?Thr?Thr?Pro?Pro?Val
355 360 365
Leu?Asp?Ser?Asp?Gly?Ser?Phe?Phe?Leu?Tyr?Ser?Lys?Leu?Thr?Val?Asp
370 375 380
Lys?Ser?Arg?Trp?Gln?Gln?Gly?Asn?Val?Phe?Ser?Cys?Ser?Val?Met?His
385 390 395 400
Glu?Ala?Leu?His?Asn?His?Tyr?Thr?Gln?Lys?Ser?Leu?Ser?Leu?Ser?Pro
405 410 415
Gly?Lys
<210>23
<211>410
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>23
Gln?Gln?Pro?Ile?Cys?Leu?Ser?Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys
1 5 10 15
Ser?Lys?Pro?Ala?Glu?Cys?Leu?Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu
20 25 30
Cys?Asn?Glu?Cys?Ile?Pro?His?Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser
35 40 45
Thr?Pro?Trp?Gln?Cys?Thr?Cys?Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys
50 55 60
Asp?Gln?Asp?Leu?Asn?Tyr?Cys?Thr?His?His?Ser?Pro?Cys?Lys?Asn?Gly
65 70 75 80
Ala?Thr?Cys?Ser?Asn?Ser?Gly?Gln?Arg?Ser?Tyr?Thr?Cys?Thr?Cys?Arg
85 90 95
Pro?Gly?Tyr?Thr?Gly?Val?Asp?Cys?Glu?Leu?Glu?Leu?Ser?Glu?Cys?Asp
100 105 110
Ser?Asn?Pro?Cys?Arg?Asn?Gly?Gly?Ser?Cys?Lys?Asp?Gln?Glu?Asp?Gly
115 120 125
Tyr?His?Cys?Leu?Cys?Pro?Pro?Gly?Tyr?Tyr?Gly?Leu?His?Cys?Glu?His
130 135 140
Ser?Thr?Leu?Ser?Cys?Ala?Asp?Ser?Pro?Cys?Phe?Asn?Gly?Gly?Ser?Cys
145 150 155 160
Arg?Glu?Arg?Asn?Gln?Gly?Ala?Asn?Tyr?Ala?Cys?Glu?Cys?Pro?Pro?Asn
165 170 175
Phe?Thr?Gly?Ser?Asn?Cys?Glu?Asp?Lys?Thr?His?Thr?Cys?Pro?Pro?Cys
180 185 190
Pro?Ala?Pro?Glu?Leu?Leu?Gly?Gly?Pro?Ser?Val?Phe?Leu?Phe?Pro?Pro
195 200 205
Lys?Pro?Lys?Asp?Thr?Leu?Met?Ile?Ser?Arg?Thr?Pro?Glu?Val?Thr?Cys
210 215 220
Val?Val?Val?Asp?Val?Ser?His?Glu?Asp?Pro?Glu?Val?Lys?Phe?Asn?Trp
225 230 235 240
Tyr?Val?Asp?Gly?Val?Glu?Val?His?Asn?Ala?Lys?Thr?Lys?Pro?Arg?Glu
245 250 255
Glu?Gln?Tyr?Asn?Ser?Thr?Tyr?Arg?Val?Val?Ser?Val?Leu?Thr?Val?Leu
260 265 270
His?Gln?Asp?Trp?Leu?Asn?Gly?Lys?Glu?Tyr?Lys?Cys?Lys?Val?Ser?Asn
275 280 285
Lys?Ala?Leu?Pro?Ala?Pro?Ile?Glu?Lys?Thr?Ile?Ser?Lys?Ala?Lys?Gly
290 295 300
Gln?Pro?Arg?Glu?Pro?Gln?Val?Tyr?Thr?Leu?Pro?Pro?Ser?Arg?Asp?Glu
305 310 315 320
Leu?Thr?Lys?Asn?Gln?Val?Ser?Leu?Thr?Cys?Leu?Val?Lys?Gly?Phe?Tyr
325 330 335
Pro?Ser?Asp?Ile?Ala?Val?Glu?Trp?Glu?Ser?Asn?Gly?Gln?Pro?Glu?Asn
340 345 350
Asn?Tyr?Lys?Thr?Thr?Pro?Pro?Val?Leu?Asp?Ser?Asp?Gly?Ser?Phe?Phe
355 360 365
Leu?Tyr?Ser?Lys?Leu?Thr?Val?Asp?Lys?Ser?Arg?Trp?Gln?Gln?Gly?Asn
370 375 380
Val?Phe?Ser?Cys?Ser?Val?Met?His?Glu?Ala?Leu?His?Asn?His?Tyr?Thr
385 390 395 400
Gln?Lys?Ser?Leu?Ser?Leu?Ser?Pro?Gly?Lys
405 410
<210>24
<211>370
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>24
Gln?Gln?Pro?Ile?Cys?Leu?Ser?Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys
1 5 10 15
Ser?Lys?Pro?Ala?Glu?Cys?Leu?Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu
20 25 30
Cys?Asn?Glu?Cys?Ile?Pro?His?Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser
35 40 45
Thr?Pro?Trp?Gln?Cys?Thr?Cys?Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys
50 55 60
Asp?Gln?Asp?Leu?Asn?Tyr?Cys?Thr?His?His?Ser?Pro?Cys?Lys?Asn?Gly
65 70 75 80
Ala?Thr?Cys?Ser?Asn?Ser?Gly?Gln?Arg?Ser?Tyr?Thr?Cys?Thr?Cys?Arg
85 90 95
Pro?Gly?Tyr?Thr?Gly?Val?Asp?Cys?Glu?Leu?Glu?Leu?Ser?Glu?Cys?Asp
100 105 110
Ser?Asn?Pro?Cys?Arg?Asn?Gly?Gly?Ser?Cys?Lys?Asp?Gln?Glu?Asp?Gly
115 120 125
Tyr?His?Cys?Leu?Cys?Pro?Pro?Gly?Tyr?Tyr?Gly?Leu?His?Cys?Glu?Asp
130 135 140
Lys?Thr?His?Thr?Cys?Pro?Pro?Cys?Pro?Ala?Pro?Glu?Leu?Leu?Gly?Gly
145 150 155 160
Pro?Ser?Val?Phe?Leu?Phe?Pro?Pro?Lys?Pro?Lys?Asp?Thr?Leu?Met?Ile
165 170 175
Ser?Arg?Thr?Pro?Glu?Val?Thr?Cys?Val?Val?Val?Asp?Val?Ser?His?Glu
180 185 190
Asp?Pro?Glu?Val?Lys?Phe?Asn?Trp?Tyr?Val?Asp?Gly?Val?Glu?Val?His
195 200 205
Asn?Ala?Lys?Thr?Lys?Pro?Arg?Glu?Glu?Gln?Tyr?Asn?Ser?Thr?Tyr?Arg
210 215 220
Val?Val?Ser?Val?Leu?Thr?Val?Leu?His?Gln?Asp?Trp?Leu?Asn?Gly?Lys
225 230 235 240
Glu?Tyr?Lys?Cys?Lys?Val?Ser?Asn?Lys?Ala?Leu?Pro?Ala?Pro?Ile?Glu
245 250 255
Lys?Thr?Ile?Ser?Lys?Ala?Lys?Gly?Gln?Pro?Arg?Glu?Pro?Gln?Val?Tyr
260 265 270
Thr?Leu?Pro?Pro?Ser?Arg?Asp?Glu?Leu?Thr?Lys?Asn?Gln?Val?Ser?Leu
275 280 285
Thr?Cys?Leu?Val?Lys?Gly?Phe?Tyr?Pro?Ser?Asp?Ile?Ala?Val?Glu?Trp
290 295 300
Glu?Ser?Asn?Gly?Gln?Pro?Glu?Asn?Asn?Tyr?Lys?Thr?Thr?Pro?Pro?Val
305 310 315 320
Leu?Asp?Ser?Asp?Gly?Ser?Phe?Phe?Leu?Tyr?Ser?Lys?Leu?Thr?Val?Asp
325 330 335
Lys?Ser?Arg?Trp?Gln?Gln?Gly?Asn?Val?Phe?Ser?Cys?Ser?Val?Met?His
340 345 350
Glu?Ala?Leu?His?Asn?His?Tyr?Thr?Gln?Lys?Ser?Leu?Ser?Leu?Ser?Pro
355 360 365
Gly?Lys
370
<210>25
<211>332
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>25
Gln?Gln?Pro?Ile?Cys?Leu?Ser?Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys
1 5 10 15
Ser?Lys?Pro?Ala?Glu?Cys?Leu?Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu
20 25 30
Cys?Asn?Glu?Cys?Ile?Pro?His?Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser
35 40 45
Thr?Pro?Trp?Gln?Cys?Thr?Cys?Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys
50 55 60
Asp?Gln?Asp?Leu?Asn?Tyr?Cys?Thr?His?His?Ser?Pro?Cys?Lys?Asn?Gly
65 70 75 80
Ala?Thr?Cys?Ser?Asn?Ser?Gly?Gln?Arg?Ser?Tyr?Thr?Cys?Thr?Cys?Arg
85 90 95
Pro?Gly?Tyr?Thr?Gly?Val?Asp?Cys?Glu?Asp?Lys?Thr?His?Thr?Cys?Pro
100 105 110
Pro?Cys?Pro?Ala?Pro?Glu?Leu?Leu?Gly?Gly?Pro?Ser?Val?Phe?Leu?Phe
115 120 125
Pro?Pro?Lys?Pro?Lys?Asp?Thr?Leu?Met?Ile?Ser?Arg?Thr?Pro?Glu?Val
130 135 140
Thr?Cys?Val?Val?Val?Asp?Val?Ser?His?Glu?Asp?Pro?Glu?Val?Lys?Phe
145 150 155 160
Asn?Trp?Tyr?Val?Asp?Gly?Val?Glu?Val?His?Asn?Ala?Lys?Thr?Lys?Pro
165 170 175
Arg?Glu?Glu?Gln?Tyr?Asn?Ser?Thr?Tyr?Arg?Val?Val?Ser?Val?Leu?Thr
180 185 190
Val?Leu?His?Gln?Asp?Trp?Leu?Asn?Gly?Lys?Glu?Tyr?Lys?Cys?Lys?Val
195 200 205
Ser?Asn?Lys?Ala?Leu?Pro?Ala?Pro?Ile?Glu?Lys?Thr?Ile?Ser?Lys?Ala
210 215 220
Lys?Gly?Gln?Pro?Arg?Glu?Pro?Gln?Val?Tyr?Thr?Leu?Pro?Pro?Ser?Arg
225 230 235 240
Asp?Glu?Leu?Thr?Lys?Asn?Gln?Val?Ser?Leu?Thr?Cys?Leu?Val?Lys?Gly
245 250 255
Phe?Tyr?Pro?Ser?Asp?Ile?Ala?Val?Glu?Trp?Glu?Ser?Asn?Gly?Gln?Pro
260 265 270
Glu?Asn?Asn?Tyr?Lys?Thr?Thr?Pro?Pro?Val?Leu?Asp?Ser?Asp?Gly?Ser
275 280 285
Phe?Phe?Leu?Tyr?Ser?Lys?Leu?Thr?Val?Asp?Lys?Ser?Arg?Trp?Gln?Gln
290 295 300
Gly?Asn?Val?Phe?Ser?Cys?Ser?Val?Met?His?Glu?Ala?Leu?His?Asn?His
305 310 315 320
Tyr?Thr?Gln?Lys?Ser?Leu?Ser?Leu?Ser?Pro?Gly?Lys
325 330
<210>26
<211>292
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic
<400>26
Gln?Gln?Pro?Ile?Cys?Leu?Ser?Gly?Cys?His?Glu?Gln?Asn?Gly?Tyr?Cys
1 5 10 15
Ser?Lys?Pro?Ala?Glu?Cys?Leu?Cys?Arg?Pro?Gly?Trp?Gln?Gly?Arg?Leu
20 25 30
Cys?Asn?Glu?Cys?Ile?Pro?His?Asn?Gly?Cys?Arg?His?Gly?Thr?Cys?Ser
35 40 45
Thr?Pro?Trp?Gln?Cys?Thr?Cys?Asp?Glu?Gly?Trp?Gly?Gly?Leu?Phe?Cys
50 55 60
Asp?Asp?Lys?Thr?His?Thr?Cys?Pro?Pro?Cys?Pro?Ala?Pro?Glu?Leu?Leu
65 70 75 80
Gly?Gly?Pro?Ser?Val?Phe?Leu?Phe?Pro?Pro?Lys?Pro?Lys?Asp?Thr?Leu
85 90 95
Met?Ile?Ser?Arg?Thr?Pro?Glu?Val?Thr?Cys?Val?Val?Val?Asp?Val?Ser
100 105 110
His?Glu?Asp?Pro?Glu?Val?Lys?Phe?Asn?Trp?Tyr?Val?Asp?Gly?Val?Glu
115 120 125
Val?His?Asn?Ala?Lys?Thr?Lys?Pro?Arg?Glu?Glu?Gln?Tyr?Asn?Ser?Thr
130 135 140
Tyr?Arg?Val?Val?Ser?Val?Leu?Thr?Val?Leu?His?Gln?Asp?Trp?Leu?Asn
145 150 155 160
Gly?Lys?Glu?Tyr?Lys?Cys?Lys?Val?Ser?Asn?Lys?Ala?Leu?Pro?Ala?Pro
165 170 175
Ile?Glu?Lys?Thr?Ile?Ser?Lys?Ala?Lys?Gly?Gln?Pro?Arg?Glu?Pro?Gln
180 185 190
Val?Tyr?Thr?Leu?Pro?Pro?Ser?Arg?Asp?Glu?Leu?Thr?Lys?Asn?Gln?Val
195 200 205
Ser?Leu?Thr?Cys?Leu?Val?Lys?Gly?Phe?Tyr?Pro?Ser?Asp?Ile?Ala?Val
210 215 220
Glu?Trp?Glu?Ser?Asn?Gly?Gln?Pro?Glu?Asn?Asn?Tyr?Lys?Thr?Thr?Pro
225 230 235 240
Pro?Val?Leu?Asp?Ser?Asp?Gly?Ser?Phe?Phe?Leu?Tyr?Ser?Lys?Leu?Thr
245 250 255
Val?Asp?Lys?Ser?Arg?Trp?Gln?Gln?Gly?Asn?Val?Phe?Ser?Cys?Ser?Val
260 265 270
Met?His?Glu?Ala?Leu?His?Asn?His?Tyr?Thr?Gln?Lys?Ser?Leu?Ser?Leu
275 280 285
Ser?Pro?Gly?Lys
290

Claims (9)

1. the purposes that can suppress the active therapeutic agent of δ sample part 4 (D114) is used for suppressing its patient of needs the development or the growth of tumor.
2. according to the purposes of claim 1, the therapeutic agent that wherein can suppress D114 is antibody or antibody fragment.
3. according to the purposes of claim 2, wherein D114 antibody or antibody fragment are polyclonal or monoclonal.
4. according to the purposes of claim 3, wherein antibody or antibody fragment are humanized, chimeric or fully human antibodies or antibody fragment.
5. according to the purposes of claim 4, wherein antibody fragment is single-chain antibody, Fab or F (ab ') 2
6. according to the purposes of claim 1, wherein the D114 antagonist is the fragment of the D114 that merges with the multimerization composition.
7. what define in the claim 1 to 6 can suppress the active therapeutic agent of D114 as first therapeutic agent, with the purposes of another kind of therapeutic agent in the medicine of preparation inhibition tumor development or growth, described another kind of therapeutic agent is VEGF (VEGF) inhibitor.
8. according to the purposes of claim 7, wherein the VEGF inhibitor is VEGF antibody or VEGF agent for capturing.
9. according to the purposes of claim 8, wherein the VEGF agent for capturing is SEQ ID NO:19.
CNA2006800473723A 2005-12-16 2006-12-15 Therapeutic methods for inhibiting tumor growth with D114 antagonists Pending CN101330925A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US75117305P 2005-12-16 2005-12-16
US60/751,173 2005-12-16
US60/771,276 2006-02-08
US60/788,456 2006-03-31
US60/830,543 2006-07-12

Publications (1)

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CN101330925A true CN101330925A (en) 2008-12-24

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SI (1) SI1962895T1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102906113A (en) * 2010-03-02 2013-01-30 Abbvie公司 Therapeutic dll4 binding proteins
CN111234003A (en) * 2020-02-07 2020-06-05 中国人民解放军第四军医大学 Short peptide for cancer targeted therapy, ultrasound response nano drug-loaded microbubble based on short peptide and application of short peptide
CN111386039A (en) * 2017-09-29 2020-07-07 瑞泽恩制药公司 Non-human animals expressing humanized C1q complexes

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102906113A (en) * 2010-03-02 2013-01-30 Abbvie公司 Therapeutic dll4 binding proteins
CN102906113B (en) * 2010-03-02 2015-08-12 Abbvie公司 Therapeutic DLL4 associated proteins
CN105037543A (en) * 2010-03-02 2015-11-11 Abbvie公司 Therapeutic DLL4 binding proteins
CN105037543B (en) * 2010-03-02 2020-11-03 Abbvie 公司 Therapeutic DLL4 binding proteins
CN111386039A (en) * 2017-09-29 2020-07-07 瑞泽恩制药公司 Non-human animals expressing humanized C1q complexes
CN111234003A (en) * 2020-02-07 2020-06-05 中国人民解放军第四军医大学 Short peptide for cancer targeted therapy, ultrasound response nano drug-loaded microbubble based on short peptide and application of short peptide
CN111234003B (en) * 2020-02-07 2022-02-01 中国人民解放军第四军医大学 Short peptide for cancer targeted therapy, ultrasound response nano drug-loaded microbubble based on short peptide and application of short peptide

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