CN109536476A - Targent fused protein, the Preparation method and use for having hyaluronidase activity - Google Patents

Abstract

The present invention provides the targent fused proteins for having hyaluronidase activity, preparation method and application, the fusion protein is the tripolymer comprising tri- peptide chains of ABC, A peptide chain is that hyaluronidase merges peptide chain, and B peptide chain is IgG antibody heavy chain mutant, and C peptide chain is IgG antibody light chain or light chain mutant.A peptide chain structure general formula is γ 1- γ 3 or γ 1- γ 2- γ 3, γ 1 are hyaluronidase similar to object, including HYALl gene, HYAL2 gene or PH20/SPAM1 expressed sequence；γ 2 is peptide linker；γ 3 is the area human IgG antibody Fc hole mutant or knob mutant, and hole mutant and knob mutant form specific dimer.When the area Fc does not retain hinge area, using peptide linker, hyaluronidase is directly fused to peptide linker N-terminal residue similar to object C-terminal residue, and C-terminal residue is directly fused to the N-terminal of hole mutant or knob mutant；When the area Fc retains part or all of hinge area, peptide linker is not used, hyaluronidase is directly fused to the N-terminal of hole mutant or knob mutant similar to the C-terminal residue of object.

Description

Targent fused protein, the Preparation method and use for having hyaluronidase activity

Technical field

The present invention relates to bio-pharmaceutical engineer technology domains, and in particular to the fusion protein for treating cancer.More specifically Ground not only has hyaluronidase activity the present invention relates to a kind of, but also can target fusion protein and its preparation side of specific target spot Method and the application in antineoplaston.

Background technique

Based on operative treatment, radiotherapy and chemotherapy, being aided with novel targeted therapy scheme is in recent years to evil The elementary tactics of property oncotherapy, and important progress is obtained in clinical practice.But the Preventive of malignant tumour and Therapeutic tolerance is still the clinical problem with researcher of puzzlement always.

A kind of hyaluronic acid (hyaluronic acid, HA) straight chain non sulphate polysaccharide.The structure of HA is fairly regular, Relative molecular mass (Mr) range is 200,000~7,000,000, belongs to large biological molecule.HA is as extracellular matrix (ECM) Important component, in addition to the physical characteristics such as its reticular structure, viscoelasticity play adjusting osmotic pressure, connection cell, shielding, Lubricating joint eases up outside the mechanical functions such as blow stress, also has and adjusts the physiological activity such as cell function, inactivation free radical, in form Plays a significant role (Turley et in generation, angiogenesis, tumour diffusion, wound healing, control pain and inflammatory reaction al.,2002,Signaling properties ofhyaluronan receptors,277:4589-4592)。

Report in recent years is shown, in tumor-infiltrated area and transfer process, the expression of HA is significantly increased (Jojovic et al.,2002,Expression ofhyaluronate and hyaluronate synthase in humanprimary tumours and their metastases in scidmice,188:181-189).Such as in colon During the malignant change of cancer along with the increase of HA expression quantity (Laurich et al., 2004, Hyaluronan mediates adhesion ofmetastatic colon carcinoma cells1,122:70-74).The source of these HA May be: the 1. interstitial cell synthesis and secretion around tumor cell induction；2. tumour cell itself synthesizes.This implies HA and swells The infiltration of tumor and migration are closely related.

The effect of HA may be in these tumours: anchorage independent growth and the proliferation of tumour cell 1. being stimulated to promote to swell Growth (Liu the et al., 2001, Hyaluronan synthase 3overexpressionpromotes the of tumor growth ofTSU prostate cancer cells,61:5207-5214)；2. breaking collagenous fibres and glycoprotein 2 Balance between reticular structure makes institutional framework deform and destroy, and for the movement of tumour cell, to provide hyperhydrated logical Road so that it be promoted to stick and migrate, and then promotes metastases；3. with the HA receptor (mainly CD44) on tumor cell membrane In conjunction with, form protectiveness shell, reduce immunocyte and drug to the sticking of tumour cell, attack and medicine effective concentration (Itano et al.,2002,Abnormal accumulation ofhyaluronan matrix diminishes contact inhibition ofcell growth and promotes cell migration,99:3609-3614)；④ After in conjunction with the HA receptor CD44 on tumor cell membrane, make the relevant tyrosine kinase phosphorylation of receptor protein, generates one Signal in series of cell, moves cytoskeleton, causes tumour cell pseudopodium sample stretching routine, to enhance tumour cell Motility and chemotaxis (G ü ler et al., 2002, Prognostic value ofCD44variant 6in Laryngeal epidermoid carcinomas, 128:393-397), and HA in conjunction with CD44 variant after can promote it is swollen Tumor is formed and the diffusion of lymphoma cell.

In addition, vascular function exception and the formation of a large amount of connective tissues are the notable features of cancer of pancreas, change has been severely impacted It treats in drug delivery to tumor tissues, this is also the reason in part for leading to pancreatic cancer chemotherapy drug resistance.In addition, the outer base of pancreatic cancer cell Hyaluronic acid rich in matter.The study found that hyaluronic acid can damage the vascular function of cancer of pancreas, chemotherapeutics is hindered Delivering, thus reduce chemotherapeutics in tumor tissues concentration (Jacobetz et al., 2012, Hyaluronan impairs vascular function and drug delivery in a mouse model ofpancreatic cancer,gutjnl-2012-302529).Therefore, removing or degradation hyalomitome acids drug is used in combination and other tumours are controlled Treating drug is the hot spot studied at present.

Hyaluronidase (hyaluronidases, EC 3.2.1.35) is a kind of enzyme family that can decompose hyaluronic acid, For being catalyzed the hydrolysis of hyaluronic acid.Mankind's hyaluronidase is encoded by six genes, wherein expression hyaluronidase activity packet Include HYALl (NP149349), HYAL2 (NP003764) and PH20/SPAM l (NP001167515).Hyaluronic acid is extracellular The constituent of matrix (extracellular matrix, ECM) reduces the viscosity of hyaluronic acid by hydrolysis hyaluronic acid, Enhance tissue permeability.

The diffusion that can promote drug and transmission (ChemRev.2006Mar is used in combination in hyaluronidase and other drugs； L06 (3): 818-839), FDA has been obtained as drug there are many hyaluronidase at present to ratify.U.S. FDA approval The hyaluronidase drug of animal origin include Hydase (PrimaPharm company), Vitrase (Bausch+Lomb company and Valeant Pharmaceuticals company), Amphadase (Amphastar Pharmaceuticals company) and Wydase.U.S. FDA is in approval Halozyme Therapeutics company and Baxter Healthcare on December 2nd, 2005 People's hyaluronidase PH-20 drug in the genetic recombination source of company, trade name Hylenex.In addition, U.S. FDA is 2014 On September 12, approval Baxter company drug HyQvia is that people's normal immunoglobulin and recombined human hyaluronidase form A kind of immunoglobulin (subcutaneous immune of the subcutaneous injection using recombined human hyaluronidase Hylenex Globulin, SCIG), these medicinal applications are in progress in the clinical test that combination tumor is treated.

However, these recombination hyaluronidases have no targeting, it is effective how to improve its drug near tumor tissues Concentration is current urgent problem to be solved.

Summary of the invention

It is an object of the present invention to rely on the studies above background, a kind of novel fusion protein is provided, is retaining its recombination On the basis of hyaluronidase activity, its targeting is increased, that is, provides a kind of targeting for having hyaluronidase activity and melts Hop protein, preparation method and use.

The first aspect of the present invention provides a kind of targent fused protein for having hyaluronidase activity.

The targent fused protein provided by the invention for having hyaluronidase activity is the trimerization comprising tri- peptide chains of A, B, C Body, A peptide chain are that hyaluronidase merges peptide chain, and B peptide chain is IgG antibody heavy chain mutant, and C peptide chain is IgG antibody light chain.

Wherein, the general structure of A peptide chain is γ 1- γ 3 or γ 1- γ 2- γ 3；

γ 1 is hyaluronidase similar to object, the expression sequence including HYALl gene, HYAL2 gene or PH20/SPAM1 gene Column.Hyaluronidase (hyaluronidases, EC 3.2.1.35) is a kind of enzyme family that can decompose hyaluronic acid, the mankind Hyaluronidase is encoded by six genes, wherein the gene of expression hyaluronidase activity includes HYALl (UniProtKB- Q12794), HYAL2 (UniProtKB-Q12891) and PH20/SPAM1 (UniProtKB-P38567), three gene codings Sequence constitute the enzyme activity region in hyaluronidase；

γ 2 is peptide linker, and the hyaluronidase fusion peptide chain can not have to peptide linker；

γ 3 is the area human IgG antibody Fc hole mutant or knob mutant, and hole mutant and knob mutant being capable of shapes At specific dimer；

When the area human IgG antibody Fc does not retain hinge area, using the peptide linker (γ 2), C of the hyaluronidase similar to object Terminal residue is directly fused to the N-terminal residue of peptide linker, and the C-terminal residue of peptide linker (γ 2) is directly fused to human IgG The N-terminal residue of antibody Fc district hole mutant or knob mutant；

When the area human IgG antibody Fc retains part or all of hinge area, peptide linker is not used, then hyaluronidase is similar to object C-terminal residue be directly fused to the N-terminal residue of the area human IgG antibody Fc hole mutant or knob mutant.

Further, when γ 3 is the area human IgG antibody Fc hole mutant and when being the area human IgG antibody Fc knob mutant, The structure of peptide chain B and peptide chain C is different, lower to be illustrated respectively.

(1) when γ 3 is the area human IgG antibody Fc hole mutant, the general structure of B peptide chain is α 1- α 2- α 3, C peptide chain General structure is β 1- β 2.

α 1 is IgG antibody heavy chain variable region VH；α 2 is the area IgG antibody heavy chain CH1；α 3 is IgG antibody Fc area knob mutation Body is mutated comprising T366W, S354C.The C-terminal residue of VH is directly fused to the N-terminal residue of the area IgG CH1 and hinge area, The C-terminal residue in the area IgG CH1 is directly fused to the N-terminal residue of the area IgG Fc knob mutant.

Β 1 is that IgG antibody light chain variable region VL, β 2 is IgG antibody constant region of light chain CL.

The structure type of this kind of fusion protein is as shown in Figure of description 1A and attached drawing 1B.

(2) when γ 3 is the area human IgG antibody Fc knob mutant, the general structure of B peptide chain is α 1- α 2- α 3, C peptide chain General structure is β 1- β 2.

α 1 is IgG antibody heavy chain variable region VH；α 2 is IgG antibody light chain CL region mutation body；α 3 is IgG antibody Fc area hole Mutant is mutated comprising T366S, L368A, Y407V and Y349C.The C-terminal residue of VH is directly fused to the N in the area IgG CL Terminal residue, the C-terminal residue in the area IgG CL are directly fused to the N-terminal residue of the area IgG Fc hole mutant.

β 1 is that IgG antibody light chain variable region VL, β 2 is the area IgG antibody heavy chain constant region CH1, and the C-terminal residue of VL is direct It is fused to the N-terminal residue in the area IgG CH1.

The structure type of this kind of fusion protein is as shown in Figure of description 1C.

Preferably, hyaluronidase has as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3 similar to object Amino acid sequence, or by being deleted in any one of amino acid sequence or several amino acid, addition or the amino replaced Acid sequence composition.Particular sequence composition is as follows:

In the present invention, there is any coding the DNA of the protein of hyaluronidase activity to be adapted to the present invention.It is such Structure include it is isolated from tissue or cell mRNA, from according to in publishing database sequence full genome synthesize, or It is obtained from other cDNA libraries.

In some preferred embodiments, peptide linker can be used to increase the flexibility of fusion peptide chain, peptide linker is Polypeptide comprising amino acid sequence [GGGGX] n, X are glutamine (Q), glutamic acid (D) or serine (S), and n 2-5, this is more Peptide includes 10 to 25 amino acid, and at least 50% is glycine residue in amino acid acid.Peptide in some preferred embodiments Connector includes the amino acid sequence as shown in SEQ ID NO.4, SEQ ID NO.5 or SEQ ID NO.6, specific as follows:

Wherein, X in peptide linker 1₁It is Q or E；X₂It is Q or E；X₃It is Q or E；X₄It is G, E, Q or is not present: X₅It is G or does not deposit : and X₆It is G or is not present.

Peptide linker is rich in glycine, to provide sufficient Conformational flexibility.Preferably, peptide linker is less than 30 amino acid It is long.In certain preferred embodiments, peptide linker is 10 to 25 amino acid longs, wherein at least the 50% of the amino acid is sweet Histidine residue.Preferred second skin connector includes sequence (GGGGX15) n, and wherein X15 is Q, E or S and n=2-5.More preferably Peptide linker have SEQ ID NO.6 amino acid sequence.In some cases, other amino acid sequence conducts also can be used Peptide linker does not use peptide linker.

Preferably, the area human IgG Fc is the area Fc from IgGl, IgG2, IgG3 or IgG4 antibody.The area IgG Fc includes SEQ Amino acid sequence shown in ID NO.7, and further C residue at the position 1 in SEQ ID NO.7 amino acid sequence N-terminal side includes some or all of amino acid found in wild type IgGl Fc sequence.

Human IgG heavy chain Fc region amino acid sequence (SEQ ID NO.7) is as follows:

DKTHTCPPCPAPELLGGPSVX₁LX₂PPKPKDTLMISRTPEVTCX₃VX₄DVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYX₅STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGX₆

Wherein X₁It is F, Q or E；X₂It is F, Q or E；X₃It is V or T；X₄It is V or T:X₅It is N, D or Q: and X₆It is K or does not deposit ?.

The mutated site of Fc knob and Fc hole mutant of the invention and non-patent literature (Schaefer et al., 2011,Immunoglobulin domain crossover as a generic approach for the production Ofbispecific IgG antibodies, 108:11187-11192) report consistent, the amino acid position reference of use IgG1 can use similar mutation method for other kinds of IgG such as IgG2, IgG3 and IgG4, but specific position is answered Carry out the mutation of corresponding site.

The meaning that term " region human IgG Fc " has the term usually given in field of immunology.Particularly, the art Language refers to the human IgG antibody's segment obtained and removing two antigen binding domain (Fab segments) from antibody.Specifically, Fc Area includes CH2 the and CH3 constant region domain of antibody, and may also comprise some or all of hinge area.

There are four kinds of IgG subclasses (G1, G2, G3 and G4) in immunoglobulin, respectively have different structures and are claimed For the biological function of effector function.These effector functions with Fc receptor (Fc γ R) generally by interacting or leading to Conjugated complement factor Clq is crossed to mediate.Being bound to Fc γ R can lead to the cell-mediated cell cracking of antibody dependent, and tie Being bonded to complement factor can lead to the cell cracking of complement-mediated.The structure and property in the area Fc of IgG subclass are that oneself knows in this field 's.Fusion protein of the invention contains the area Fc from any IgG subclass, although Gl and G3 ratio G2 and G4 antibody are with higher Receptor combine and effector function activity, be therefore preferred.

Moreover, it relates to encode the polynucleotides of any one of fusion protein of the invention.Encode above-mentioned melt The polynucleotides of hop protein can be the form of RNA or DNA comprising cDNA and synthetic DNA, and it can be double-strand or list Chain.Encode albumen of the invention coded sequence can due to genetic code redundancy or degeneracy and change.

It may include following for encoding the polynucleotides of fusion protein of the invention: the only coded sequence of albumen, the coding of albumen Sequence and additional coding sequence (such as leading or secretion sequence or preceding protein sequence): the coded sequence and non-coding sequence of albumen (non-coding sequences at 5 ' and/or 3 ' ends of the coded sequence of such as introne or albumen).Therefore, term " encodes the more of albumen Nucleotide " not only cover may include albumen coded sequence polynucleotides, but also cover including additionally encoding and/or non-coding The polynucleotides of sequence.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:24, SEQ Shown in ID NO:26, SEQ ID NO:28, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:25, SEQ ID Shown in NO:27, SEQ ID NO:29.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:42, SEQ Shown in ID NO:44, SEQ ID NO:46, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:43, SEQ ID Shown in NO:45, SEQ ID NO:47.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:52, SEQ Shown in ID NO:54, SEQ ID NO:56, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:53, SEQ ID Shown in NO:55, SEQ ID NO:57.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:58, SEQ Shown in ID NO:60, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:59, SEQ ID Shown in NO:61, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:62, SEQ Shown in ID NO:64, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:63, SEQ ID Shown in NO:65, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:66, SEQ Shown in ID NO:68, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:67, SEQ ID Shown in NO:69, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:70, SEQ Shown in ID NO:72, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:71, SEQ ID Shown in NO:73, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:74, SEQ Shown in ID NO:76, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:75, SEQ ID Shown in NO:77, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:78, SEQ Shown in ID NO:80, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:79, SEQ ID Shown in NO:81, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:82, SEQ Shown in ID NO:84, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:83, SEQ ID Shown in NO:85, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:86, SEQ Shown in ID NO:88, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:87, SEQ ID Shown in NO:89, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:90, SEQ Shown in ID NO:92, SEQ ID NO:26, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:91, SEQ ID Shown in NO:93, SEQ ID NO:27.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:24, SEQ Shown in ID NO:28, SEQ ID NO:94, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:25, SEQ ID Shown in NO:29, SEQ ID NO:95.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:42, SEQ Shown in ID NO:46, SEQ ID NO:96, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:43, SEQ ID Shown in NO:47, SEQ ID NO:97.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:66, SEQ Shown in ID NO:68, SEQ ID NO:94, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:67, SEQ ID Shown in NO:69, SEQ ID NO:95.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:54, SEQ Shown in ID NO:56, SEQ ID NO:98, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:55, SEQ ID Shown in NO:57, SEQ ID NO:99.

In a preferred embodiment of the invention, the amino acid sequence of the fusion protein such as SEQ ID NO:74, SEQ Shown in ID NO:76, SEQ ID NO:94, the nucleotide sequence of encoding said fusion protein such as SEQ ID NO:75, SEQ ID Shown in NO:77, SEQ ID NO:95.

The second aspect of the present invention provides a kind of pharmaceutical composition of targent fused protein for having hyaluronidase activity Object.The pharmaceutical composition further includes medically acceptable in addition to including the targent fused protein for having hyaluronidase activity Pharmaceutical carrier.

Fusion protein of the invention and pharmaceutically acceptable auxiliary material forms pharmaceutical preparations composition together, thus more steady Surely curative effect is played, these preparations can guarantee that the conformation of bispecific antibody amino acid core sequence disclosed by the invention is complete Property, while the polyfunctional group of protected protein matter is also wanted, prevent its degradation (including but not limited to cohesion, deamination or oxidation).

Under normal conditions, liquid preparation can save under the conditions of 2 DEG C -8 DEG C and at least stablize 1 year, and lyophilized preparation is at 30 DEG C Holding at least six months is stablized.The preparations, preferably water needle or freeze-drying such as preparation can commonly be suspended for pharmaceutical field, water needle, freeze-drying Preparation.

For the water needle or lyophilized preparation of above-mentioned fusion protein disclosed by the invention, pharmaceutically acceptable auxiliary material includes One or a combination set of surfactant, solution stabilizer, isotonic regulator and buffer.Wherein, surfactant include it is non-from Subtype surfactant such as Polyoxyethylene Sorbitol Fatty Acid Esters (polysorbas20 or 80)；Poloxamer (such as poloxamer188)； Triton；Lauryl sodium sulfate (SDS)；Sodium Laurylsulfate；Myristyl, sub- oil base or octadecyl sarcosine； Pluronics；MONAQUATTM etc., additional amount should make the granulating trend of difunctional bispecific antibody albumen minimum；It is molten Liquid stabilizer can be carbohydrate, including reducing sugar and nonreducing sugar, amino acids include monosodium glutamate or histidine, alcohol Class includes one or a combination set of trihydroxylic alcohol, advanced sugar alcohol, propylene glycol, polyethylene glycol, and the additional amount of solution stabilizer should make most The preparation those skilled in the art formed afterwards thinks to reach stable time interior holding stable state；Isotonic regulator can be with For one of sodium chloride, mannitol；Buffer can be one of TRIS, histidine buffering liquid, phosphate buffer.

Above-mentioned preparation is the composition comprising fusion protein, after to animal administration including people, antitumous effect Obviously.Specifically, effectively to the prevention of tumour and/or treatment, it can be used as anti-tumor drug use.

For fusion protein and combinations thereof when to animal administration including people, dosage is because patient's in the present invention Age and weight, disease traits and seriousness and administration route and it is different, can refer to zoopery result and various feelings Condition, total dosage is no more than a certain range.The dosage being specifically injected intravenously is 1~1800mg/ days.

The third aspect of the present invention provides a kind of purposes of targent fused protein for having hyaluronidase activity, tool Body is purposes in the preparation of antitumor drugs.

Preferably, which also refers to the targent fused protein for having hyaluronidase activity and other anti-tumor drugs joint It uses.

The so-called anti-tumor drug of the present invention, refers to the drug for inhibiting and/or treating tumour, may include with tumour The delay of related symptoms development and/or the reduction of these severity of symptom are grown, it further comprises already present tumour It grows the mitigation of simultaneous phenomenon and prevents the appearance of other symptoms, still reduce or prevent transfer.

These antineoplastics include 1, cytotoxic drug: (1) acting on the drug of DNA chemical structure: alkylating agent such as nitrogen Mustard class, nitrous urinate class, methane sulfonic acid esters；Platinum-like compounds such as cis-platinum, carboplatin and oxalic acid platinum etc.；Mitomycin (MMC)；(2) Influence the drug of nucleic acid synthesis: dihydrofolate reductase inhibitor such as methopterin (MTX) and Alimta etc.；Thymus nucleoside synthesis Enzyme inhibitor such as fluorouracil (5FU, FT-207, capecitabine) etc.；Purine nucleosides synthetase inhibitors such as 6- sulfydryl is fast Purine (6-MP) and 6-TG etc.；Ribonucleotide reductase inhibitor such as hydroxycarbamide (HU) etc.；DNA poly enzyme inhibitor such as cytarabine (Ara-C) and gemzar (Gemz) etc.；(3) act on the drug of transcribed nucleic acid: selectively acting inhibits DNA to rely in DNA profiling RNA polymerase, so that the drug for inhibiting RNA to synthesize is such as: actinomycin D, daunorubicin, adriamycin, Epi-ADM, Accra are mould Element, mithramycin etc.；(4) mainly act on the drug of tubulin synthesis: taxol, taxotere, vinblastine, Changchun are auspicious Shore, Podophyllum emodi var chinense alkali class, homoharringtonine；(5) other Cytotoxic drugs: L-Asparaginasum mainly inhibits the synthesis of protein；2, swash Plain class: such as anti-estrogens: tamoxifen, Droloxifene, Exemestane；Arimedex: aminoglutethimide, Lactel Grand, Letrozole, auspicious Ningde etc.；Antiandrogen: its ammonia RH-LH agonist/antagonist of fluorine: Zoladex, enatone etc.；3, biology is anti- Answer regulator: main that tumour class drug, such as interferon are inhibited by body's immunity；Interleukin 2；Thymic；4, Monoclonal antibodies: such as Mabthera (MabThera), Trastuzumab (Trastuzumab), Bevacizumab (Avastin) is immunized Checkpoint blocking agent, such as anti-PD1 antibody；5, various radiotherapy；6, it is unknown and need to include some current mechanism for other The drug further studied；Cell-differentiation inducers such as retinoids；Cell death inducer.Fusion protein disclosed by the invention and Its composition can be with one or a combination set of above-mentioned anti-tumor drug drug combination.

Signified tumour of the invention, including gland cancer, leukaemia, lymthoma, melanoma, sarcoma, the source of tumor tissues Including but not limited to adrenal gland, gall-bladder, bone, marrow, brain, mammary gland, bile duct, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovum Nest, pancreas, parathyroid gland, penis, prostate, skin, salivary gland, spleen, testis, thymus gland, thyroid gland and uterus.In addition to above-mentioned Tumour outside, it may also be used for tumour of central nervous system such as spongiocyte diversity tumor, astrocytoma etc., furthermore eye is swollen Tumor includes basal-cell carcinoma, squamous cell carcinoma, melanoma etc., further include endocrine disrupting effects, neuroendocrine system tumour, Gastrointestinal tract pancreatic endocrine system tumor, genital system and head and neck neoplasm etc..Here it will not enumerate.

The fourth aspect of the present invention provides a kind of preparation method of fusion protein.

When the structure type of fusion protein belongs to the fusion protein of aforementioned (1) class, preparation method includes following step It is rapid:

(1) full genome synthesis human IgG antibody's heavy chain object segment similar with the variable region gene of light chain and hyaluronidase, is obtained VH, VL segment and hyaluronidase for obtaining IgG antibody are similar to object segment；Full genome synthesizes human IgG antibody's constant region of light chain CL, again Chain constant region CH1 and Fc segment,

(2) the Fc segment of acquisition is introduced into catastrophe point T366W and S354C, PCR product using the method for overlap PCR It through agarose gel electrophoresis purification and recovery and is cloned into carrier, confirmation obtains correct clone after sequence verification, obtains Fc Segment knob mutant,

(3) method that the Fc segment of acquisition uses overlap PCR again is introduced into catastrophe point T366S, L368A, Y407V And Y349C, PCR product is through agarose gel electrophoresis purification and recovery and is cloned into carrier, and confirmation obtains after sequence verification Correctly clone obtains Fc segment hole mutant,

(4) the Fc piece for obtaining heavy chain variable region VH, the heavy chain constant region CH1 and step (2) that obtain in above-mentioned steps (1) Section knob mutant is template, by above three segment composition and is fitted into expression vector using overlap round pcr, is constructed The expression vector of encoding heavy chain knob mutant is obtained, that is, obtains the expression vector of coding peptide chain B,

(5) hyaluronidase will be obtained in step (1) similar to object segment, the Fc section hole mutant that step (3) obtains is Template by above-mentioned two a segment composition and is fitted into expression vector using overlap round pcr, obtains encoding hyaluronan Enzyme merges the expression vector of peptide chain, that is, peptide linker can be added if necessary in the expression vector for obtaining coding peptide chain A,

(6) using the light chain variable region VL and constant region of light chain CL that obtain in step (1) as template, overlap is utilized Round pcr is by above-mentioned segment composition and is fitted into expression vector, obtains the expression vector of coding IgG antibody light chain, that is, is compiled The expression vector of code peptide chain C,

(7) above three expression vector is introduced in host cell to the expression for carrying out fusion protein.

When the structure type of fusion protein belongs to the fusion protein of aforementioned (2) class, preparation method includes following step It is rapid:

(1) full genome synthesis human IgG antibody's heavy chain object segment similar with the variable region gene of light chain and hyaluronidase, is obtained VH, VL segment and hyaluronidase for obtaining IgG antibody are similar to object segment；Full genome synthesizes human IgG antibody's constant region of light chain CL, again Chain constant region CH1 and Fc segment,

(2) the Fc segment of acquisition is introduced into catastrophe point T366W and S354C, PCR product using the method for overlap PCR It through agarose gel electrophoresis purification and recovery and is cloned into carrier, confirmation obtains correct clone after sequence verification, obtains Fc Segment knob mutant,

(3) method that the Fc segment of acquisition uses overlap PCR again is introduced into catastrophe point T366S, L368A, Y407V And Y349C, PCR product is through agarose gel electrophoresis purification and recovery and is cloned into carrier, and confirmation obtains after sequence verification Correctly clone obtains Fc segment hole mutant,

(4) the Fc piece for obtaining heavy chain variable region VH, the constant region of light chain CL and step (3) that obtain in above-mentioned steps (1) Section hole mutant is template, by above three segment composition and is fitted into expression vector using overlap round pcr, is constructed The expression vector of encoding heavy chain hole mutant is obtained, that is, obtains the expression vector of coding peptide chain B,

(5) hyaluronidase will be obtained in step (1) similar to object segment, the Fc section knob mutant that step (2) obtains is Template by above-mentioned two a segment composition and is fitted into expression vector using overlap round pcr, obtains encoding hyaluronan Enzyme merges the expression vector of peptide chain, that is, peptide linker can be added if necessary in the expression vector for obtaining coding peptide chain A,

(6) using the light chain variable region VL and heavy chain constant region CH1 that obtain in step (1) as template, overlap is utilized Round pcr is by above-mentioned segment composition and is fitted into expression vector, obtains the expression vector of coding IgG antibody light chain, that is, is compiled The expression vector of code peptide chain C,

(7) above three expression vector is introduced in host cell to the expression for carrying out fusion protein.

In the present invention, any suitable carrier can be used, can for pGEM-T, pcDNA3.1, pEE6.4, One of pEE12.4, pDHFR, pDR1 include the fusion dna for being connected with suitable transcription and translation and adjusting sequence in expression vector Sequence.

The expression of mammal or insect host cell culture systems fusion protein for use in the present invention, COS, CHO, HEK293, NS0, sf9 and sf21 etc. may be applicable to the present invention.

Available host cell is the prokaryotic cell containing above-mentioned carrier, can be DH5a, Top10, BL21 (DE3), TG1 One of.

Fusion protein of the invention can easily generate in following cell: mammalian cell, such as CHO, NSO, HEK293, BHK or COS cell；Bacterial cell, such as Escherichia coli, withered grass bud are from bacillus or Pseudomonas fluorescens；Insect is thin Born of the same parents or fungi or yeast cells, the cell use known technology culture in this field.

However, insect and yeast or other fungal cells generate inhuman N glycan, therefore what is generated in such cell has The glycosylated albumen of N connection can cause immunogenic response if being applied to patient.Production in such cell needs to eliminate The glycosylation site of N- connection and/or genetic engineering transformation is carried out to the cell, to use in this field known technology Generate people N- glycan.See, for example, (Hamilton et al., 2003, Production ofcomplex human Glycoproteins in yeast, 301:1244-1246) (in August, 2003).

It is preferred for carrying out production in mammalian cells, and the mammalian host cell selected is containing glutamine The CHOK1SV cell line (referring to U.S. Patent number 5,122,464) of synzyme (GS) expression system.Well-known side can be passed through Carrier comprising subject polynucleotide sequence (for example, fusion protein and expression control sequence) is transferred in host cell by method, The method can change according to the type of cell host.For example, calcium oxide conversion is commonly used in prokaryotic cell, and at calcium phosphate Reason or electroporation can be used for other cell hosts.

The preparation method of fusion protein disclosed in the present invention is to cultivate above-mentioned host cell under expression condition, from And expressed fusion protein, fusion protein described in isolated or purified.

Using the above method, bispecific antibody can be purified as substantially uniform substance, such as in SDS-PAGE electricity It is single band in swimming.

The method that can use affinity chromatography isolates and purifies fusion protein disclosed by the invention, according to what is utilized The characteristic of affinity column can be used conventional method such as high-salt buffer, change the methods of PH elution of bound on affinity column Fusion protein polypeptide.

Various method for purifying proteins can be used, and such method is known in this field and is described in for example (Wilchek and Bayer,1990,Methods in enzymology)(Scopes,2013,Protein purification:principles andpractice)。

Beneficial guarantee of the invention and effect:

The present invention provides a kind of targent fused proteins for having hyaluronidase activity, preparation method and its usage, should Fusion protein is the tripolymer that peptide chain, IgG antibody heavy chain mutant, IgG antibody light chain are merged comprising hyaluronidase, is both had Hyaluronidase activity can enable fusion protein of the invention to target specific cancer anti-in combination with specific target spot again Original, and using the hyaluronic acid in hyaluronidase degradation tumor tissues, it effectively realizes to tumor-infiltrated and transfer inhibition, By being combined with other anti-tumor drugs, has wide potential applicability in clinical practice.

Detailed description of the invention

Fig. 1 is the structural schematic diagram of fusion protein, and wherein A is the structural schematic diagram of P-P20 fusion protein, B Pe-P20 The structural schematic diagram of fusion protein；C is the structural schematic diagram of T-P20 fusion protein；

Fig. 2 is that P-P20 fusion protein inhibits HCC827 cell activity experimental result；

Fig. 3 is that T-P20 fusion protein inhibits BT474 cell interior tumor experiment result；

Fig. 4 is that a variety of fusion proteins inhibit HCC827 cell activity experimental result；

Fig. 5 is that a variety of fusion proteins without peptide linker inhibit HCC827 cell activity experimental result.

Specific embodiment

The present invention is further detailed in following embodiment, experimental example, should not be construed as limiting the invention.It is real Applying example does not include detailed descriptions of conventional methods, such as the method that those draw for carrier construction and matter, will encode the base of albumen Plasmid is introduced method as the method for host cell for this field by the method drawn by carrier as being inserted into and matter In be well-known with the personnel of ordinary skill, and be all described in many publications, including Sambrook, J., Fritsch, E.F.andManiais, T. (1989) Molecular Cloning:A Laboratory Manual, 2^ndEdition, Cold spring Harbor Laboratory Press.

The building and expression of embodiment 1, P-P20 fusion protein

(1) variable region gene and hyaluronidase PH20 of full genome synthesis panitumumab heavy chain of antibody and light chain (36-482) segment obtains VH, VL segment and PH20 segment (amino acid sequence and nucleotide sequence such as SEQ of Panitumumab Shown in ID NO:8-13).Full genome synthesizes human immunoglobulin(HIg) constant region of light chain CL, IgG1 heavy chain constant region CH1's and IgG1 Fc segment (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:14-19).

(2) by the Fc segment of acquisition, catastrophe point: T366W and S354C is introduced using the method for overlap PCR.PCR is produced Object is through agarose gel electrophoresis purification and recovery and is cloned into pGEM-T carrier, and confirmation obtains correct clone after sequence verification (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:20-21) obtains Fc sections of knob mutant.

(3) separately by acquisition Fc segment use again overlap PCR method introduce catastrophe point: T366S, L368A, Y407V and Y349C.PCR product is through agarose gel electrophoresis purification and recovery and is cloned into pGEM-T carrier, after sequence verification really Recognize and obtain correctly clone (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:22-23), obtains Fc sections of hole Mutant.

(4) the Fc segment for obtaining the panitumumab heavy chain variable region and step (2) that obtain in above-mentioned steps (1) Knob mutant is template, by above-mentioned two segment composition and is fitted into expression vector using overlap round pcr, building obtains It obtains panitumumab heavy chain knob mutant (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:24-25), that is, obtains The expression vector of peptide chain B must be encoded.

(5) the Fc section hole mutant that PH20 segment and step (3) obtain will be obtained in step (1) is template, is used Overlap round pcr is by above-mentioned two a segment composition and is fitted into expression vector.Peptide linker is added simultaneously, that is, obtains PH20-Fc_hole_mut merges segment (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:26-27), that is, obtains Encode the expression vector of peptide chain A.

(6) it using the panitumumab light chain variable region obtained in step (1) and constant region of light chain CL as template, utilizes Overlap round pcr optimizes above-mentioned segment composition, i.e. acquisition panitumumab light chain to the sequence, dashes forward Become (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:28-29), that is, obtains the expression vector of coding peptide chain C.

(7) expressing fusion protein and purifying

3 × 10 are inoculated in 3.5cm tissue culture dishes⁵A CHO-K1 cell, cell culture to 80%-85% merge when into Row transfection: heavy chain plasmid and each 10 μ g of P20 chain plasmid, 4 μ g of light chain plasmids and 30 μ l Lipofectamine2000Reagent are taken (Invitrogen Products) are dissolved in respectively in 800 μ l plasma-free DMEM mediums, are stored at room temperature 5 minutes, by both the above Liquid mixing is replaced with the DMEM culture medium of 3ml serum-free therebetween so that DNA- liposome complex is formed for incubation at room temperature 20 minutes The serum-containing media in culture dish is changed, then the DNA- liposome complex of formation is added in plate, CO₂Incubator culture 4 The DMEM complete medium that 2ml contains 10% serum is added after hour, is placed in CO₂Continue to cultivate in incubator.Transfection is thin after carrying out for 24 hours Born of the same parents, which change, screens resistance clone containing the Selective agar medium of 500 μ g/ml G418 and 300 μ g/ml Zeocin.

The high-expression clone that screening is obtained is expanded with serum free medium to be cultivated, with Protein A affinity column (GE company Product) isolate and purify P-P20.P-P20 is dialysed with PBS, finally with UV absorption standard measure.The structure of P-P20 is as schemed Shown in 1A.

The building and expression of embodiment 2.Pe-P20 fusion protein

(1) variable region gene of full genome synthesis pembrolizumab heavy chain of antibody and light chain, obtains VH, VL segment of pembrolizumab (nucleotide sequence and amino acid sequence are as shown in SEQ ID NO:30-33).Full genome Synthesize 4 heavy chain constant region CH1 and Fc segment of human IgG (amino acid sequence and nucleotide sequence such as SEQ ID NO:34-37 institute Show).

(2) by the IgG4-Fc segment of acquisition, catastrophe point is introduced using the method for overlap PCR: T366W's and S354C Corresponding site.PCR product is through agarose gel electrophoresis purification and recovery and is cloned into pGEM-T carrier, and confirmation obtains after sequence verification It obtained correct clone (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:38-39), and obtained IgG4-Fc sections of knob Mutant.

(3) method that the IgG4-Fc segment of acquisition uses overlap PCR again is separately introduced to the mutation of corresponding position Point: T366S, L368A, Y407V and Y349C.PCR product is through agarose gel electrophoresis purification and recovery and is cloned into pGEM-T carrier In, confirmation obtains correctly clone (amino acid sequence and nucleotide sequence such as SEQ ID NO:40-41 institute after sequence verification Show), that is, obtain IgG4-Fc sections of hole mutant.

(4) the Fc segment for obtaining the pembrolizumab heavy chain variable region and step (2) that obtain in above-mentioned steps (1) Knob mutant is template, by above-mentioned two segment composition and is fitted into expression vector using overlap round pcr, building obtains It obtains pembrolizumab heavy chain knob mutant (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:42-43), i.e., Obtain the expression vector of coding peptide chain B.

(5) by PH20 segment, the IgG4-Fc section hole mutant that step (3) obtains is template, using overlap PCR Technology is by above-mentioned two a segment composition and is fitted into expression vector.Peptide linker is added simultaneously, obtains PH20-IgG4-Fc_ Hole_mut merges segment (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:44-45), that is, obtains coding peptide chain A Expression vector.

(6) using the pembrolizumab light chain variable region obtained in step (1) and constant region of light chain CL as template, benefit With overlap round pcr by above-mentioned segment composition, i.e. acquisition pembrolizumab light chain, and the sequence is optimized, into Row mutation (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:46-47), that is, the expression for obtaining coding peptide chain C carry Body.

(7) expressing fusion protein and purifying

3 × 10 are inoculated in 3.5cm tissue culture dishes⁵A CHO-K1 cell, cell culture to 80%-85% merge when into Row transfection: heavy chain plasmid and each 10 μ g of P20 chain plasmid, 4 μ g of light chain plasmids and 30 μ l Lipofectamine2000Reagent are taken [Invitrogen Products] are dissolved in 800 μ l plasma-free DMEM mediums respectively, are stored at room temperature 5 minutes, by above 2 kinds of liquid Mixing, incubation at room temperature 20 minutes so that DNA- liposome complex is formed, therebetween with the DMEM culture medium replacement training of 3ml serum-free The serum-containing media in ware is supported, then the DNA- liposome complex of formation is added in plate, CO₂Incubator culture 4 hours The DMEM complete medium that 2ml contains 10% serum is added afterwards, is placed in CO₂Continue to cultivate in incubator.Cell changes after transfection carries out for 24 hours Resistance clone is screened containing the Selective agar medium of 500 μ g/ml G418 and 300 μ g/ml Zeocin.

The high-expression clone that screening is obtained is expanded with serum free medium to be cultivated, with Protein A affinity column (GE company Product) isolate and purify Pe-P20.Pe-P20 is dialysed with PBS, finally with UV absorption standard measure.The structure of Pe-P20 is such as Shown in Figure 1B.

The building and expression of embodiment 3.T-P20 fusion protein

(1) variable region gene of full genome synthesis Trastuzumab heavy chain of antibody and light chain, obtains Trastuzumab's VH, VL segment (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:48-51), it is light that full genome synthesizes human IgG1's antibody Chain constant region CL, heavy chain constant region CH1 and Fc segment.

It (2) is template by PH20 segment and Fc segment knob mutant, using overlap round pcr by above-mentioned two Duan Ronghe is simultaneously fitted into expression vector, and building obtains PH20-knob mutant (amino acid sequence and nucleotide sequence such as SEQ ID Shown in NO:52-53), that is, obtain the expression vector of coding peptide chain A.

(3) Trastuzumab heavy chain variable region, CL and Fc sections of hole mutant of constant region of light chain will be obtained in step (1) It for template, by above three segment composition and is fitted into expression vector using overlap round pcr, obtains Trastuzumab VH-CL-Hing-Fc_hole_mut merges segment (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:54-55), Obtain the expression vector of coding peptide chain B.

(4) using the Trastuzumab light chain variable region obtained in step (1) and IgG heavy chain constant region CH1 as template, Using overlap round pcr by above-mentioned segment composition, obtains Trastuzumab VL-CH1 fusion segment and be packed into expression load In body (amino acid sequence and nucleotide sequence are as shown in SEQ ID NO:56-57), that is, obtain the expression vector of coding peptide chain C.

(5) expressing fusion protein and purifying

3 × 10 are inoculated in 3.5cm tissue culture dishes⁵A CHO-K1 cell, cell culture to 80%-85% merge when into Row transfection: heavy chain plasmid and each 10 μ g of P20 chain plasmid, 4 μ g of light chain plasmids and 30 μ l Lipofectamine2000Reagent are taken [Invitrogen Products] are dissolved in 800 μ l plasma-free DMEM mediums respectively, are stored at room temperature 5 minutes, by above 2 kinds of liquid Mixing, incubation at room temperature 20 minutes so that DNA- liposome complex is formed, therebetween with the DMEM culture medium replacement training of 3ml serum-free The serum-containing media in ware is supported, then the DNA- liposome complex of formation is added in plate, CO₂Incubator culture 4 hours The DMEM complete medium that 2ml contains 10% serum is added afterwards, is placed in CO₂Continue to cultivate in incubator.Cell changes after transfection carries out for 24 hours Resistance clone is screened containing the Selective agar medium of 500 μ g/ml G418 and 300 μ g/ml Zeocin.

The high-expression clone that screening is obtained is expanded with serum free medium to be cultivated, with Protein A affinity column (GE company Product) isolate and purify T-P20.T-P20 is dialysed with PBS, finally with UV absorption standard measure.The structure of T-P20 is as schemed Shown in 1C.

Embodiment 4.Biacore analysis

Polyclonal anti-human Fc antibodies (Jackson ImmunoResearch company) are coated on CM5M5 chip (GE company) On, it captures after being detected antibody, the affinity of each fusion protein is detected with Biacore T100 (GE Healthcare), specifically Detection affinity numerical value is shown in Table 1.

Table 1.Biacore analyzes result

Embodiment 5:P-P20 inhibits non-small cell lung cancer cell viability experiment

The good HCC827 cell (ATCC) of growth conditions is taken, adjustment cell concentration is 5 × 10³It is thin to be inoculated in 96 holes by/ml Born of the same parents' culture plate, 200 holes μ l/, in 37 DEG C, 5%CO₂After cultivating for 24 hours in incubator, it is added final concentration of 5nmol's in culture solution EGF and P-P20, panitumumab of various concentration gradient, P20, panitumumab+P20, unrelated human IgG (Rituximab is purchased from Roche company), after 3 days, cell viability CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, WI) detection.

Experimental result is as shown in Figure 2.The experimental results showed that the suppressible HCC827 cell viability of P-P20, than Panitumumab and P20 has more significant inhibitory effect, the double antibody group effect with panitumumab and P-P20 use in conjunction It is similar or more excellent similar with bispecific antibody CT16 effect.

Inhibit tumour growth experiment in embodiment 6:T-PH20 body

For antitumor activity in detection T-PH20 body, BT474 cell is used first, is inoculated in BALB/c nude mice right flank side skin Under, nude mice subcutaneously should bury estrogen sustained release tablets, and tumor formation region is inoculated with matrix in advance.Tail vein injection after tumor formation, 5mg/kg are each The following human cytokines drug of group: trastuzumab, Ph20, T-PH20, unrelated control human IgG, trastuzumab and Each 2.5mg/kg use in conjunction of two kinds of albumen of PH20 is injected 1 time weekly, is continued to the excessive execution of mouse tumor.Measurement is swollen daily The length and width of tumor calculate gross tumor volume.

Tumor growth curve is as shown in Figure 3.The result shows that: the T-PH20 treatment group tumors speed of growth significantly less than Trastuzumab and Ph20 treatment group (after 35 days, P < 0.01, Mann-Whitney are examined).And the therapeutic effect of T-PH20 by In with trastuzumab and PH20 use in conjunction effect (after 35 days, P < 0.01, Mann-Whitney examine).

Embodiment 7: the preparation of a variety of targent fused proteins

Using the method in embodiment 1,2,3, a variety of fusion proteins are further prepared, specifying information is shown in Table 2.

2 fusion protein information of table

The good HCC827 cell (ATCC) of growth conditions is taken, adjustment cell concentration is 5 × 10³It is thin to be inoculated in 96 holes by/ml Born of the same parents' culture plate, 200 holes μ l/, in 37 DEG C, 5%CO₂After cultivating for 24 hours in incubator, 1 μ g/ml concentration of final concentration is added in culture solution Fusion protein, by unrelated human IgG be control (Rituximab is purchased from Roche company), after 3 days, cell viability use CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, WI) detection.

Experimental result is as shown in Figure 4.The experimental results showed that each fusion protein can inhibit HCC827 cell living in various degree Power.Statistical result showed each group has statistical difference to control group (P < 0.01 is examined between variance analysis and Tukey group).

Embodiment 8: the preparation without peptide linker targent fused protein

In the above-described embodiments, the construction method of targent fused protein is all made of the method fusion hyaluronidase of peptide linker The region Fc of analog and Immunoglobulin IgG.Construction method without containing peptide linker is similar in embodiment 1 and embodiment 2 The construction method of description, difference is that the Overlap PCR in step (5) is added without peptide linker, and is directly merged.Pass through This method constructs a variety of fusion protein information such as table 3.

3 fusion protein information of table

The good HCC827 cell (ATCC) of growth conditions, adjustment cell concentration are 5 × 10³/ ml is inoculated in 96 hole cells Culture plate, 200 holes μ l/, in 37 DEG C, 5%CO₂After cultivating for 24 hours in incubator, 1 μ g/ml concentration of final concentration is added in culture solution Fusion protein is control (Rituximab is purchased from Roche company) by unrelated human IgG, and after 3 days, cell viability is used CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, WI) detection.

Experimental result is as shown in Figure 5.The experimental results showed that each fusion protein can inhibit HCC827 cell living in various degree Power.Statistical result showed each group has statistical difference to control group (P < 0.01 is examined between variance analysis and Tukey group).

The preferred embodiment of the present invention has been described in detail above, but the invention be not limited to it is described Embodiment, those skilled in the art can also make various equivalent on the premise of not violating the inventive spirit of the present invention Variation or replacement, these equivalent variation or replacement are all included in the scope defined by the claims of the present application.

SEQUENCE LISTING

<110>Feng tide medical sci-tech (Shanghai) Co., Ltd.

<120>have targent fused protein, the Preparation method and use of hyaluronidase activity

<130>claims specification

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<170> PatentIn version 3.5

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

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Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr Tyr

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Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

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

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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 Xaa

225

<210> 8

<211> 119

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 8

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly

20 25 30

Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr

85 90 95

Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 9

<211> 357

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 9

caagttcagc tgcaagaaag cggacccggt ttagtgaagc ctagcgagac tttatcttta 60

acttgtacag tgtccggagg cagcgtgagc agcggcgatt actactggac ttggattcgt 120

cagagccccg gtaagggttt agagtggatt ggccacatct actacagcgg caacaccaac 180

tacaacccct ctttaaagtc tcgtctgacc atcagcatcg acaccagcaa gacccagttc 240

tctttaaagc tgagcagcgt gaccgctgcc gacaccgcca tctactactg cgtgagggat 300

cgtgtgaccg gcgccttcga catctgggga caaggtactt tagtgaccgt gagctcc 357

<210> 10

<211> 107

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu

85 90 95

Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 11

<211> 321

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 11

gacatccaga tgacccagag ccctagctct ttaagcgcca gcgtgggcga tagggtgacc 60

atcacttgtc aagcctctca agatatcagc aactatttaa actggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctacgac gcctccaatc tggagaccgg cgtgccctct 180

cgttttagcg gaagcggcag cggcaccgac ttcaccttca ccatcagctc tttacagccc 240

gaggacatcg ccacctactt ctgtcagcac ttcgaccatt tacctctggc ctttggccaa 300

ggtaccaagg tggagatcaa g 321

<210> 12

<211> 447

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 12

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr

435 440 445

<210> 13

<211> 1341

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 13

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta c 1341

<210> 14

<211> 107

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 14

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

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

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 15

<211> 321

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 15

aggaccgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60

ggaactgcct ctgttgtgtg cctgctgaat aacttctacc ccagagaagc caaagtgcag 120

tggaaggtgg acaacgccct gcagagcgga aacagccagg aaagcgtgac agagcaggat 180

tccaaggatt ccacatacag cctgagcagc acactgacac tgtccaaggc cgactacgag 240

aagcacaagg tgtacgcctg cgaagtgaca caccagggac tgtcctcccc tgtgacaaag 300

agcttcaaca gaggagaatg c 321

<210> 16

<211> 103

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 16

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

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

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

85 90 95

Lys Val Glu Pro Lys Ser Cys

100

<210> 17

<211> 309

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 17

gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaacctgt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgt 309

<210> 18

<211> 227

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 18

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> 19

<211> 681

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 19

gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60

ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120

tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180

ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240

cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300

tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360

gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 420

aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480

tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540

gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600

aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660

ctctccctgt ctccgggtaa a 681

<210> 20

<211> 227

<212> PRT

<213>artificial sequence (Artificial Sequence)

<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 Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

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

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

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

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Lys

225

<210> 21

<211> 681

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 21

gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60

ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120

tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180

ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240

cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300

tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360

gggcagcccc gagaaccaca ggtgtacacc ctgcccccat gccgggatga gctgaccaag 420

aaccaggtca gcctgtggtg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480

tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540

gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600

aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660

ctctccctgt ctccgggtaa a 681

<210> 22

<211> 227

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 22

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

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

130 135 140

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

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

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

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Lys

225

<210> 23

<211> 681

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 23

gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60

ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120

tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180

ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240

cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300

tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360

gggcagcccc gagaaccaca ggtgtgcacc ctgcccccat cccgggatga gctgaccaag 420

aaccaggtca gcctgtcctg cgcggtcaaa ggcttctatc ccagcgacat cgccgtggag 480

tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540

gacggctcct tcttcctcgt cagcaagctc accgtggaca agagcaggtg gcagcagggg 600

aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660

ctctccctgt ctccgggtaa a 681

<210> 24

<211> 449

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 24

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly

20 25 30

Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr

85 90 95

Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly

100 105 110

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

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

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

145 150 155 160

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

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

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

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

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

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

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

305 310 315 320

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

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp

355 360 365

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

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 25

<211> 1347

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 25

caagttcagc tgcaagaaag cggacccggt ttagtgaagc ctagcgagac tttatcttta 60

acttgtacag tgtccggagg cagcgtgagc agcggcgatt actactggac ttggattcgt 120

cagagccccg gtaagggttt agagtggatt ggccacatct actacagcgg caacaccaac 180

tacaacccct ctttaaagtc tcgtctgacc atcagcatcg acaccagcaa gacccagttc 240

tctttaaagc tgagcagcgt gaccgctgcc gacaccgcca tctactactg cgtgagggat 300

cgtgtgaccg gcgccttcga catctgggga caaggtactt tagtgaccgt gagctccgct 360

agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aacctgtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660

tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780

gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840

gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960

tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020

gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1080

accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1140

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260

caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320

aagagcctct ccctgtctcc gggtaaa 1347

<210> 26

<211> 684

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 26

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Ile

435 440 445

Glu Gly Arg Met Asp Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro

450 455 460

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

465 470 475 480

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

485 490 495

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

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

645 650 655

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

660 665 670

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680

<210> 27

<211> 2052

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 27

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta catcgagggc cgcatggacc ccaaatcttg tgacaaaact 1380

cacacatgcc caccgtgccc agcacctgaa ctcctggggg gaccgtcagt cttcctcttc 1440

cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1500

gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1560

gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1620

agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1680

tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 1740

cgagaaccac aggtgtgcac cctgccccca tcccgggatg agctgaccaa gaaccaggtc 1800

agcctgtcct gcgcggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1860

aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1920

ttcttcctcg tcagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1980

tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2040

tctccgggta aa 2052

<210> 28

<211> 214

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 28

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu

85 90 95

Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

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

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 29

<211> 642

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 29

gacatccaga tgacccagag ccctagctct ttaagcgcca gcgtgggcga tagggtgacc 60

atcacttgtc aagcctctca agatatcagc aactatttaa actggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctacgac gcctccaatc tggagaccgg cgtgccctct 180

cgttttagcg gaagcggcag cggcaccgac ttcaccttca ccatcagctc tttacagccc 240

gaggacatcg ccacctactt ctgtcagcac ttcgaccatt tacctctggc ctttggccaa 300

ggtaccaagg tggagatcaa gaggaccgtg gccgccccta gcgtgttcat cttcccccct 360

agcgacgagc agctgaagag cggcaccgct agcgttgtgt gcctgctgaa taacttctac 420

cccagagaag ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg aaacagccag 480

gaaagcgtga cagagcagga ttccaaggat tccacataca gcctgagcag cacactgaca 540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac acaccaggga 600

ctgtcctccc ctgtgacaaa gagcttcaac agaggagaat gc 642

<210> 30

<211> 120

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 30

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 31

<211> 360

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 31

caagtgcagc tggtccagtc cggcgtggag gtgaagaagc ccggagcttc cgtgaaggtg 60

tcttgtaaag ccagcggcta caccttcaca aattactaca tgtactgggt gcggcaagct 120

cccggacaag gtctggaatg gatgggcggc atcaatccta gcaacggcgg caccaacttc 180

aacgagaagt tcaagaatcg tgtgacttta accaccgact ccagcacaac caccgcctac 240

atggagctga aatctttaca gttcgacgac accgctgtgt actattgcgc tcgtcgggac 300

tataggttcg acatgggctt tgactactgg ggacaaggta ccacagttac agtgagctcc 360

<210> 32

<211> 111

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 32

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 33

<211> 333

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 33

gagatcgtgc tgacccagag ccccgctact ttatctttat cccccggtga gagggctacc 60

ttatcttgta gggcctccaa gggcgtgagc acctccggct actcctattt acactggtac 120

cagcagaagc ccggacaagc tcctcggctg ctgatctatt tagcctccta tttagagtcc 180

ggagtgcccg ctaggttctc cggaagcggc tccggcaccg acttcacttt aaccatctcc 240

tctttagagc ccgaggactt cgccgtgtac tactgccagc actctcgtga tttacctctg 300

acctttggcg gcggcaccaa ggtggagatc aag 333

<210> 34

<211> 101

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 34

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Arg Val Glu Ser Lys

100

<210> 35

<211> 303

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 35

gctagcacca agggacccag cgtgttccct ctggcccctt gctcccggtc cacaagcgaa 60

tccaccgccg ctctgggctg tttagtcaag gattactttc ccgagcccgt tacagttagc 120

tggaactccg gcgctctgac atccggagtg cacacctttc ccgccgtgct gcagtccagc 180

ggtttatact ctttaagcag cgtggtgacc gtgccctcca gctctttagg aacaaagaca 240

tacacttgta acgtggacca taagcccagc aacacaaagg tcgacaagcg ggtggagtcc 300

aag 303

<210> 36

<211> 226

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 36

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly

1 5 10 15

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

20 25 30

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

35 40 45

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

50 55 60

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg

65 70 75 80

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

85 90 95

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

100 105 110

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

115 120 125

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

130 135 140

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

145 150 155 160

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

165 170 175

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp

180 185 190

Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His

195 200 205

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu

210 215 220

Gly Lys

225

<210> 37

<211> 678

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 37

tacggccctc cttgtcctcc ttgtcccgcc cccgaatttc tcggcggccc ctccgtgttt 60

ctgtttcctc ccaagcccaa ggatacttta atgatctctc gtacccccga ggtgacttgt 120

gtggtggtgg atgtgtccca agaagacccc gaagtccagt tcaactggta cgtggacgga 180

gtggaggtgc acaatgccaa aaccaagccc cgggaggagc agtttaacag cacctaccgg 240

gtggtgagcg ttttaaccgt gctgcatcaa gattggctga acggaaagga atacaaatgt 300

aaggtcagca acaagggttt acctagctcc atcgagaaga ccatctccaa ggctaaggga 360

cagcctcggg agccccaagt ttacacactg cccccctccc aagaagagat gaccaagaac 420

caagtgagcc tcacatgttt agtgaaggga ttctacccct ccgacatcgc tgtcgagtgg 480

gagagcaacg gccagcccga gaacaactat aagaccacac cccccgtttt agatagcgac 540

ggctccttct ttttatactc tcgtctgacc gtcgacaagt ctcgttggca agaaggcaat 600

gtgttttctt gttccgtgat gcacgaggcc ctccacaatc actacaccca gaaatcttta 660

tccttatctt taggcaag 678

<210> 38

<211> 226

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 38

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly

1 5 10 15

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

20 25 30

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

35 40 45

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

50 55 60

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg

65 70 75 80

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

85 90 95

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

100 105 110

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

115 120 125

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

130 135 140

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

145 150 155 160

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

165 170 175

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp

180 185 190

Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His

195 200 205

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu

210 215 220

Gly Lys

225

<210> 39

<211> 678

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 39

tacggccctc cttgtcctcc ttgtcccgcc cccgaatttc tcggcggccc ctccgtgttt 60

ctgtttcctc ccaagcccaa ggatacttta atgatctctc gtacccccga ggtgacttgt 120

gtggtggtgg atgtgtccca agaagacccc gaagtccagt tcaactggta cgtggacgga 180

gtggaggtgc acaatgccaa aaccaagccc cgggaggagc agtttaacag cacctaccgg 240

gtggtgagcg ttttaaccgt gctgcatcaa gattggctga acggaaagga atacaaatgt 300

aaggtcagca acaagggttt acctagctcc atcgagaaga ccatctccaa ggctaaggga 360

cagcctcggg agccccaagt ttacacactg cccccctgtc aagaagagat gaccaagaac 420

caagtgagcc tctggtgttt agtgaaggga ttctacccct ccgacatcgc tgtcgagtgg 480

gagagcaacg gccagcccga gaacaactat aagaccacac cccccgtttt agatagcgac 540

ggctccttct ttttatactc tcgtctgacc gtcgacaagt ctcgttggca agaaggcaat 600

gtgttttctt gttccgtgat gcacgaggcc ctccacaatc actacaccca gaaatcttta 660

tccttatctt taggcaag 678

<210> 40

<211> 226

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 40

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly

1 5 10 15

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

20 25 30

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

35 40 45

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

50 55 60

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg

65 70 75 80

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

85 90 95

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

100 105 110

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys

115 120 125

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

130 135 140

Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

145 150 155 160

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

165 170 175

Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp

180 185 190

Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His

195 200 205

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu

210 215 220

Gly Lys

225

<210> 41

<211> 678

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 41

tacggccctc cttgtcctcc ttgtcccgcc cccgaatttc tcggcggccc ctccgtgttt 60

ctgtttcctc ccaagcccaa ggatacttta atgatctctc gtacccccga ggtgacttgt 120

gtggtggtgg atgtgtccca agaagacccc gaagtccagt tcaactggta cgtggacgga 180

gtggaggtgc acaatgccaa aaccaagccc cgggaggagc agtttaacag cacctaccgg 240

gtggtgagcg ttttaaccgt gctgcatcaa gattggctga acggaaagga atacaaatgt 300

aaggtcagca acaagggttt acctagctcc atcgagaaga ccatctccaa ggctaaggga 360

cagcctcggg agccccaagt ttgtacactg cccccctccc aagaagagat gaccaagaac 420

caagtgagcc tcagctgtgc cgtgaaggga ttctacccct ccgacatcgc tgtcgagtgg 480

gagagcaacg gccagcccga gaacaactat aagaccacac cccccgtttt agatagcgac 540

ggctccttct ttttagtctc tcgtctgacc gtcgacaagt ctcgttggca agaaggcaat 600

gtgttttctt gttccgtgat gcacgaggcc ctccacaatc actacaccca gaaatcttta 660

tccttatctt taggcaag 678

<210> 42

<211> 447

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 42

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

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

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

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

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

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

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

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

385 390 395 400

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

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 43

<211> 1341

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 43

caagtgcagc tggtccagtc cggcgtggag gtgaagaagc ccggagcttc cgtgaaggtg 60

tcttgtaaag ccagcggcta caccttcaca aattactaca tgtactgggt gcggcaagct 120

cccggacaag gtctggaatg gatgggcggc atcaatccta gcaacggcgg caccaacttc 180

aacgagaagt tcaagaatcg tgtgacttta accaccgact ccagcacaac caccgcctac 240

atggagctga aatctttaca gttcgacgac accgctgtgt actattgcgc tcgtcgggac 300

tataggttcg acatgggctt tgactactgg ggacaaggta ccacagttac agtgagctcc 360

gctagcacca agggacccag cgtgttccct ctggcccctt gctcccggtc cacaagcgaa 420

tccaccgccg ctctgggctg tttagtcaag gattactttc ccgagcccgt tacagttagc 480

tggaactccg gcgctctgac atccggagtg cacacctttc ccgccgtgct gcagtccagc 540

ggtttatact ctttaagcag cgtggtgacc gtgccctcca gctctttagg aacaaagaca 600

tacacttgta acgtggacca taagcccagc aacacaaagg tcgacaagcg ggtggagtcc 660

aagtacggcc ctccttgtcc tccttgtccc gcccccgaat ttctcggcgg cccctccgtg 720

tttctgtttc ctcccaagcc caaggatact ttaatgatct ctcgtacccc cgaggtgact 780

tgtgtggtgg tggatgtgtc ccaagaagac cccgaagtcc agttcaactg gtacgtggac 840

ggagtggagg tgcacaatgc caaaaccaag ccccgggagg agcagtttaa cagcacctac 900

cgggtggtga gcgttttaac cgtgctgcat caagattggc tgaacggaaa ggaatacaaa 960

tgtaaggtca gcaacaaggg tttacctagc tccatcgaga agaccatctc caaggctaag 1020

ggacagcctc gggagcccca agtttacaca ctgcccccct gtcaagaaga gatgaccaag 1080

aaccaagtga gcctctggtg tttagtgaag ggattctacc cctccgacat cgctgtcgag 1140

tgggagagca acggccagcc cgagaacaac tataagacca caccccccgt tttagatagc 1200

gacggctcct tctttttata ctctcgtctg accgtcgaca agtctcgttg gcaagaaggc 1260

aatgtgtttt cttgttccgt gatgcacgag gccctccaca atcactacac ccagaaatct 1320

ttatccttat ctttaggcaa g 1341

<210> 44

<211> 681

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 44

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Ile

435 440 445

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

450 455 460

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

465 470 475 480

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

485 490 495

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

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

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

645 650 655

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

660 665 670

Lys Ser Leu Ser Leu Ser Leu Gly Lys

675 680

<210> 45

<211> 2043

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 45

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta catcgagggc cgcatggact ccaagtacgg ccctccttgt 1380

cctccttgtc ccgcccccga atttctcggc ggcccctccg tgtttctgtt tcctcccaag 1440

cccaaggata ctttaatgat ctctcgtacc cccgaggtga cttgtgtggt ggtggatgtg 1500

tcccaagaag accccgaagt ccagttcaac tggtacgtgg acggagtgga ggtgcacaat 1560

gccaaaacca agccccggga ggagcagttt aacagcacct accgggtggt gagcgtttta 1620

accgtgctgc atcaagattg gctgaacgga aaggaataca aatgtaaggt cagcaacaag 1680

ggtttaccta gctccatcga gaagaccatc tccaaggcta agggacagcc tcgggagccc 1740

caagtttgta cactgccccc ctcccaagaa gagatgacca agaaccaagt gagcctcagc 1800

tgtgccgtga agggattcta cccctccgac atcgctgtcg agtgggagag caacggccag 1860

cccgagaaca actataagac cacacccccc gttttagata gcgacggctc cttcttttta 1920

gtctctcgtc tgaccgtcga caagtctcgt tggcaagaag gcaatgtgtt ttcttgttcc 1980

gtgatgcacg aggccctcca caatcactac acccagaaat ctttatcctt atctttaggc 2040

aag 2043

<210> 46

<211> 218

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 46

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

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

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 47

<211> 654

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 47

gagatcgtgc tgacccagag ccccgctact ttatctttat cccccggtga gagggctacc 60

ttatcttgta gggcctccaa gggcgtgagc acctccggct actcctattt acactggtac 120

cagcagaagc ccggacaagc tcctcggctg ctgatctatt tagcctccta tttagagtcc 180

ggagtgcccg ctaggttctc cggaagcggc tccggcaccg acttcacttt aaccatctcc 240

tctttagagc ccgaggactt cgccgtgtac tactgccagc actctcgtga tttacctctg 300

acctttggcg gcggcaccaa ggtggagatc aagaggaccg tggctgcacc atctgtcttc 360

atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420

aataacttct accccagaga agccaaagtg cagtggaagg tggacaacgc cctgcagagc 480

ggaaacagcc aggaaagcgt gacagagcag gattccaagg attccacata cagcctgagc 540

agcacactga cactgtccaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 600

acacaccagg gactgtcctc ccctgtgaca aagagcttca acagaggaga atgc 654

<210> 48

<211> 120

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 48

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 49

<211> 360

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 49

gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60

tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120

ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180

gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240

ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300

ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360

<210> 50

<211> 107

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 50

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 51

<211> 321

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 51

gacatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggttacc 60

atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120

ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180

cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240

gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300

ggtaccaagg tggagatcaa a 321

<210> 52

<211> 684

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 52

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Ile

435 440 445

Glu Gly Arg Met Asp Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro

450 455 460

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

465 470 475 480

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

485 490 495

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

645 650 655

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

660 665 670

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680

<210> 53

<211> 2052

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 53

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta catcgagggc cgcatggacc ccaaatcttg tgacaaaact 1380

cacacatgcc caccgtgccc agcacctgaa ctcctggggg gaccgtcagt cttcctcttc 1440

cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1500

gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1560

gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1620

agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1680

tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 1740

cgagaaccac aggtgtacac cctgccccca tgccgggatg agctgaccaa gaaccaggtc 1800

agcctgtggt gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1860

aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1920

ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1980

tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2040

tctccgggta aa 2052

<210> 54

<211> 454

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 54

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro Ser Val

115 120 125

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

130 135 140

Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

145 150 155 160

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

165 170 175

Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu

180 185 190

Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu

195 200 205

Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

290 295 300

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

325 330 335

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

340 345 350

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

355 360 365

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

370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Ser Leu Ser Pro Gly Lys

450

<210> 55

<211> 1362

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 55

gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60

tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120

ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180

gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240

ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300

ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360

gctagcgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 420

ggaactgcct ctgttgtgtg cctgctgaat aacttctacc ccagagaagc caaagtgcag 480

tggaaggtgg acaacgccct gcagagcgga aacagccagg aaagcgtgac agagcaggat 540

tccaaggatt ccacatacag cctgagcagc acactgacac tgtccaaggc cgactacgag 600

aagcacaagg tgtacgcctg cgaagtgaca caccagggac tgtcctcccc tgtgacaaag 660

agcttcaaca gaggagaatg cgacaaaact cacacatgcc caccgtgccc agcacctgaa 720

ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 780

tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 840

aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 900

gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 960

ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1020

aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtgcac cctgccccca 1080

tcccgggatg agctgaccaa gaaccaggtc agcctgtcct gcgcggtcaa aggcttctat 1140

cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1200

acgcctcccg tgctggactc cgacggctcc ttcttcctcg tcagcaagct caccgtggac 1260

aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1320

aaccactaca cgcagaagag cctctccctg tctccgggta aa 1362

<210> 56

<211> 212

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 56

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ala Ser Thr

100 105 110

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

115 120 125

Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

130 135 140

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

145 150 155 160

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

165 170 175

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys

180 185 190

Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu

195 200 205

Pro Lys Ser Cys

210

<210> 57

<211> 636

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 57

gacatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggttacc 60

atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120

ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180

cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240

gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300

ggtaccaagg tggagatcaa atcctccgct agcaccaagg gcccatcggt cttccccctg 360

gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 420

tacttccccg aacctgtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 480

accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 540

ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 600

accaaggtgg acaagaaagt tgagcccaaa tcttgt 636

<210> 58

<211> 450

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 58

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Ser Ser

20 25 30

Tyr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Ala Gly Thr Gly Ser Pro Ser Tyr Asn Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Arg Asp Tyr Tyr Ser Asn Ser Leu Thr Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

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

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

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

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

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

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

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

355 360 365

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

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

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

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 59

<211> 1350

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 59

caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60

tcctgcaagg cctccggcta caccttcagg tcctcctaca tctcctgggt gaggcaggcc 120

cccggccagg gcctggagtg gatgggctgg atctacgccg gcaccggctc cccctcctac 180

aaccagaagc tgcagggcag ggtgaccatg accaccgaca cctccacctc caccgcctac 240

atggagctga ggtccctgag gtccgacgac accgccgtgt actactgcgc caggcacagg 300

gactactact ccaactccct gacctactgg ggccagggca ccctggtgac cgtgtcctcc 360

gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaacctgt gacggtgtcg 480

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 660

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020

aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatg ccgggatgag 1080

ctgaccaaga accaggtcag cctgtggtgc ctggtcaaag gcttctatcc cagcgacatc 1140

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320

cagaagagcc tctccctgtc tccgggtaaa 1350

<210> 60

<211> 220

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 60

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser

20 25 30

Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 61

<211> 660

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 61

gacatcgtga tgacccagtc ccccgactcc ctggccgtgt ccctgggcga gagggccacc 60

atcaactgca agtcctccca gtccgtgctg aactccggca accagaagaa ctacctgacc 120

tggtaccagc agaagcccgg ccagcccccc aagctgctga tctactgggc ctccaccagg 180

gagtccggcg tgcccgacag gttctccggc tccggctccg gcaccgactt caccctgacc 240

atctcctccc tgcaggccga ggacgtggcc gtgtactact gccagtccga ctactcctac 300

ccctacacct tcggccaggg caccaagctg gagatcaaga ggaccgtggc tgcaccatct 360

gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420

ctgctgaata acttctaccc cagagaagcc aaagtgcagt ggaaggtgga caacgccctg 480

cagagcggaa acagccagga aagcgtgaca gagcaggatt ccaaggattc cacatacagc 540

ctgagcagca cactgacact gtccaaggcc gactacgaga agcacaaggt gtacgcctgc 600

gaagtgacac accagggact gtcctcccct gtgacaaaga gcttcaacag aggagaatgc 660

<210> 62

<211> 449

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 62

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

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

20 25 30

Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly

100 105 110

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

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

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

145 150 155 160

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

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

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

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

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

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

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

305 310 315 320

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

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp

355 360 365

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

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 63

<211> 1347

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 63

gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggcggctc cctgaggctg 60

tcctgcgccg cctccggctt caccttcacc gactacacca tggactgggt gaggcaggcc 120

cccggcaagg gcctggagtg ggtggccgac gtgaacccca actccggcgg ctccatctac 180

aaccagaggt tcaagggcag gttcaccctg tccgtggaca ggtccaagaa caccctgtac 240

ctgcagatga actccctgag ggccgaggac accgccgtgt actactgcgc caggaacctg 300

ggcccctcct tctacttcga ctactggggc cagggcaccc tggtgaccgt gtcctccgct 360

agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aacctgtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660

tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780

gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840

gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960

tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020

gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1080

accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1140

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260

caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320

aagagcctct ccctgtctcc gggtaaa 1347

<210> 64

<211> 214

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 64

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

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

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 65

<211> 642

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 65

gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga cagggtgacc 60

atcacctgca aggcctccca ggacgtgtcc atcggcgtgg cctggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactcc gcctcctaca ggtacaccgg cgtgccctcc 180

aggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 240

gaggacttcg ccacctacta ctgccagcag tactacatct acccctacac cttcggccag 300

ggcaccaagg tggagatcaa gaggaccgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctac 420

cccagagaag ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg aaacagccag 480

gaaagcgtga cagagcagga ttccaaggat tccacataca gcctgagcag cacactgaca 540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac acaccaggga 600

ctgtcctccc ctgtgacaaa gagcttcaac agaggagaat gc 642

<210> 66

<211> 449

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 66

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr

50 55 60

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

65 70 75 80

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

85 90 95

Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly

100 105 110

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

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

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

145 150 155 160

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

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

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

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

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

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

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

305 310 315 320

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

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp

355 360 365

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

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 67

<211> 1347

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 67

caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60

acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120

ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaacac agactataat 180

acacctttca catccagact gagcatcaac aaggacaatt ccaagagcca agttttcttt 240

aaaatgaaca gtctgcaatc taatgacaca gccatatatt actgtgccag agccctcacc 300

tactatgatt acgagtttgc ttactggggc caagggactc tggtcactgt ctctgcagct 360

agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aacctgtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660

tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780

gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840

gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960

tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020

gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1080

accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1140

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260

caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320

aagagcctct ccctgtctcc gggtaaa 1347

<210> 68

<211> 214

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 68

Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn

20 25 30

Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile

35 40 45

Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

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

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 69

<211> 642

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 69

gacatcctgc tgacccagtc ccccgtgatc ctgtccgtgt cccccggcga gagggtgtcc 60

ttctcctgca gggcctccca gtccatcggc accaacatcc actggtacca gcagaggacc 120

aacggctccc ccaggctgct gatcaagtac gcctccgagt ccatctccgg catcccctcc 180

aggttctccg gctccggctc cggcaccgac ttcaccctgt ccatcaactc cgtggagtcc 240

gaggacatcg ccgactacta ctgccagcag aacaacaact ggcccaccac cttcggcgcc 300

ggcaccaagc tggagctgaa gaggaccgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctac 420

cccagagaag ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg aaacagccag 480

gaaagcgtga cagagcagga ttccaaggat tccacataca gcctgagcag cacactgaca 540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac acaccaggga 600

ctgtcctccc ctgtgacaaa gagcttcaac agaggagaat gc 642

<210> 70

<211> 448

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 70

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

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

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

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

145 150 155 160

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

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

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

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

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

340 345 350

Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys

355 360 365

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

370 375 380

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

385 390 395 400

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

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 71

<211> 1344

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 71

Gly Ala Gly Gly Thr Gly Cys Ala Gly Cys Thr Gly Gly Thr Gly Gly

1 5 10 15

Ala Gly Thr Cys Cys Gly Gly Cys Gly Gly Cys Gly Gly Cys Cys Thr

20 25 30

Gly Gly Thr Gly Cys Ala Gly Cys Cys Cys Gly Gly Cys Gly Gly Cys

35 40 45

Thr Cys Cys Cys Thr Gly Ala Gly Gly Cys Thr Gly Thr Cys Cys Thr

50 55 60

Gly Cys Gly Cys Cys Gly Cys Cys Thr Cys Cys Gly Gly Cys Thr Thr

65 70 75 80

Cys Ala Cys Cys Thr Thr Cys Thr Cys Cys Gly Ala Cys Thr Cys Cys

85 90 95

Thr Gly Gly Ala Thr Cys Cys Ala Cys Thr Gly Gly Gly Thr Gly Ala

100 105 110

Gly Gly Cys Ala Gly Gly Cys Cys Cys Cys Cys Gly Gly Cys Ala Ala

115 120 125

Gly Gly Gly Cys Cys Thr Gly Gly Ala Gly Thr Gly Gly Gly Thr Gly

130 135 140

Gly Cys Cys Thr Gly Gly Ala Thr Cys Thr Cys Cys Cys Cys Cys Thr

145 150 155 160

Ala Cys Gly Gly Cys Gly Gly Cys Thr Cys Cys Ala Cys Cys Thr Ala

165 170 175

Cys Thr Ala Cys Gly Cys Cys Gly Ala Cys Thr Cys Cys Gly Thr Gly

180 185 190

Ala Ala Gly Gly Gly Cys Ala Gly Gly Thr Thr Cys Ala Cys Cys Ala

195 200 205

Thr Cys Thr Cys Cys Gly Cys Cys Gly Ala Cys Ala Cys Cys Thr Cys

210 215 220

Cys Ala Ala Gly Ala Ala Cys Ala Cys Cys Gly Cys Cys Thr Ala Cys

225 230 235 240

Cys Thr Gly Cys Ala Gly Ala Thr Gly Ala Ala Cys Thr Cys Cys Cys

245 250 255

Thr Gly Ala Gly Gly Gly Cys Cys Gly Ala Gly Gly Ala Cys Ala Cys

260 265 270

Cys Gly Cys Cys Gly Thr Gly Thr Ala Cys Thr Ala Cys Thr Gly Cys

275 280 285

Gly Cys Cys Ala Gly Gly Ala Gly Gly Cys Ala Cys Thr Gly Gly Cys

290 295 300

Cys Cys Gly Gly Cys Gly Gly Cys Thr Thr Cys Gly Ala Cys Thr Ala

305 310 315 320

Cys Thr Gly Gly Gly Gly Cys Cys Ala Gly Gly Gly Cys Ala Cys Cys

325 330 335

Cys Thr Gly Gly Thr Gly Ala Cys Cys Gly Thr Gly Thr Cys Cys Thr

340 345 350

Cys Cys Gly Cys Thr Ala Gly Cys Ala Cys Cys Ala Ala Gly Gly Gly

355 360 365

Cys Cys Cys Ala Thr Cys Gly Gly Thr Cys Thr Thr Cys Cys Cys Cys

370 375 380

Cys Thr Gly Gly Cys Ala Cys Cys Cys Thr Cys Cys Thr Cys Cys Ala

385 390 395 400

Ala Gly Ala Gly Cys Ala Cys Cys Thr Cys Thr Gly Gly Gly Gly Gly

405 410 415

Cys Ala Cys Ala Gly Cys Gly Gly Cys Cys Cys Thr Gly Gly Gly Cys

420 425 430

Thr Gly Cys Cys Thr Gly Gly Thr Cys Ala Ala Gly Gly Ala Cys Thr

435 440 445

Ala Cys Thr Thr Cys Cys Cys Cys Gly Ala Ala Cys Cys Thr Gly Thr

450 455 460

Gly Ala Cys Gly Gly Thr Gly Thr Cys Gly Thr Gly Gly Ala Ala Cys

465 470 475 480

Thr Cys Ala Gly Gly Cys Gly Cys Cys Cys Thr Gly Ala Cys Cys Ala

485 490 495

Gly Cys Gly Gly Cys Gly Thr Gly Cys Ala Cys Ala Cys Cys Thr Thr

500 505 510

Cys Cys Cys Gly Gly Cys Thr Gly Thr Cys Cys Thr Ala Cys Ala Gly

515 520 525

Thr Cys Cys Thr Cys Ala Gly Gly Ala Cys Thr Cys Thr Ala Cys Thr

530 535 540

Cys Cys Cys Thr Cys Ala Gly Cys Ala Gly Cys Gly Thr Gly Gly Thr

545 550 555 560

Gly Ala Cys Cys Gly Thr Gly Cys Cys Cys Thr Cys Cys Ala Gly Cys

565 570 575

Ala Gly Cys Thr Thr Gly Gly Gly Cys Ala Cys Cys Cys Ala Gly Ala

580 585 590

Cys Cys Thr Ala Cys Ala Thr Cys Thr Gly Cys Ala Ala Cys Gly Thr

595 600 605

Gly Ala Ala Thr Cys Ala Cys Ala Ala Gly Cys Cys Cys Ala Gly Cys

610 615 620

Ala Ala Cys Ala Cys Cys Ala Ala Gly Gly Thr Gly Gly Ala Cys Ala

625 630 635 640

Ala Gly Ala Ala Ala Gly Thr Thr Gly Ala Gly Cys Cys Cys Ala Ala

645 650 655

Ala Thr Cys Thr Thr Gly Thr Gly Ala Cys Ala Ala Ala Ala Cys Thr

660 665 670

Cys Ala Cys Ala Cys Ala Thr Gly Cys Cys Cys Ala Cys Cys Gly Thr

675 680 685

Gly Cys Cys Cys Ala Gly Cys Ala Cys Cys Thr Gly Ala Ala Cys Thr

690 695 700

Cys Cys Thr Gly Gly Gly Gly Gly Gly Ala Cys Cys Gly Thr Cys Ala

705 710 715 720

Gly Thr Cys Thr Thr Cys Cys Thr Cys Thr Thr Cys Cys Cys Cys Cys

725 730 735

Cys Ala Ala Ala Ala Cys Cys Cys Ala Ala Gly Gly Ala Cys Ala Cys

740 745 750

Cys Cys Thr Cys Ala Thr Gly Ala Thr Cys Thr Cys Cys Cys Gly Gly

755 760 765

Ala Cys Cys Cys Cys Thr Gly Ala Gly Gly Thr Cys Ala Cys Ala Thr

770 775 780

Gly Cys Gly Thr Gly Gly Thr Gly Gly Thr Gly Gly Ala Cys Gly Thr

785 790 795 800

Gly Ala Gly Cys Cys Ala Cys Gly Ala Ala Gly Ala Cys Cys Cys Thr

805 810 815

Gly Ala Gly Gly Thr Cys Ala Ala Gly Thr Thr Cys Ala Ala Cys Thr

820 825 830

Gly Gly Thr Ala Cys Gly Thr Gly Gly Ala Cys Gly Gly Cys Gly Thr

835 840 845

Gly Gly Ala Gly Gly Thr Gly Cys Ala Thr Ala Ala Thr Gly Cys Cys

850 855 860

Ala Ala Gly Ala Cys Ala Ala Ala Gly Cys Cys Gly Cys Gly Gly Gly

865 870 875 880

Ala Gly Gly Ala Gly Cys Ala Gly Thr Ala Cys Ala Ala Cys Ala Gly

885 890 895

Cys Ala Cys Gly Thr Ala Cys Cys Gly Thr Gly Thr Gly Gly Thr Cys

900 905 910

Ala Gly Cys Gly Thr Cys Cys Thr Cys Ala Cys Cys Gly Thr Cys Cys

915 920 925

Thr Gly Cys Ala Cys Cys Ala Gly Gly Ala Cys Thr Gly Gly Cys Thr

930 935 940

Gly Ala Ala Thr Gly Gly Cys Ala Ala Gly Gly Ala Gly Thr Ala Cys

945 950 955 960

Ala Ala Gly Thr Gly Cys Ala Ala Gly Gly Thr Cys Thr Cys Cys Ala

965 970 975

Ala Cys Ala Ala Ala Gly Cys Cys Cys Thr Cys Cys Cys Ala Gly Cys

980 985 990

Cys Cys Cys Cys Ala Thr Cys Gly Ala Gly Ala Ala Ala Ala Cys Cys

995 1000 1005

Ala Thr Cys Thr Cys Cys Ala Ala Ala Gly Cys Cys Ala Ala Ala

1010 1015 1020

Gly Gly Gly Cys Ala Gly Cys Cys Cys Cys Gly Ala Gly Ala Ala

1025 1030 1035

Cys Cys Ala Cys Ala Gly Gly Thr Gly Thr Ala Cys Ala Cys Cys

1040 1045 1050

Cys Thr Gly Cys Cys Cys Cys Cys Ala Thr Gly Cys Cys Gly Gly

1055 1060 1065

Gly Ala Thr Gly Ala Gly Cys Thr Gly Ala Cys Cys Ala Ala Gly

1070 1075 1080

Ala Ala Cys Cys Ala Gly Gly Thr Cys Ala Gly Cys Cys Thr Gly

1085 1090 1095

Thr Gly Gly Thr Gly Cys Cys Thr Gly Gly Thr Cys Ala Ala Ala

1100 1105 1110

Gly Gly Cys Thr Thr Cys Thr Ala Thr Cys Cys Cys Ala Gly Cys

1115 1120 1125

Gly Ala Cys Ala Thr Cys Gly Cys Cys Gly Thr Gly Gly Ala Gly

1130 1135 1140

Thr Gly Gly Gly Ala Gly Ala Gly Cys Ala Ala Thr Gly Gly Gly

1145 1150 1155

Cys Ala Gly Cys Cys Gly Gly Ala Gly Ala Ala Cys Ala Ala Cys

1160 1165 1170

Thr Ala Cys Ala Ala Gly Ala Cys Cys Ala Cys Gly Cys Cys Thr

1175 1180 1185

Cys Cys Cys Gly Thr Gly Cys Thr Gly Gly Ala Cys Thr Cys Cys

1190 1195 1200

Gly Ala Cys Gly Gly Cys Thr Cys Cys Thr Thr Cys Thr Thr Cys

1205 1210 1215

Cys Thr Cys Thr Ala Cys Ala Gly Cys Ala Ala Gly Cys Thr Cys

1220 1225 1230

Ala Cys Cys Gly Thr Gly Gly Ala Cys Ala Ala Gly Ala Gly Cys

1235 1240 1245

Ala Gly Gly Thr Gly Gly Cys Ala Gly Cys Ala Gly Gly Gly Gly

1250 1255 1260

Ala Ala Cys Gly Thr Cys Thr Thr Cys Thr Cys Ala Thr Gly Cys

1265 1270 1275

Thr Cys Cys Gly Thr Gly Ala Thr Gly Cys Ala Thr Gly Ala Gly

1280 1285 1290

Gly Cys Thr Cys Thr Gly Cys Ala Cys Ala Ala Cys Cys Ala Cys

1295 1300 1305

Thr Ala Cys Ala Cys Gly Cys Ala Gly Ala Ala Gly Ala Gly Cys

1310 1315 1320

Cys Thr Cys Thr Cys Cys Cys Thr Gly Thr Cys Thr Cys Cys Gly

1325 1330 1335

Gly Gly Thr Ala Ala Ala

1340

<210> 72

<211> 214

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 72

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

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

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 73

<211> 642

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 73

gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga cagggtgacc 60

atcacctgca gggcctccca ggacgtgtcc accgccgtgg cctggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactcc gcctccttcc tgtactccgg cgtgccctcc 180

aggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 240

gaggacttcg ccacctacta ctgccagcag tacctgtacc accccgccac cttcggccag 300

ggcaccaagg tggagatcaa gaggaccgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctac 420

cccagagaag ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg aaacagccag 480

gaaagcgtga cagagcagga ttccaaggat tccacataca gcctgagcag cacactgaca 540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac acaccaggga 600

ctgtcctccc ctgtgacaaa gagcttcaac agaggagaat gc 642

<210> 74

<211> 445

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 74

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ala Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ile Phe Tyr Thr Thr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

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

115 120 125

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

130 135 140

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

145 150 155 160

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

165 170 175

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

180 185 190

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys

340 345 350

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

355 360 365

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

370 375 380

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

385 390 395 400

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 75

<211> 1335

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 75

gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggcggctc cctgaggctg 60

tcctgcgccg cctccggctt caccttctcc tcctccggca tgtcctgggt gaggcaggcc 120

cccggcaagg gcctggagtg ggtgtccgtg atcgcctcct ccggctccaa cacctactac 180

gccgactccg tgaagggcag gttcaccatc tccagggaca actccaagaa caccctgtac 240

ctgcagatga actccctgag ggccgaggac accgccgtgt actactgcgc caggtccatc 300

ttctacacca cctggggcca gggcaccctg gtgaccgtgt cctccgctag caccaagggc 360

ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420

ggctgcctgg tcaaggacta cttccccgaa cctgtgacgg tgtcgtggaa ctcaggcgcc 480

ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540

agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600

aatcacaagc ccagcaacac caaggtggac aagaaagttg agcccaaatc ttgtgacaaa 660

actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720

ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780

gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840

gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 900

gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960

gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020

ccccgagaac cacaggtgta caccctgccc ccatgccggg atgagctgac caagaaccag 1080

gtcagcctgt ggtgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140

agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200

tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260

ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320

ctgtctccgg gtaaa 1335

<210> 76

<211> 215

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 76

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Asn

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Val Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Phe Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala

100 105 110

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

115 120 125

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

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

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

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 77

<211> 645

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 77

gacatcgtgc tgacccagtc ccccgccacc ctgtccctgt cccccggcga gagggccacc 60

ctgtcctgca gggcctccca gtccgtgagg tccaactacc tggcctggta ccagcagaag 120

cccggccagg cccccaggct gctgatctac ggcgcctcct ccagggccac cggcgtgccc 180

gccaggttct ccggctccgg ctccggcacc gacttcaccc tgaccatctc ctccctggag 240

cccgaggact tcgccgtgta ctactgccag cagtactcca acttccccat caccttcggc 300

cagggcacca aggtggagat caagaggacc gtggctgcac catctgtctt catcttcccg 360

ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420

taccccagag aagccaaagt gcagtggaag gtggacaacg ccctgcagag cggaaacagc 480

caggaaagcg tgacagagca ggattccaag gattccacat acagcctgag cagcacactg 540

acactgtcca aggccgacta cgagaagcac aaggtgtacg cctgcgaagt gacacaccag 600

ggactgtcct cccctgtgac aaagagcttc aacagaggag aatgc 645

<210> 78

<211> 451

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 78

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Arg Gly Tyr

20 25 30

Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Gln Ile Leu Pro Gly Thr Gly Arg Thr Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Phe Asp Gly Asn Tyr Gly Tyr Tyr Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

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

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

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

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

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

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

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

355 360 365

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

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

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

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 79

<211> 1353

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 79

caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaagatc 60

tcctgcaagg tgtccggcta caccctgagg ggctactgga tcgagtgggt gaggcaggcc 120

cccggcaagg gcctggagtg gatcggccag atcctgcccg gcaccggcag gaccaactac 180

aacgagaagt tcaagggcag ggtgaccatg accgccgaca cctccaccga caccgcctac 240

atggagctgt cctccctgag gtccgaggac accgccgtgt actactgcgc caggttcgac 300

ggcaactacg gctactacgc catggactac tggggccagg gcaccaccgt gaccgtgtcc 360

tccgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420

gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc tgtgacggtg 480

tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540

tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600

acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660

cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720

ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780

cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840

tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900

aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960

aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020

tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgccgggat 1080

gagctgacca agaaccaggt cagcctgtgg tgcctggtca aaggcttcta tcccagcgac 1140

atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200

gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260

tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320

acgcagaaga gcctctccct gtctccgggt aaa 1353

<210> 80

<211> 215

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 80

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Thr

35 40 45

Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro

100 105 110

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

115 120 125

Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp Phe Tyr Pro

130 135 140

Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys Val

145 150 155 160

Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala

165 170 175

Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg

180 185 190

Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val Glu Lys Thr

195 200 205

Val Ala Pro Ala Glu Cys Ser

210 215

<210> 81

<211> 645

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 81

caggccgtgg tgacccagga gccctccctg accgtgtccc ccggcggcac cgtgaccctg 60

acctgcaggt cctccaccgg cgccgtgacc acctccaact acgccaactg gttccagcag 120

aagcccggcc aggcccccag gaccctgatc ggcggcacca acaacagggc ccccggcgtg 180

cccgccaggt tctccggctc cctgctgggc ggcaaggccg ccctgaccct gtccggcgcc 240

cagcccgagg acgaggccga gtactactgc gccctgtggt actccaacca ctgggtgttc 300

ggcggcggca ccaagctgac cgtgctgggc cagcccaagg ccgccccctc cgtgaccctg 360

ttccccccct cctccgagga gctgcaggcc aacaaggcca ccctggtgtg cctggtgtcc 420

gacttctacc ccggcgccgt gaccgtggcc tggaaggccg acggctcccc cgtgaaggtg 480

ggcgtggaga ccaccaagcc ctccaagcag tccaacaaca agtacgccgc ctcctcctac 540

ctgtccctga cccccgagca gtggaagtcc cacaggtcct actcctgcag ggtgacccac 600

gagggctcca ccgtggagaa gaccgtggcc cccgccgagt gctcc 645

<210> 82

<211> 449

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 82

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr

20 25 30

Tyr Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

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

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

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

145 150 155 160

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

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

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

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

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

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

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

305 310 315 320

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

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp

355 360 365

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

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 83

<211> 1347

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 83

caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaagatc 60

tcctgcaagg cctccggcta ctccttcacc gcctactaca tccactgggt gaagcaggcc 120

cccggccagg gcctggagtg gatcggctac atctcctcct acaacggcgc caccaactac 180

aaccagaagt tcaagggcag ggtgaccttc accaccgaca cctccacctc caccgcctac 240

atggagctga ggtccctgag gtccgacgac accgccgtgt actactgcgc cagggactac 300

gactacgacg tgggcatgga ctactggggc cagggcaccc tggtgaccgt gtcctccgct 360

agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aacctgtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660

tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780

gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840

gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960

tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020

gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1080

accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1140

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260

caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320

aagagcctct ccctgtctcc gggtaaa 1347

<210> 84

<211> 218

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 84

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Ile Ser Phe Met Lys Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

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

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Lys

85 90 95

Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

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

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 85

<211> 654

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 85

gacatcgtga tgacccagtc ccccgactcc ctggccgtgt ccctgggcga gagggccacc 60

atctcctgca gggcctccga gtccgtggac aactacggca tctccttcat gaagtggttc 120

cagcagaagc ccggccagcc ccccaagctg ctgatctacg ccgcctccaa ccagggctcc 180

ggcgtgcccg acaggttctc cggctccggc tccggcaccg acttcaccct gaccatctcc 240

tccctgcagg ccgaggacgt ggccgtgtac tactgccagc agtccaagga ggtgccctgg 300

accttcggcg gcggcaccaa ggtggagatc aagaggaccg tggctgcacc atctgtcttc 360

atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420

aataacttct accccagaga agccaaagtg cagtggaagg tggacaacgc cctgcagagc 480

ggaaacagcc aggaaagcgt gacagagcag gattccaagg attccacata cagcctgagc 540

agcacactga cactgtccaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 600

acacaccagg gactgtcctc ccctgtgaca aagagcttca acagaggaga atgc 654

<210> 86

<211> 448

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 86

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr

20 25 30

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

35 40 45

Ser Val Ile Ser Gly Asp Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

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

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

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

145 150 155 160

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

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

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

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

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

340 345 350

Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys

355 360 365

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

370 375 380

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

385 390 395 400

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

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 87

<211> 1344

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 87

gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggcggctc cctgaggctg 60

tcctgcgccg cctccggctt caccttctcc cactacaccc tgtcctgggt gaggcaggcc 120

cccggcaagg gcctggagtg ggtgtccgtg atctccggcg acggctccta cacctactac 180

gccgactccg tgaagggcag gttcaccatc tcctccgaca actccaagaa caccctgtac 240

ctgcagatga actccctgag ggccgaggac accgccgtgt actactgcgc caggaacttc 300

atcaagtacg tgttcgccaa ctggggccag ggcaccctgg tgaccgtgtc ctccgctagc 360

accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420

gcggccctgg gctgcctggt caaggactac ttccccgaac ctgtgacggt gtcgtggaac 480

tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540

tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600

tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga gcccaaatct 660

tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720

gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780

acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840

gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900

taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960

aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020

aaagggcagc cccgagaacc acaggtgtac accctgcccc catgccggga tgagctgacc 1080

aagaaccagg tcagcctgtg gtgcctggtc aaaggcttct atcccagcga catcgccgtg 1140

gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200

tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260

gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320

agcctctccc tgtctccggg taaa 1344

<210> 88

<211> 213

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 88

Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly Ser Phe Tyr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Lys Ser Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

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

65 70 75 80

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

85 90 95

Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala

100 105 110

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

115 120 125

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

130 135 140

Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val

145 150 155 160

Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser

165 170 175

Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr

180 185 190

Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala

195 200 205

Pro Thr Glu Cys Ser

210

<210> 89

<211> 639

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 89

gacatcgagc tgacccagcc cccctccgtg tccgtggccc ccggccagac cgccaggatc 60

tcctgctccg gcgacaacat cggctccttc tacgtgcact ggtaccagca gaagcccggc 120

caggcccccg tgctggtgat ctacgacaag tccaacaggc cctccggcat ccccgagagg 180

ttctccggct ccaactccgg caacaccgcc accctgacca tctccggcac ccaggccgag 240

gacgaggccg actactactg ccagtcctac gccaacaccc tgtccctggt gttcggcggc 300

ggcaccaagc tgaccgtgct gggccagccc aaggccgccc cctccgtgac cctgttcccc 360

ccctcctccg aggagctgca ggccaacaag gccaccctgg tgtgcctgat ctccgacttc 420

taccccggcg ccgtgaccgt ggcctggaag gccgactcct cccccgtgaa ggccggcgtg 480

gagaccacca ccccctccaa gcagtccaac aacaagtacg ccgcctcctc ctacctgtcc 540

ctgacccccg agcagtggaa gtcccacagg tcctactcct gccaggtgac ccacgagggc 600

tccaccgtgg agaagaccgt ggcccccacc gagtgctcc 639

<210> 90

<211> 455

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 90

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Gly Ser

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Trp Ile Asn Pro Tyr Arg Gly Tyr Ala Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Tyr Ser Gly Trp Gly Gly Ser Ser Val Gly Tyr Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr

115 120 125

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

130 135 140

Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys

195 200 205

Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

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

340 345 350

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

355 360 365

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

370 375 380

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

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Leu Ser Leu Ser Pro Gly Lys

450 455

<210> 91

<211> 1365

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 91

gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggcggctc cctgaggctg 60

tcctgcgccg cctccggctt ctccctgtcc ggctcctgga tccactgggt gaggcaggcc 120

cccggcaagg gcctggagtg ggtgggctgg atcaacccct acaggggcta cgcctactac 180

gccgactccg tgaagggcag gttcaccatc tccgccgaca cctccaagaa caccgcctac 240

ctgcagatga actccctgag ggccgaggac accgccgtgt actactgcgc cagggagtac 300

tccggctggg gcggctcctc cgtgggctac gccatggact actggggcca gggcaccctg 360

gtgaccgtgt cctccgctag caccaagggc ccatcggtct tccccctggc accctcctcc 420

aagagcacct ctgggggcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480

cctgtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct 540

gtcctacagt cctcaggact ctactccctc agcagcgtgg tgaccgtgcc ctccagcagc 600

ttgggcaccc agacctacat ctgcaacgtg aatcacaagc ccagcaacac caaggtggac 660

aagaaagttg agcccaaatc ttgtgacaaa actcacacat gcccaccgtg cccagcacct 720

gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 780

atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 840

gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 900

gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 960

tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1020

gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1080

ccatgccggg atgagctgac caagaaccag gtcagcctgt ggtgcctggt caaaggcttc 1140

tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1200

accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1260

gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1320

cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1365

<210> 92

<211> 214

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 92

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

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

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 93

<211> 642

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 93

gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga cagggtgacc 60

atcacctgca gggcctccca ggacgtgtcc accgccgtgg cctggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactcc gcctccttcc tgtactccgg cgtgccctcc 180

aggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 240

gaggacttcg ccacctacta ctgccagcag tcctacacca ccccccccac cttcggccag 300

ggcaccaagg tggagatcaa gaggaccgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctac 420

cccagagaag ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg aaacagccag 480

gaaagcgtga cagagcagga ttccaaggat tccacataca gcctgagcag cacactgaca 540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac acaccaggga 600

ctgtcctccc ctgtgacaaa gagcttcaac agaggagaat gc 642

<210> 94

<211> 679

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 94

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Glu

435 440 445

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

450 455 460

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

465 470 475 480

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

485 490 495

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

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

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

645 650 655

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

660 665 670

Leu Ser Leu Ser Pro Gly Lys

675

<210> 95

<211> 2037

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 95

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta cgagcccaaa tcttgtgaca aaactcacac atgcccaccg 1380

tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1440

gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1500

gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1560

acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1620

ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1680

ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1740

tgcaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gtcctgcgcg 1800

gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1860

aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctcgtcagc 1920

aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1980

catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 2037

<210> 96

<211> 676

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 96

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Glu

435 440 445

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

450 455 460

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

465 470 475 480

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

485 490 495

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

500 505 510

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

595 600 605

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

610 615 620

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

625 630 635 640

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

645 650 655

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

660 665 670

Ser Leu Gly Lys

675

<210> 97

<211> 2028

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 97

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta cgagtccaag tacggccctc cttgtcctcc ttgtcccgcc 1380

cccgaatttc tcggcggccc ctccgtgttt ctgtttcctc ccaagcccaa ggatacttta 1440

atgatctctc gtacccccga ggtgacttgt gtggtggtgg atgtgtccca agaagacccc 1500

gaagtccagt tcaactggta cgtggacgga gtggaggtgc acaatgccaa aaccaagccc 1560

cgggaggagc agtttaacag cacctaccgg gtggtgagcg ttttaaccgt gctgcatcaa 1620

gattggctga acggaaagga atacaaatgt aaggtcagca acaagggttt acctagctcc 1680

atcgagaaga ccatctccaa ggctaaggga cagcctcggg agccccaagt ttgtacactg 1740

cccccctccc aagaagagat gaccaagaac caagtgagcc tcagctgtgc cgtgaaggga 1800

ttctacccct ccgacatcgc tgtcgagtgg gagagcaacg gccagcccga gaacaactat 1860

aagaccacac cccccgtttt agatagcgac ggctccttct ttttagtctc tcgtctgacc 1920

gtcgacaagt ctcgttggca agaaggcaat gtgttttctt gttccgtgat gcacgaggcc 1980

ctccacaatc actacaccca gaaatcttta tccttatctt taggcaag 2028

<210> 98

<211> 679

<212> PRT

<213>artificial sequence (Artificial Sequence)

<400> 98

Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp

1 5 10 15

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

20 25 30

Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala

35 40 45

Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr

50 55 60

Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro

65 70 75 80

Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile

85 90 95

Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp

100 105 110

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

115 120 125

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

130 135 140

Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala

145 150 155 160

Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg

165 170 175

Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His

180 185 190

His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile

195 200 205

Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu

210 215 220

Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr

225 230 235 240

Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile

245 250 255

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

260 265 270

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

275 280 285

Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp

290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp

305 310 315 320

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

325 330 335

Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys

340 345 350

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

355 360 365

Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly

370 375 380

Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys

385 390 395 400

Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp

405 410 415

Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala

420 425 430

Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Glu

435 440 445

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

450 455 460

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

465 470 475 480

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

485 490 495

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

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

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

645 650 655

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

660 665 670

Leu Ser Leu Ser Pro Gly Lys

675

<210> 99

<211> 2037

<212> DNA

<213>artificial sequence (Artificial Sequence)

<400> 99

ctgaatttca gagcacctcc tgttattcca aatgtgcctt tcctctgggc ctggaatgcc 60

ccaagtgaat tttgtcttgg aaaatttgat gagccactag atatgagcct cttctctttc 120

ataggaagcc cccgaataaa cgccaccggg caaggtgtta caatatttta tgttgataga 180

cttggctact atccttacat agattcaatc acaggagtaa ctgtgaatgg aggaatcccc 240

cagaagattt ccttacaaga ccatctggac aaagctaaga aagacattac attttatatg 300

ccagtagaca atttgggaat ggctgttatt gactgggaag aatggagacc cacttgggca 360

agaaactgga aacctaaaga tgtttacaag aataggtcta ttgaattggt tcagcaacaa 420

aatgtacaac ttagtctcac agaggccact gagaaagcaa aacaagaatt tgaaaaagca 480

gggaaggatt tcctggtaga gactataaaa ttgggaaaat tacttcggcc aaatcacttg 540

tggggttatt atctttttcc ggattgttac aaccatcact ataagaaacc cggttacaat 600

ggaagttgct tcaatgtaga aataaaaaga aatgatgatc tcagctggtt gtggaatgaa 660

agcactgctc tttacccatc catttatttg aacactcagc agtctcctgt agctgctaca 720

ctctatgtgc gcaatcgagt tcgggaagcc atcagagttt ccaaaatacc tgatgcaaaa 780

agtccacttc cggtttttgc atatacccgc atagttttta ctgatcaagt tttgaaattc 840

ctttctcaag atgaacttgt gtatacattt ggcgaaactg ttgctctggg tgcttctgga 900

attgtaatat ggggaaccct cagtataatg cgaagtatga aatcttgctt gctcctagac 960

aattacatgg agactatact gaatccttac ataatcaacg tcacactagc agccaaaatg 1020

tgtagccaag tgctttgcca ggagcaagga gtgtgtataa ggaaaaactg gaattcaagt 1080

gactatcttc acctcaaccc agataatttt gctattcaac ttgagaaagg tggaaagttc 1140

acagtacgtg gaaaaccgac acttgaagac ctggagcaat tttctgaaaa attttattgc 1200

agctgttata gcaccttgag ttgtaaggag aaagctgatg taaaagacac tgatgctgtt 1260

gatgtgtgta ttgctgatgg tgtctgtata gatgcttttc taaaacctcc catggagaca 1320

gaagaacctc aaattttcta cgagcccaaa tcttgtgaca aaactcacac atgcccaccg 1380

tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1440

gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1500

gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1560

acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1620

ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1680

ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1740

tacaccctgc ccccatgccg ggatgagctg accaagaacc aggtcagcct gtggtgcctg 1800

gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1860

aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1920

aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1980

catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 2037

Claims (12)

1. a kind of targent fused protein for having hyaluronidase activity, which is characterized in that for three comprising tri- peptide chains of A, B, C Aggressiveness, wherein A peptide chain is that hyaluronidase merges peptide chain, and B peptide chain is IgG antibody heavy chain mutant, and C peptide chain is that IgG antibody is light Chain or light chain mutant,

The general structure of the A peptide chain is γ 1- γ 3 or γ 1- γ 2- γ 3,

γ 1 is hyaluronidase similar to object, the expressed sequence including HYALl gene, HYAL2 gene or PH20/SPAM1 gene,

γ 2 is peptide linker,

γ 3 is the area human IgG antibody Fc hole mutant or knob mutant, and the hole mutant and the knob are mutated physical efficiency It is enough to form specific dimer,

When the area human IgG antibody Fc does not retain hinge area, using the peptide linker, C-terminal of the hyaluronidase similar to object Residue is directly fused to the N-terminal residue of the peptide linker, and the C-terminal residue of the peptide linker is directly fused to human IgG The N-terminal residue of antibody Fc district hole mutant or knob mutant；

When the area human IgG antibody Fc retains part or all of hinge area, the peptide linker is not used, the hyaluronidase is similar The C-terminal residue of object is directly fused to the N-terminal residue of the area human IgG antibody Fc hole mutant or knob mutant.

2. the targent fused protein according to claim 1 for having hyaluronidase activity, it is characterised in that:

Wherein, when γ 3 is the area human IgG antibody Fc hole mutant, the general structure of the B peptide chain is α 1- α 2- α 3, the C The general structure of peptide chain is β 1- β 2,

α 1 is IgG antibody heavy chain variable region VH；α 2 is the area IgG antibody heavy chain CH1 and hinge area；α 3 is IgG antibody Fc area knob Mutant is mutated comprising T366W, S354C,

The C-terminal residue of VH is directly fused to the C of the N-terminal residue of the area IgG CH1 and hinge area, the area IgG CH1 and hinge area Terminal residue is directly fused to the N-terminal residue of the area IgG Fc knob mutant,

β 1 is that IgG antibody light chain variable region VL, β 2 is IgG antibody constant region of light chain CL.

3. the targent fused protein according to claim 1 for having hyaluronidase activity, it is characterised in that:

Wherein, when γ 3 is the area human IgG antibody Fc knob mutant, the general structure of the B peptide chain is α 1- α 2- α 3- α 4, institute The general structure for stating C peptide chain is β 1- β 2,

α 1 is IgG antibody heavy chain variable region VH；α 2 is IgG antibody light chain CL region mutation body；α 3 is IgG antibody hinge area；α 4 is The area IgG antibody Fc hole mutant is mutated comprising T366S, L368A, Y407V and Y349C,

The C-terminal residue of VH is directly fused to the N-terminal residue in the area IgG CL, and the C-terminal residue in the area IgG CL is directly fused to The N-terminal residue of hinge area, the C-terminal residue of hinge area are directly fused to the N-terminal residue of the area IgG Fc hole mutant,

β 1 is that IgG antibody light chain variable region VL, β 2 is the area IgG antibody heavy chain constant region CH1, and the C-terminal residue of VL directly merges To the N-terminal residue in the area IgG CH1.

4. the targent fused protein according to claim 1 for having hyaluronidase activity, it is characterised in that:

Wherein, the hyaluronidase has as shown in SEQ ID NO.1, SEQ ID NO.2 or SEQ ID NO.3 similar to object Amino acid sequence, or be deleted by any one or several amino acid in the amino acid sequence, addition or the ammonia replaced Base acid sequence composition.

5. the targent fused protein according to claim 1 for having hyaluronidase activity, it is characterised in that:

Wherein, the peptide linker is the polypeptide comprising amino acid sequence [GGGGX] n, and X is glutamine, glutamic acid or silk ammonia Acid, n 2-5, the polypeptide include 10 to 25 amino acid, and at least 50% is glycine residue in amino acid acid,

The peptide linker includes the amino acid sequence as shown in SEQ ID NO:4, SEQ ID NO.5 or SEQ ID NO.6.

6. the targent fused protein according to claim 1 for having hyaluronidase activity, it is characterised in that:

Wherein, the area the human IgG Fc is the area Fc from IgGl, IgG2, IgG3 or IgG4 antibody,

The area the IgG FC includes amino acid sequence shown in SEQ ID NO:7, and further in SEQ ID NO.7 amino acid The N-terminal side of the C residue at position 1 in sequence includes some or all of amino found in wild type IgGl Fc sequence Acid.

7. the pharmaceutical composition containing the described in any item targent fused proteins for having hyaluronidase activity of claim 1~6 Object, which is characterized in that further include medically acceptable pharmaceutical carrier.

8. the described in any item targent fused proteins for having hyaluronidase activity of claim 1~6 are preparing antineoplastic Purposes in object.

9. the targent fused protein according to claim 8 for having hyaluronidase activity is in the preparation of antitumor drugs Purposes, it is characterised in that:

Wherein, the targent fused protein for having hyaluronidase activity and other anti-tumor drugs are used in combination.

10. the preparation method of the targent fused protein as claimed in claim 2 for having hyaluronidase activity, which is characterized in that The following steps are included:

(1) full genome synthesis human IgG antibody's heavy chain object segment similar with the variable region gene of light chain and hyaluronidase, obtains VH, VL segment and hyaluronidase of IgG antibody are similar to object segment；Full genome synthesizes human IgG antibody's constant region of light chain CL, heavy chain Constant region CH1 and Fc segment,

(2) the Fc segment of acquisition is introduced into catastrophe point T366W and S354C using the method for overlap PCR, PCR product is through fine jade Sepharose Purified in electrophoresis is recycled and is cloned into carrier, and confirmation obtains correct clone after sequence verification, obtains Fc segment Knob mutant,

(3) by the Fc segment of acquisition use again overlap PCR method introduce catastrophe point T366S, L368A, Y407V and Y349C, PCR product is through agarose gel electrophoresis purification and recovery and is cloned into carrier, and confirmation obtains correct after sequence verification Clone, obtain Fc segment hole mutant,

(4) the Fc segment for obtaining heavy chain variable region VH, the heavy chain constant region CH1 and step (2) that obtain in above-mentioned steps (1) Knob mutant is template, by above three segment composition and is fitted into expression vector using overlap round pcr, building obtains The expression vector of encoding heavy chain knob mutant is obtained, that is, obtains the expression vector of coding peptide chain B,

(5) hyaluronidase will be obtained in step (1) similar to object segment, the Fc section hole mutant that step (3) obtains is template, It by above-mentioned two a segment composition and is fitted into expression vector using overlap round pcr, while joint peptide is added, compiled The expression vector of code hyaluronidase fusion peptide chain, that is, obtain the expression vector of coding peptide chain A,

(6) using the light chain variable region VL and constant region of light chain CL that obtain in step (1) as template, overlap PCR skill is utilized Art is by above-mentioned segment composition and is fitted into expression vector, obtains the expression vector of coding IgG antibody light chain, that is, obtains coding peptide chain The expression vector of C,

(7) above three expression vector is introduced in host cell to the expression for carrying out fusion protein, and is isolated and purified.

11. the preparation method of the targent fused protein as claimed in claim 3 for having hyaluronidase activity, which is characterized in that The following steps are included:

(1) full genome synthesis human IgG antibody's heavy chain object segment similar with the variable region gene of light chain and hyaluronidase, obtains VH, VL segment and hyaluronidase of IgG antibody are similar to object segment；Full genome synthesizes human IgG antibody's constant region of light chain CL, heavy chain Constant region CH1 and Fc segment,

(2) the Fc segment of acquisition is introduced into catastrophe point T366W and S354C using the method for overlap PCR, PCR product is through fine jade Sepharose Purified in electrophoresis is recycled and is cloned into carrier, and confirmation obtains correct clone after sequence verification, obtains Fc segment Knob mutant,

(3) by the Fc segment of acquisition use again overlap PCR method introduce catastrophe point T366S, L368A, Y407V and Y349C, PCR product is through agarose gel electrophoresis purification and recovery and is cloned into carrier, and confirmation obtains correct after sequence verification Clone, obtain Fc segment hole mutant,

(4) the Fc segment for obtaining heavy chain variable region VH, the constant region of light chain CL and step (3) that obtain in above-mentioned steps (1) Hole mutant is template, by above three segment composition and is fitted into expression vector using overlap round pcr, building obtains The expression vector of encoding heavy chain hole mutant is obtained, that is, obtains the expression vector of coding peptide chain B,

(5) hyaluronidase will be obtained in step (1) similar to object segment, the Fc section knob mutant that step (2) obtains is template, It by above-mentioned two a segment composition and is fitted into expression vector using overlap round pcr, while joint peptide is added, compiled The expression vector of code hyaluronidase fusion peptide chain, that is, obtain the expression vector of coding peptide chain A,

(6) using the light chain variable region VL and heavy chain constant region CH1 that obtain in step (1) as template, overlap PCR skill is utilized Art is by above-mentioned segment composition and is fitted into expression vector, obtains the expression vector of coding IgG antibody light chain, that is, obtains coding peptide chain The expression vector of C,

(7) above three expression vector is introduced in host cell to the expression for carrying out fusion protein, and is isolated and purified.

12. have the preparation method of the targent fused protein of hyaluronidase activity described in 0 or 11 according to claim 1, It is characterized in that:

Wherein, the expression vector be pGEM-T, pcDNA3.1, pEE6.4, pEE12.4 or pDHFR,

The host cell is mammalian cell.