CN101636080A

CN101636080A - Be used for the treatment of psoriatic method

Info

Publication number: CN101636080A
Application number: CN200880008553A
Authority: CN
Inventors: J·M·瓦尔德斯; E·K·查塔什; W·T·巴楚克; S·K·保罗森; A·B·金鲍尔
Original assignee: Abbott Laboratories
Current assignee: AbbVie Inc
Priority date: 2007-01-16
Filing date: 2008-01-16
Publication date: 2010-01-27

Abstract

The invention provides a kind of by giving physical efficiency antibody in conjunction with the p40 subunit of IL-12 and/or IL-23, thereby psoriatic method in the treatment individuality.

Description

Be used for the treatment of psoriatic method

Related application

The application requires the U.S. Provisional Application the 60/880th of submission on January 16th, 2007, the U.S. Provisional Application the 60/904th that on February 27th, No. 767 1 submitted to, the U.S. Provisional Application the 60/925th that on April 24th, No. 022 1 submitted to, the U.S. Provisional Application the 60/961st that on July 24th, No. 960 1 submitted to, the U.S. Provisional Application the 60/997th that No. 764 and on September 28th, 2007 submit to, No. 012 rights and interests, the full text of above-mentioned every piece of provisional application all is incorporated herein by reference at this.

Background of invention

Psoriasis is the cell-mediated inflammatory disease of a kind of T, is considered to one of modal autoimmune disease, although the global incidence of disease alters a great deal, but still infect adult (the Stern R.S. of about 2%-3%, Deng, J Investig Dermatol Symp Proc 2004,9:136-39; DavidsonA and Diamond B.N Engl J Med 2001,345:340-50; Langley R.G.B., etc., Ann Rheum Dis 2005,64 (Suppl II): ii18-23).Psoriasis to quality of life have bigger influence (de Korte J, etc., J Investig Dermatol Symp Proc 2004,9:140-7; Krueger G, etc., Arch Dermatol 2001,137:280-4; Finlay AY and Coles EC, Br J Dermatol 1995,132:236-44) and relevant with many psychology with social mentality's problem (Kimball AB, etc., Am J Clin Dermatol 2005,6:383-92; Russo PA, etc., Australas J Dermatol 2004,45:155-9).Many traditional psoriasis therapies have toxic and side effect; Therefore, limited (Lebwohl M. and Ali S., J Am AcadDermatol 2001,45:487-98 of their long-term use; Lebwohl M. and Ali S., J Am Acad Dermatol2001,45:649-61).In addition, many psoriatics to traditional remedies dissatisfied (Stern RS, etc., J Investig Dermatol Symp Proc 2004,9:136-39; Finlay AY and OrtonneJP, J Cutan Med Surg 2004,8:310-20); Therefore, the therapy that needs safer and easier use really and can adopt for a long time.

Il-1 2 (IL-12) and relevant cell factor IL-23 are that (Anderson EJR is etc., Springer SeminImmunopathol 2006,27:425-42) for the member that enjoys the IL-12 cell factor superfamily of common p40 subunit.These two kinds of cell factors all help the development of II type auxiliary cell (Th1) immune response in the psoriasis, but each self-applying completely different (Rosmarin D and Strober BE, J Drugs Dermatol 2005,4:318-25; Hong K, etc., J Immunol1999,162:7480-91; Yawalkar N, etc., J Invest Dermatol 1998,111:1053-57).IL-12 mainly stimulates the Th1 cell differentiation and secretes interferon-subsequently, IL-23 then preferentially stimulates inmature T cell differentiation to become effect t helper cell (Th 17) (Rosmarin D and the Strober BE of secretion IL-17 (a kind of short inflammatory mediator), J Drugs Dermatol 2005,4:318-25; Harrington Le, etc., Nature Immunol 2005,6:1123-32; Park H waits NatureImmunol 2005,6:1132-41).IL-12 p40 and IL-23 p40 mRNA are crossed to express and are hinted that the neutralizing antibody inhibition IL-12 and the IL-23 that use at IL-12/23 p40 protein subunit can provide a kind of psoriatic effective therapy (Yawalkar N that is used for the treatment of in psoriatic lesion, Deng, JInvest Dermatol 1998,111:1053-57; Lee E, etc., J Exp Med 2004,199:125-30; Shaker OG, etc., Clin Biochem 2006,39:119-25; Piskin G, etc., JImmunol 2006,176:1908-15).Obviously need so psoriatic therapy that is used for the treatment of in the art.

Summary of the invention

The invention provides antibody or its antigen-binding portion thereof of use, be used for the Treatment and composition for of psoriasis such as chronic psoriasis in conjunction with people IL-12 and/or human IL-2 3.

In one aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprise every biweekly, weekly or single dose gives individual antibody or its antigen-binding portion thereof at people IL-12 and/or human IL-2 3.

In one embodiment, individual to every biweekly, antibody or its antigen-binding portion thereof weekly or single dose keep one period duration, as at least about 12 week or replying at least about 24 weeks.

In another embodiment, every biweekly, after weekly or single dose gives individual antibody or its antigen-binding portion thereof at people IL-12 and human IL-2 3, individuality keeps at least that PASI 75 replys one period duration.In another embodiment, every biweekly, after weekly or single dose gives individual antibody or its antigen-binding portion thereof at people IL-12 and human IL-2 3, individuality keeps at least that PASI 90 replys one period duration.In a further embodiment, every biweekly, after weekly or single dose gives individual antibody or its antigen-binding portion thereof at people IL-12 and human IL-2 3, individuality keeps at least that PASI 100 replys one period duration.

In one embodiment, the dosage at people IL-12 and/or human IL-2's 3 antibody is about 200mg or about 100mg.

In one embodiment, psoriasis is psoriasis in plaques (plaque psoriasis), as chronic psoriasis in plaques.In another embodiment, psoriasis is a chronic psoriasis, as chronic psoriasis in plaques.In another embodiment, psoriasis is middle severe psoriasis, as middle severe psoriasis in plaques, middle severe chronic psoriasis or middle severe chronic psoriasis in plaques.

In one embodiment, antibody or its antigen-binding portion thereof are used through subcutaneous administration.

In yet another aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises step: the individuality of (i) selecting to suffer from chronic psoriasis; (ii) give antibody or its antigen-binding portion thereof of a physical efficiency in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23; Thereby the chronic psoriasis in the treatment individuality.

In one embodiment, the individual psoriasis clinical diagnosis that has had at least 6 months.In another embodiment, the individual stable psoriasis in plaques of having suffered from least 2 months.

In yet another aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises step: (i) select do not have the individuality that is selected from following situation: experience systematicness or biology to resist-the IL-12 treatment before; Non-psoriasis in plaques; Before treatment, can not stop local at least 2 weeks of curing psoriasis; At least 2 weeks of UV-B phototherapy before treatment; At least 4 weeks of psoralen-ultraviolet phototherapy before treatment; At least 4 weeks of systemic treatment before treatment; At least 12 weeks of biological therapy before treatment; In therapeutic process, need to take in oral or injectable corticoid; Sb.'s illness took a turn for the worse to need the asthma of being in hospital before screening in the period of 10; The infection of severe infections or hazards; Malignant tumour history except that the basal-cell carcinoma that success is treated is as squamous cell carcinoma or original position cervical carcinoma history; With to containing the main immune response history of immunoglobulin G medicine such as intravenous injection gamma globulin, fusion or monoclone antibody, as serum sickness or anaphylactoid reaction; (ii) give antibody or its antigen-binding portion thereof of a physical efficiency in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23; Thereby the psoriasis in the treatment individuality.

In yet another aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises step: (i) be chosen in the individuality of not inoculating the live virus agent in 1 month; (ii) give antibody or its antigen-binding portion thereof of a physical efficiency in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23; Thereby the psoriasis in the treatment individuality.

Aspect another, the invention provides psoriatic method in a kind of treatment individuality, described method comprises step: (i) give antibody or its antigen-binding portion thereof of a physical efficiency in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23; (ii) the monitoring individuality is selected from the following laboratory result of significant abnormal clinically: aspartate transaminase or the alanine aminotransferase＞5 times normal value upper limit; Serum total bilirubin＞3 times normal value the upper limit; Serum creatinine＞3 times normal value the upper limit; Cretinephosphokinase＞5 times normal value the upper limit; Haemoglobin＜8g/dL; White blood cell count(WBC)＜2 * 10 ⁹/ L; And platelet count＜75 * 10 ⁹/ L; (iii) stop to give wherein to detect individual antibody or its antigen-binding portion thereof of significant abnormal laboratory result clinically; Thereby the psoriasis in the treatment individuality.

In one embodiment, whenever biweekly give antibody or its antigen-binding portion thereof.In another embodiment, give antibody or its antigen-binding portion thereof once in a week or with single dose.

In one embodiment, the dosage with about 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg or 220mg gives antibody or its antigen-binding portion thereof.

In one embodiment, when p40 subunit during in conjunction with the p35 subunit of IL-12, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.In another embodiment, when p40 subunit during in conjunction with the p19 subunit of IL-23, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.In another embodiment, when the p40 subunit in conjunction with the p35 subunit of IL-12 and when p40 subunit during in conjunction with the p19 subunit of IL-23, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.

In one embodiment, psoriasis is a chronic psoriasis, as chronic psoriasis in plaques, as middle severe chronic psoriasis in plaques.

In yet another aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually keep after giving antibody or its antigen-binding portion thereof for the first time at least that PASI 90 replys one period duration, thus the psoriasis in the treatment individuality.

In one embodiment, the duration was at least about for 12,13,14,15,16,17,18,19,20,21,22,23 or 24 weeks.

In one embodiment, whenever biweekly give antibody or its antigen-binding portion thereof.In another embodiment, give antibody or its antigen-binding portion thereof once in a week.In another embodiment, give antibody with single dose.

In yet another aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individual keeping after giving antibody or its antigen-binding portion thereof for the first time made zero or minimum one period duration of PGA grade, thus the psoriasis in the treatment individuality.

In one embodiment, the duration position is at least about 12,13,14,15,16,17,18,19,20,21,22,23 or 24 weeks.

In a further aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individuality is giving antibody or its antigen-binding portion thereof for the first time after about 8 weeks show the PASI scores of improving, thus the psoriasis in the treatment individuality.

In one embodiment, individuality is giving antibody or its antigen-binding portion thereof for the first time after about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks or about 1 week show the PASI scores of improving.

In yet another aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually after stopping to give antibody or its antigen-binding portion thereof, keep at least that PASI 50 replys one period duration, thus the psoriasis in the treatment individuality.

In a related aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually after stopping to give antibody or its antigen-binding portion thereof, keep at least that PASI 75 replys one period duration, thus the psoriasis in the treatment individuality.

In another related aspect, the invention provides psoriatic method in a kind of treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually after stopping to give antibody or its antigen-binding portion thereof, keep at least that PASI 90 replys one period duration, thus the psoriasis in the treatment individuality.

In one embodiment, the duration that stops to give behind the antibody was at least about for 12 weeks.

In one embodiment, give antibody at least about 12 weeks.

In one embodiment, whenever biweekly give antibody or its antigen-binding portion thereof.In another embodiment, give antibody or its antigen-binding portion thereof once in a week.In another embodiment, give antibody or its antigen-binding portion thereof with single dose.

In one embodiment, being used for the antibody of the inventive method or its antigen-binding portion thereof can be in conjunction with the epi-position of the p40 subunit of IL-12.

In another embodiment, when p40 subunit during in conjunction with the p35 subunit of IL-12, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.In another embodiment, when p40 subunit during in conjunction with the p19 subunit, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.In one embodiment, when the p40 subunit in conjunction with the p35 subunit of IL-12 and when p40 subunit during in conjunction with the p19 subunit, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.

In one embodiment, antibody or its antigen-binding portion thereof are in conjunction with the epi-position of the p40 subunit of the IL-12 of the antibodies that is selected from Y61 and J695.

In another embodiment, antibody capable is further combined with first heterodimer, and can also be in conjunction with second heterodimer, wherein first heterodimer comprises the p40 subunit of I1-12 and the p35 subunit of I1-12, and wherein second heterodimer comprises p40 subunit and the p19 subunit of IL-12.

In another embodiment, the antibody activity of first heterodimer that neutralizes.In another embodiment, the antibody activity of second heterodimer that neutralizes.In another embodiment, the neutralize activity of first heterodimer and second heterodimer of antibody.

In another embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof with 1 * 10 ^-9M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation, or with 1 * 10 ^-10M or littler IC ₅₀Suppressing people IFN γ produces.

In one embodiment, as measuring, be used for the antibody of the inventive method or its antigen-binding portion thereof with 1 * 10 by the resonance of surperficial plasmon ^-10M or littler K _dOr with 1 * 10 ^-3s ^-1Or littler k _OffSpeed constant (rate constant) is dissociated from the p40 subunit of IL-12.

In one embodiment, the antibody that is used for the inventive method of separation or its antigen-binding portion thereof are chimeric antibody, humanized antibody or people's antibody.

In another embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof and have heavy chain CDR3 that comprises amino acid sequence SEQ ID NO:25 and the light chain CDR3 that comprises amino acid sequence SEQ ID NO:26;

In another embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof and have heavy chain CDR2 that comprises amino acid sequence SEQ ID NO:27 and the light chain CDR2 that comprises amino acid sequence SEQ ID NO:28.

In one embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof and have heavy chain CDR1 that comprises amino acid sequence SEQ ID NO:29 and the light chain CDR1 that comprises amino acid sequence SEQ ID NO:30.

In another embodiment, being used for the antibody of the inventive method or its antigen-binding portion thereof can be in conjunction with the interleukin that comprises the p40 subunit.In one embodiment, interleukin comprises p40 subunit and p35 subunit, is IL-12 as this interleukin.In another embodiment, interleukin comprises p40 subunit and p19 subunit.In another embodiment, in antibody or its antigen-binding portion thereof and the activity of interleukin.

In one embodiment, antibody or its antigen-binding portion thereof are in conjunction with the epi-position of p40 subunit.

In one embodiment, antibody or its antigen-binding portion thereof give individuality with the pharmaceutical composition that comprises this antibody or its antigen-binding portion thereof and pharmaceutically acceptable carrier.Pharmaceutical composition also can comprise other medicine, and therapeutic agent for example is as budesonide, epidermal growth factor, corticoid, cyclosporin, salicylazosulfapyridine, aminosalicylate, Ismipur, azathioprine, flagyl, lipoxidase inhibitor, mesalazine, Olsalazine, Balsalazide, antioxidant, the thromboxane inhibitor, the IL-1 receptor antagonist, anti--IL-1 β monoclone antibody, anti--the IL-6 monoclone antibody, growth factor, elastatinal, pyridine radicals-imidazolium compounds, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, the antibody of FGF and PDGF or activator, CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, the antibody of CD90 or their part, amethopterin, cyclosporin, FK506, rapamycin, MMF, leflunomide, NSAIDs, brufen, corticoid, prednisolone, phosphodiesterase inhibitor, adenosine agonists, antithrombotic, complement inhibitor, adrenergic agent, IRAK, NIK, IKK, p38, map kinase inhibitor, IL-1 'beta ' converting emzyme inhibitor, TNF α converting enzyme inhibitor, T-cellular signal transduction inhibitor, metal protease inhibitors, salicylazosulfapyridine, azathioprine, Ismipur, angiotensin-converting enzyme inhibitor, soluble cytokine receptor, solubility p55 TNF acceptor, solubility p75 TNF acceptor, sIL-1RI, sIL-1RII, sIL-6R, anti-inflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and TGF β.

In another embodiment, the therapeutic agent that gives in the individual pharmaceutical composition can be selected from anti-TNF antibody and antibody fragment, TNFR-Ig construction, tace inhibitor, PDE4 inhibitor, corticoid, budesonide, dexamethasone, salicylazosulfapyridine, 5-Para-amino-salicylic acid, Olsalazine, IL-1 'beta ' converting emzyme inhibitor, IL-1ra, tyrosine kinase inhibitor, Ismipur and IL-11.

In another embodiment, therapeutic agent can be selected from corticoid, prednisolone, medrat, azathioprine, cyclophosphamide, cyclosporin, amethopterin, 4-aminopyridine, Tizanidine, interferon-beta 1a, interferon-beta 1b, Copolymer 1, hyperbaric oxygen, drip-feed immunoglobulin, Cladribine, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, the antibody of PDGF or activator, CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, the antibody of CD90 or their part, amethopterin, cyclosporin, FK506, rapamycin, MMF, leflunomide, NSAID, brufen, corticoid, prednisolone, phosphodiesterase inhibitor, adenosine agonists, antithrombotic, complement inhibitor, adrenergic agent, IRAK, NIK, IKK, p38 or map kinase inhibitor, IL-1 'beta ' converting emzyme inhibitor, tace inhibitor, T-cellular signal transduction inhibitor, inhibitors of kinases, metal protease inhibitors, salicylazosulfapyridine, azathioprine, Ismipur, angiotensin-converting enzyme inhibitor, soluble cytokine receptor, solubility p55TNF acceptor, solubility p75 TNF acceptor, sIL-1RI, sIL-1RII, sIL-6R, sIL-13R, anti--P7s, p-selects albumen metalloprotein part (PSGL), anti-inflammatory cytokines, IL-4, IL-10, IL-13 and TGF β.

In one embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof respectively in conjunction with people IL-12 and/or human IL-2 3, and as measuring by surperficial plasmon resonance, with 1 * 10 ^-10M or littler K _dWith with 1 * 10 ^-3s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-4s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.In another embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-5s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.

In another embodiment, antibody or its antigen-binding portion thereof be respectively in conjunction with people IL-12 and/or human IL-2 3, and as measuring by surperficial plasmon resonance, with 1 * 10 ^-2s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.In another embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-3s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.In a further embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-4s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.In another embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-5s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12 and/or human IL-2 3.

In another embodiment, antibody or its antigen-binding portion thereof be in conjunction with people IL-12 and/or human IL-2 3, and with 1.34 * 10 ^-10M or littler K _dDissociate from people IL-12 and/or human IL-2 3 respectively.In another embodiment, antibody or its antigen-binding portion thereof be in conjunction with people IL-12 and/or human IL-2 3, and with 9.74 * 10 ^-11M or littler K _dDissociate from people IL-12 and/or human IL-2 3 respectively.In one embodiment, antibody or its antigen-binding portion thereof are recombinant antibodies or its antigen-binding portion thereof.

In one embodiment, the antibody or its antigen-binding portion thereof that are used for the inventive method are neutralizing antibodies, as in and people IL-12 and/or human IL-2's 3 activity.In one embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-9M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In another embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-10M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In another embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-11M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In another embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-7M or littler IC ₅₀In external phytolectin blastocyte proliferation assay (PHA mensuration), suppress phytolectin blastocyte propagation.In another embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-8M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In one embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-10M or littler IC ₅₀Suppressing people IFN γ produces.In another embodiment, neutralizing antibody or its antigen-binding portion thereof are with 1 * 10 ^-11M or littler IC ₅₀Suppressing people IFN γ produces.In a further embodiment, neutralizing antibody or its antigen-binding portion thereof are with 5 * 10 ^-12M or littler IC ₅₀Suppressing people IFN γ produces.

In one embodiment, the antibody or its antigen-binding portion thereof that are used for the inventive method

A) with 1 * 10 ^-9M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation;

B) has the heavy chain CDR3 that comprises amino acid sequence SEQ ID NO:25; With

C) has the light chain CDR3 that comprises amino acid sequence SEQ ID NO:26.In one embodiment, antibody further has the heavy chain CDR2 that comprises amino acid sequence SEQ ID NO:27; With the light chain CDR2 that comprises amino acid sequence SEQ ID NO:28.In another embodiment, antibody or its antigen-binding portion thereof further have the heavy chain CDR1 that comprises amino acid sequence SEQ ID NO:29; With the light chain CDR1 that comprises amino acid sequence SEQ ID NO:30.In another embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-10M or littler IC ₅₀In measuring, further suppresses external PHA phytolectin blastocyte propagation.In another embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-11M or littler IC ₅₀In measuring, further suppresses external PHA phytolectin blastocyte propagation.

In one embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof and have variable region of heavy chain that comprises amino acid sequence SEQ ID NO:31 and the variable region of light chain that comprises amino acid sequence SEQID NO:32.

In one embodiment, antibody or its antigen-binding portion thereof that is used for the inventive method comprises the CH that is selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE constant region.In one embodiment, the heavy chain of antibody constant region is IgG1.In another embodiment, antibody is Fab fragment, F (ab ') ₂Fragment or strand Fv fragment.

In one embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof with 1 * 10 ^-10M or littler K _dFrom people IL-12 and/or human IL-2 3 dissociates and in conjunction with the epi-position on people IL-12 and/or human IL-2's 3 the p40 subunit.

In one embodiment, the antibody or its antigen-binding portion thereof that are used for the inventive method are people's antibody or its antigen-binding portion thereof, its

A) as measuring, with 1 * 10 by surperficial plasmon resonance ^-3s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12;

C) has the light chain CDR3 that comprises amino acid sequence SEQ ID NO:26.

In another embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof with 1 * 10 ^-4s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12.In another embodiment, people's antibody or its antigen-binding portion thereof are with 1 * 10 ^-5s ^-1Or littler k _OffSpeed constant is dissociated from people IL-12.

In one embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof and be people's antibody or its antigen-binding portion thereof, and comprise in conjunction with people IL-12:

The light chain CDR3 district that comprises amino acid sequence SEQ ID NO:26; With

The heavy chain CDR3 district that comprises amino acid sequence SEQ ID NO:25.

In one embodiment, antibody or its antigen-binding portion thereof have variable region of light chain (LCVR), this variable region of light chain has the CDR3 district that comprises amino acid sequence SEQ ID NO:26, and have variable region of heavy chain (HCVR), this variable region of heavy chain has the CDR3 district that comprises amino acid sequence SEQID NO:25.In another embodiment, antibody or its antigen-binding portion thereof comprise the LCVR that further has the CDR2 district that comprises amino acid sequence SEQ ID NO:28 and further comprise the HCVR in the CDR2 district of containing amino acid sequence SEQ ID NO:27.In another embodiment, LCVR further has the CDR1 district that comprises amino acid sequence SEQ ID NO:30, and HCVR has the CDR1 district that comprises amino acid sequence SEQ ID NO:29.

In one embodiment, antibody or its antigen-binding portion thereof be in conjunction with people IL-12 and/or human IL-2 3, and be antibody J695 (being also referred to as ABT-874) or its antigen-binding portion thereof.

In one embodiment, antibody or its antigen-binding portion thereof are in conjunction with people IL-12 and/or human IL-2 3, with 1.34 * 10 ^-10M or littler K _dDissociate from people IL-12, and in and people IL-12 and/or human IL-2 3.In one embodiment, antibody or its antigen-binding portion thereof are with 9.74 * 10 ^-11M or littler K _dDissociate from people IL-12 and/or human IL-2 3.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-7M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-8M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-9M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-10M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-11M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-10M or littler IC ₅₀Suppressing people IFN γ produces.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-11M or littler IC ₅₀Suppressing people IFN γ produces.In one embodiment, antibody or its antigen-binding portion thereof are with 5 * 10 ^-12M or littler IC ₅₀Suppressing people IFN γ produces.

In one embodiment, be used for the antibody of the inventive method or its antigen-binding portion thereof with 1 * 10 ^-9M or littler IC ₅₀, in IL-12 or IL-23 receptors bind mensuration (RBA), suppress IL-12 and/or IL-23 respectively in conjunction with its acceptor.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-10M or littler IC ₅₀, in IL-12 or IL-23 receptors bind mensuration (RBA), suppress IL-12 and/or IL-23 respectively in conjunction with its acceptor.In one embodiment, antibody or its antigen-binding portion thereof are with 1 * 10 ^-11M or littler IC ₅₀, in IL-12 or IL-23 receptors bind mensuration (RBA), suppress IL-12 and/or IL-23 respectively in conjunction with its acceptor.

The accompanying drawing summary

Fig. 1 has shown patient's test configurations.(term " eow " refers to administration week about)

Fig. 2 has shown in 12 all test portion processes to have at least 75% and improve the patient's of (PASI 75) percentage in psoriasis area and severity index.To the 8th week, based on variance analysis to purpose treatment crowd observed data, compare with placebo respectively, except that 200mg * 1 group, in each ABT-874 treatment group, has the patient's that PASI 75 replys percentage significantly higher statistically (p＜0.001) (term " eow " refers to administration week about).

Fig. 3 has shown the average percentage improvement in psoriasis area and severity index (PASI) score from baseline.Data show is based on the variance analysis to purpose treatment crowd observed data, on all time points, compare with placebo, for each ABT-874 treatment group * p＜0.001 (removing) (term " eow " refers to administration week about) at the 100mg in the 1st week eow, outside the p=0.023.

Fig. 4 A-C showed in the 24th week of test, promptly in the 12nd week that stops to give antibody, kept the patient's that PASI 50, PASI 75 and PASI 90 reply percentage respectively.

Fig. 4 D has shown the percentage of keeping the patient that PASI 75 replys at the duration of test in whole 24 weeks.

Detailed Description Of The Invention

For the present invention can more easily be understood, at first define some term.

Term " increased activity amino acid residue " comprises the amino acid residue that improves the antibody activity. Be to be understood that the increased activity amino acid residue can replace be in the contact position, high displacement is put or the amino acid residue of preferential selective mutagenesis position, and further, can be present among one or more CDRs more than one increased activity amino acid residue. The increased activity amino acid residue comprises and improves antibody, for example in conjunction with people IL-12 anti--amino acid residue of the binding specificity/affinity of people IL-12 antibody. The increased activity amino acid residue also is intended to comprise and improves antibody, for example suppresses the amino acid residue that the neutralization of the people IL-12 antibody of people IL-12 is tired.

Term " antibody " comprises by four polypeptide chains--two weight (H) chains and two immunoglobulin molecules that light (L) chain consists of of being connected to each other by disulfide bond. Every heavy chain consists of by weight chain variable district (being abbreviated as HCVR or VH at this) and the constant district of heavy chain. The constant district of heavy chain is made of three district CH1, CH2 and CH3. Every light chain consists of by light chain variable district (being abbreviated as LCVR or VL at this) and the constant district of light chain. The constant district of light chain is made of a district CL. VH and VL district can further be divided into the Gao Bianqu that is called complementary determining area (CDRs) again, wherein scatter the more conservative district that is called framework district (FR). Each VH and VL form by three CDRs and four FRs, and be as follows to putting in order of carboxyl end from amino terminal: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In one embodiment, the antibody that is used for the compositions and methods of the invention is United States Patent (USP) the 6th, 914, and the antibody described in No. 128 is incorporated herein by reference at this. In another embodiment, the antibody for the compositions and methods of the invention is that antibody A BT-874 (is also referred to as J695; Abbott Laboratories).

" antigen-binding portion thereof " of term antibody (or " antibody moiety ") comprises the antibody fragment that keeps specific binding antigen (such as hIL-12) ability. Already shown the antigen binding function that to fulfil antibody by the fragment of full length antibody. The example that is contained in the binding fragment in " antigen-binding portion thereof " of term antibody comprises (i) Fab fragment--by the unit price fragment of VL, VH, CL and CH1 district group; (ii) F (ab ')₂Fragment--be included in the hinge district by the divalence fragment of two Fab fragments of disulfide bridge bond connection; (iii) Fd fragment--the fragment that is formed by VH and CH1 district; (iv) Fv fragment is comprised of VL and the VH district of antibody single armed, (v) dAb fragment (Ward etc., (1989) Nature 341:544-546), and it is comprised of the VH district; The complementary determining area (CDR) of (vi) separating. In addition, although two districts of Fv fragment--VL is different coded by said gene with VH, but can use recombination method that they are connected by synthetic joint, the albumen strand of VL and VH district pairing formation monovalent molecule (be known as scFv (scFv) so that they are prepared as wherein; Referring to such as (1988) Science 242:423-426 such as Bird; With (1988) Proc.Natl.Acad. Sci.USA 85:5879-5883 such as Huston). Such single-chain antibody also is intended to be contained in " antigen-binding portion thereof " of term antibody. The single-chain antibody of other types, for example two antibody are also included within wherein. Two antibody are divalence, bispecific antibody, wherein express at single chain polypeptide in VH and VL district, but use joint too short so that can not between two districts on the same chain, match, thereby make the complementation district pairing of this district and another chain and produce two antigens and be combined the site (referring to such as Holliger, P., wait (1993) Proc.Natl.Acad.Sci.USA 90:6444-6448; Poljak, R.J. waits (1994) Structure 2:1121-1123).

Further, antibody or its antigen-binding portion thereof can be the parts that molecule is sticked in larger immunity, and it is by covalently or non-covalently associating antibody or antibody moiety and one or more other albumen or peptide formed that molecule is sticked in this larger immunity. The example that molecule is sticked in such immunity comprises with antibiotin albumen streptavidin core district and prepares tetramer scFv molecule (Kipriyanov, S.M., Deng (1995) Human Antibodies and Hybridomas 6:93-101) and prepare divalence and biological elementization scFv molecule (Kipriyanov with cysteine residues, a kind of mark peptide and the terminal polyhistidine label of C-, S.M., wait (1994) Mol.Immunol. 31:1047-1058). Can use routine techniques, for example respectively with pawpaw protease or pepsin digestion whole antibody, by whole antibody Dispersal risk part for example Fab and F (ab ')₂Fragment. In addition, can use recombinant DNA technology acquisition antibody, antibody moiety and the immunity of the standard of describing to stick molecule herein. Preferred antigen-binding portion thereof is the pairing in complete district or complete district.

Term " back mutation " refers to that a kind of amino acid of some or all body cell sudden change of wherein people antibody is for being that the corresponding kind of antibody sequence is the method that residue replaces from the homology kind. With the heavy chain of people's antibody of the present invention and light chain sequence respectively with the VBASE database in kind be that sequence is compared, have the sequence of highest homology with evaluation. By the different amino acid whose nucleotide position of coding of sudden change regulation, it kind is sequence that such difference in people's antibody of the present invention is returned to. Should investigate evaluation like this as each amino acid of back mutation material standed for antigen in conjunction with in direct or indirect effect, and any amino acid that is found to affect any expectation characteristic of people's antibody after sudden change should be included in final people's antibody; For example, the increased activity amino acid of identifying by selective mutagenesis method should not carry out back mutation. For making the amino acid whose number that carries out back mutation reduce to minimum, can keep that to be found to be different from immediate kind be sequence but be those amino acid positions that corresponding amino acid is identical in the sequence with another kind, prerequisite is in the amino acid whose both sides of discussing, and to be sequence have at least 10, preferred 12 amino acid with the sequence of people's antibody of the present invention to this another kind is identical or linear corresponding. Back mutation can be carried out in any stage of antibody optimization; Preferably, before and after selective mutagenesis method, at once carry out back mutation. More preferably, before selective mutagenesis method, at once carry out back mutation.

When using herein, phrase " human interleukin-11 2 " (being abbreviated as hIL-12 or IL-12 at this) comprises and is mainly macrophage and the secreted human cell factor of dendritic cells. This term comprises the different dimer protein that comprises the 35kD that links together by disulfide bridge bond inferior basic (p35) and the inferior base of 40kD (p40). This different dimer protein is called as " the inferior base of p70 ". The structure of people IL-12 is further described in for example Kobayashi, waits (1989) J.Exp Med.170:827-845; Seder waits (1993) Proc.Natl.Acad.Sci.90:10188-10192; Ling waits (1995) J.Exp Med. 154:116-127; Podlaski waits among (1992) Arch.Biochem.Biophys.294:230-237. Term people IL-12 is intended to comprise rHuIL-12 (rh IL-12), and it can be prepared by the recombinant expression method of standard.

Term " Kabat numbering ", " Kabat definition " and " Kabat mark " are commutative use herein. For these terms known in the field refer to the amino acid residue numbering system, these amino acid residues are more variable (being alterable height) (Kabat etc. (1971) Ann.NY Acad, Sci. than the heavy chain of antibody or its antigen-binding portion thereof and other amino acid residues in the light chain variable district190: 382-391 and Kabat, E.A. waits (1991) Sequences of Proteins of Immunological Interest, and the 5th edition, U.S.Department of Health and Human Services, NIH publication numbering 91-3242). For the weight chain variable district, the high district CDR1 that becomes is positioned at the 31st to the 35th in amino acid, and CDR2 is positioned at the 50th to the 65th in amino acid, and CDR3 is positioned at the 95th to the 102nd in amino acid. For the light chain variable district, the high district CDR1 that becomes is positioned at the 24th to the 34th in amino acid, and CDR2 is positioned at the 50th to the 56th in amino acid, and CDR3 is positioned at the 89th to the 97th in amino acid.

The Kabat numbering is used to indicate the amino acid modified position of carrying out in antibody of the present invention herein. For example, (H31S → E) maybe can be tyrosine (Y) (L94G → Y) with the 94th glycine (G) sudden change of light chain CDR3 for glutamic acid (E) in the 31st serine (S) sudden change that can Y61 is anti--IL-12 antibody heavy chain CDR1.

Term " people's antibody " comprises having corresponding to Kabat etc. (referring to Kabat, Deng (1991) Sequences of Proteins of Immunological Interest, the 5th edition, U.S.Department of Health and Human Services, NIH publication numbering 91-3242) described ethnic group is the variable district of immunoglobulin sequences and the antibody in constant district. People's antibody of the present invention can comprise and not be that ethnic group is the coded amino acid residue of immunoglobulin sequences (such as the sudden change that imports by body cell sudden change at random external or site-specific mutagenesis or the body), for example in CDRs and especially in CDR3. Preferred use " the selective mutagenesis method " described herein imports this sudden change. People's antibody can have at least one for being not that ethnic group is the coded amino acid residue of immunoglobulin sequences, the position that replaces such as the increased activity amino acid residue. People's antibody can have nearly 20 for not being that ethnic group is the position that the amino acid residue of the part of immunoglobulin sequences replaces. In other embodiments, nearly 10, nearly 5, nearly 3 or nearly 2 positions be substituted.

In a preferred embodiment, as detailed below, these replacements are arranged in the CDR district. Yet when using herein, term " people's antibody " also is not intended to the antibody that comprises wherein already grafting of CDR sequence on people's Frame sequence and derive from the kind system of another mammalian species such as mouse.

Phrase " recombinant human antibody " comprises the people's antibody by recombinant means preparation, expression, generation or separation, for example use the antibody (being further described in the following II joint) of the recombinant expression carrier expression that is transfected in host's cell, separate the antibody (being further described in the following III joint) from people's antibody library restructuring, combination, separate from the antibody that has changed human immunoglobulin gene's animal (such as mouse) over to (referring to such as Taylor, L.D., wait (1992) Nucl.Acids Res.20:6287-6295) or enter the antibody that additive method in other dna sequence dnas is prepared, express, produce or separate by relating to montage human immunoglobulin gene sequence. Such recombinant human antibody has variable district that the ethnic group of deriving from is immunoglobulin sequences and constant district (referring to Kabat, E.A., Deng (1991) Sequences of Proteins of Immunological Interest, the 5th edition, U.S.Department of Health and Human Services, NIH publication numbering 91-3242). Yet, in certain embodiments, such recombinant human antibody is carried out external mutagenesis (maybe when use changes the animal of people Ig sequence gene over to, body cell mutagenesis in the body), thereby the amino acid sequence in the VH of recombinant antibodies and VL district is such sequence, although namely derive from and with ethnic group be VH and VL Serial relation, can not naturally be present in that people's antibody kind is in all constituents in the body. Yet in certain embodiments, such recombinant antibodies is selective mutagenesis method or back mutation or both results.

" antibody of separation " comprises the antibody that is substantially devoid of other antibody with different antigen-specifics (antibody such as the separation of specific binding hIL-12 is to be substantially devoid of the antibody that specific binding is different from the antigen of hIL-12). The antibody of the separation of specific binding hIL-12 can be in conjunction with the IL-12 molecule (following further in detail discussion) from other species. In addition, the antibody of separation can be substantially devoid of other cell material and/or chemicals.

" in and antibody " (or the antibody of hIL-12 activity " in and ") comprises the antibody that causes the biologically active that suppresses hIL-12 in conjunction with hIL-12. Can estimate by the indicant of measuring one or more hIL-12 biologically actives the inhibition of the biologically active of this hIL-12, the for example inhibition of people plant agglutinin blastocyte propagation in plant agglutinin blastocyte proliferation assay (PHA), or in people IL-12 receptors bind is measured the inhibition of receptors bind (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 3-interferon-γ is induced mensuration). Can estimate the indicant (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 3) of these hIL-12 biologically actives by in the external or in vivoassay of several standards known in the art one or more.

Term " activity " comprises such as the activity of antibody to the binding specificity/affinity of antigen, for example, anti--hIL-12 antibody is tired in conjunction with the neutralization of IL-12 antigen and/or antibody, for example, in conjunction with hIL-12 anti--biologically active of hIL-12 antibody suppression hIL-12, as suppress PHA blastocyte propagation or in people IL-12 receptors bind is measured, suppress receptors bind (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 3).

Phrase " surperficial plasmon resonance " comprises and for example uses (the Pharmacia Biosensor AB of BIAcore system, Uppsala, Sweden and Piscataway, NJ), change by protein concentration in the detection of biological sensor matrix, be provided for the optics phenomenon of real-time biospecific interaction analysis. Details are referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 5 Hes

U., wait (1993) Ann.Biol.Clin.51:19-26;

U., wait (1991) Biotechniques 11:620-627; Johnsson, B. waits (1995) J.Mol.Recognit.8:125-131; And Johnnson, B. waits (1991) Anal.Biochem.198:268-277.

When using herein, term " K_off" mean the disassociation speed constant (off rate constant) that antibody dissociates from the antibody/antigen compound.

When using herein, term " K_d" mean the disassociation constant (dissociation constant) that specific antibodies-antigen interacts.

Phrase " nucleic acid molecules " comprises dna molecular and RNA molecule. Nucleic acid molecules can be strand or two strands, but double-stranded DNA preferably.

The nucleic acid that comprises " antibody of separation " in conjunction with antibody or the antibody moiety (such as VH, VL, CDR3) of hIL-12 about coding, when using herein, phrase " nucleic acid molecules of separation " comprises that the nucleotides sequence of encoding antibody wherein or antibody moiety does not contain coding in conjunction with the nucleic acid molecules of other nucleotides sequences of the antibody of the antigen except hIL-12 or antibody moiety, these other sequence can be in the human gene group DNA this nucleic acid of natural ground side joint. Therefore, for example, the nucleic acid of the separation of the present invention in the VH district of the anti--IL-12 antibody of encoding does not contain coding in conjunction with other sequences in other VH districts of the antigen except IL-12. Phrase " nucleic acid molecules of separation " also is intended to comprise the sequence of coding divalence, bispecific antibody, and for example encode wherein VH and VL district do not contain the sequence of two antibody of other sequences that are different from this pair antibody sequence.

Term " carrier " comprises the nucleic acid molecules of another nucleic acid delivery that it can be connected. One type carrier is " plasmid ", and it refers to wherein can connect the double-stranded dna circle of ring-type of other DNA section. The carrier of another type is viral vectors, and wherein other DNA section can be connected in the viral genome. Some carrier can independently copy bacteria carrier and the free type mammal carrier of bacterium origin of replication (as have) in importing their host's cell. Other carriers (such as non-free type mammal carrier) can be integrated in the genome of host's cell in importing host's cell the time, thereby copy with host genome. In addition, some carrier can instruct the expression of the gene that they are operably connected. Such carrier is referred to here as " recombinant expression carrier " (or referred to as " expression vector "). Generally speaking, the expression vector of using in recombinant DNA technology often is to exist with the plasmid form. In this manual, " plasmid " and " carrier " can exchange use, because plasmid is the carrier format of normal use. Yet, the invention is intended to comprise other forms of such expression vector, viral vectors (such as replication defect type reverse transcription virus, adenovirus and adenovirus correlated virus) for example, they play equal function.

Phrase " recombinant host cell " (or referred to as " host's cell ") comprises the cell that has wherein imported recombinant expression carrier. Be to be understood that this term not only means specific object cell, also means the offspring of such cell. Because because sudden change or ambient influnence may exist some to change in the offspring, such offspring in fact may be different from parental cell, but still are included in the scope of term as used herein " host's cell ".

When using herein, term " modification " means to change the one or more amino acid in antibody or its antigen-binding portion thereof. Can produce this change by adding, replace in one or more positions or lacking amino acid. Can use known technology for example PCR mutagenesis produce this change.

Phrase " contact position " is included in 26 known antibodies-antigen structure a certain, is the occupied CDR1, the CDR2 that are in antibody heavy chain variable region or light chain variable district of the amino acid of contact antigen or the amino acid position among the CDR3. If 26 cdr amino acid contact antigens in any of antibody-antigenic compound of solution structure, then this amino acid can be regarded as having occupied the contact position. Compare with non-contacting position, the contact position has the higher occupied probability of amino acid for contact antigen. Preferably, the contact position be contain 26 structures more than 3 (＞11.5%) in contact the amino acid whose CDR position of antigen. Most preferably, the contact position be contain 25 structures more than 8 (＞32%) in contact the amino acid whose CDR position of antigen.

Term " high displacement is put " comprises weight chain variable district or CDR1, the CDR2 in light chain variable district or the amino acid residue of the position in the CDR3 district that occupies antibody, and this position is considered to have in the affinity maturation high change of body cell of high-frequency or probability in the body of antibody. The body cell of high-frequency or the probability " high become " is included in the body of antibody that the residue of about 40% probability of 5-can experience high frequency or the probability that becomes of body cell in the affinity maturation. All scopes in this specified scope that are to be understood that also are intended to become a part of the present invention, and are about 30% such as 5-, about 15% such as 5-, such as 15-about 30%.

Term " preferential selective mutagenesis position " comprises the CDR1, the CDR2 that occupy weight chain variable district or light chain variable district or the amino acid residue of the position in the CDR3 district, and this position can be considered to contact the position and high displacement is put.

Phrase " selective mutagenesis method " comprises a kind of by put and/or contact the method that position selection and the CDR residue that suddenlys change separately improve the antibody activity at least one preferential selective mutagenesis position, high displacement. " selective sudden change " people's antibody is a kind of antibody that uses selective mutagenesis to suddenly change in the position through selecting that comprises. In another embodiment, selective mutagenesis method is intended to provide a kind of CDR1, CDR2 or CDR3 (following respectively referred to as H1, H2 and H3) of weight chain variable district of preferential sudden change antibody, or the method for the single amino acids residue through selecting among the CDR1 in light chain variable district, CDR2 or the CDR3 (following respectively referred to as L1, L2 and L3). Amino acid residue can be selected from preferential selective mutagenesis position, contact position or high displacement and put. Based on they positions in light chain or weight chain variable district, select single amino acids. Be to be understood that it also may be the contact position that high displacement is put. In one embodiment, selective mutagenesis method is a kind of " orientation method ". Wording " orientation method " is intended to comprise with preferentially suddenly change CDR1, CDR2 or CDR1, the CDR2 in CDR3 or light chain variable district or the method for the single amino acids residue through selecting among the CDR3 in weight chain variable district of antibody of oriented approach, such as " Group-wise orientation method " or " CDR-wise orientation method ". In " Group-wise orientation method ", the single amino acids residue particularly is directed in groups for selective sudden change, comprise group I (comprising L3 and H3), II (comprising H2 and L1) and III (comprising L2 and H1), with the preferential suitable sequence set that is used for orientation. In " CDR-wise orientation method ", single amino acids residue particularly CDRs is directed for selective sudden change, has following priority for orientation: H3, L3, H2, L1, H1 and L2. Amino acid residue through selecting is suddenlyd change is for example at least two kinds of other amino acid residues, and measures the effect of sudden change antagonist activity. Activity is measured as the change that the neutralization of the binding specificity/affinity of antibody and/or antibody is tired. Be to be understood that selective mutagenesis method can be used for optimizing any antibody that derives from any source, described source comprise bacteriophage show, with the human IgG kind be gene transgenic animal, separate the people's antibody from people B-cell. Preferably, selective mutagenesis method is used on the antibody that can't further use display technique of bacteriophage optimization. Be to be understood that can be before and after selective mutagenesis method to comprising that from any source bacteriophage shows, is that the animal of gene transgenic, the antibody that separates from people's antibody of people B-cell carry out back mutation with the human IgG kind.

Term " increased activity amino acid residue " comprises the amino acid residue that improves the antibody activity. Be to be understood that the increased activity amino acid residue can replace preferential selective mutagenesis position, contact position or the high amino acid residue that becomes the position, in addition, can be present among one or more CDRs more than one increased activity amino acid residue. The increased activity amino acid residue comprises and improves antibody, for example in conjunction with people IL-12 anti--amino acid residue of the binding specificity/affinity of people IL-12 antibody. The increased activity amino acid residue also is intended to comprise and improves antibody, for example suppresses the amino acid residue that the neutralization of the people IL-12 antibody of people IL-12 is tired.

When using herein, term " administration " is showed and is given material (such as anti--IL-12, anti--IL-23 antibody) to reach therapeutic purposes (such as the treatment rheumatoid arthritis).

When using herein, term " every biweekly give regimen ", " every administration biweekly " and " whenever biweekly administration " are showed and are given individual material (such as anti--IL-12, resist-IL-23 antibody) to reach the time-histories of therapeutic purposes, wherein this time-histories is every a week (eow). Every biweekly to regimen be not intended to comprise weekly to regimen. Preferably, give material one time in every 9-19 days, more preferably, gave material one time in every 11-17 days, also more preferably, gave material one time in every 13-15 days, and most preferably, gave one time material in per 14 days.

When in phrase " the first medicine and second medication combined ", term " associating " comprises and gives simultaneously the first medicine and the second medicine, it for example is dissolvable in water or sneaks in the same pharmaceutically acceptable carrier, or give first the first medicine, then give the second medicine, or give first the second medicine, then give the first medicine. Therefore, the present invention includes method and the combined medicinal composition of therapeutic alliance processing.

When in phrase " is followed therapeutic treatment ", term " is followed " and is included in the second medicine and gives medicine under existing. Follow the therapeutic treatment method to comprise wherein first, second, third or the method that given simultaneously of other medicine. Follow the therapeutic treatment method also comprise wherein second or other medicine in the presence of give first or the method for other medicine, wherein second or other medicine for example can formerly give. Follow the therapeutic treatment method progressively to carry out by different participants. For example, a participant can give individual the first medicine, can give individual the second medicine with another participant, and this dosing step can carry out simultaneously or almost simultaneously or in the time at interval, as long as the first medicine (with other medicine) afterwards in the presence of the second medicine (with other medicine). This participant can be identical entity (such as the people) with individuality.

When using herein, term " therapeutic alliance " is showed and is given two or more therapeutic substances, such as anti--IL-12, anti--IL-23 antibody and other medicine. This other medicine can follow anti--IL-12, anti--IL-23 antibody to give and give, gave before anti--IL-12, anti--IL-23 antibody give or give after giving at anti--IL-12, anti--IL-23.

When using herein, term " reagent box " refers to comprise the packaging product be used to the component that gives of the present invention resisting-IL-12, anti--IL-23 Antybody therapy IL-12 associated conditions. The reagent box preferably comprises box or the container that accommodates this kit components. The treatment scheme of this box or container label or Food and Drug Administration's approval. This box or container accommodate component of the present invention, and this component preferably is contained in plastics, polyethylene, polypropylene, ethene or the propylene container. This container can be pipe or bottle with cover. The reagent box also can comprise be used to resisting-operation instruction of IL-12, anti--IL-23 antibody.

Various aspects of the present invention are described in further detail in following trifle.

I. People's antibody in conjunction with people IL-12

The invention provides the method and composition that uses people's antibody or its antigen-binding portion thereof in conjunction with people IL-12 to be used for the treatment of psoriasis. The present invention also comprises the method and composition that uses in conjunction with the antibody of IL-12 and IL-23. Preferably, the people's antibody for the present invention is that people restructuring, neutralization resists-hIL-12 antibody.

In one embodiment, the antibody for this name is antibody A BT-874 (referring to United States Patent (USP) the 6th, 914, No. 128). ABT-874 is the human antibody of a kind of anti-interleukin 12 (IL-12) and IL-23. Its with high-affinity in conjunction with the inferior base of the common p40 of IL-12 and IL-23--the target through confirming in psoriasis (Ps) treatment.

Can be by for example screening one or more people VL and VH cDNA library with hIL-12, as by the display technique of bacteriophage described in the embodiment 1 of No. the 6th, 914,128, United States Patent (USP), select the antibody in conjunction with people IL-12. Screening people VL and VH cDNA library have been identified a series of resisting-IL-12 antibody at first, and wherein a kind of antibody is selected for further exploitation referred to here as " Joe 9 " (or " Joe 9 wild types "). Joe 9 is people IL-12 antibody (0.1s according to appointment of a kind of relative low-affinity^-1K_off), but for specific binding and detection hIL-12 or useful. By carrying out heavy chain and light chain CDRs mutagenesis, produce one group of " being mixed " light chain and weight chain variable district and further sudden change, produce numerous other resisting-hIL-12 antibody to hIL-12 affinity with increase, thereby improved the affinity of Joe 9 antibody (referring to United States Patent (USP) the 6th, 914, the sequence comparison of Figure 1A-D that No. the 6th, 914,128, No. 128 embodiment 1, table 2 (referring to appendix A) and United States Patent (USP)).

In these antibody, the people who is referred to herein as Y61 is anti--hIL-12 antibody confirm on binding affinity be improved significantly (according to appointment 2 * 10^-4s ^-1K_off). Select Y61 anti--that hIL-12 antibody is used for further affinity by the particular amino acid residue among separately sudden change heavy chain and the light chain CDRs is ripe. Based on the amino acid residue that occupies preferential selective mutagenesis position, contact position and/or high displacement and put, select the amino acid residue of Y61 to be used for site-specific sudden change (selective mutagenesis method). The summary that position through selecting in heavy chain and light chain CDRs replaces is shown in United States Patent (USP) the 6th, 914, among Fig. 2 A-2H of No. 128. A kind ofly (be also referred to as in the restructuring preferred of the present invention of ABT-874 (Abbott Laboratories) and antibody, produce from the light chain CDR2 of Y61 the 50th and locate Tyr the 94th of the light chain CDR3 of the replacement of Gly and Y61 located Tyr to the replacement of Gly referred to here as J695.

From Joe 9 wild types on the pedigree of J695, one group be used for the present invention anti--heavy chain of IL-12 antibody and the comparison of the amino acid sequence in light chain variable district be shown in United States Patent (USP) the 6th, 914, among Figure 1A-1D of No. 128. The comparison of these sequences can be used in the pedigree from Joe 9 to J695, identifies total sequence for preferred heavy chain and light chain variable district in conjunction with the antibody of the present invention of hIL-12, and identifies for CDR3, CDR2 and CDR1 and to have sequence. In addition, being summarized in that Y61 mutagenesis among Fig. 2 A-2H analyzes can be for having from the modification of Y61 but still keep the pedigree from Y61 to J695 of the sequence of good hIL-12 binding characteristic comprising, identify total sequence for heavy chain and light chain variable district in conjunction with hIL-12, and identify total sequence for CDR3, CDR2 and the CDR1 in conjunction with hIL-12. Be summarized in down by the preferred CDR of the determined the present invention of sequence identifier, VH and VL sequence (comprising total sequence) in the additional sequence table.

SEQ ID NO：	The antibody chain	The zone	Sequence
SEQ ID NO：	The antibody chain	The zone	Sequence	1	Total sequence Joe 9-J695	CDR H3	(H/S)-G-S-(H/Y)-D-(N/T/Y)
2	Total sequence Joe 9-J695	CDR L3	Q-(S/T)-Y-(D/E)-(S/R/K)-(S/G/Y)-(L/F/T/S)-(R/S/T/ W/H)-(G/P)-(S/T/A/L)-(R/S/M/T/L)-(V/I/T/M/L)	1	Total sequence Joe 9-J695	CDR H3	(H/S)-G-S-(H/Y)-D-(N/T/Y)
2	Total sequence Joe 9-J695	CDR L3		3	Total sequence Joe 9-J695	CDR H2	F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G
4	Total sequence Joe 9-J695	CDR L2	(G/Y)-N-(D/S)-(Q/N)-R-P-S	3	Total sequence Joe 9-J695	CDR H2	F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G
4	Total sequence Joe 9-J695	CDR L2	(G/Y)-N-(D/S)-(Q/N)-R-P-S	5	Total sequence Joe 9-J695	CDR H1	F-T-F-S-(S/E)-Y-G-M-H
6	Total sequence Joe 9-J695	CDR L1	(S/T)-G-(G/S)-(R/S)-S-N-I-(G/V)-(S/A)-(N/G/Y)-(T/ D)-V-(K/H)	5	Total sequence Joe 9-J695	CDR H1	F-T-F-S-(S/E)-Y-G-M-H
6	Total sequence Joe 9-J695	CDR L1		7	Total sequence Joe 9-J695	VH	(complete VH sequence; Referring to sequence table)

8	Total sequence Joe 9-J695	VL	(complete VL sequence; Referring to sequence table)
8	Total sequence Joe 9-J695	VL	(complete VL sequence; Referring to sequence table)	9	Total sequence Y61-J695	CDR H3	H-(G/V/C/H)-(S/T)-(H/T/V/R/I)-(D/S)-(N/K/A/T/S/F/ W/H)
10	Total sequence Y61-J695	CDR L3	Q-S-Y-(D/S)-(Xaa)-(G/D/Q/L/F/R/H/N/Y)-T-H-P-A- L-L	9	Total sequence Y61-J695	CDR H3	H-(G/V/C/H)-(S/T)-(H/T/V/R/I)-(D/S)-(N/K/A/T/S/F/ W/H)
10	Total sequence Y61-J695	CDR L3	Q-S-Y-(D/S)-(Xaa)-(G/D/Q/L/F/R/H/N/Y)-T-H-P-A- L-L	11	Total sequence Y61-J695	CDR H2	(F/T/Y)-I-(R/A)-Y-(D/S/E/A)-(G/R)-S-(Xaa)-K-(Y/E )-Y-A-D-S-V-K-G
12	Total sequence Y61-J695	CDR L2	(G/Y/S/T/N/Q)-N-D-Q-R-P-S	11	Total sequence Y61-J695	CDR H2
12	Total sequence Y61-J695	CDR L2	(G/Y/S/T/N/Q)-N-D-Q-R-P-S	13	Total sequence Y61-J695	CDR H1	F-T-F-(Xaa)-(Xaa)-(Y/H)-(G/M/A/N/S)-M-H
14	Total sequence Y61-J695	CDR L1	S-G-G-R-S-N-I-G-(S/C/R/N/D/T)-(N/M/I)-(T/Y/D/H/ K/P)-V-K	13	Total sequence Y61-J695	CDR H1	F-T-F-(Xaa)-(Xaa)-(Y/H)-(G/M/A/N/S)-M-H
14	Total sequence Y61-J695	CDR L1	S-G-G-R-S-N-I-G-(S/C/R/N/D/T)-(N/M/I)-(T/Y/D/H/ K/P)-V-K	15	Total sequence Y61-J695	VH	(complete VH sequence; Referring to sequence table)
16	Total sequence Y61-J695	VL	(complete VL sequence; Referring to sequence table)	15	Total sequence Y61-J695	VH	(complete VH sequence; Referring to sequence table)
16	Total sequence Y61-J695	VL	(complete VL sequence; Referring to sequence table)	17	Y61	CDR H3	H-G-S-H-D-N
18	Y61	CDR L3	Q-S-Y-D-R-G-T-H-P-A-L-L	17	Y61	CDR H3	H-G-S-H-D-N
18	Y61	CDR L3	Q-S-Y-D-R-G-T-H-P-A-L-L	19	Y61	CDR H2	F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G
20	Y61	CDR L2	G-N-D-Q-R-P-S	19	Y61	CDR H2	F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G
20	Y61	CDR L2	G-N-D-Q-R-P-S	21	Y61	CDR H1	F-T-F-S-S-Y-G-M-H
22	Y61	CDR L1	S-G-G-R-S-N-I-G-S-N-T-V-K	21	Y61	CDR H1	F-T-F-S-S-Y-G-M-H
22	Y61	CDR L1	S-G-G-R-S-N-I-G-S-N-T-V-K	23	Y61	VH	(complete VH sequence; Referring to sequence table)
24	Y61	VL	(complete VL sequence; Referring to sequence table)	23	Y61	VH	(complete VH sequence; Referring to sequence table)
24	Y61	VL	(complete VL sequence; Referring to sequence table)	25	J695	CDR H3	H-G-S-H-D-N
26	J695	CDR L3	Q-S-Y-D-R-Y-T-H-P-A-L-L	25	J695	CDR H3	H-G-S-H-D-N
26	J695	CDR L3	Q-S-Y-D-R-Y-T-H-P-A-L-L	27	J695	CDR H2	F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G
28	J695	CDR L2	Y-N-D-Q-R-P-S	27	J695	CDR H2	F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G
28	J695	CDR L2	Y-N-D-Q-R-P-S	29	J695	CDR H1	F-T-F-S-S-Y-G-M-H

30	J695	CDR L1	S-G-S-R-S-N-I-G-S-N-T-V-K
30	J695	CDR L1	S-G-S-R-S-N-I-G-S-N-T-V-K	31	J695	VH	(complete VH sequence; Referring to sequence table)
32	J695	VL	(complete VL sequence; Referring to sequence table)	31	J695	VH	(complete VH sequence; Referring to sequence table)

Measure K by surperficial plasmon resonance analyzing_dAnd K_offSpeed has been identified the antibody that produces from Joe 9 wild type affinity maturations in function. Produced and a series ofly had at about 0.1s^-1-Yue 1 * 10^-5s ^-1K in the scope_offSpeed, and more preferably from about 1 * 10^-4s ^-1-1×10 ^-5s ^-1Or less K_offAntibody. Such as United States Patent (USP) the 6th, 914, described in No. 128 the embodiment 3, also in the external ability of having identified antibody suppression plant agglutinin (PHA) blastocyte propagation. Produced and a series of had about 1 * 10^-6M-about 1 * 10^-11M, more preferably from about 1 * 10^-10M-1 ×10 ^-11M or less IC₅₀The antibody of value.

Therefore, in one aspect, the invention provides for the people's antibody that separates or the method and composition of its antigen-binding portion thereof, people's antibody of this separation or its antigen-binding portion thereof in conjunction with people IL-12 and as by surperficial plasmon resonance measure with 0.1s^-1Or less K_offThe speed constant dissociates from people IL-12, or with 1 * 10^-6M or less IC₅₀In external plant agglutinin blastocyte proliferation assay (PHA mensuration), suppress plant agglutinin blastocyte propagation. In preferred embodiments, the people IL-12 antibody of separation or its antigen-binding portion thereof are with 1 * 10^-2s ^-1Or less K_offThe speed constant dissociates from people IL-12, or with 1 * 10^-7M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation. In a more preferred embodiment, the people IL-12 antibody of separation or its antigen-binding portion thereof are with 1 * 10^-3s ^-1Or less K_offThe speed constant dissociates from people IL-12, or with 1 * 10^-8M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation. In a more preferred embodiment, the people IL-12 antibody of separation or its antigen-binding portion thereof are with 1 * 10^-4s ^-1Or less K_offThe speed constant dissociates from people IL-12, or with 1 * 10^-9M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation. In a more preferred embodiment, the people IL-12 antibody of separation or its antigen-binding portion thereof are with 1 * 10^-5s ^-1Or less K_offThe speed constant dissociates from people IL-12, or with 1 * 10^-10M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation. In preferred embodiment also, the people IL-12 antibody of separation or its antigen-binding portion thereof are with 1 * 10^-5s ^-1Or less K_offThe speed constant dissociates from people IL-12, or with 1 * 10^-11M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation.

Can measure by surperficial plasmon resonance the disassociation speed constant (K of IL-12 antibody_off) (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 5). Usually, use BIAcore (the Pharmacia Biosensor of system, Piscataway, NJ) by surperficial plasmon resonance (SPR), surperficial plasmon resonance analyzing is measured the real-time binding interactions between part (being fixed on the rHuIL-12 on the bio-sensing device matrix) and the analyte (antibody in the solution). Also can and introduce part (rIL-12 in the solution) and carry out surperficial plasmon analysis by fixing analyte (antibody on the bio-sensing device matrix). Can use one or more assessment IL-12 antibody in several suitable external tests or the neutralization active (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 3) of its antigen-binding portion thereof.

The well-known antibody heavy chain in this area and light chain CDRs play an important role in the antibody binding specificity/affinity for antigen. Therefore, the present invention includes light chain with Joe 9 and people's antibody of heavy chain CDRs, and other antibody with the CDRs that is modified to improve antibody binding specificity/affinity. Such as United States Patent (USP) the 6th, 914, prove among No. 128 the embodiment 1 that the people that a series of modifications to light chain and heavy chain CDRs have produced the affinity maturation resists-hIL-12 antibody. The heavy chain of a series of people's antibody in conjunction with people IL-12 from Joe 9 wild types to J695 and the comparison of light chain variable region amino acid sequence are shown in United States Patent (USP) the 6th, 914, among Figure 1A-1D of No. 128. Can from the sequence comparison, determine the total sequence motifs of antibody CDRs. For example, for the VH CDR3 from Joe 9 to J695 pedigrees, total basic order comprises amino acid sequence: (H/S)-G-S-(H/Y)-D-(N/T/Y) (SEQ ID NO:1), it comprises the amino acid from the 95-102 position of the total HCVR shown in the SEQ ID NO:7. For VL CDR3, total basic order comprises amino acid sequence: Q-(S/T)-Y-(D/E)-(S/R/K)-(S/G/Y)-(L/F/T/S)-(R/S/T/W/H)-(G/P)-(S/T/A/L)-(R/S/M/T/L-V/I/T/M/L) (SEQ ID NO:2), it comprises the amino acid from the 89-97 position of the total LCVR shown in the SEQ ID NO:8.

Therefore, in yet another aspect, the invention provides the people's antibody or its antigen-binding portion thereof method and composition that comprise separation, this people's antibody or its antigen-binding portion thereof have following characteristic:

A) with 1 * 10^-6M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation;

B) has the heavy chain CDR3 that comprises amino acid sequence SEQ ID NO:1; With

C) has the light chain CDR3 that comprises amino acid sequence SEQ ID NO:2.

In a preferred embodiment, antibody further comprises and contains amino acid sequence: the VH CDR2 of F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G (SEQ ID NO:3) (it comprises the amino acid of the 50-65 position of the total HCVR that comes self-contained amino acid sequence SEQ ID NO:7), and further comprise and contain amino acid sequence: (G/Y)-and the VL CDR2 of N-(D/S)-(Q/N)-R-P-S (SEQ ID NO:4) (it comprises to come the amino acid of 50-56 position of the total LCVR of self-contained amino acid sequence SEQ ID NO:8).

In another preferred embodiment, antibody further comprises and contains amino acid sequence: the VH CDR1 of F-T-F-S-(S/E)-Y-G-M-H (SEQ ID NO:5) (it comprises the amino acid of the 27-35 position of the total HCVR that comes self-contained amino acid sequence SEQ ID NO:7), and further and comprise and contain amino acid sequence: (S/T)-and the VL CDR1 of G-(G/S)-(R/S)-S-N-I-(G/V)-(S/A)-(N/G/Y)-(T/D)-V-(K/H) (SEQ ID NO:6) (it comprises to come the amino acid of 24-34 position of the total LCVR of self-contained amino acid sequence SEQ ID NO:8).

In still another preferred embodiment, being used for antibody of the present invention comprises the HCVR that contains amino acid sequence SEQ ID NO:7 and comprises the LCVR that contains amino acid sequence SEQ ID NO:8.

Based on the sudden change analysis (being summarized in United States Patent (USP) the 6th, 914, among Fig. 2 A-2H of No. 128) to the performed generation J695 antibody of Y61, can determine other total basic order. Such as United States Patent (USP) the 6th, 914, to scheme to confirm shown in Fig. 2 A-2H of No. 128, some residue of the heavy chain of Y61 and light chain CDRs can be substituted and basically not damage the hIL-12 binding property of antibody. For example, the independent replacement of carrying out with 12 different amino acid residues at the 30th place of CDR H1 can not reduce the K of antibody basically_offSpeed shows that it is to be used for the position that multiple different aminoacids residue replaces. Therefore, analyze (can with position among the Y61 of other amino acid residues replacements) based on sudden change and determined total basic order. For heavy chain and light chain CDR3s, total basic order is shown in SEQ ID NOs:9 and 10, and for heavy chain and light chain CDR2s, total basic order is shown in SEQ ID NOs:11 and 12, and for heavy chain and light chain CDR1s, total basic order is shown in SEQ ID NOs:13 and 14. For VH and VL district, total basic order is shown in SEQ ID NOs:15 and 16.

Therefore, in one aspect, the present invention includes a kind of people's antibody or its antigen-binding portion thereof of separation, it has following characteristic:

A) with 1 * 10^-9M or less IC₅₀In measuring, suppresses external PHA plant agglutinin blastocyte propagation;

B) has the heavy chain CDR3 that comprises amino acid sequence SEQ ID NO:9; With

C) has the light chain CDR3 that comprises amino acid sequence SEQ ID NO:10.

In a preferred embodiment, antibody further comprises the VH CDR2 that contains amino acid sequence SEQ ID NO:11 and further comprises the VL CDR2 that contains amino acid sequence SEQ ID NO:12.

In another preferred embodiment, antibody further comprises the VH CDR1 that contains amino acid sequence SEQ ID NO:13 and further comprises the VL CDR1 that contains amino acid sequence SEQ ID NO:14.

In still another preferred embodiment, the antibody for the present invention comprises the HCVR that contains amino acid sequence SEQ ID NO:15 and the LCVR that contains amino acid sequence SEQ ID NO:16.

Can be ripe through the affinity of the PCR of CDR3 mutagenesis by Joe 9 wild types (such as United States Patent (USP) the 6th, 914, No. 128 embodiment 1 described in) generation be used for the present invention's preferred antibody--the people is anti--hIL-12 antibody Y61. Y61 has the specificity/binding affinity of the improvement of measuring by surperficial plasmon resonance and external neutralization. The heavy chain of Y61 and light chain CDR3s are shown in SEQ ID NOs:17 and 18, and the heavy chain of Y61 and light chain CDR2s are shown in SEQ ID NOs:19 and 20, and the heavy chain of Y61 and light chain CDR1s are shown in SEQ ID NOs:21 and 22. The VL that the VH of Y61 has amino acid sequence SEQ ID NO:23 and a Y61 has amino acid sequence SEQ ID NO:24 (these sequences also are shown in United States Patent (USP) the 6th, 914, among No. 128 Figure 1A-1D that compares with Joe9).

Therefore, in yet another aspect, the invention provides a kind of people's antibody of separation or the application of its antigen-binding portion thereof, its

B) has the heavy chain CDR3 that comprises amino acid sequence SEQ ID NO:17; With

C) has the light chain CDR3 that comprises amino acid sequence SEQ ID NO:18.

In a preferred embodiment, be used for people's antibody or the heavy chain CDR2 that its antigen-binding portion thereof has the amino acid sequence SEQ ID NO:19 that comprises and the light chain CDR2 that comprises amino acid sequence SEQ ID NO:20 of the separation of method and composition of the present invention.

In another preferred embodiment, the people's antibody or its antigen-binding portion thereof that are used for the separation of method and composition of the present invention have the heavy chain CDR1 that comprises amino acid sequence SEQ ID NO:21 and the light chain CDR1 that comprises amino acid sequence SEQ ID NO:22.

In still another preferred embodiment, the people's antibody or its antigen-binding portion thereof that are used for the separation of method and composition of the present invention comprise the weight chain variable district of containing amino acid sequence SEQ ID NO:23 and the light chain variable district of containing amino acid sequence SEQ ID NO:24.

In certain embodiments, full length antibody comprises the constant district of heavy chain, the constant district of IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE and such as any of the same race special-shaped variant (Kabat described in the Kabat for example, E.A., Deng (1991) Sequences of Proteins of Immunological Interest, the 5th edition, U.S.Department of Health and Human Services, NIH publication numbering 91-3242). Preferably, the constant district of antibody heavy chain is the constant district of IgG1 heavy chain. Perhaps, antibody moiety can be Fab fragment, F (ab '₂) fragment or Single-Chain Fv Fragment of Murine.

The modification of the single residue of Y61 is caused having produced one group be shown in United States Patent (USP) the 6th, 914, the antibody among Fig. 2 A-2H of No. 128. Measured the specificity/binding affinity of each antibody by surperficial plasmon resonance and/or external neutralization.

Therefore, in yet another aspect, the invention provides a kind of people's antibody or its antigen-binding portion thereof of separation, its

B) has the heavy chain CDR3 that comprises the amino acid sequence that is selected from SEQ ID NO:404-SEQ ID NO:469; With

C) has the light chain CDR3 that comprises the amino acid sequence that is selected from SEQ ID NO:534-SEQ ID NO:579.

In preferred embodiments, the people's antibody or its antigen-binding portion thereof that are used for the separation of method and composition of the present invention have the heavy chain CDR2 that comprises the amino acid sequence that is selected from SEQ ID NO:335-SEQ ID NO:403; With the light chain CDR2 that comprises the amino acid sequence that is selected from SEQ ID NO:506-SEQ ID NO:533.

In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have the heavy chain CDR1 that comprises the amino acid sequence that is selected from SEQ ID NO:288-SEQ ID NO:334; With the light chain CDR1 that comprises the amino acid sequence that is selected from SEQ ID NO:470-SEQ ID NO:505.

In still another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof comprise variable region of heavy chain that contains amino acid sequence SEQ ID NO:23 and the variable region of light chain that contains amino acid sequence SEQID NO:24.

In certain embodiments, full length antibody comprise CH for example IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE constant region and as any allograft variant described in the Kabat (, Kabat, E.A., Deng (1991) Sequences of Proteins ofImmunological Interest, the 5th edition, U.S.Department of Health and HumanServices, NIH publication numbering 91-3242).Preferably, the heavy chain of antibody constant region is the IgG1 CH.Perhaps, antibody moiety can be Fab fragment, F (ab ' ₂) fragment or strand Fv fragment.

Particularly preferred reorganization neutralizing antibody J695 among a kind of the present invention of can be used for is (referring to the United States Patent (USP) the 6th, 914, No. 128 embodiment 2 and following joint III) by the site-directed mutagenesis generation of the contact of antibody Y61 and hypermutation amino acid residue.J695 is different from the Y61 part and is that at light chain CDR2 the 50th locates Tyr and replaced Gly and located Tyr the 94th of light chain CDR3 and replaced Gly.The heavy chain of J695 and light chain CDR3s are shown in respectively in SEQ ID NOs:25 and 26, and the heavy chain of J695 and light chain CDR2s are shown in respectively in SEQ ID NOs:27 and 28, and the heavy chain of J695 and light chain CDR1s are shown in respectively in SEQ ID NOs:29 and 30.The VL that the VH of J695 has amino acid sequence SEQ ID NO:31 and a J695 has amino acid sequence SEQ ID NO:32 (these sequences also are shown among Figure 1A-1D with No. the 6th, 914,128, the United States Patent (USP) of Joe9 comparison).

Therefore, in yet another aspect, the invention provides a kind of people's antibody or its antigen-binding portion thereof of separation, it is a) with 1 * 10 ^-9M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation; B) has the heavy chain CDR3 that comprises amino acid sequence SEQ ID NO:25; And c) has the light chain CDR3 that comprises amino acid sequence SEQ ID NO:26.

In preferred embodiments, people's antibody of separation or its antigen-binding portion thereof that is used for the present invention has heavy chain CDR2 that comprises amino acid sequence SEQ ID NO:27 and the light chain CDR2 that comprises amino acid sequence SEQ ID NO:28.

In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof that is used for the present invention has heavy chain CDR1 that comprises amino acid sequence SEQ ID NO:29 and the light chain CDR1 that comprises amino acid sequence SEQ ID NO:30.

In still another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof that is used for the present invention has variable region of heavy chain that comprises amino acid sequence SEQ ID NO:31 and the variable region of light chain that comprises amino acid sequence SEQ ID NO:32.

In certain embodiments, full length antibody comprises CH, for example IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE constant region and as any allograft variant (Kabat described in the Kabat, E.A., Deng (1991) Sequences of Proteins of ImmunologicalInterest, the 5th edition, U.S.Department of Health and Human Services, NIH publication numbering 91-3242).Preferably, the heavy chain of antibody constant region is the IgG1 CH.Perhaps, antibody moiety can be Fab fragment, F (ab ' ₂) fragment or strand Fv fragment.

On the pedigree of Joe 9 to J695, or on the pedigree from Y61 to J695, can in preferred consensus sequence, carry out other sudden change at CDR3, CDR2 and the CDR1 of antibody, so that other of the present invention anti--IL-12 antibody to be provided.Can use the Protocols in Molecular Biology of standard to carry out such method of modifying, for example by PCR mutagenesis, single contact among target light chain and/or the heavy chain CDRs or hypermutation amino acid residue, succeeded by the dynamics of the antibody of modification as described herein and functional analysis (as United States Patent (USP) the 6th, neutralization described in 914, No. 128 the embodiment 3 is measured and as United States Patent (USP) the 6th, BIAcore described in 914, No. 128 the embodiment 5 analyzes).

Therefore, in one aspect of the method, the invention provides a kind of people's antibody of separation or the application of its antigen-binding portion thereof, its

A) with 1 * 10 ^-6M or littler IC ₅₀In measuring, suppresses external PHA phytolectin blastocyte propagation;

B) comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:1, the heavy chain CDR2 and the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:5 that contain amino acid sequence SEQ ID NO:3, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:1, the heavy chain CDR2 that contains amino acid sequence SEQ ID NO:3 compares with the antibody of the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:5, and described mutant has and is not higher than 10-k doubly _OffSpeed; With

C) comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:2, the light chain CDR2 and the light chain CDR1 that contains amino acid sequence SEQ ID NO:6 that contain amino acid sequence SEQ ID NO:4, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:2, the light chain CDR2 that contains amino acid sequence SEQ ID NO:4 compares with the antibody of the light chain CDR1 that contains amino acid sequence SEQ ID NO:6, and described mutant has and is not higher than 10-k doubly _OffSpeed.

In one aspect of the method, the invention provides a kind of people's antibody of separation or the application of its antigen-binding portion thereof, its

B) comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:9, the heavy chain CDR2 and the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:13 that contain amino acid sequence SEQ ID NO:11, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:9, the heavy chain CDR2 that contains amino acid sequence SEQ ID NO:11 compares with the antibody of the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:13, and described mutant has and is not higher than 10-k doubly _OffSpeed; With

C) comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:10, the light chain CDR2 and the light chain CDR1 that contains amino acid sequence SEQ ID NO:14 that contain amino acid sequence SEQ ID NO:12, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:10, the light chain CDR2 that contains amino acid sequence SEQ ID NO:12 compares with the antibody of the light chain CDR1 that contains amino acid sequence SEQ ID NO:14, and described mutant has and is not higher than 10-k doubly _OffSpeed.

But those skilled in the art it should also be understood that the CDR district of antagonist and carry out other sudden change, for example in Y61 or J695, so that other of the present invention anti--IL-12 antibody to be provided.As mentioned above, can use the Protocols in Molecular Biology of standard to carry out such method of modifying.Can be as United States Patent (USP) the 6th, 914, among the embodiment 5 that No. the 6th, 914,128, No. 128 embodiment 3 and United States Patent (USP) the function of the antibody of modifying and dynamic analysis are described respectively.The modification of independent residue that causes identifying the Y61 of J695 is shown in United States Patent (USP) the 6th, 914, among Fig. 2 A-2H of No. 128, and is described in United States Patent (USP) the 6th, 914, among No. 128 the embodiment 2.

B) comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:17, the heavy chain CDR2 and the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:21 that contain amino acid sequence SEQ ID NO:19, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:17, the heavy chain CDR2 that contains amino acid sequence SEQ ID NO:19 compares with the antibody of the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:21, and described mutant has and is not higher than 10-k doubly _OffSpeed; With

C) comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:18, the light chain CDR2 and the light chain CDR1 that contains amino acid sequence SEQ ID NO:22 that contain amino acid sequence SEQ ID NO:20, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:18, the light chain CDR2 that contains amino acid sequence SEQ ID NO:20 compares with the antibody of the light chain CDR1 that contains amino acid sequence SEQ ID NO:22, and described mutant has and is not higher than 10-k doubly _OffSpeed.

B) comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:25, the heavy chain CDR2 and the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:29 that contain amino acid sequence SEQ ID NO:27, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the heavy chain CDR3 that contains amino acid sequence SEQ ID NO:25, the heavy chain CDR2 that contains amino acid sequence SEQ ID NO:27 compares with the antibody of the heavy chain CDR1 that contains amino acid sequence SEQ ID NO:29, and described mutant has and is not higher than 10-k doubly _OffSpeed; With

C) comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:26, the light chain CDR2 and the light chain CDR1 that contains amino acid sequence SEQ ID NO:30 that contain amino acid sequence SEQ ID NO:28, in preferential selectivity mutagenesis position or the hypermutation position have its mutant of one or more aminoacid replacement, wherein with comprise the light chain CDR3 that contains amino acid sequence SEQ ID NO:26, the light chain CDR2 that contains amino acid sequence SEQ ID NO:28 compares with the antibody of the light chain CDR1 that contains amino acid sequence SEQ ID NO:30, and described mutant has and is not higher than 10-k doubly _OffSpeed.

In another embodiment, the invention provides in a kind of people's antibody of separation or its antigen-binding portion thereof and people IL-12 and at least a activity that is selected from the other primate IL-12 of baboon IL-12, marmoset monkey IL-12, chimpanzee IL-12, macaque IL-12 and rhesus macaque IL-12, but not and the application of the activity of mouse IL-12.

II The selection of recombinant human antibody

Can be by screening reorganization combinatorial antibody library, preferably screen the recombinant human antibody that scFv phage display library separation energy is used for the present invention, this scFv phage display library is to use preparation from the people VL of mRNA that derives from human lymphocyte and VH cDNAs preparation.The method that is used for identifying the antibody that can be used for method and composition of the present invention is described in United States Patent (USP) the 6th, 914, in No. 128, is incorporated herein by reference at this.The method that is used to prepare and screens such library is known in the art.Be used to produce the kit of phage display library (as Pharmacia recombinant phages antibody system (Recombinant Phage Antibody System), cat. no 27-9400-01 except that commercially available; With Stratagene SurfZAP ^TMPhage display kit, cat. no 240612) outside, is specially adapted to produce and screen the method for antibody display libraries and the example of reagent for example is found in, PCT publications such as Kang numbering WO 92/18619; PCT publications such as Winter numbering WO 92/20791; PCT publications such as Breitling numbering WO 93/01288; PCT publications such as McCafferty numbering WO 92/01047; PCT publications such as Garrard numbering WO 92/09690; Fuchs etc. (1991) Bio/Technology 9: 1370-1372; Hay etc. (1992) Hum Antibod Hybridomas 3: 81-85; Huse etc. (1989) Science 246: 1275-1281; McCafferty etc., Nature (1990) 348:552-554; Griffiths etc. (1993) EMBO J 12:725-734; Hawkins etc. (1992) J Mol Biol 226: 889-896; Clackson etc. (1991) Nature 352: 624-628; Gram etc. (1992) PNAS 89: 3576-3580; Garrad etc. (1991) Bio/Technology 9: 1373-1377; Hoogenboom etc. (1991) Nuc Acid Res 19: 4133-4137; With (1991) PNAS such as Barbas 88: 7978-7982.

The antibody library that is used for this method preferably prepares the scFv library from people VL and VH cDNAs.The preferred recombined human IL-12 that uses selects to have at the combination of IL-12 active people's heavy chain and sequence of light chain as antigen, thereby screens this scFv antibody library.For selecting to be specific to the p35 subunit of IL-12 or the antibody of p70 heterodimer, in the presence of excessive free p40 subunit, carry out filler test.Can be for example by as United States Patent (USP) the 6th, 914, subunit preferences (preference) is determined in the little-Friguet titration described in No. 128 the embodiment 1.

In case selected initial people VL and VH section, just carry out wherein testing through the VL of selection and screened " being mixed " of different pairings of VH section to the IL-12 combination, select preferred VL/VH to combination (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 1).In addition, for further improving the hIL-12 binding affinity and/or reducing dissociation rate constant to the hIL-12 combination, to be similar to the method for somatic mutation method in the body that in innate immunity answering, causes affinity matured antibody, but VL that the preferred VL/VH of random mutation is right and VH section preferably carry out random mutation in the CDR3 district of VH and/or VL.Can realize this external affinity maturation by the PCR primer amplification VH and the VL district of use and VH CDR3 or the complementation of VL CDR3 difference, described primer " had mixed " random mixture of four kinds of nucleotide bases already in some position, so that encode random mutation wherein of resulting PCR product has imported the VH and the VL section in VH and/or VL CDR3 district.Can carry out in conjunction with the selection again of hIL-12 and screening again the VH of these random mutations and VL section, and can select to have sequence the high-affinity and the low dissociation rate of IL-12 combination.Table 2 (referring to United States Patent (USP) the 6th, 914, No. 128 appendix A) has shown the antibody of showing the binding specificity/affinity of the change that is produced as external affinity maturation result.

After selecting, separate and screen of the present invention resisting-hIL-12 antibody from the recombination immunoglobulin display libraries, can from phage particle (Tathagata is from the phage genome), reclaim the nucleic acid of the antibody of coding, and go in other the expression vector by the recombinant DNA technology subclone of standard through selecting.If necessary, can further operate nucleic acid to produce other antibody types of the present invention (as being connected to the other immunoglobulin domain of coding, the nucleic acid of for example other constant region).Be to express the recombinant human antibody that separates by the screening combinatorial libraries,, go into the dna clone of encoding antibody in the recombinant expression carrier and import in the mammalian host cell as being described in further detail in the following IV joint.

The method of the people IL-12 binding antibody of selecting by display technique of bacteriophage, and by CDR district at random or site-directed mutagenesis affinity maturation be described in further detail in United States Patent (USP) the 6th, 914 through the method for the antibody of selection, among No. 128 the embodiment 1.

As United States Patent (USP) the 6th, 914, No. 128 embodiment 1 is described, and a series of resisting-IL-12 antibody identified in screening people VL and VHcDNA library, wherein selects Joe 9 antibody to be used for further exploitation.Relatively the variable region of heavy chain of Joe 9 is a sequence with the heavy chain kind that is selected from the VBASE database, and having disclosed Joe 9, to be similar to the COS-3 kind be sequence.COS-3 belongs to V _HIt is sequence that 3 families plant.

V _H3 families are that people VH kind is the part of repertoire, and people VH kind is that repertoire is 7 families--V based on the nucleotide sequence homology grouping _H1-V _H7 (Tomlinson etc. (1992) J.Mol.Biol., 227, (1995) Immunology Today such as 776-798 and Cook, 16,237-242).V _H3 families comprise the member of maximum numbers, are that the repertoire contribution is maximum for kind therefore.For any given people V _H3 kinds is antibody sequence, whole V _HAmino acid sequence identity in 3 families be high (referring to as (1992) J.Mol.Biol. such as Tomlinson, 227, (1995) ImmunologyToday such as 776-798 and Cook, 16,237-242).Any two V _HThe kind of 3 families be the scope of amino acid sequence identity between the VH sequence in about 100 VH residues, have 69-98 identical within (promptly at any two amino acid sequence homologies that kind is 69-98% between the VH sequence).For several are that sequence is right mostly, there are at least 80 or more a plurality of identical amino acid residue (i.e. at least 80% amino acid sequence homology).V _HAmino acid sequence high homology between 3 family members causes some amino acid residue to be present on the CDR and the key position in the framework region of VH chain.These amino acid residues are given the architectural feature at CDRs.

The research of antagonist structure has shown that based on the key amino acid residue that occupies some position in CDR and the framework region CDR conformation can be grouped into the CDR structure family of standard.Therefore, in different antibody, there are similar Local C DR conformation (Chothia etc. (1987) J.Mol.Biol., 196, (1989) Nature such as 901-917 and Chothia with the norm structure that has identical key amino acid residue, 342,877-883).At V _HIn 3 families, for CDR1 and CDR2 norm structure, exist at the critical sites place conservative amino acid residue homogeneity (Chothia etc. (1992) J.Mol.Biol., 227,799-817).

The COS-3 kind is that the VH gene is V _H3 family members, and be that 3-30 (DP-49) kind is the allelic variant of VH.COS-3 and Joe9 VH amino acid sequence difference only are 5 positions.Between Joe9 VH and COS-3 and at Joe9 VH and other V _HThe high homology of the amino acid sequence between 3 family members has also been given high homology (Chothia etc. (1992) J.Mol.Biol., 227, the 799-817 of CDR structure; Chothia etc. (1987) J.Mol.Biol., 196, (1989) Nature such as 901-917 and Chothia, 342,877-883).

Those skilled in the art be to be understood that based on homoamino acid sequence and the norm structure similitude of Joe 9, other V _H3 family members also can be used for producing the antibody in conjunction with people IL-12.This can carry out by the following method, for example by selecting suitable VL (Winter etc. (1994) Annual Rev.Immunol. through the chain shuffling technology, 12,433-55) or by comprise from rodent or other people antibody CDRs from antibody of the present invention with the CDRs grafting to V _HOn 3 family's frameworks.

Based on nucleotide sequence homology, with people V1 λ kind be the repertoire grouping be 10 families (Williams etc. (1996) J.Mol.Biol., 264,220-232).Is that sequence compares with the variable region of light chain of Joe 9 with the light chain kind that is selected from the VBASE database, has disclosed Joe 9 and has been similar to DPL8 λ kind system.This Joe9VL and DPL8 sequence difference only are four frame positions, and height homology and other V _λ1 family member's framework sequence.Based on high autoploidy of amino acid sequence and the norm structure similitude to Joe 9, other V _λ1 family member also can be used for producing the antibody in conjunction with people IL-12.This can be for example by selecting suitable VH (Winter etc. are on seeing) through the chain shuffling technology, or by comprise from rodent or other people antibody CDRs from antibody of the present invention with the CDRs grafting to V _λOn 1 family's framework and carried out.

Method of the present invention is intended to comprise the recombinant antibodies in conjunction with hIL-12, and this recombinant antibodies comprises and derives from V _H3 kinds are sequence family member's variable region of heavy chain and derive from V _λ1 kind is sequence family member's variable region of light chain.In addition, those skilled in the art are to be understood that any V _HThe 3 sequence of heavy chain members of family can with any V _λThe 1 sequence of light chain member of family combines.

Those skilled in the art it should also be understood that and cause kind of a dna sequence polymorphism that is the amino acid sequence change can be present in the colony (as the crowd).Because natural allelomorph changes, therefore such kind is that genetic polymorphism in the sequence can be present between the individuality in the colony.Natural allelomorph like this changes the variation that can produce 1-5% usually in the nucleotide sequence of gene.As natural allelomorph change result's any and all such nucleotide changes and the kind that is produced is that amino acid polymorphism all is prescribed within the scope of the invention in the sequence.

Therefore, in one aspect, the invention provides a kind of people's antibody or its antigen-binding portion thereof of separation, it has following characteristic:

A) in conjunction with people IL-12 and as measuring, with 0.1s by surperficial plasmon resonance ^-1Or k still less _OffSpeed constant is dissociated from people IL-12, or with 1 * 10 ^-6M or littler IC ₅₀In external phytolectin blastocyte proliferation assay (PHA mensuration), suppress phytolectin blastocyte propagation.

B) have to comprise and be selected from V _H3 kinds is the variable region of heavy chain of family member's amino acid sequence, and wherein variable region of heavy chain has with the sudden change of increased activity amino acid residue in contact position or hypermutation position.

C) have to comprise and be selected from V _λ1 kind is the variable region of light chain of family member's amino acid sequence, and wherein variable region of light chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position.

In a preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have sudden change in heavy chain CDR3.In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have sudden change in light chain CDR3.In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have sudden change in heavy chain CDR2.In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have sudden change in light chain CDR2.In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have sudden change in heavy chain CDR1.In another preferred embodiment, people's antibody of separation or its antigen-binding portion thereof have sudden change in light chain CDR1.

Those skilled in the art are to be understood that based on V _H3 kinds is family member or light chain V _λ1 kind is the high similitude of amino acid sequence between the family member, is that the sudden change of sequence can provide the additional antibody in conjunction with people IL-12 to kind.United States Patent (USP) the 6th, 914, No. 128 table 1 (also the 6th, 914, No. 128 appendix As of referring to United States Patent (USP)) has shown V _H3 family members' kind is sequence and has shown significant sequence homology in the family member.Also at United States Patent (USP) the 6th, 914, shown in No. 128 the table 1 is V _λ1 family member's kind is a sequence.Provide the heavy chain of Joe 9 and sequence of light chain as a comparison.For example can with to the sudden change (as the sudden change in Joe 9) that antibody of the present invention carried out in identical amino acid position carry out V _H3 or V _λIt is the sudden change of sequence that 1 family member plants.Can use the Protocols in Molecular Biology of standard to carry out this modification, for example by PCR mutagenesis, the target kind is the single amino acids residue in the sequence, succeeded by the dynamics of the antibody of modification as described herein and functional analysis (as United States Patent (USP) the 6th, neutralization described in 914, No. 128 the embodiment 3 is measured, and United States Patent (USP) the 6th, BIAcore described in 914, No. 128 the embodiment 5 analyzes).

Therefore, in one aspect, the invention provides a kind of people's antibody of separation or the application of its antigen-binding portion thereof, it has following characteristic:

A) have the variable region of heavy chain that comprises the amino acid sequence that is selected from SEQ ID NOs:595-667, wherein variable region of heavy chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position.

B) have the variable region of light chain that comprises the amino acid sequence that is selected from SEQ ID NOs:669-675, wherein variable region of light chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position.

Those skilled in the art are to be understood that based on Joe 9 and COS-3 heavy chain kind be between the sequence and Joe 9 and DPL8 λ kind are homoamino acid sequence similarity between the sequence, and these kinds are that other sudden changes in sequence C DR district can provide the additional antibody in conjunction with people IL-12.Can use the Protocols in Molecular Biology of above-mentioned standard to carry out such method of modifying.

Therefore, in one aspect, the invention provides the people's antibody of separation or the application of its antigen-binding portion thereof, this people's antibody or its antigen-binding portion thereof have following characteristic:

A) in conjunction with people IL-12 and as by the resonance of surperficial plasmon measured with 0.1s ^-1Or k still less _OffSpeed constant is dissociated from people IL-12, or with 1 * 10 ^-6M or littler IC ₅₀In external phytolectin blastocyte proliferation assay (PHA mensuration), suppress phytolectin blastocyte propagation.

B) have and comprise the variable region of heavy chain that the COS-3 kind is an amino acid sequence, wherein variable region of heavy chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position.

C) have and comprise the variable region of light chain that the DPL8 kind is an amino acid sequence, wherein variable region of light chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position.

Because some amino acid residue in occupation of the CDR of light chain and variable region of heavy chain and the key position in the framework region, has therefore been given architectural feature in these location.Particularly, CDR2 and CDR1 district have been carried out the norm structure classification.Owing between the family member, have the high homology of amino acid sequence, so these standard features are present between the family member.Those skilled in the art are to be understood that the modification at the amino acid residue place that gives these norm structures can produce the other antibody in conjunction with IL-12.Can use the Protocols in Molecular Biology of above-mentioned standard to carry out this modification.

Therefore, in yet another aspect, the invention provides the people's antibody of separation or the application of its antigen-binding portion thereof, this people's antibody or its antigen-binding portion thereof have following characteristic:

B) have to comprise and be selected from V _H3 kinds is the variable region of heavy chain of family member's amino acid sequence, and wherein variable region of heavy chain comprises and structurally is similar to from other V _H3 kinds be the family member CDR2s CDR2 and structurally be similar to from other V _H3 kinds is the CDR1 of family member's CDR1s, and wherein variable region of heavy chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position;

C) have to comprise and be selected from V _λ1 kind is the variable region of light chain of family member's amino acid sequence, and wherein variable region of light chain comprises and structurally is similar to from other V _λ1 kind be the family member CDR2s CDR2 and structurally be similar to from other V _λ1 kind is the CDR1 of family member's CDR1s, and wherein variable region of light chain has with the sudden change of increased activity amino acid residue in preferential selectivity mutagenesis position, contact position or hypermutation position.

The recombinant human antibody that is used for the present invention have with the ethnic group that is selected from the VBASE database be the variable region and the constant region of immunoglobulin sequences homology.Sudden change recombinant human antibody (as by random mutagenesis or PCR mutagenesis) has produced and has not been the coded amino acid of people's racial immunity globulin sequence.Equally, because the somatic mutation of the normal processes that occurs during the B-cell development, it is the antibody sequence of sequence that the recombinant antibodies library that derives from people's donor can comprise different their corresponding kinds.It should be noted that if " planting system " sequential coding that obtains by pcr amplification is amino acid difference in the framework region of configuration from true kind (be that sequence is compared with true kind promptly, difference in the sequence of amplification), then may expect these amino acid difference will be changed back real the kind is sequence (being that framework residue " back mutation " is a configuration to planting).Therefore, the present invention can randomly comprise the back mutation step.For carrying out this step, at first will plant is that the heavy chain of coding and the amino acid sequence of light chain (example is being seen in the VBASE database) compare with the heavy chain immunoglobulin and the light chain framework amino acid sequence of suddenling change, to be different from the amino acid residue that immediate kind is a sequence in the immunoglobulin framework sequence of identifying sudden change.Then, use genetic code should carry out to determine which nucleotide changes, thus with the suitable nucleotide back mutation of the immunoglobulin sequences of sudden change being sequence corresponding to kind.By the method for standard, for example the mutagenesis to the immunoglobulin framework sequence of sudden change is carried out in the mutagenesis (wherein Tu Bian nucleotide is impregnated in the PCR primer, makes the PCR product comprise this sudden change) of PCR-guidance or site-directed mutagenesis.Should investigate identified as each of back mutation material standed for amino acid whose act on antigen in conjunction with in be directly effect or indirectly-acting actually, and any amino acid that influences anyone antibody desired characteristic after the sudden change of being found should not be included in final people's antibody; As an example, the increased activity amino acid of identifying by the selectivity mutagenesis does not carry out back mutation.Determine to produce determination method from the antibody characteristic of mutagenesis and can comprise in ELISA, competitive ELISA, the external and body that neutralization measures (referring to as United States Patent (USP) the 6th, 914, No. 128 embodiment 3) and/or use immunohistochemistry from the histologic section of separate sources (comprising people, primate and/or other species).

For making the amino acid whose number that carries out back mutation reduce to minimum, can keep and be found that to be different from immediate kind be sequence but be corresponding those identical amino acid positions of amino acid in the sequence with another kind, prerequisite is in the amino acid whose both sides of being discussed, and to be sequence have at least 10, preferred 12 amino acid with the sequence of people's antibody of the present invention to this another kind is identical or linear corresponding.This can guarantee that any to pass immune peptide epitopes can not be external source for full-time antigen presenting cell in the individuality that uses Antybody therapy of the present invention is, but is equal to autoantigen, and being this another kind is the coded immunoglobulin of sequence.Back mutation can appear at any stage that antibody is optimized; Preferably, before and after the selectivity mutagenesis, carry out back mutation at once.More preferably, before the selectivity mutagenesis, carry out back mutation at once.

III. Modification to preferential selectivity mutagenesis position, contact position and/or hypermutation position

Usually, as above-mentioned II joint with described in No. the 6th, 914,128, this United States Patent (USP) that is incorporated herein by reference, can use the phage display method to have the selection of antibody of the affinity of improvement.Can and produce the big library that comprises different sequence antibody by the combination of random mutation CDR residue and realize such selection.Yet for these systems of selection of working, antibody-antigen-reactive must trend towards balance, to pass by in time so that the preferential conjugated antigen of the antibody of high-affinity more.Improve the affinity of anti--IL-12 antibody when using the phage display method through selecting, during the firm affinity (being the affinity of antibody Y61) that reaches the expection of certain level, the alternative condition that just can't determine balance is set up (may be because between antigen and the phage particle due to the other non-specific interaction).Therefore, have even the antibody of higher affinity may be selected by the phage display method.Thereby for some antibody or antigen at least, the phage display method is subject to the ability that their select to have the antibody of high binding specificity/affinity of improving.Therefore, set up a kind of method that is called the selectivity mutagenesis that need not the phage displaying antibody affinity maturation, the invention provides this method to overcome this limitation.Although developed this selectivity mutagenesis, should be noted that this method also can use with phage display system to overcome the limitation of using phage display system.In addition, this selectivity mutagenesis can be used for improving the activity of any antibody.

Activity (active as affinity or neutralization) for improving antibody is intended to each the CDR position in heavy chain and the light chain is sported every other possible amino acid residue ideally.Yet owing to there are 70 CDR positions on an average in antibody, therefore this method will very consuming time and labour intensive.Therefore, method of the present invention is allowed some residue through selecting among only pass through to suddenly change heavy chain and/or the light chain CDRs, thereby improves the activity of antibody.In addition, method of the present invention is allowed other desired characteristics that improve antibody activity and do not influence antibody.

Based on primary sequence or their positions in the variable region, the amino acid residue of determining antibody variable region contacts with antigen can make accurately predicting.However, visibly different CDRs as regional area in the variable region between antibody (Kabat etc. (1971) Ann.NY Acad, Sci. have been identified in the not homospecific antibody sequence comparison that has that Kabat etc. carried out 190: 382-393, Kabat, E.A. waits (1991) Sequences of Proteins ofImmunological Interest, and the 5th edition, U.S.Department of Health and HumanServices, NIH publication numbering 91-3242).Structural research has shown that the antigen mating surface is because the amino acid residue that is present among the CDRs forms.Other outer amino acid residues of also known CDR play structure function or directly relate to the antigen combination.Therefore, right for each Ag-Ab, the inside and outside amino acid residue of CDRs all may be important.

The sequence alignment research of Tomlison etc. has been identified among heavy chain and light chain CDR1 and the CDR2 and the many positions in the part of κ chain CDR3, and these positions are positions that take place frequently (Tomlison etc. (1996) J.Mol.Biol.256:813-817) of somatic mutation.Particularly, position H31, H31B, H33, H33B, H52B, H56, H58, L30, L31, L31A, L50, L53, L91, L92, L93 and L94 are accredited as the position that takes place frequently of somatic mutation.Yet this analysis has been got rid of and knownly is positioned at the antibody combining site center and may provides and the important interactional important heavy chain CDR3 district of antigen and the part of light chain CDR3.In addition, proposition somatic cell diversity such as Tomlison can not predict separately specific amino acids antigen in conjunction with in effect, and the amino acid residue of guarding that contacts with antigen of hint is with the various amino acid residues that do not contact with antigen.This conclusion obtained at the further support of the mutation research of somatic mutation antagonist affinity effect (Sharon, (1990), PNAS, 87:4814-7).High-affinity anti--to benzeneazo arsonate (Ars) antibody in, the sudden change of 19 individual cells is that residue replaces by the corresponding kind with them simultaneously, produces to have the resisting of 200 times of loss of activity-phylotype of Ars antibody.Anti--Ars the antibody of this complete affinity can only be restored by 3 of recovering in this 19 individual cells sudden change, has proved the many somatic mutations that do not help antigen-binding activity of tolerable.

This result can be able to partial interpretation by the multifarious character of antibody self.Children's B-cell can produce the low-affinity antibody of multiple self or non-autoantigen of identification at first.In addition, antibody can experience the sequence variation that can cause autoreactivity during affinity maturation.The hypermutation of such low-affinity antibody can be used for eliminating autoreactivity (" the negative selection ") also increases the affinity to exogenous antigen.Therefore, can't provide a kind of prediction (1) with respect to reducing at unwanted antigen in the process of affinity to the one-level of lot of antibodies and the analysis of structured data, the effect of somatic hypermutation site in the affinity maturation process, or how (2) given amino acid helps the method for the right character of specific Ag-Ab.

By analyzing the crystal structure of a large amount of antigen-antibody complexes, other trials (MacCallum etc. (1996) J.Mol.Biol.262:732-745) have been carried out at the effect of particular amino acid residue in antigen recognizing.Indicated the latent effect that is positioned at the inside and outside position of CDRs.26 analytical structure surpass 10 in relate to position among the CDRs of antigen combination and comprise H31, H33, H50, H52, H53, H54, H56, H58, H95, H96, H97, H98 and H100 in the heavy chain and L30A, L32, L91, L92, L93, L94, the L96 in the light chain.Yet this author mentions especially and uses these and other structured data prediction antigen contacts may cross prediction or be not enough to predict contact position, causes such conjecture, and promptly different antibody may have to use different strategies.

Pini etc. have described a plurality of residues in the antibody CDR sequence in the big phage display library of randomization with quick increase affinity of antibody (Pini etc. (1998) J.Biol Chem.273:21769-21776).Yet, the high-affinity antibody that Pini etc. discussed has sudden change on 8 positions altogether, and the regression analysis for this change of the affinity sin qua non who improves antibody becomes unrealistic, and reason is the amino acid for required minimal amount, test a large amount of possible combinations.

In addition, a plurality of residues of randomization differ and keep other desirable properties of antibody surely.The desirable properties of antibody or characteristic are well known in the art, and for example comprise, keep as with the non-cross reactivity of other albumen or people's tissue, and keep and approach antibody sequence that ethnic group is an immunoglobulin sequences, improve neutralization and tire.Other desirable propertieses or characteristic comprise the ability that keeps cross reactivity between kind, the ability that keeps the specific ability of epi-position and be retained in albumen high expression level in the mammalian cell.Can use technology well known in the art to observe or measure desirable properties or characteristic, described technology includes but not limited to ELISA, competitive ELISA, neutralization is measured (referring to as United States Patent (USP) the 6th in the external and body, 914, No. 128 embodiment 3), uses immunohistochemistry, and use moment expression or stably express at the research of expressing in the mammalian cell from the histologic section of the separate sources that comprises other sources that people, primate maybe may need.

In addition, the method for Pini etc. may import the minimal number of improving affinity institute actual needs and more change, and may cause antibody to trigger Anti-Human's antibody (HAMA) generation in individual human.

In addition, as discussing elsewhere, comprise that at this phage display that obtains proving or other correlation technique ribosomal display can't suitably work to reach a certain affinity between antibody and antigen, and because extra interaction comprises and the interaction of other phage or ribosome composition and antigen that therefore reaching the required condition of balance can't reasonably determined in the time limit.

Those skilled in the art can find the interested scientific information about the antibody diversity source from the instruction of the list of references of above-mentioned discussion.Yet, the invention provides a kind of right affinity of antibody of specific antigen-antibody that increases, keep the method for other antibody correlated characteristic or desired characteristic simultaneously.When considering that when giving the expectation that multiple different qualities comprises the antigen combination to specific antibodies, this is even more important.

If initial antibody has the desirable properties or the characteristic that need be retained, then the selectivity mutagenesis may be to be used to keep the best strategy that these desirable propertieses improve antibody activity simultaneously.For example, in the mutagenesis of Y61, target is to increase the affinity to hIL-12, and the neutralization that improves antibody tires, and keeps the character of expectation simultaneously.The character of the expectation of Y61 comprises that (1) remaines in the non-cross reactivity of other albumen or people's tissue, (2) keep good epitope specificity, promptly preferentially at p70 (p40/p35) thus in the environment of heterodimer identification p40 epi-position stop free, solubility p40 in conjunction with disturbing; (3) produce and to have the heavy chain that approaches their corresponding racial immunity globulin sequences as far as possible and the antibody of light-chain amino acid sequence.

In one embodiment, method of the present invention provides a kind of and has improved the tire selectivity mutagenesis of strategy of affinity and/or neutralization simultaneously as the desirable properties that keeps antibody or characteristic.Term " selectivity mutagenesis " as defined above and comprise the method for the amino acid residue of a kind of independent sudden change through selecting.The amino acid residue that will be suddenlyd change can at first be selected from preferential selectivity mutagenesis position, then be contact position, then be the hypermutation position.This single position through selecting can be sported at least two kinds of other amino acid residues, and measure this prominent effect that the antibody character and the antibody activity of expectation are improved.

This selectivity mutagenesis comprises step:

Select candidate's position 1 in the following order) preferential selectivity mutagenesis position; 2) contact position; 3) hypermutation position, and based on heavy chain and this position of the positional alignment in the variable region of light chain (CDR3 is better than CDR2 and is better than CDR1) at antibody, described position;

With the order of being arranged candidate's preferential selectivity mutagenesis position, hypermutation position and/or contact position sported all possible other amino acid residue separately, and analyze this effect of sudden change antagonist activity separately, so that determine the increased activity amino acid residue;

If necessary, progressively make up independent increased activity amino acid residue and analyze the effect of different combination antagonist activity; Selection has the saltant antibody of increased activity amino acid residue and based on the position and the identity of aminoacid replacement of immunogenicity potentiality about them saltant antibody is sorted.The highest rank comprised almost to be equal in kind be the amino acid sequence of the variable region sequences described in the database, or have the saltant antibody with the comparable amino acid sequence of other people's antibody.The saltant antibody that will lower rank be included in the aminoacid replacement that seldom occurs in kind of the sequence that is sequence or other people antibody.It is the saltant antibody that does not have the aminoacid replacement of appearance in sequence or others antibody sequence that minimum rank is included in kind.As mentioned above, saltant antibody comprises and is arranged in CDR3 and is better than at least one increased activity amino acid residue that CDR2 is better than CDR1.The CDRs of variable region of heavy chain is better than the CDRs of variable region of light chain.

Also can study the activity of saltant antibody and improve, as when comparing with their corresponding parental antibodies.Can for example improve (referring to United States Patent (USP) the 6th, 914, No. 128 embodiment 3) by neutralization mensuration or through the activity that surperficial plasmon resonance analyzing binding specificity/affinity is measured this saltant antibody.Preferably, compare with parental antibody, this activity improvement may be up to few 2-20 doubly.Compare with parental antibody, this activity improvement may be up to few " x ₁"-" x ₂" doubly, " x wherein ₁" and " x ₂" be between 2-20 and comprise the integer of 2-20, be included in the scope in the specified scope, as 2-15, as 5-10.

Also can study to determine that after sudden change whether at least a other the character of expectation kept saltant antibody with increased activity amino acid residue.For example, antagonism-hIL-12 antibody test (1) keeps the non-cross reactivity with other albumen or people's tissue, (2) keep epi-position identification, promptly preferentially at p70 (p40/p35) thus in the environment of heterodimer identification p40 epi-position stop free, solubility p40 in conjunction with disturbing; (3) produce and to have the heavy chain that approaches their corresponding racial immunity globulin sequences as far as possible and the antibody of light-chain amino acid sequence, and based on kind be that the number of sequence difference determines that this antibody can unlikely initiation human immune.Can be to having more than an increased activity amino acid residue, carry out identical observation as the antibody of at least two or at least three increased activity amino acid residues, with the reservation of the character or the characteristic that determine whether to exist expectation.

In Y61 mutagenesis, use a case description of " selectivity mutagenesis " as follows.Sudden change H31S → E, L50 → Y or L94G → Y have improved the neutralization activity of antibody separately separately.Yet when the test combination clone, the activity of combination clone H31S → E+L50 → Y+L94G → Y and L50 → Y+L94G → Y (J695) is similar.Therefore, for the activity of improving J695 than Y61, be that to change into Glu be unnecessary to amino acid residue Ser with the 31st the kind of CDR1.Thereby this selectivity mutagenesis has been identified the change that helps final active minimal amount, thereby has reduced the immunogenicity potentiality of final antibody and kept the character of other expectations of antibody.

Described in the IV joint, can change coding into full length antibody chain gene, Fab fragment gene such as scFV gene by the VH of the method for mutagenesis generation of selection and the separated DNA of VL.In order to express VH and the VL district that produces by the method for mutagenesis of selecting, the expression vector of encoding heavy chain and light chain can be transfected into as in the various host cells that in the IV joint, described in detail.Preferred host cell comprises prokaryotic host cell, for example Escherichia coli, or eukaryotic host cell, and yeast cells for example is as saccharomyces cerevisiae (S.cerevisae).Most preferred eukaryotic host cell is the mammalian host cell that describes in detail in the IV joint.

The selectivity mutagenesis provides the method for the antibody of the activity that a kind of generation has improvement, carries out affinity matured antibody the preceding by other means.The selectivity mutagenesis provides the method for the antibody of the affinity that a kind of generation has improvement, and this antibody has carried out back mutation.The selectivity mutagenesis also provides a kind of method of activity of the antibody that improves affinity maturation.

Those skilled in the art will be appreciated that the selectivity mutagenesis can be used in the standard antibody operating technology known in the art.Example includes but not limited to the Fab fragment of CDR grafted antibody, chimeric antibody, scFv fragment, full length antibody and originates as people's antibody of transgenic mice from other.

The rapid large-scale mutation analysis of antibody comprise the in-vitro transcription of using the ribosomal display technology and translation (referring to as Hanes etc., (1997) Proc.Natl.Acad.Sci.94:4937-4942; Dall Acqua etc., (1998) Curr.Opin.Struc.Biol.8:443-450; And the United States Patent (USP) the 5th, 643, No. 768 and the 5th, 658, No. 754 of awarding to Kawasaki He etc., (1997) nucleic acid Res.25:5132-5134).The selectivity mutagenesis also provides the method for the antibody of the activity that a kind of generation has improvement, and this antibody can use the ribosomal display technology to select.

In the method for the invention, antibody or its antigen-binding portion thereof are further modified by single position among the CDRs that changes HCVR and/or LCVR.Although these modifications can be carried out in the antibody of phage display, the favourable part of this method is that the antibody of expressing in host system that it can be used in other types such as bacterium, yeast or the mammalian cell expression system carries out.The single position of CDRs through selecting to be used for modifying is based on the position of contact position and/or hypermutation position.

As defined herein preferred contact position and hypermutation position are shown in United States Patent (USP) the 6th, 914, in No. 128 the table 3 (referring to United States Patent (USP) the 6th, 914, No. 128 appendix A), and be specified in United States Patent (USP) the 6th, 914 according to the modification that the inventive method is carried out them, among No. 128 the embodiment 2.Preferred contact position is selected from H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96.Preferred hypermutation position is selected from H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53 and L93.Preferred amino acid residue (being called " preferential selectivity mutagenesis position ") is contact position and hypermutation position, and is selected from H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94.Particularly preferred contact position is selected from L50 and L94.

Preferred increased activity amino acid residue has replaced and has been positioned at the locational amino acid residue that is selected from H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96.Preferred increased activity amino acid residue has replaced the amino acid residue that is positioned on position H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, the L94.Particularly preferred increased activity amino acid residue has replaced and has been positioned at the locational amino acid residue that is selected from L50 and L94.

Generally speaking, method of the present invention comprises specific preferential selectivity mutagenesis position among the CDR of the heavy chain of selecting purpose parental antibody or its antigen-binding portion thereof or light chain, contact position and/or hypermutation position, this single position of random mutagenesis is (as passing through the genetics means, " the little library " that the oligonucleotides of use mutagenesis produces the antibody of modification), the amino acid that maybe this position is sported specific expectation strengthens amino acid residue with identified activity, express and antibody (as in non-phage display host system) that purifying is modified, measure the antibody of this modification to the activity of antigen (as by BIAcore assay determination k _OffSpeed), when needing, these steps are repeated in CDR position to other, and combination shows the independent sudden change of the activity with improvement, and test whether this combination results has than parental antibody or its antigen-binding portion thereof even the antibody of high activity (tiring as affinity or neutralization) more.

Therefore, in one embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

B) select 1 in the complementary determining region (CDR) successively) preferential selectivity mutagenesis position, 2) contact position or 3) the hypermutation position is used for sudden change, thus preferential selectivity mutagenesis position, contact position or the hypermutation position of evaluation through selecting;

C) described preferential selectivity mutagenesis position, contact position or hypermutation position through selecting sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change;

D), estimate the antibody of this group sudden change or the activity of its antigen-binding portion thereof with respect to parental antibody or its antigen-binding portion thereof;

E) randomly, other preferential selectivity mutagenesis positions, contact position or hypermutation position repeating step be a)-d) at least one;

F) the independent sudden change that the combination demonstration has the activity of improvement in parental antibody or its antigen-binding portion thereof is to produce combinatorial antibody or its antigen-binding portion thereof; With

G), estimate the activity of this combinatorial antibody or its antigen-binding portion thereof with respect to parental antibody or its antigen-binding portion thereof;

Until obtaining to have antibody or its antigen-binding portion thereof of the activity of improvement with respect to parental antibody or its antigen-binding portion thereof.Preferably, an antibody or a plurality of antibody through selecting have the activity of improvement, and do not lose or keep at least a above-mentioned parental antibody desired characteristic or character.By using techniques well known, those skilled in the art can measure or observe this desired characteristic or character.

Preferred contact position is selected from H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96.Preferred hypermutation position is selected from H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53 and L93.Preferred preferential selectivity mutagenesis position is selected from H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93 and L94.Particularly preferred contact position is selected from L50 and L94.

In another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

B) select preferential selectivity mutagenesis position, contact position or hypermutation position in the complementary determining region (CDR) to be used for sudden change;

D), estimate the antibody of this group sudden change or the activity of its antigen-binding portion thereof, thereby identified activity strengthens amino acid residue with respect to parental antibody or its antigen-binding portion thereof;

F) two independent increased activity amino acid residues that demonstration has the activity of improvement of combination in parental antibody or its antigen-binding portion thereof are to produce combinatorial antibody or its antigen-binding portion thereof; With

G) with respect to parental antibody or its antigen-binding portion thereof, evaluation has this combinatorial antibody of two increased activity amino acid residues or the activity of its antigen-binding portion thereof;

Until obtaining to have antibody or its antigen-binding portion thereof of the activity of improvement with respect to parental antibody or its antigen-binding portion thereof.

A) provide parental antibody or its antigen-binding portion thereof;

F) three independent increased activity amino acid residues that demonstration has the activity of improvement of combination in parental antibody or its antigen-binding portion thereof are to produce combinatorial antibody or its antigen-binding portion thereof; With

Preferably, the increased activity amino acid residue has replaced and has been positioned at the locational amino acid residue that is selected from H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96.

After independent position mutagenesis, can check order to the clone of sudden change to identify which amino acid residue has been directed in the position of selection in each clone through selecting.Can select a small amount of clone (24 according to appointment) to be used for order-checking, it should produce 10-15 unique antibody statistically, clone's (as greater than 60) of bigger quantity is checked order then can guarantee to identify the antibody that has every kind of possible replacement in the position through selecting.

In one embodiment, at first select contact position and/or hypermutation position in the CDR3 district of heavy chain and/or light chain to be used for mutagenesis.Yet for the antibody of phage display selection by the external affinity maturation of random mutagenesis in CDR3 district, it may preferably at first select CDR1 or the contact position among the CDR2 and/or the hypermutation position of heavy chain and/or light chain.

In a preferred embodiment, at first select the preferential selectivity mutagenesis position in the CDR3 district of heavy chain and/or light chain to be used for mutagenesis.Yet for the antibody of phage display selection by the external affinity maturation of random mutagenesis in CDR3 district, it may preferably at first select the CDR1 of heavy chain and/or light chain or the preferential selectivity mutagenesis position among the CDR2.

In another preferred embodiment, by the selectivity mutagenesis optimization of the antibody through selecting is carried out according to following order: the preferential selectivity mutagenesis position that at first will be selected from H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 sports at least 2 other amino acid (preferred 5-14 other amino acid) separately, and resulting antibody is identified the affinity, the neutralization that increase tire (possible words are also identified at least a other the characteristic or the character of being discussed elsewhere of reservation).If the sudden change of single preferential selectivity mutagenesis position can't be fundamentally or is increased affinity fully or neutralization is tired, if and even replaced the amino acid whose combination of amino acid whose a plurality of increased activity in the preferential selectivity mutagenesis position and also can't produce the combinatorial antibody that meets targeted activity (comprise affinity and/or neutralization tire), then should select to be selected from H35, H50, H53, H54, H95, H96, H97, H98, the other amino acid residue of L30A and L96 is used for selectivity mutagenesis, they are sported at least 2 other amino acid (preferred 5-14 other amino acid) separately, and resulting antibody is identified the affinity that increases, neutralization tire (possible words are also identified at least a other the characteristic or the character of being discussed elsewhere of reservation).

If be selected from H35, H50, H53, H54, H95, H96, H97, H98, that the sudden change of the single amino acids residue of L30A and L96 can't or be not enough to increase at all is active (comprise affinity and/or neutralization tire), if and even be substituted in the amino acid whose combination of amino acid whose a plurality of increased activity in those positions and can't produce the combinatorial antibody that meets targeted activity (comprise the neutralization of affinity and/or target tire), then should be from H33B, H52B, select other amino acid residue to be used for selectivity mutagenesis in the group that L31A forms, and sport at least 2 other amino acid (preferred 5-14 other amino acid) separately, identify the affinity of the increase of resulting antibody then, neutralization tire (and other retention characteristic or the character that also will discuss at least a other places is if possible identified).

In case be to be understood that and identified to have the expectation antibody of active (comprise affinity and neutralization tire), this select progressively mutagenesis just can be in any step termination of above general introduction.If the increased activity amino acid residue has been identified in the mutagenesis of the position of Xuan Zeing in advance, but this combinatorial antibody still can't satisfy the goal-setting at active (comprise affinity and neutralization tire), therefore if and/or identified that increased activity amino acid also influences other desired characteristics and can't accept the time, can carry out mutagenesis (referring to the IV joint) to remaining CDR residue.

The activity that method of the present invention can be used for improving antibody or its antigen-binding portion thereof is to reach predetermined targeted activity (tire as predetermined affinity and/or neutralization, and/or desirable properties or characteristic).

Therefore, the invention provides a kind of activity of improving antibody or its antigen-binding portion thereof to reach the method for predetermined targeted activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

B) be selected from the preferential selectivity mutagenesis position of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94;

C) at least two kinds of other amino acid residues be will preferential selectivity mutagenesis position sport separately, thereby antibody or its antigen-binding portion thereof of first group of sudden change produced through selecting;

D) estimate the antibody of first group of sudden change or the activity of its antigen-binding portion thereof, produced antibody or its antigen-binding portion thereof with the sudden change that determines whether single selectivity mutagenesis position with predetermined targeted activity or part targeted activity;

E) in parental antibody or its antigen-binding portion thereof, make up the independent sudden change that shows activity in progressively mode, to produce combinatorial antibody or its antigen-binding portion thereof with improvement.

F) activity of evaluation combinatorial antibody or its antigen-binding portion thereof has predetermined targeted activity or part targeted activity to determine whether this combinatorial antibody or its antigen-binding portion thereof.

G) if step d) or f) can't produce antibody or its antigen-binding portion thereof with predeterminated target activity, maybe can't produce the only active antibody of tool part, the other amino acid residue that just will be selected from H35, H50, H53, H54, H95, H96, H97, H98, L30A and L96 sports at least two kinds of other amino acid residues, thereby produces antibody or its antigen-binding portion thereof of second group of sudden change;

H) estimate the antibody of second group of sudden change or the activity of its antigen-binding portion thereof, produce with the sudden change of the single amino acids residue that determines whether to be selected from H35, H50, H53, H54, H95, H96, H97, H98, L30A and L96 and have predetermined targeted activity or active antibody or its antigen-binding portion thereof of part;

I) in parental antibody or its antigen-binding portion thereof, the independent sudden change of making up the step g) that shows the activity with improvement in progressively mode is to produce combinatorial antibody or its antigen-binding portion thereof;

J) activity of evaluation combinatorial antibody or its antigen-binding portion thereof has predetermined targeted activity or part targeted activity to determine whether this combinatorial antibody or its antigen-binding portion thereof;

K) if step h) or j) can't produce antibody or its antigen-binding portion thereof with predeterminated target activity, maybe can't produce the only active antibody of tool part, the other amino acid residue that just will be selected from H33B, H52B and L31A sports at least two kinds of other amino acid residues, thereby produces antibody or its antigen-binding portion thereof of the 3rd group of sudden change;

L) estimate the antibody of the 3rd group of sudden change or the activity of its antigen-binding portion thereof, produce with the sudden change of the single amino acids residue that determines whether to be selected from H33B, H52B and L31A and have predetermined targeted activity or active antibody or its antigen-binding portion thereof of part;

M) in parental antibody or its antigen-binding portion thereof, make up the step k that shows activity in progressively mode with improvement) independent sudden change, to produce combinatorial antibody or its antigen-binding portion thereof;

N) activity of evaluation combinatorial antibody or its antigen-binding portion thereof has predetermined targeted activity to determine whether this combinatorial antibody or its antigen-binding portion thereof, thereby produces antibody or its antigen-binding portion thereof with predetermined targeted activity.

Multiple method of mutagenesis be can use, PCR assembling, Kunkel (dut-ung-) and thiosulfates (Amersham Sculptor kit) oligonucleotides-directed mutagenesis comprised.

Multiple host expression system can be used for expressing the antibody of sudden change, comprises bacterium, yeast, baculoviral and mammalian expression systems (and phage display expression system).An example of suitable bacterial expression vector is pUC119 (Sfi).Other antibody expression systems are known in the art and/or are described in the following IV joint.

Do not rely on the phage display method that is used to select, can identify antibody or its antigen-binding portion thereof of the modification that produces by method of the present invention.Therefore, for improve in phage display system by select acquisition but its activity can't be further by the activity of the improved reorganization parental antibody of mutagenesis or its antigen-binding portion thereof in phage display system, method of the present invention is particularly advantageous.

Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof affinity, described method comprises:

A) provide reorganization parental antibody or its antigen-binding portion thereof; This reorganization parental antibody or its antigen-binding portion thereof obtain by selection in phage display system, but its activity can't further improve by mutagenesis in described phage display system;

B) select preferential selectivity mutagenesis position, contact position or hypermutation position in the complementary determining region (CDR) to be used for sudden change, thereby identify contact position or hypermutation position through selecting;

C) described preferential selectivity mutagenesis position, contact position or hypermutation position through selecting sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change, and in non-phage display system, express described group;

E) randomly, other preferential selectivity mutagenesis position, contact position or hypermutation position repeating step b at least one)-d);

Preferred contact position is selected from H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96.Preferred hypermutation position is selected from H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53and L93.Preferred preferential selectivity mutagenesis position is selected from H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93 and L94.Particularly preferred contact position is selected from L50 and L94.

Use existing method, the binding affinity and the neutralization that make antibody have increase are tired, and keeping as discussed above simultaneously, other character or the characteristic of antibody are impossible or require great effort very much.Yet method of the present invention can easily be identified such antibody.The antibody that is suitable for the inventive method can be from any source.

Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide reorganization parental antibody or its antigen-binding portion thereof;

B) select preferential selectivity mutagenesis position, contact position or hypermutation position at the complementary determining region that is used for suddenling change (CDR), thereby identify preferential selectivity mutagenesis position, contact position or hypermutation position through selecting;

C) described preferential selectivity mutagenesis position, contact position or hypermutation position through selecting sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change, and express described group in suitable expression system;

E) with respect to parental antibody or its antigen-binding portion thereof, estimate at least a other the character or the characteristic of the antibody of this group sudden change or its antigen-binding portion thereof, wherein this character or characteristic are one of the character that need keep in antibody or characteristic; Until obtaining to have activity and the character of at least a reservation or antibody or its antigen-binding portion thereof of characteristic of improvement with respect to parental antibody or its antigen-binding portion thereof.

In a preferred embodiment, contact position is selected from H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96, and other characteristic is selected from 1) keep the non-cross reactivity with other albumen or people's tissue, 2) reservation epi-position identification, thereby promptly preferentially the prevention of identification p40 epi-position dissociates in the environment of p70 p40/p35 heterodimer, the combination interference and/or 3 of solubility p40) produces the antibody that approaches racial immunity globulin sequence.

In another preferred embodiment, the hypermutation position is selected from H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53 and L93, and other characteristic is selected from 1) keep the non-cross reactivity with other albumen or people's tissue, 2) keep epi-position identification, thus promptly preferential in the environment of p70 p40/p35 heterodimer identification p40 epi-position stop free, solubility p40 in conjunction with disturb and/or 3) produce the antibody that approaches racial immunity globulin sequence.

In a preferred embodiment, the residue that is used for selectivity mutagenesis is selected from from H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, the preferential selectivity mutagenesis position of L94, and other characteristic is selected from 1) keep the non-cross reactivity with other albumen or people's tissue, 2) reservation epi-position identification, thereby promptly preferentially the prevention of identification p40 epi-position dissociates in the environment of p70p40/p35 heterodimer, the combination interference and/or 3 of solubility p40) produces the antibody that approaches racial immunity globulin sequence.

In a preferred embodiment, contact position is selected from L50 and L94, and other characteristic is selected from 1) keep the non-cross reactivity with other albumen or people's tissue, 2) keep epi-position identification, thus promptly preferential in the environment of p70 p40/p35 heterodimer identification p40 epi-position stop free, solubility p40 in conjunction with disturb and/or 3) produce the antibody that approaches racial immunity globulin sequence.

Therefore, if should improve at the affinity of the antibody of specific antigen, and the phage display related system of ribosomal display (or comprise) method is no longer feasible, and should keep other desirable propertieses or characteristic, then can use method of the present invention.Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

B) select preferential selectivity mutagenesis position, contact position or hypermutation position in the complementary determining region (CDR) to be used for sudden change, thereby identify preferential selectivity mutagenesis position, contact position or hypermutation position through selecting;

D), estimate the antibody of this group sudden change or the activity of its antigen-binding portion thereof with respect to parental antibody or its antigen-binding portion thereof; Thereby identified activity strengthens amino acid residue;

E) with respect to parental antibody or its antigen-binding portion thereof, estimate at least a other the character or the characteristic of the antibody of this group sudden change or its antigen-binding portion thereof, wherein this character or characteristic are to need one of the character that keeps or characteristic; Until obtaining to have activity and the character of at least a reservation or antibody or its antigen-binding portion thereof of characteristic of improvement with respect to parental antibody or its antigen-binding portion thereof.

F) randomly, other preferential selectivity mutagenesis position, contact position or hypermutation position repeating step be a)-e) at least one;

G) in parental antibody or its antigen-binding portion thereof, make up activity and the character of at least a reservation or the independent increased activity amino acid residue of characteristic that at least two demonstrations have improvement, to produce combinatorial antibody or its antigen-binding portion thereof; With

H), estimate the activity of this combinatorial antibody or its antigen-binding portion thereof with respect to parental antibody or its antigen-binding portion thereof;

Until obtaining to have activity and other character of at least a reservation or antibody or its antigen-binding portion thereof of characteristic of improvement with respect to parental antibody or its antigen-binding portion thereof.

B) preferential selectivity mutagenesis position, contact position or the hypermutation position that selection is used to suddenly change in complementary determining region (CDR), thereby the contact position or the hypermutation position of evaluation through selecting;

E) with respect to parental antibody or its antigen-binding portion thereof, estimate at least a other the character or the characteristic of the antibody of this group sudden change or its antigen-binding portion thereof, wherein this character or characteristic are to need one of the character that keeps or characteristic; Until obtaining, have antibody or its antigen-binding portion thereof of the characteristic of the activity of improvement and at least a reservation with respect to parental antibody or its antigen-binding portion thereof.

G) at least two demonstrations of combination have other the independent increased activity amino acid residue of characteristic of the activity of improvement and at least a reservation in parental antibody or its antigen-binding portion thereof, to produce combinatorial antibody or its antigen-binding portion thereof; With

H), estimate the activity of this combinatorial antibody or its antigen-binding portion thereof with respect to parental antibody or its antigen-binding portion thereof; Until obtaining to have activity and the character of at least a reservation or antibody or its antigen-binding portion thereof of characteristic of improvement with respect to parental antibody or its antigen-binding portion thereof.

IV. The modification of other CDR residues

Finally, with any means identified given antibody-antigen centering as the increased activity amino acid residue needed and/or that directly or indirectly need for conjugated antigen and/or that be used to keep antibody other desirable properties or all CDR residues of characteristic.Such CDR residue is called as " preferential selectivity mutagenesis position ".It should be noted that under specific situation preferential selectivity mutagenesis residue also can comprise that antibody and antigen cocrystallization and branch submodule are built by other means to be identified.

If above-mentioned focus on preferential selectivity mutagenesis position, contact position or hypermutation position to strengthen amino acid whose preferred trial at identified activity useless, or other if desired improvement can the remaining CDR residue of modification as described below.Be to be understood that according to embodiment discussed above antibody can be modified already, but still may need further improvement on any one or more contact positions or hypermutation position.Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

B) except that H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96, in complementary determining region (CDR), select amino acid residue to be used for sudden change;

C) described position through selecting is sported for example at least two kinds of other amino acid residues separately, thereby produce a kind of antibody of sudden change or antibody or its antigen-binding portion thereof of one group of sudden change;

D) with respect to parental antibody or its antigen-binding portion thereof, the antibody of estimating this sudden change is the antibody of this group sudden change or the activity of its antigen-binding portion thereof maybe; Thereby identified activity strengthens amino acid residue;

E) with respect to parental antibody or its antigen-binding portion thereof, the antibody of estimating this sudden change maybe the antibody of this group sudden change or its antigen-binding portion thereof at least a other character or the change in the characteristic, until the antibody or its antigen-binding portion thereof that obtain to have the activity of improvement with respect to parental antibody or its antigen-binding portion thereof.

Preferably, other characteristic or character are selected from 1) keep the non-cross reactivity with other albumen or people's tissue, 2) keep epi-position identification, thus promptly preferential in the environment of p70 p40/p35 heterodimer identification p40 epi-position stop free, solubility p40 in conjunction with disturb and/or 3) produce the antibody that approaches racial immunity globulin sequence.

If the mutagenesis of single residue is not enough, then can comprise other residues; Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

C) described position through selecting is sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change;

E) other the CDR position repeating step b at least one)-d), this position is not at b) in the position selected, neither be in the position of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

F) at least two independent increased activity amino acid residues that demonstration has the activity of improvement of combination in parental antibody or its antigen-binding portion thereof are to produce combinatorial antibody or its antigen-binding portion thereof; With

G) with respect to parental antibody or its antigen-binding portion thereof, estimate this and have the combinatorial antibody of two increased activity amino acid residues or the activity of its antigen-binding portion thereof, until obtaining to have antibody or its antigen-binding portion thereof of the activity of improvement with respect to parental antibody or its antigen-binding portion thereof.

If above-mentioned focus on contact position or hypermutation position to strengthen amino acid whose preferred trial at identified activity useless, or other if desired improvement, and the antibody of being discussed can't further be optimized with phage display (or relevant ribosomal display) method by mutagenesis, can the remaining CDR residue of modification as described below.Be to be understood that embodiment according to the above discussion, antibody can be modified on any one or more preferential selectivity mutagenesis position, contact position or hypermutation position already, but still may need further improvement.

B) except that H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and, in complementary determining region (CDR), select amino acid residue to be used for sudden change;

C) described contact position or hypermutation position through selecting sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change, and in non-phage display system, express described group;

E) with respect to parental antibody or its antigen-binding portion thereof, estimate the antibody of this group sudden change or its antigen-binding portion thereof at least a other character or the change in the characteristic, until the antibody or its antigen-binding portion thereof that obtain to have the activity of improvement with respect to parental antibody or its antigen-binding portion thereof.

If mutagenesis is not enough to increase the affinity of antibody separately, then other residues can be included in this mutagenesis.Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof; This reorganization parental antibody or its antigen-binding portion thereof obtain by selection in phage display system, but its activity can't further improve by mutagenesis in described phage display system;

C) described position through selecting is sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change, and in non-phage display system, express;

E) other the position repeating step b at least one)-d), this position is not at b) in the position selected, neither be in the position of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94;

G) at least two independent increased activity amino acid residues that demonstration has the activity of improvement of combination in parental antibody or its antigen-binding portion thereof are to produce combinatorial antibody or its antigen-binding portion thereof; With

H), estimate this and have the combinatorial antibody of two increased activity amino acid residues or the activity of its antigen-binding portion thereof with respect to parental antibody or its antigen-binding portion thereof;

Described focus on preferential selectivity mutagenesis position, contact position or hypermutation position to strengthen amino acid whose preferred trial at identified activity may be useless, maybe may need other improvement, and for keeping other character or characteristic of antibody, it is important.

Therefore, in another embodiment, it is active and do not influence the method for other characteristic to the invention provides a kind of antibody or its antigen-binding portion thereof improved, and described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

E) with respect to parental antibody or its antigen-binding portion thereof, estimate the antibody of this group sudden change or its antigen-binding portion thereof at least a other character or the change in the characteristic, until obtaining, have the active of improvement and keep other the character or antibody or its antigen-binding portion thereof of characteristic with respect to parental antibody or its antigen-binding portion thereof.

If the mutagenesis of single residue is not enough, then other residues can be included in wherein; Therefore, in another embodiment, the invention provides a kind of method of improving antibody or its antigen-binding portion thereof activity, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof;

E.) with respect to parental antibody or its antigen-binding portion thereof, estimate the antibody of this group sudden change or its antigen-binding portion thereof at least a other characteristic or the change in the character;

E) other the CDR position repeating step b at least one)-e), this position is not at b) in the position selected, neither be in the position of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

F) in parental antibody or its antigen-binding portion thereof at least two demonstrations of combination have the activity of improvement and do not influence at least a other character or the independent increased activity amino acid residue of characteristic, with generation combinatorial antibody or its antigen-binding portion thereof; With

G) with respect to parental antibody or its antigen-binding portion thereof, estimate this combinatorial antibody or its antigen-binding portion thereof with two increased activity amino acid residues activity and at least a other character or the reservation of characteristic, until obtaining with respect to parental antibody or its antigen-binding portion thereof, have the activity of improvement and at least a reservation other character or antibody or its antigen-binding portion thereof of characteristic.

The mutagenesis of preferential selectivity mutagenesis position, contact and hypermutation residue possibly can't increase the affinity of antibody sufficiently, and mutagenesis may be die on phage display method (or relevant ribosomal display method) and other characteristic or character of at least a antibody should keep.

Therefore, in another embodiment, the invention provides a kind of method of improving the affinity of antibody or its antigen-binding portion thereof, described method comprises:

A) provide parental antibody or its antigen-binding portion thereof, this parental antibody or its antigen-binding portion thereof obtain by selection in phage display system, but its activity can't further improve by mutagenesis in described phage display system;

E) with respect to parental antibody or its antigen-binding portion thereof, estimate the antibody of this group sudden change or its antigen-binding portion thereof at least a other character or the change in the characteristic, until obtaining to have antibody or its antigen-binding portion thereof of the activity of improvement with respect to parental antibody or its antigen-binding portion thereof.

B) except that H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96, select the amino acid residue in the complementary determining region (CDR) to be used for sudden change;

C) described position through selecting is sported at least two kinds of other amino acid residues separately, thereby produce antibody or its antigen-binding portion thereof of one group of sudden change and in non-phage display system, express;

D) with respect to parental antibody or its antigen-binding portion thereof, estimate the antibody of this group sudden change or its antigen-binding portion thereof activity and at least a other characteristic or the reservation of character, thereby identified activity strengthens amino acid residue;

G) with respect to parental antibody or its antigen-binding portion thereof, estimate the reservation of activity and at least a character or the characteristic of this combinatorial antibody or its antigen-binding portion thereof with two increased activity amino acid residues, until obtaining with respect to parental antibody or its antigen-binding portion thereof, have improvement activity and at least a other the characteristic of reservation or antibody or its antigen-binding portion thereof of character.

V. Antibody expression

Can prepare antibody of the present invention or antibody moiety by recombinant expressed light chain immunoglobulin and heavy chain gene in host cell.Be the reorganization expressing antibodies, recombinant expression carrier transfection host cell with the dna fragmentation of one or more light chain immunoglobulins that carry encoding antibody and heavy chain, make and in this host cell, express light chain and heavy chain, and preferably be secreted in the medium of cultivating this host cell, thereby can reclaim antibody from this medium.The recombinant DNA method of standard, for example at Sambrook, Fritsch and Maniatis (volume), Molecular Cloning; A LaboratoryManual, the 2nd edition, Cold Spring Harbor, N.Y., (1989), Ausubel, F.M. etc. (volume) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989) and those technology described in No. the 4th, 816,397, the United States Patent (USP) of Boss etc., be used to obtain heavy chain of antibody and light chain gene, these gene integrations are gone in the recombinant expression carrier and with carrier to import in the host cell.

Be the dna fragmentation of the variable region of heavy chain that obtains the relevant antibody of coding Joe 9wt or Joe 9wt-, described in the II joint, screening is specific to the antibody of people IL-12 and suddenlys change from the people library.In case obtain the relevant VH of coding Joe 9wt or Joe 9wt-and the dna fragmentation of VL section, carry out the mutagenesis of these sequences by the method for standard, the for example site-directed mutagenesis of the PCR (mutagenesis that PCR-instructs, wherein Tu Bian nucleotide is impregnated in the PCR primer, makes the PCR product comprise this sudden change) or other site-directed mutagenesis.Further operate the people IL-12 antibody of for example J695 of the activity that shows certain level and binding specificity/affinity and expectation by the recombinant DNA technology of standard, for example variable region gene is changed into full length antibody chain gene, Fab fragment gene or scFv gene.In these operations, VL-or VH-coding DNA fragment be may be operably coupled to the dna fragmentation of the other albumen (for example antibody constant region or flexible joint) of another coding.When using in context, term " is operably connected " and means the connection like this of two dna fragmentations so that remain in the frame for these two coded amino acid sequences of dna fragmentation.

Can be by the dna molecular of another encoding heavy chain constant region (CH1, CH2 and CH3) that the VH-coding DNA is operably connected, thus change the DNA in separated coding VH district into the total length heavy chain gene.The sequence of people's weight chain constant area gene is known in the art (referring to as Kabat, E.A., Deng (1991) Sequences of Proteins of Immunological Interest, the 5th edition, U.S.Department of Health and Human Services, and can obtain comprise the dna fragmentation in these districts NIH publication numbering 91-3242), by the pcr amplification of standard.CH can be IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region and as Kabat (, Kabat, E.A., Deng (1991) Sequences of Proteins ofImmunological Interest, the 5th edition, U.S.Department of Health and HumanServices, NIH publication numbering 91-3242) any allograft variant wherein described in, but most preferably be IgG1 or IgG4 constant region.For Fab fragment heavy chain gene, VH-coding DNA another only dna molecular of encoding heavy chain CH1 constant region that can be operably connected.

Can be by dna molecular of another coding constant region of light chain CL that the VL-coding DNA is operably connected, thus change the DNA in separated coding VL district into full-length light chains gene (and Fab light chain gene).The sequence of people's constant region of light chain gene is known in the art (referring to as Kabat, E.A., Deng (1991) Sequences of Proteins of Immunological Interest, the 5th edition, U.S.Department of Health and Human Services, and can obtain comprise the dna fragmentation in these districts NIH publication numbering 91-3242), by the pcr amplification of standard.Constant region of light chain can be κ or λ constant region, but most preferably is the λ constant region.

Be to produce the scFv gene, VH-and VL-coding DNA fragment be may be operably coupled to the fragment of another coding flexible joint, as encoding amino acid sequence (Gly4-Ser) ₃Fragment, make VH and VL sequence can be used as a continuous single chain protein with the VL that is connected by flexible joint and VH district and expressed (referring to as (1988) Science such as Bird 242: 423-426; Huston etc. (1988) Proc.Natl.Acad.Sci.USA 85: 5879-5883; McCafferty etc., Nature (1990) 348: 552-554).

For expressing antibody of the present invention or antibody moiety, the coded portion of acquisition as mentioned above or the DNA of full-length light chains and heavy chain are inserted in the expression vector, make this gene be operably connected and transcribe and translate control sequence.In context, term " is operably connected " to mean antibody gene is connected in the carrier, makes the effect of transcribing and translating of the adjusting antibody gene of transcribing and translate their expections of control sequence performance in the carrier.Select expression vector and expression control sequenc with compatible with employed expression host cell.Light chain of antibody gene and heavy chain of antibody gene can be inserted in the carrier separately, or more typically, two genes all be inserted in the same expression vector.Method by standard is inserted antibody gene in the expression vector (as connecting restriction site complementary on antibody gene fragment and the carrier, or if there is no carry out flush end under the restriction site connect).Before inserting J695 or J695-relevant light chain or sequence of heavy chain, expression vector can carry the antibody constant region sequence.For example, the method that a kind of VH that J695 or J695-is relevant and VL sequence change the full length antibody gene into is that they are inserted respectively in the expression vector of encoding heavy chain constant region and constant region of light chain, make in carrier this VH section be operably connected the CH section and in this carrier the VL section CL section that is operably connected.In addition or alternatively, the recombinant expression carrier codified helps the signal peptide that antibody chain is secreted from host cell.The antibody chain gene clone can be gone in the carrier, make signal peptide be connected by the amino terminal of reading frame with the antibody chain gene.Signal peptide can be immunoglobulin signal peptide or allos the signal peptide signal peptide of the albumen of NIg (promptly from).

Except that the antibody chain gene, recombinant expression carrier of the present invention carries the adjusting sequence that control antibody chain gene is expressed in host cell.Term " adjusting sequence " is intended to comprise other expression regulation elements (as polyadenylation signal) of promotor, enhancer and genetic transcription of control antibody chain or translation.Such adjusting sequence description is in for example Goeddel; Gene Expression Technology:Methods in Enzymology 185, Academic Press, San Diego is among the CA (1990).Those skilled in the art are to be understood that the design of expression vector comprises that select regulating sequence can be depending on such as select will be by the factor of transformed host cells, desirable protein expression etc.The adjusting sequence that is preferred for the mammalian host cell expression is included in the viral element that instructs high-level protein expression in the mammalian cell, for example derives from promotor and/or the enhancer of cytomegalovirus (CMV) (for example CMV promotor/enhancer), simian virus 40 (SV40) (for example SV40 promotor/enhancer), adenovirus (as adenovirus major late promoter (AdMLP)) and polyomavirus.For further describing of viral regulating element and sequence thereof, referring to United States Patent (USP) the 5th, 168 as Stinski, No. 062, the United States Patent (USP) the 4th, 510 of Bell etc., the United States Patent (USP) the 4th of No. 245 and Schaffner etc., 968, No. 615, the United States Patent (USP) the 5th of Bujard etc., 464, No. the 5th, 654,168, the United States Patent (USP) of No. 758 and Bujard etc.

Except that antibody chain gene and adjusting sequence, the other sequence of recombinant expression carrier portability of the present invention is for example regulated sequence (as origin of replication) and selectable marker gene that carrier duplicates in host cell.Selectable marker gene helps the selection that carrier imported host cell wherein (referring to as the United States Patent (USP) of Axel etc. the 4th, 399, No. 216, the 4th, 634, No. 665 and the 5th, 179, No. 017).For example, usually selectable marker gene is given host cell that carrier imported at the medicine resistance of G418, hygromycin or amethopterin for example.Preferred selectable marker gene comprises dihyrofolate reductase (DHFR) gene (being used to utilize the dhfr-host cell of amethopterin selection/amplification) and neo gene (being used for G418 selects).

In order to express light chain and heavy chain, be transfected in the host cell by the expression vector of standard techniques with encoding heavy chain and light chain.Multi-form term " transfection " is intended to comprise and multiple being usually used in foreign DNA is imported technology in protokaryon or the eukaryotic host cell, as electroporation, calcium phosphate precipitation, the transfection of DEAE-glucan etc.Although might in protokaryon or eukaryotic host cell, express antibody of the present invention in theory, but in eukaryotic and expressing antibodies in mammalian host cell most preferably, it is that most preferred reason is such eukaryotic, and particularly mammalian cell is easier to assemble the correctly folding and immunocompetent antibody of tool of justacrine than prokaryotic.The mammalian host cell that is preferred for expressing recombinant antibodies of the present invention comprises that Chinese hamster ovary (Chinese hamster ovary celI) (comprises the dhfr-CHO cell, is described in Urlaub and Chasin, (1980) Proc.Natl.Acad.Sci.USA 77: 4216-4220, but use the DHFR selected marker, AsAt R.J.Kaufman and P.A.Sharp (1982) Mol.Biol. 159: described in the 601-621), NS0 myeloma cell, COS cell and SP2 cell.When the recombinant expression carrier with the encoding antibody gene imports mammalian host cell, by being cultivated one section, this host cell is enough to allow that the time of expressing antibodies in this host cell produces antibody, or more preferably, antibody-secreting is gone in the medium that this host cell grows.Can use the method for purifying proteins of standard from medium, to reclaim antibody.

Host cell also can be used for the being born part of complete antibody, for example Fab fragment or scFv molecule.Be to be understood that the change to above-mentioned steps is in the scope of the present invention.For example, the DNA transfection host cell with the light chain of code book invention antibody or heavy chain (but non-both) is desirable.Recombinant DNA technology also can be used for removing coding for part or all of DNA that in conjunction with hIL-12 is unwanted light chain and heavy chain.The molecule of being expressed by the dna molecular of such brachymemma is also included within the antibody of the present invention.In addition, by Chemical Crosslinking Methods that antibody of the present invention is mutually crosslinked with another antibody with standard, can produce a kind of like this bifunctional antibody, wherein a heavy chain and a light chain are antibody of the present invention, and other heavy chain and light chain are specific to the antigen that is different from hIL-12.

In the preferred systems that is used for recombinant expressed antibody of the present invention or its antigen-binding portion thereof, in the recombinant expression carrier importing dhfr-CHO cell of transfection by the calcium phosphate mediation with encoding antibody heavy chain and light chain of antibody.In recombinant expression carrier, heavy chain of antibody and light chain gene are operably connected enhancers/promoters regulating element (as deriving from SV40, CMV, adenovirus etc., for example cmv enhancer/AdMLP modulator promoter element or SV40 enhancer/AdMLP modulator promoter element) separately to drive high-caliber genetic transcription.Recombinant expression carrier also carries the DHFR gene, and it is allowed and uses amethopterin selection/amplification to select to use the Chinese hamster ovary celI of carrier transfection.The transformed host cell of cultivation through selecting to be being used for expressing antibodies heavy chain and light chain, and reclaim complete antibody from medium.The Protocols in Molecular Biology of standard is used for preparing recombinant expression carrier, transfection host cell, selection transformant, cultivates host cell and reclaims antibody from medium.Antibody of the present invention or its antigen-binding portion thereof can be expressed (referring to as Taylor, L.D. etc. (1992) Nucl.Acids Res.20:6287-6295) in changing human immunoglobulin gene's animal (as mouse) over to.Plant cell also can be modified the genetically modified plants of expressing antibody of the present invention or its antigen-binding portion thereof to produce.

In view of foregoing, another aspect of the present invention relates to nucleic acid, carrier and the host cell composition that can be used for recombinant expressed antibody of the present invention and antibody moiety.Preferably, the invention provides the nucleic acid of the separation of the complete heavy chain of the coding CDRs of J695 or J695 and/or variable region of light chain.Therefore, in one embodiment, the invention provides a kind of nucleic acid of separation of encoding antibody variable region of heavy chain, its coding comprises the J695 heavy chain CDR3 of amino acid sequence SEQ ID NO:25.Preferably, the nucleic acid of encoding antibody variable region of heavy chain is further encoded and is comprised the J695 heavy chain CDR2 of amino acid sequence SEQ ID NO:27.More preferably, the nucleic acid of encoding antibody variable region of heavy chain is further encoded and is comprised the J695 heavy chain CDR1 of amino acid sequence SEQ ID NO:29.Also more preferably, the nucleic acid coding of this separation comprises the antibody heavy chain variable region in amino acid sequence SEQ ID NO:31 (the complete VH district of J695).

In other embodiments, the invention provides a kind of nucleic acid of separation of encoding antibody variable region of light chain, its coding comprises the J695 light chain CDR3 of amino acid sequence SEQ ID NO:26.Preferably, the nucleic acid of this encoding antibody variable region of light chain is further encoded and is comprised the J695 light chain CDR2 of amino acid sequence SEQID NO:28.More preferably, the nucleic acid of this encoding antibody variable region of light chain is further encoded and is comprised the J695 light chain CDR1 of amino acid sequence SEQ ID NO:30.Also more preferably, the nucleic acid coding of separation comprises the antibody chain variable region in amino acid sequence SEQ ID NO:32 (the complete VL district of J695).

The present invention also provides the recombinant expression carrier of encoding antibody heavy chain and light chain of antibody.For example, in one embodiment, the invention provides a kind of recombinant expression carrier, described vector encoded:

A) has the heavy chain of antibody of the variable region that comprises amino acid sequence SEQ ID NO:31; With

B) has the light chain of antibody of the variable region that comprises amino acid sequence SEQ ID NO:32.

The present invention also provides the host cell that has wherein imported one or more recombinant expression carriers of the present invention.Preferably, host cell is a mammalian host cell, and more preferably, host cell is Chinese hamster ovary celI, NS0 cell or COS cell.It is a kind of by cultivate the method for the synthetic recombinant human antibody of the present invention that host cell of the present invention is synthesized until recombinant human antibody of the present invention in proper culture medium that the present invention further provides.This method can further comprise separates recombinant human antibody from medium.

VI. Pharmaceutical composition and administration

Antibody of the present invention and antibody moiety can mix and be suitable for giving in the individual pharmaceutical composition.Usually, pharmaceutical composition comprises antibody of the present invention or antibody moiety and pharmaceutically acceptable carrier.When using in this article, " pharmaceutically acceptable carrier " comprises any and whole solvent compatible on the physiology, dispersion medium, dressing, antibacterium and antifungal agent, isotonic agent and absorption delay agent etc.The example of pharmaceutically acceptable carrier comprises one or more water, salt solution, phosphate buffered saline (PBS), glucose, glycerine, ethanol etc., and their combination.As a rule, in composition, preferably include isotonic agent, carbohydrate for example, polyalcohol such as mannitol, sorbitol or sodium chloride.Pharmaceutically acceptable carrier can further comprise the shelf life of a spot of increase antibody or antibody moiety or the complementary material of validity, for example wetting agent or emulsifier, preservative or buffer.

Antibody of the present invention and antibody moiety can mix in the pharmaceutical composition that is suitable for parenteral.Preferably, antibody or antibody moiety should be prepared as the injectable solution that comprises 0.1-250mg/ml antibody.This injectable solution can be made up of the liquid or the freeze-dried formulation that are in flint glass phial or faint yellow phial, ampoule or the prefilled syringe.Buffer can be L-histidine (1-50mM), and best 5-10mM is in pH 5.0-7.0 (best pH 6.0).Other buffers that are fit to include but not limited to sodium succinate, sodium citrate, sodium phosphate or potassium phosphate.Can change the toxicity of the solution of 0-300mM (for the best 150mM of liquid dosage form) concentration with sodium chloride.Freeze-dried formulation can comprise cryoprotector, mainly is 0-10% sucrose (best 0.5-1.0%).Other suitable cryoprotectors comprise trehalose and lactose.Freeze-dried formulation can comprise filler, mainly is 1-10% mannitol (best 2-4%).Stabilizing agent can be used in liquid and the freeze-dried formulation, mainly is 1-50mML-methionine (best 5-10mM).Other suitable fillers comprise glycine, arginine, can comprise 0-0.05% Polyoxyethylene Sorbitan Monooleate (best 0.005-0.01%).Other surfactant comprises but is not limited to polysorbate20 and BRIJ surfactant.

In a preferred embodiment, pharmaceutical composition comprises the antibody that exists with about 100mg-200mg dosage.

Composition of the present invention can multiple formulation exist.These comprise for example liquid, semisolid and solid dosage forms, for example liquid solution (but as injectable and solution infusion), dispersion liquid or supensoid agent, tablet, pill, pulvis, liposome and suppository.Preferred formulation depends on the administering mode and the treatment application of expection.But typical preferred composition is the solution form with injectable or infusion to be existed, and for example is similar to be used to use other antibody to carry out the composition of those compositions of people's passive immunity.Preferred administering mode be parenteral (as in intravenous, subcutaneous, the peritonaeum, intramuscular) administration.In a preferred embodiment, antibody gives by hypodermic injection.

Under manufacturing and holding conditions, therapeutic combination must be aseptic and stable usually.Composition can be formulated as solution, microemulsion, dispersant, liposome or other are suitable for the ordered structure of high drug concentration.Can mix suitable above-mentioned the enumerating in the composition solvent of (as required) a kind of or combination that have by active substance (being antibody or antibody moiety) with requirement, succeeded by filtration sterilization, the preparation sterile injectable solution.Usually, prepare dispersant by active substance being mixed in the aseptic excipient that contains basic dispersion medium and required other compositions from above-mentioned those compositions of enumerating.As for the aseptic freeze-dried pulvis of the solution that is used to prepare sterile injectable, preferred manufacturing procedure is that vacuum drying and atomized drying produce the pulvis that active component adds any other required composition, and described composition is from the solution of its aseptic filtration before.Can for example pass through to use dressing such as lecithin to keep suitable flow of solution, then pass through the granularity that keeps required and pass through to use surfactant as for dispersant.Can be by comprising a kind of material that postpones to absorb for example Monostearate and gelatin at composition, thus bring the prolongation of Injectable composition to absorb.

Can give antibody of the present invention and antibody moiety by multiple methods known in the art, although use for many treatments, preferred method of administration/mode is hypodermic injection, intravenous injection or infusion.But be to be understood that as those skilled in the art method of administration and/or mode can depend on desired result and change.In certain embodiments, but the active substance participant protects the carrier of the anti-rapid release of this material to prepare together, and for example controlled release form comprises implant, dermal patch and microencapsulation delivery system.Can use biodegradable, biocompatible polymer, for example ethylene acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters and PLA.Many methods that are used to prepare such prescription are patented methods or extensively know for those skilled in the art.Referring to as Sustained and Controlled Release Drug Delivery Systems, J.R.Robinson compiles Marcel Dekker, Inc., New York, 1978.

In certain embodiments, antibody of the present invention or antibody moiety can for example give with inert diluent or assimilable edible carrier per os.Described compound (with other compositions, if necessary) also be encapsulated in hard or soft shell capsule in, be pressed into tablet or directly mix in the individual diet.For oral therapeutic administration, compound can with excipient fusion and use mutually with the form of ingestible tablet, buccal tablet, lozenge, capsule, elixir, supensoid agent, syrup, wafer etc.For giving compound of the present invention, may need to give by this compound or with this compound with the material bag that stops the compound inactivation by the approach except that parenteral.

The active substance that replenishes also can mix in the composition.In certain embodiments, antibody of the present invention or antibody moiety and one or more are for to treat IL-12 activity wherein be the useful common preparation of other therapeutic agent of the illness that is harmful to and/or give jointly.For example, of the present invention anti--additional antibody (as the antibody in conjunction with other cell factors or cell surface binding molecule) that hIL-12 antibody or antibody moiety can combine other targets with one or more prepares jointly and/or gives jointly.In addition, one or more antibody of the present invention can be linked together with two or more aforementioned therapies agent.Such therapeutic alliance can advantageously utilize the therapeutic agent that is given than low dosage, thereby has avoided possible toxicity or the complication relevant with various monotherapies.Skilled practitioners is to be understood that when antibody of the present invention during as therapeutic alliance a part of, with compare when giving individuality separately antibody, than the antibody of low dosage may be desirable (as can reaching coordinating effect by using therapeutic alliance, then allow use than the antibody of low dosage to reach the curative effect of expectation).

With the multiple pathology that relate to the immunity and the disease association of inflammatory key element in interleukin 12 play a part key.These diseases include but not limited to rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, adjuvant arthritis, spondyloarthropathy, systemic loupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes mellitus, thyroiditis, asthma, allergic disease, psoriasis, the dermatitis chorionitis, atopic dermatitis, graft versus host disease(GVH disease), the organ-graft refection, acute or the chronic immunological disease that organ transplant is relevant, sarcoidosis, atherosclerotic, disseminated intravascular coagulation, Kawasaki disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, Wei Geneishi granuloma disease, the Henoch-Schoenlein purpura, kidney smallness vasculitis, CAH, uveitis, septic shock, TSS, septicemia syndrome, cachexia, infectious disease, parasitosis, acquired immunodeficiency syndrome, acute transverse myelitis, hungtington's chorea, Parkinson's disease, Alzheimer's, apoplexy, primary biliary cirrhosis of liver, hemolytic anemia, malignant tumour, in heart failure, myocardial infarction, Addison's disease, sporadic I type polyadenous lacks and II type polyadenous lacks, Schmidt's syndrome, adult's (acute) Respiratory Distress Syndrome(RDS), alopecia, alopecia areata, seronegative arthropathy, joint disease, Reiter's disease, arthropathia psoriatica, ulcer colon joint disease, the enteropathy synovitis, Chlamydia, the joint disease that yersinia's genus is relevant with Salmonella, spondyloarthropathy, atheromatous disease/arteriosclerosis, atopic allergology, autoimmunity bleb disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, the positive hemolytic anemia of Coombs, acquired pernicious anaemia, juvenile pernicious anaemia, myalgia brain inflammation/Royal Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary hardening hepatitis, agnogenic oneself immunity hepatitis, acquired immunodeficiency disease syndrome, the disease that acquired immunodeficiency is relevant, hepatitis C, common immune deficiency miscellaneous (common blood gamma globulin miscellaneous reduces disease), dilated cardiomyopathy, female infertility, ovarian function failure, premature ovarian failure, fibrotic lung disease, CFA, interstitial lung disease after the inflammation, interstitial pneumonia, the interstitial lung disease that CTD is relevant, the tuberculosis that MCTD is relevant, the relevant interstitial lung disease of whole body sclerosis, the interstitial lung disease that rheumatoid arthritis is relevant, the tuberculosis that systemic loupus erythematosus is relevant, the tuberculosis that dermatomyositis/polymyositis is relevant;

The sick relevant tuberculosis of family name, the tuberculosis that ankylosing spondylitis is relevant, vasculitis dispersivity tuberculosis, the hemorrhage relevant tuberculosis of siderosis, drug induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, the chronic eosinophilic pneumonia, lymphocytic infiltration tuberculosis, infect the back interstitial lung disease, urarthritis, oneself immunity hepatitis, 1 type oneself immunity hepatitis (typical autoimmunity or lupoid hepatitis), 2 type oneself immunity hepatitis (anti--LKM antibody hepatitis), the hypoglycemia of autoimmunity mediation, Type B insulin resistance with acanthosis nigricans, hypoparathyroidism, the acute immunological disease relevant with organ transplant, the chronic immunological disease relevant with organ transplant, osteoarthritis, primary sclerotic cholangitis, the special property sent out leukopenia, the autoimmunity neutropenia, ephrosis NOS, glomerulonephritis, kidney smallness vasculitis, Lyme disease, lupus erythematosus discoides, idiopathic male infertility or NOS, the seminal fluid autoimmunity, multiple sclerosis (all hypotypes), insulin-dependent diabetes mellitus, sympathetic ophthalmia, connective tissue disease Secondary cases pulmonary hypertension, Goodpasture, the lung performance of polyarteritis nodosa, acute rheumatic fever, rheumatoid, Still disease, systemic sclerosis, pulseless disease/arteritis, the autoimmunity decrease of platelet, the special property sent out decrease of platelet, AITD, hyperthyroidism, goitre systemic autoimmune hypothyroidism (HashimotoShi disease), atrophic autoimmunity hypothyroidism, the primary myxoedema, crystalline lens originality uveitis, primary vasculitis and leucoderma.People's antibody of the present invention and antibody moiety can be used for treating autoimmunity disease, and those particularly relevant with inflammation autoimmunity diseases comprise rheumatoid, allergy, autoimmune diabetes, autoimmunity uveitis.

Preferably, as institute in the VII joint in greater detail, antibody of the present invention or its antigen-binding portion thereof are used for the treatment of rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and psoriasis.

People's antibody of the present invention or antibody moiety also can give with one or more other therapeutic agents useful in autoimmunity and the treatment of inflammatory diseases.

Antibody of the present invention or its antigen-binding portion thereof can be used separately or unite to make and be used for treating above-mentioned disease.Be to be understood that IL-12 antibody of the present invention or its antigen-binding portion thereof can be used separately or unite use with other medicine such as therapeutic agent, described other medicine is that those skilled in the art are selected according to its intended purposes.For example, this other medicine can be art-recognized to treating disease or the useful therapeutic agent of illness that antibody of the present invention is treated.This other medicine can also be a kind of medicine that gives the therapeutic combination beneficial characteristics, promptly as a kind of medicine that influences the viscosity of said composition.

Should further understand comprise in the present invention to unite be that those are useful associatings for their its intended purposes.Following listed medicine is as two locking projections and notches and be not intended to restriction.Associating as a part of the present invention can be antibody of the present invention and at least a other medicine that is selected from following tabulation.If this is united is a kind of like this so that the composition that is produced can be carried out the associating of its expectation function, then this unites the other medicine that also can comprise more than a kind of, as two or three other medicine.In addition, be used for not limiting the illness of their ownership treatments with IL-12 antibody described here other medicine linked together.

Preferably uniting is the nonsteroidal anti-inflammatory drug that is also referred to as NSAIDS, and it comprises the medicine such as brufen.Other are preferably united is that corticoid comprises prednisolone; When with of the present invention anti--during the antibody combined treatment of IL-12 patient, can be by reducing required steroids dosage gradually, thus reduction or even eliminate the well-known side effect of employed steroids.Can comprise as follows with the limiting examples of the therapeutic agent that is used for rheumatoid arthritis of antibody of the present invention or antibody moiety associating: the anti-inflammatory drug (CSAIDs) that suppresses cell factor; Other people cell factor or growth factor, for example TNF (antibody or the antagonist that comprise adalimumab/HUMIRA), LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF and PDGF.Antibody of the present invention or its antigen-binding portion thereof can for example antibody or their part of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90 comprise that CD154 (gp39 or CD40L) is linked together with cell surface molecule.

Preferred therapeutic agent associating can be disturbed on the different loci in autoimmunity and the inflammatory cascade subsequently; Preferred examples comprises the TNF antagonist, as chimeric, humanization or people TNF antibody, and D2E7 (the U. S. application sequence number 08/599,226 that on February 9th, 1996 submitted to), cA2 (Remicade ^TM), CDP 571, anti-TNF antibody fragment (as CDP870) and solubility p55 or p75 TNF acceptor, its derivative (p75TNFR1gG (Enbrel ^TM) or p55TNFR1gG (Lenercept), solubility IL-13 acceptor (sIL-13) and TNF α invertase (TACE) inhibitor; Similarly, owing to identical reason IL-1 inhibitor (as il-1-converting enzyme inhibitor, for example Vx740 or IL-1RA etc.) may be effective.Other are preferably united and comprise that interleukin 11, anti--P7s and p-select albumen metalloprotein part (PSGL).Another is preferably united is to depend on the IL-12 function or echo mutually with the IL-12 function, can play the crucial participant of other autoimmune responses of parallel action; Especially preferred is the IL-18 antagonist, comprise IL-18 antibody or solubility IL-18 acceptor, or IL-18 is in conjunction with albumen.Having shown that IL-12 and IL-18 have overlaps but distinct function, and therefore the associating of antagonist at both may be the most effective.Another is preferably united is the anti--CD4 inhibitor of non-exhaustion.Other preferably unite the antagonist that comprises common stimulation path CD80 (B7.1) or CD86 (B7.2), comprise antibody, soluble recepter or antagonism part.

Anti--IL12 antibody or its antigen-binding portion thereof also can be linked together with other drug, for example amethopterin, 6-MP, azathioprine, salicylazosulfapyridine, mesalazine, Olsalazine, chloroquine/hydroxychloroquine, penicillamine, gold Thiomalate (intramuscular injection or oral), azathioprine, colchicin, corticoid is (oral, suck and local injection), the beta-2-adrenoceptor activator (relaxes and breathes heavily spirit, terbutaline, salmeteral), xanthine (theophylline, aminophylline), cromoglycate, nedocromil, Ketotifen, ipratropium and oxitropine, cyclosporin, FK506, rapamycin, MMF, leflunomide, NSAIDs is brufen for example, corticoid is prednisolone for example, phosphodiesterase inhibitor, adenosine agonists, antithrombotic, complement inhibitor, adrenergic agent, disturb by proinflammatory cytokine for example the medicine of the signal conduction of TNF α or IL-1 (as IRAK, NIK, IKK, p38 or map kinase inhibitor), IL-1 'beta ' converting emzyme inhibitor (as Vx740), anti--P7s, p-selects albumen metalloprotein part (PSGL), TNF α invertase (TACE) inhibitor, T-cellular signal transduction inhibitor is inhibitors of kinases for example, metal protease inhibitors, salicylazosulfapyridine, azathioprine, Ismipur, angiotensin-converting enzyme inhibitor, soluble cytokine receptor and derivative thereof are (as solubility p55 or p75 TNF acceptor and derivative p75TNFRIgG (Enbrel ^TM) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII, sIL-6R, solubility IL-13 acceptor (sIL-13)) and anti-inflammatory cytokines (as IL-4, IL-10, IL-11, IL-13 and TGF β).Preferably unite and comprise amethopterin or leflunomide and under moderate or severe rheumatoid arthritis case, cyclosporin.

Can comprise as follows with the limiting examples of the therapeutic agent that is used for inflammatory bowel disease of anti--IL-12 antibody or antibody moiety associating: budesonide; Epidermal growth factor; Corticoid; Cyclosporin, salicylazosulfapyridine; Aminosalicylate; Ismipur; Azathioprine; Flagyl; Lipoxidase inhibitor; Mesalazine; Olsalazine; Balsalazide; Antioxidant; The thromboxane inhibitor; The IL-1 receptor antagonist; Anti--IL-1 β monoclone antibody; Anti--the IL-6 monoclone antibody; Growth factor; Elastatinal; Pyridine radicals-imidazolium compounds; The antibody or the antagonist of other people cell factor or growth factor, for example TNF (comprises adalimumab/HUMIRA), LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF and PDGF.Antibody of the present invention or its antigen-binding portion thereof can for example antibody or their part of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 be linked together with cell surface molecule.Antibody of the present invention or its antigen-binding portion thereof also can be linked together with following medicine, described medicine is amethopterin for example, cyclosporin, FK506, rapamycin, MMF, leflunomide, NSAIDs, brufen for example, corticoid is prednisolone for example, phosphodiesterase inhibitor, adenosine agonists, antithrombotic, complement inhibitor, adrenergic agent, the medicine that disturbs the signal conduction by proinflammatory cytokine such as TNF α or IL-1 is (as IRAK, NIK, IKK, p38 or map kinase inhibitor), IL-1 'beta ' converting emzyme inhibitor (as Vx740), anti--P7s, p-selects albumen metalloprotein part (PSGL), TNF α converting enzyme inhibitor, and T-cellular signal transduction inhibitor is inhibitors of kinases for example, metal protease inhibitors, salicylazosulfapyridine, azathioprine, Ismipur, angiotensin-converting enzyme inhibitor, soluble cytokine receptor and derivative thereof are (as solubility p55 or p75TNF acceptor, sIL-1RI, sIL-1RII, sIL-6R, solubility IL-13 acceptor (sIL-13)) and anti-inflammatory cytokines (as IL-4, IL-10, IL-11, IL-13 and TGF β).

Wherein can comprise as follows with the preferred examples of the therapeutic agent that is used for Crohn's disease of antibody or antigen-binding portion thereof associating: the TNF antagonist, anti-TNF antibody for example, D2E7 (adalimumab/HUMIRA), cA2 (Remicade ^TM), CDP 571, anti-TNF antibody fragment (as CDP870), TNFR-Ig construction (p75TNFRIgG (Enbrel ^TM) and p55TNFRIgG (Lenercept)), anti--P7s, p-selects albumen metalloprotein part (PSGL), solubility IL-13 acceptor (sIL-13) and PDE4 inhibitor.Antibody of the present invention or its antigen-binding portion thereof can for example budesonide and dexamethasone be linked together with corticoid.Antibody also can be linked together with following medicine, and for example salicylazosulfapyridine, 5-Para-amino-salicylic acid and Olsalazine and interference proinflammatory cytokine such as IL-1 are synthetic or the medicine of effect, for example IL-1 'beta ' converting emzyme inhibitor (as Vx740) and IL-1ra.Antibody or its antigen-binding portion thereof also can with T cellular signal transduction inhibitor for example the tyrosine kinase inhibitor Ismipur use.Antibody or its antigen-binding portion thereof can be linked together with IL-11.

Can comprise as follows with the limiting examples of the therapeutic agent that is used for multiple sclerosis of antibody or antibody moiety associating: corticoid; Prednisolone; Medrat; Azathioprine; Cyclophosphamide; Cyclosporin; Amethopterin; 4-aminopyridine; Tizanidine; Interferon-beta 1a (Avonex; Biogen); Interferon-beta 1b (Betaseron; Chiron/Berlex); Copolymer 1 (Cop-1; The acetic acid lattice draw for beautiful; Teva Pharmaceutical Industries, Inc.); Hyperbaric oxygen; The drip-feed immunoglobulin; Cladribine; The antibody or the antagonist of other people cell factor or growth factor, for example TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF and PDGF.Antibody of the present invention or its antigen-binding portion thereof can for example antibody or their part of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 be linked together with cell surface molecule.Antibody of the present invention or its antigen-binding portion thereof also can be linked together with following medicine, amethopterin for example, cyclosporin, FK506, rapamycin, MMF, leflunomide, NSAIDs, brufen for example, corticoid is prednisolone for example, phosphodiesterase inhibitor, adenosine agonists, antithrombotic, complement inhibitor, adrenergic agent, the medicine of the signal conduction of interference by proinflammatory cytokine such as TNF α or IL-1 is (as IRAK, NIK, IKK, p38 or map kinase inhibitor), IL-1 'beta ' converting emzyme inhibitor (as Vx740), anti--P7s, p-selects albumen metalloprotein part (PSGL), tace inhibitor, T-cellular signal transduction inhibitor is inhibitors of kinases for example, metal protease inhibitors, salicylazosulfapyridine, azathioprine, Ismipur, angiotensin-converting enzyme inhibitor, soluble cytokine receptor and derivative thereof are (as solubility p55 or p75 TNF acceptor, sIL-1RI, sIL-1RII, sIL-6R, solubility IL-13 acceptor (sIL-13)) and anti-inflammatory cytokines (as IL-4, IL-10, IL-13 and TGF β).

Wherein can comprise interferon-beta, for example IFN β 1a and IFN β 1b with the preferred examples of the therapeutic agent that is used for multiple sclerosis of antibody or antibody moiety associating; The acetic acid lattice draw for beautiful, corticoid, IL-1 inhibitor, the antibody of tnf inhibitor and CD40 part and CD80.

Antibody, antibody moiety can be linked together with the dermopathic medicine of other treatment.For example, antibody of the present invention, antibody moiety or other IL-12 inhibitor and PUVA therapy are linked together.PUVA is used for the treatment of the many different dermopathic psoralens (P) and the combination of long-wave UV radiation (UVA).Antibody of the present invention, antibody moiety or other IL-12 inhibitor also can be linked together with Elidel.In another embodiment, antibody of the present invention is used for the treatment of psoriasis, wherein antibody and tacrolimus administering drug combinations.In another embodiment, tacrolimus and IL-12 inhibitor and amethopterin and/or cyclosporin administering drug combinations.In another embodiment, IL-12 inhibitor of the present invention uses with being used for the treatment of psoriatic excimer laser treatment.

Pharmaceutical composition of the present invention can comprise the antibody of the present invention or the antibody moiety of " treatment effective dose " or " prevention effective dose "." treatment effective dose " refers to a kind of amount that effectively reaches the expectation result of treatment on dosage and required a period of time.The treatment effective dose of antibody or antibody moiety can change with the factor that causes the ability that expectation replys such as disease condition, age, sex and whose body weight and this antibody or antibody moiety in individuality.The treatment effective dose still wherein the treatment beneficial effect of antibody or antibody moiety surpassed so a kind of amount of any toxicity or harmful effect." prevention effective dose " refers to a kind of amount that effectively obtains the expectation preventive effect on dosage and in required a period of time.Usually and since preventive dose before seizure of disease or outbreak be used for individuality in early days, therefore prevent the effective dose should be less than the treatment effective dose.

Can regulate dosage regimen and reply (replying) as treatment or prevention so that best expectation to be provided.For example, the situation is critical that incident is needed according to treatment, can give single bolus, and can give several divided doses or dosage in time in the past can reduce or increase in proportion.For the uniformity of easy administration and dosage, be particularly advantageous with dosage unit form preparation parenteral composition.When using in this article, dosage unit form refers to be suitable as the physically separated unit of the single dosage that is used for the mammalian subject that will be treated; The active substance that each unit comprises scheduled volume as calculated produces the curative effect of expectation to combine with essential pharmaceutical carrier.The domination of the specification of dosage unit form of the present invention from and directly depend on the peculiar property of (a) active substance and the specific treatment that will reach or preventive effect institute its, (b) for treating susceptibility in the individuality, prepare inherent limitation in the field of above-mentioned active substance.

In one embodiment, IL-12 antibody or its antigen-binding portion thereof for example comprise with every relieve pain biweekly, the dosage of every about 50-300mg biweekly, the about 200mg of about 100mg-and the about 175mg of about 125-.Perhaps, IL-12 antibody can be used as single dose and gives, and comprises the dosage of for example about 200mg, about 100mg.In another embodiment, the relieve pain that IL-12 antibody can be weekly comprises the dosage of for example about 50-300mg, the about 200mg of about 100mg-and the about 175mg of about 125-.It should be noted that the dosage in the specified scope is also included within herein, as 85mg, 97mg etc.

In another embodiment, people IL-12 antibody or its antigen-binding portion thereof have wherein as single dose that the IL-12 activity is illness such as the psoriatic individuality that is harmful to, and it produces treatment.In individuality, can keep one period duration to replying of IL-12 antibody or its antigen-binding portion thereof.Can be according to keeping that the illness monitoring of just treating is replied.For example, can reply by the PASI 75 of the individuality of passing by in time and determine that IL-12 antibody or its antigen-binding portion thereof are used for the treatment of psoriatic keeping of replying.

It should be noted that dose value can change with the type and the order of severity of the illness that will be alleviated.Should further understand for any specific individuality, the personage's who gives according to individual need and management or supervision group compound professional judgement, specific dosage regimen should be regulated in time, and only be exemplary, and be not intended to the scope or the practice of the composition that restriction advocates as the dosage range herein.

VII. Application of the present invention

The invention provides a kind of inhibition and suffer from the method for IL-12 activity in the individuality that IL-12 activity wherein is the illness that is harmful to.In one embodiment, the invention provides the psoriatic method of a kind of treatment, described method comprises IL-12 antibody or its antigen-binding portion thereof that gives single dose.

IL-12 had involved Pathological Physiology (Windhagen etc., (1995) J.Exp.Med.182:1985-1996 of various disease conditions already; Morita etc. (1998) Arthritis and Rheumatism.41:306-314; Bucht etc., (1996) Clin.Exp.Immunol.103:347-367; Fais etc. (1994) J.Interferon Res.14:235-238; Parronchi etc., (1997) Am.J.Path.15O:823-832; Monteleone etc., (1997) Gastroenterology.112:1169-1178 and Berrebi etc., (1998) Am.J.Path 152:667-672; Parronchi etc. (1997) Am.J.Path.150:823-832).The invention provides the method for IL-12 activity in the individuality of suppress suffering from such illness, this method comprises and gives individual antibody of the present invention or antibody moiety, makes IL-12 activity inhibited in the individuality.Preferably, IL-12 is that people IL-12 and individuality are individual human.Perhaps, individuality can be the mammal of the IL-12 of expression and antibody cross reaction of the present invention.Further, individuality can be to have imported the hIL-12 mammal of (as by giving hIL-12 or passing through to express the hIL-12 transgenosis).Antibody administration of human individuality of the present invention can be used for the treatment of purpose (further being discussed at down).In addition, for animal doctor's purpose or as human disease's animal model, antibody of the present invention can be expressed the non-human mammal of the IL-12 of this antibody cross reaction.About the latter, such animal model can be used for estimating the curative effect (as test dosage and time-histories) of antibody of the present invention.

When using in this article, phrase " wherein the IL-12 activity is the illness that is harmful to " is intended to comprise such disease or other illnesss, wherein in suffering from the individuality of this illness the existence of IL-12 shown already or be under a cloud be cause this illness Pathological Physiology reason or help to worsen the factor of this illness.Therefore, wherein the IL-12 activity is that the illness that is harmful to is that a kind of wherein expectation suppresses the illness of IL-12 activity with relief of symptoms and/or illness progress.Such illness can be for example by for example use above-mentioned anti--IL-12 antibody can be detected in the biofluid of the individuality of suffering from this illness IL-12 concentration increase (concentration as IL-12 in the serum of individuality, blood plasma, the synovia etc. increases) and confirmed.Exist many wherein IL-12 activity and be the example of the illness that is harmful to.In one embodiment, antibody or its antigen-binding portion thereof can be used for treating the therapy of disease described herein or illness.In another embodiment, antibody or its antigen-binding portion thereof can be used for making the medicine that is used for the treatment of disease described herein or illness.The application in several nonrestrictive concrete illnesss of treatment of antibody of the present invention and antibody moiety further is discussed at down:

A. rheumatoid arthritis:

Il-1 2 relates in the inflammatory disease such as rheumatoid arthritis plays a role.From the patient with rheumatoid arthritis synovia, detected derivable IL-12p40 courier, and shown that IL-12 comes across in the synovia of patient with rheumatoid arthritis (referring to as Morita etc., (1998) Arthritis and Rheumatism 41: 306-314).Found that the IL-12 positive cell is present in the lining lower floor of rheumatoid arthritis synovial membrane.People's antibody of the present invention and antibody moiety can be used for treating for example rheumatoid arthritis, juvenile rheumatoid arthritis, Lyme arthritis, rheumatoid, osteoarthritis and urarthritis.Usually, antibody or antibody moiety are that whole body gives, although for some illness, topical administration antibody or antibody moiety may be favourable.Antibody of the present invention or antibody moiety also can give with one or more useful additional treatment agent in the treatment autoimmunity disease.

Be used for the collagen-induced arthritis of rheumatoid arthritis (CIA) mouse model, before the arthritis outbreak, use anti--IL-12mAb (rat anti-mouse IL-12 monoclone antibody, C17.15) the treatment mouse has suppressed outbreak fully, and has reduced the order of severity of the incidence of disease and disease.Reduce the order of severity with anti--IL-12mAb treatment in early days in arthritis outbreak back, but after seizure of disease, with anti--IL-12mAb treatment mouse disease severity has then been had minimum effect slightly late.

B. Crohn's disease

Il-1 2 also plays certain effect in inflammatory bowel disease, Crohn's disease.IFN-. that exist to increase in Crohn's disease patient's the intestinal mucosa and IL-12 express (referring to as Fais etc., (1994) J.Interferon Res. 14: 235-238; Parronchi etc., (1997) Amer.J.Pathol.150:823-832; Monteleone etc., (1997) Gastroenterology 112: 1169-1178; Berrebi etc., (1998) Amer.J.Pathol. 152: 667-672).Shown that in mouse models of colitis anti--IL-12 antibody suppresses disease, the colitis IL-2 knock out mice that brings out as TNBS and recently in the IL-10 knock out mice.Therefore, antibody of the present invention and antibody moiety can be used for treating inflammatory bowel disease.

C. multiple sclerosis

Il-1 2 relates to the crucial amboceptor as multiple sclerosis.The expression of provable derivable IL-12 p40 courier or IL-12 self (Windhagen etc., (1995) J.Exp.Med. in the infringement of patients with multiple sclerosis 182: 1985-1996, Drulovic etc., (1997) J.Neurol.Sci. 147: 145-150).The chronic progressive external patients with multiple sclerosis has the IL-12 cyclical level of rising.The a series of self-holding immunity interaction that the research that T-cell and antigen presenting cell (APCs) from patients with multiple sclerosis are carried out has disclosed as carrying out property multiple sclerosis basis has caused Th1-type immune response.The IFN-secretion of the T cell that increases causes the IL-12 of the APCs that increases to produce, and it is keeping the Th1-type immune activation that causes chronic states and circulation (Balashov etc., (1997) Proc.Natl.Acad.Sci. of disease 94: 599-603).Used the mouse and rat experiment allergic encephalomyelitis (EAE) model of multiple sclerosis to investigate the effect of IL-12 in multiple sclerosis.In the multiple sclerosis recurrence-alleviation EAE of mouse model, postponed paralysis and reduced clinical score with anti--IL-12mAb preliminary treatment.Reduced clinical score in the paralysis peak period or in paracmastic process subsequently with anti--IL-12mAb treatment.Therefore, antibody of the present invention or its antigen-binding portion thereof can be used to alleviate the symptom relevant with multiple sclerosis in the people.

D. insulin-dependent diabetes mellitus

Il-1 2 has related to as a kind of important insulin-dependent diabetes mellitus (IDDM) medium.In the NOD mouse, induced IDDM by giving IL-12, anti--IL-12 antibody tool protective effect in IDDM adoptive transfer model.The IDDM patient of early onset thereof has experienced so-called " honeymooners " usually, during some residual islet cell function kept.These residual islet cellss produce insulin and give insulin can better regulate blood sugar level.Patient with anti--these early onset thereofs of IL-12 Antybody therapy can stop islet cells further to destroy, thereby has kept insulin endogenous source.

E. psoriasis

Il-1 2 (IL-12) relates to as medium crucial in the psoriasis with relevant cell factor IL-23.Psoriasis comprises that the acute and chronic skin relevant with TH1-cytokines expression pattern decreases (Hamid etc. (1996) J.Allergy Clin.Immunol.1:225-231; Turka etc. (1995) Mol.Med.1:690-699).IL-12 and IL-23 help the development of 1 type t helper cell (Th1) immune response in the psoriasis.In addition, IL-12 p40 and IL-23p40 mRNA are crossed expression in psoriatic's skin decreases.Therefore, antibody of the present invention or its antigen-binding portion thereof can be used for for example psoriasis of relieve chronic skin disorder.

In one embodiment, the invention provides the psoriatic method of a kind of treatment.Psoriatic treatment is generally included local corticoid, novel vitamin D analogues and local or oral biostearin or their associating.In one embodiment, one of these common treatment are united or existed to IL-12 and/or one of IL-23 antibody and these common treatment.Can be used for the treatment of psoriatic other therapeutic agent and be specified in down with IL-12 and/or IL-23 are antibody combined.

Usually based on skin appearance diagnosis psoriasis.In addition, may need to carry out skin biopsy or scraping blade and skin spot cultivates to get rid of other skin diseases.If arthralgia exists and do not stop, then can using x-radiological survey X psoriatic arthritis.

Can be by psoriatic improvement in individual psoriasis area and severity index score (PASI) the monitoring individuality.The method that is used to measure PASI has been described in Fredriksson and (1989) Arch Dermatol 125:235 kinds such as Pettersson (1978) Dermatologica 157:238 and Marks.In brief, (0=is asymptomatic based on using 5 subscales for this index; 1=is slight; The 2=moderate; 3=is significant; The 4=highly significant) to four regions of anatomy, comprise head, upper limbs, trunk and lower limb, to the evaluation of erythema, scleroma and furfur.Based on the degree of damaging in the given region of anatomy, to the area distributions numerical value (0=0 of influence; 1=＜10%; 2=10-29%; 3=30-49%; 4=50-69%; 5=70=89%; 6=90-100%).Calculate the PASI score then, wherein the possible range of PASI score is at 0.0-72.0, and the highest score has been represented the erythroderma of the integral body of the order of severity.

In one embodiment of the invention, IL-12 and/or IL-23 antibody are used for the treatment of psoriasis, comprise chronic psoriasis in plaques, psoriasis guttata, skin pleat psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermic psoriasis disease, the psoriasis relevant with inflammatory bowel disease (IBD) and with the relevant psoriasis of rheumatoid arthritis (RA).In another embodiment, IL-12 and/or IL-23 antibody, for example J695/ABT-874 is used for the treatment of the individuality of suffering from psoriasis merging PsA.The psoriasis that is included in the particular type in the methods of treatment of the present invention is specified in down:

A. chronic psoriasis in plaques

Chronic psoriasis in plaques (being also referred to as psoriasis vulgaris) is modal psoriasis type.Chronic psoriasis in plaques is characterised in that the skin patch that reddens of protuberance, scope from coin-size to very big.In chronic psoriasis in plaques, patch can be single or multiple, and their big I are from several millimeters to several centimetres.Patch normally has the red surface of scales of skin that peel off shape, can be reflective when scratching gently, produce a kind of " silver color " effect.The infringement of chronic psoriasis in plaques (it often is symmetrical) spreads all over whole body, but preference appears at the face of stretching, and comprises knee, elbow, lumbosacral region, scalp and nail.Chronic psoriasis in plaques can be existing by chance in penis, vulva and deflection, but do not have the scales of skin that peel off usually.Usually based on above-mentioned Clinical symptoms diagnosing chronic psoriasis in plaques patient.Particularly, the distribution that damages in the chronic psoriasis in plaques, color and the typical silver color scales of skin that peel off all are features of chronic psoriasis in plaques.

B. psoriasis guttata

Psoriasis guttata refers to a kind of psoriasis type that is characterised in that droplet-shaped scales of skin that peel off patch.The outbreak of psoriasis guttata is accompanied by infection usually, and the most significant is the streptococcus throat infection.Usually based on skin appearance and the fact diagnosis psoriasis guttata that often has the sore-throat medical history recently.

C. skin pleat psoriasis

Skin pleat psoriasis (inverse psoriasis) is a kind of wherein unlike the scales of skin that peel off relevant with psoriasis in plaques, and the patient has the psoriasis type of the skin area of red and inflammation smooth, common humidity.Skin pleat psoriasis is also referred to as intertriginous psoriasis or flexural psoriasis.Skin pleat psoriasis is the most normal to appear at armpit, groin, breast down and in other skin pleats around sexual organ and the buttocks, and owing to occur at these positions, friction and perspire and can stimulate affected zone.

D. pustular psoriasis

Pustular psoriasis is also referred to as volar psoriasis, be a kind of cause different sizes and position fill the pus blister, but often appear at brothers' psoriasis type.This blister can be positioned at or be dispersed on the large tracts of land health.Pustular psoriasis not only sensitivity but also pain can cause heating.

E. other psoriasis

The psoriatic example of other of available IL-12 and/or IL-23 Antybody therapy comprises red skin silver bits, the psoriasis vulgaris relevant with IBD, the psoriasis relevant with the arthritis that comprises rheumatoid arthritis.

The present invention is further specified by the following example, and such embodiment should not be considered as restriction by any way.The content of the patent application of the list of references that the document of all references comprises, granted patent and announcement clearly is incorporated herein by reference at this when quoting in the application's full text.Should be understood that further that all full text that invest No. the 6th, 914,128, this table content (referring to United States Patent (USP) the 6th, 914, No. 128 appendix A) and United States Patent (USP) all are incorporated herein by reference at this.

Embodiment

Embodiment 1: the curative effect of total man IL-12/IL-23 monoclone antibody ABT-874 in middle severe psoriasis in plaques treatment

ABT-874 is the human antibody of anti-il-1 2 (IL-12) and IL-23.It combines with the p40 subunit that IL-12 and IL-23 have with high-affinity, and IL-12 and IL-23 both are confirmed to be in the target in psoriasis (Ps) treatment.

The purpose of following research is to estimate the curative effect of hypodermic injection ABT-874 in middle severe psoriasis in plaques patient treatment.

At the baseline place 〉=10% corpus surface area (BSA) is got involved and the adult psoriatic of psoriasis area and severity index (PASI) score 〉=12 is suitable for research this 12-week, double blinding, placebo.The patient is assigned in 6 groups 1 group at random: 1) week about once (eow), 100-mgABT-874 continued for 12 weeks; 2) in the 0th week, 200-mg ABT-874, dose; 3) weekly, 200-mg ABT-874 continued for 4 weeks; 4) week about once, 200-mg ABT-874 continued for 12 weeks; 5) weekly, 200-mg ABT-874 continued for 12 weeks; Or 6) placebo.First end of the final point is to reply at the 12nd week 〉=PASI75.Other curative effect assessments comprise PASI50 and doctor's overall evaluation (PGA).That the patient who meets this first end of the final point enters 36-week is blind/and treat the phase again and time supervision is replied loss.

180 patients altogether in this research, have been recruited, 30 every group.Baseline characteristics between every group is similarly, and severe psoriasis (except that the % male sex, all are mean value) in showing: age, 46 years old, 74% male sex; 21 years psoriasis duration; PASI 19; Get involved with 25%BSA.In the 12nd week, for the patient in each group of 5 ABT-874 group, compare with placebo, reach 〉=patient's of PASI75 percentage is significantly higher statistically (to be respectively 93%, 63%, 90%, 93%, 90% pair 3%, p＜0.001, ITT).In addition, for the patient in each group of 5 ABT-874 group, compare, reach 〉=patient's of PASI50 percentage significantly higher statistically (being respectively 100%, 77%, 97%, 97% and 100% pair 17%, p＜0.001) with placebo.In the ABT-874 group, reduce (improvement) in the 12nd all PASI average percentage and be respectively 90%, 70%, 92%, 92% and 90%, and placebo is 26%.Similarly, in ABT-874 group, have make zero/patient's of minimum PGA percentage is respectively 83%, 50%, 73%, 87% and 87%, and placebo is 3%.

In a word, ABT-874 is obviously more effective than placebo in middle severe psoriasis in plaques treatment.

Embodiment 2: safety and the curative effect of total man IL-12/-23 monoclone antibody ABT-874 in middle severe psoriasis in plaques treatment

ABT-874 is the human antibody of anti-il-1 2 (IL-12) and IL-23.It combines with the p40 subunit that IL-12 and IL-23 have with high-affinity, and IL-12 and IL-23 both are confirmed to be in the target in psoriasis (Ps) treatment.The purpose studied of this II phase is to investigate curative effect and the safety of hypodermic injection ABT-874 in middle severe psoriasis in plaques treatment.

〉=10% corpus surface area (BSA) is got involved and the adult psoriatic of PASI score 〉=12 is suitable for research this 12-week, double blinding, placebo.The patient is assigned in 6 groups 1 group at random: 1) week about once (eow), 100-mg ABT-874 continued for 12 weeks; 2) in the 0th week, 200-mg ABT-874, dose; 3) weekly, 200-mg ABT-874 continued for 4 weeks; 4) week about once, 200-mg ABT-874 continued for 12 weeks; 5) weekly, 200-mg ABT-874 continued for 12 weeks; Or 6) placebo.First end of the final point is to reply at the 12nd week 〉=PASI75.That the patient who meets this first end of the final point enters 36-week is blind/and treat the phase again and time supervision is replied loss.To the safety of all patient evaluations in whole 54 weeks.

180 patients have been recruited, 30 every group.Baseline characteristics between every group is similar (except that the % male sex, all are mean value): age, 46 years old, 74% male sex; 21 years psoriasis duration; PASI 19; Get involved with 25%BSA.In the 12nd week, in each group of 5 ABT-874 group, compare with placebo, have 〉=patient's of PASI75 % significantly higher statistically (be respectively 93%, 63%, 90%, 93%, 90% pair 3%, p＜0.001, ITT).During 12 weeks, DB phase, organize infectious AEs scope at 23-43% for ABT-874, then be 23% for placebo, modal is that (7-17% is for ABT-874 for nasopharyngitis; 3%, for placebo).Between each group, there is not significant difference on the statistics.Do not have severe infections AEs report, do not occur dead.

As if in a word, ABT-874 is obviously more effective than placebo in middle severe psoriasis in plaques treatment, and have favourable safety distribution.

Embodiment 3: what total man IL-12/-23 monoclone antibody ABT-874 replied in middle severe psoriasis in plaques treatment keeps

Curative effect and the safety of ABT-874 in 12-week, II phase, randomization check experiment and 36-week follow-up period, have been assessed.The purpose of following embodiment was to analyze during second 12 week that the II phase of hypodermic injection ABT-874 is studied in the treatment of severe psoriasis in plaques in this, and that replys after stopping to treat keeps.

〉=10% corpus surface area (BSA) is got involved and the adult psoriatic of PASI score 〉=12 is suitable for research this 12-week, double blinding, placebo.The patient is assigned in 6 groups 1 group at random:

1) week about once (eow), 100-mg ABT-874 continued for 12 weeks;

2) in the 0th week, 200-mg ABT-874, dose;

3) weekly, 200-mg ABT-874 continued for 4 weeks;

4) week about once, 200-mg ABT-874 continued for 12 weeks;

5) weekly, 200-mg ABT-874 continued for 12 weeks; Or

6) placebo.

First end of the final point is to reply at the 12nd week 〉=PASI75.That the patient who meets this first end of the final point enters 36-week is blind/treat the phase again.Stop using the treatment of research medicine, and the time supervision patient is replied loss, and (any time in all follow-up period processes of 36-, the PASI score is reduced to＜PASI50).Assess keeping that PASI replys in whole 24 weeks.

180 patients have altogether been recruited, 30 every group.Baseline characteristics between every group is similar (except that the % male sex, all are mean value): age, 46 years old, 74% male sex; 21 years psoriasis duration; PASI 19; Get involved with 25%BSA.

In the 12nd week, in each group of 5 ABT-874 group, compare with placebo, have 〉=patient's of PASI75 percentage significantly higher (table 1) statistically.In the 24th week, PASI 75 respondents of quite big percentage have and keep at least that PASI 50 replys in the active treatment group.

The 24-week curative effect of table 1:ABT-874

	At the 12nd week, 〉=PASI75	Keeping PASI replys: the 24th week is to the 12nd week
	At the 12nd week, 〉=PASI75	Keeping PASI replys: the 24th week is to the 12nd week	Week about once, 100 mg continued for 12 weeks	??28/30(93％) ^*	??24/28(86％)
200mg, dose	??19/30(63％) ^*	??15/19(79％)	Week about once, 100 mg continued for 12 weeks	??28/30(93％) ^*	??24/28(86％)
200mg, dose	??19/30(63％) ^*	??15/19(79％)	Once in a week, 200-mg continued for 4 weeks	??27/30(90％) ^*	??23/27(85％)
Week about once, 200-mg continued for 12 weeks	??28/30(93％) ^*	??26/28(93％)	Once in a week, 200-mg continued for 4 weeks	??27/30(90％) ^*	??23/27(85％)
Week about once, 200-mg continued for 12 weeks	??28/30(93％) ^*	??26/28(93％)	Once in a week, 200-mg continued for 12 weeks	??27/30(90％) ^*	??26/27(96％)
Placebo	??1/30(3％)	??-	Once in a week, 200-mg continued for 12 weeks	??27/30(90％) ^*	??26/27(96％)

^*P＜0.001 pair placebo, NRI.

In a word, ABT-874 is obviously more effective than placebo in middle severe psoriasis in plaques treatment.After active treatment stopped, PASI 75 respondents of quite big percentage were still keeping these to reply in the 24th week.

Embodiment 4: safety and the curative effect of total man IL-12/-23 monoclone antibody ABT-874 in middle severe chronic psoriasis in plaques treatment

The purpose of following embodiment is to confirm to compare people IL-12/23 monoclone antibody (ABT-874) dosage range curative effect and safety with placebo in the stable clinically middle severe chronic psoriasis in plaques patient treatment.

I. material and method

A. research and design: following research is the test of 12-week of carrying out at 24 centers of the U.S. (16 place) and Canada (8 place), polycentric, randomized, double blinding, II phase, placebo.(Abbott Laboratories, Abbott Park are a kind ofly to have IL-12/23 p40 protein subunit human monoclonal antibody high-affinity, that have genetically engineered complementary determining region IL) to ABT-874.With the patient with 1: 1: 1: a kind in 6 kinds of treatments is accepted in ratio randomization in 1: 1: 1: in the 0th week, 200mg ABT-874,1 dosage (200mg * 1); Week about once (eow), 100mg ABT-874 continues 12 weeks (100mg eow); Once in a week, 200mg ABT-874 continues 4 week (200mg * 4); Week about once, 200mg ABT-874 continues 12 weeks (200mg eow); Once in a week, 200mg ABT-874.Continue 12 weeks (200mg weekly); Or placebo.After 12 weeks, all reach at least 75% and reduce and patient that severity index (PASI 75) is replied continues to enter the blind observation in 36-week/treat the phase again on the psoriasis area.

B. patient: the patient has 〉=age of 18 years old and have the psoriasis clinical diagnosis that continues at least 6 months and (visit definite by the patient, and the physical examination carried out of personnel is made a definite diagnosis by inquiry), continue at least 2 months in screening forward stability psoriasis in plaques, and by the definite baseline visit place of individual access, in the severe psoriasis in plaques be defined as at the baseline visit place 〉=10% corpus surface area (BSA) gets involved, in the PASI of baseline visit place 〉=12 score, and doctor's overall evaluation (PGA) of moderate disease at least at the baseline visit place.

Experiencing systematicness or biology before if the patient has resisted-the IL-12 treatment; Non-psoriasis in plaques; Before baseline visit, can not stop following treatment: local at least 2 weeks of curing psoriasis before baseline visit, at least 2 weeks of UV-B phototherapy before baseline visit, at least 4 weeks of psoralen-ultraviolet phototherapy before baseline visit, before baseline visit at least 4 weeks of systemic treatment and before baseline visit at least 12 weeks of biological therapy; In research process, need to take in oral or injectable corticoid (sucking corticoid for stable medical condition is to allow); Sb.'s illness took a turn for the worse to need the asthma of being in hospital before screening in the period of 10; The infection of severe infections or hazards; Except that the basal-cell carcinoma (eliminating has the patient of squamous cell carcinoma history) of success treatment or the malignant tumour history the original position cervical carcinoma; Or to containing the main immune response history (as serum sickness or anaphylactoid reaction) of immunoglobulin G medicine (as intravenous injection gamma globulin, fusion or monoclone antibody); Then they are underproof.

In research process, allow the patient their palm, sole, face, territory, inframammary region and inguinal region to be continued treatment with the medicated shampoo that does not contain corticoid, gentle (do not contain β-or 'alpha '-hydroxy acids) emollient or VI or the local corticoid of VII class poor efficiency.The application of these local curing psoriasis does not appear in 24 hours of research visit.In research process, in preceding 1 month or giving behind the last Research on dose medicine not allow to inoculate in 1 month the live virus agent with the ABT-874 administration.

Occur any following laboratory result of significant abnormal clinically all cause immediately the patient is withdrawn from from this research: aspartate transaminase or the alanine aminotransferase＞5 times normal value upper limit; Serum total bilirubin＞3 times normal value the upper limit; Serum creatinine＞3 times normal value the upper limit; Cretinephosphokinase＞5 times normal value the upper limit; Haemoglobin＜8g/dL; White blood cell count(WBC)＜2 * 10 ⁹/ L; Or platelet count＜75 * 10 ⁹/ L.

C. efficacy evaluation: main curative effect assessment is at the percentage that reaches the patient that PASI 75 replys the 12nd week, be defined as with respect to the baseline score at least the 75%PASI score reduce.PASI is the seriousness (according to erythema, scleroma and decortication) of a kind of psoriasis infringement and BSA the measuring of degree of getting involved.The PASI score from 0 (no psoriasis) to 72 (serious diseases) (Fredriksson T, PetterssonU.Dermatologica 1978; 157:238-44).Other curative effects are measured to be included in and the 1st, 2,4 and 8 weeks were reached the patient's of PASI 75 percentage at least; Percentage the patient who reaches PASI 50 at least or PASI 90 the 1st, 2,4,8 and 12 weeks; With make zero or the patient's of minimum PGA percentage in the 12nd week with reaching in the 1st, 2,4 and 8 weeks.(KoH-S.Clinical trial design in psoriasis. attends the order of severity of the 6 subscales mensuration disease of this PGA basis from 0 (no disease, or make zero (clear)) to 5 (very serious): 49th Meeting of theDermatologic and Ophthalmologic Advisory Committee; On March 20th, 1998; Bethesda, MD).

D. safety evaluation: in whole research, assess adverse events, laboratory data and vital sign.Monitor patient infection, malignant tumour and immune response sign closely.The AEs that treats-appear suddenly be defined as those the 0th week and after the research drug dose of last nothing leakage 45 days with event between 1 day (patient who continues for those to test in 36-week) before the therapeutic dose more early or for the first time.

E. statistical analysis: use nQuery

4.0 (Statistical Solutions, Saugus MA) calculate sample size.Suppose that in placebo 15% patient reaches PASI 75 at the 12nd weekly assembly and replys, the Fisher that use has 90% possibility on 0.05 2-side significance definitely checks, and this research and design person determines that in each dosage group 26 sample size is enough to detect the difference from treatment group at least 45%.This research is designed to recruit about 180 patients, every group of 30 patients.

Purpose treatment colony comprises all patients in the 0th all randomizations and the injection of at least 1 research of acceptance medicine; This colony is used for efficacy analysis.Time carry out all checks in α=0.05.The nonresponder lays the blame on and is used for all efficacy analysis; Any in any visit have the PASI of leakage or the patient of PGA score is regarded as nonresponder in this visit.Be the influence of assessment missing data, use and continue to use the sensitivity analysis that last observation (last-observation-carried-forward) method of carrying down is finished 12 weekly datas.Analyze so that multiplicity is regulated the first time that the PASI 75 that uses following order to carry out in the 12nd week replys: 200mg is once in a week to placebo, 200mg is week about once to placebo, 100mg is week about once to placebo, 200mg * 4 pair placebo and 200mg * 1 pair placebo.Use has baseline PASI score and treatment group and as the variance analysis of the factor average percentage of PASI score is changed the treatment difference of estimating between each ABT-874 treatment group and placebo tissue.Use comprises that all safety colonies that accept the patient of at least 1 research medicine injection carry out safety analysis.

II. result

A. patient: recruited 180 patients altogether and be randomized into 1 group (Fig. 1) in 6 treatment groups.Most patient (patient of 76.7% placebo treatment and 98% all ABT-874 treatment group patients) has finished the 12-circumferential portion of this research.

About demographic characteristics and disease activity, patient's be evenly distributed (table 1) between the treatment group.The male sex among the patient (74.4%) and white man's (92.2%) preponderate.Average BSA get involved be 25% and mean P ASI must be divided into 18.8.

B. curative effect: compare with placebo (3.3%, 1/30), in all ABT-874 treatment group (200mg * 1:63.3%, 19/30; 100mg eow:93.3%, 28/30; 200mg * 4:90.0%, 27/30; 200mg eow:93.3%, 28/30; 200mg, weekly: 90.0%, 27/30) at the patient's who reaches first end of the final point that PASI 75 replys the 12nd week percentage significantly higher statistically (p＜0.001).For this test of short relatively duration, except that 200mg * 1 treatment group, to reply all are similar (Fig. 2) to PASI 75 in all ABT-874 treatment groups.

By demography (sex, age, race and body weight), baseline disease characteristic (psoriatic arthritis medical history, BSA and PASI score) and in accepting 12 months of research treatment, the group of psoriatic baseline treatment (systemic biology and abiology, part and phototherapy) is analyzed the patient that confirmed ABT-874-treatment in different groups and allly consistently reach high-caliber PASI 75 and reply the 12nd.

Through 12 weeks, almost 100% higher ABT-874 dosage group reaches at least that PASI 50 replys (200mg * 1:76.7%, 23/30; 100mg eow:100.0%, 30/30; 200mg * 4:96.7%, 29/30; 200mg eow:96.7%, 29/30; 200mg, weekly: 100.0%, 30/30; Placebo: 16.7%, 5/30; Compare p＜0.001 for each and placebo).When comparing with placebo, in all groups except the ABT-874 treatment group of 1 group (200mg * 1), at the percentage significantly higher statistically (p＜0.001) that reaches the patient that PASI 90 at least replys the 12nd week, as follows: 200mg * 1:16.7%, 5/30; 100mgeow:53.3%, 16/30; 200mg * 4:63.3%, 19/30; 200mg eow:76.6%, 23/30; 200mg, weekly: 53.3%, 16/30; And placebo: 0%, 0/30.In addition, through 12 weeks, compare with patient in the placebo, the patient of obviously more (p＜0.001) has to reach and makes zero or minimum PGA grade in all ABT-874 treatment groups, and is as follows: 200mg * 1:50.0%, 15/30; 100mg eow:83.3%, 25/30; 200mg * 4:73.3%, 22/30; 200mg eow:86.7%, 26/30; 200mg, weekly: 86.7%, 26/30; To placebo: 3.3%, 1/30.

Compare with placebo (0%, 0/30), in following ABT-874 treatment group (200mg eow:46.7%, 14/30; 200mg, weekly: 36.7%, 11/30), at the patient's who reaches first end of the final point that PASI 100 replys the 12nd week percentage significantly higher statistically (p＜0.001).

To replying of ABT-874 is fast.Improve increase (Fig. 3) in time for all ABT-874 treatment groups from the average percentage of baseline PASI score, and on each time point, compare with placebo, significantly higher statistically (p＜0.001 of each ABT-874 treatment group, except that 100mg eow organizes the 1st week, p=0.023).

C. (table 2) that safety: ABT-874 treatment is normally well tolerable.Because the local skin variable color, one (0.7%) stops this research with the patient of ABT-874 treatment; 2 (6.7%) stops this research with the patient of placebo treatment, and 1 is because of arthropathia psoriatica, and 1 is because oophoroma in addition.Two (1.1%) patient experience serious adverse effects (AEs); The patient of 1 placebo treatment was diagnosed as oophoroma at the 37th day, and the patient (200mg * 1) of 1 ABT-874-treatment was enclosed costal chondritis at the 10th day by diagnosis.Do not have patient experience cardiac muscle or cerebral infarction, do not have death yet.

Compare with the patient who accepts placebo, the patient who accepts the ABT-874 of any dosage be obviously (p=0.033) more likely experience at least may be in AE (ABT-874:36.0%, 54/150 that the research medicine is correlated with; Placebo: 10.0%, 3/30; Table 2); Most these AEs relevant with the injection site (injection site reaction, erythema, itch or stimulation).

Most of AEs be slight (slight AEs appears at 46.0%[69/150] the patient and the 30.0%[9/30 of ABT-874-treatment] among the patient of placebo treatment).Modal AE is an injection site reaction, appears among the patient of any dosage ABT-874 treatment of 16.7% (25/150) usefulness and (for the patient of placebo treatment, does not report injection site reaction; P=0.028; Table 3).Compare with the patient of placebo treatment, in the patient of ABT-874-treatment, do not have statistically-significant difference between the incidence of other AEs.Secondly the AEs of normal report is the nasopharyngitis and the infection of the upper respiratory tract.

Whole patients (placebo: 23.3%, 7/30 32.8% (59/180); The patient of whole ABT-874-treatments: reported infectious AEs 34.7%, 52/150).For any ABT-874 treatment group the most infectious AEs of common report be nasopharyngitis (12.0%, 18/150), the infection of the upper respiratory tract (10.7%, 16/150) and bronchitis and virus infections (both 2.7%, 4/150).Do not report serious infectious AEs.

Reported that in this research process two patients get malignant tumour.The patient of a placebo treatment is diagnosed as oophoroma, and it was development in the 129th day.The patient (200mg * 4) of an ABT-874-treatment is diagnosed as non-melanoma skin cancer (squamous cell carcinoma), and it left at the 133rd day.This patient's medical history is included in and extracts optimum skin growth in March, 2005.

Compare with placebo, significant hematology, chemistry (comprising blood sugar concentration) or vital signs do not change clinically.

III. conclusion

The II phase of Miao Shuing, polycentric, at random, double blinding, placebo-check experiment have confirmed statistics and the significant clinically curative effect of ABT-874 in middle severe chronic psoriasis in plaques treatment in this embodiment.Through 12 weeks, except that ABT-874 200mg * 1 treatment group, in all ABT-874 treatment groups 90% or more patient reach PASI 75 or bigger, the patient of placebo treatment only is 3.3% by comparison.Even in the group of only accepting 1 Research on dose medicine (200mg * 1), through 12 weeks, great majority (63.3%) patients have and reach PASI75 at least.In addition, through 12 weeks, almost 100% the patient with the ABT-874 treatment reaches PASI 50 or bigger, this is considered to improve significantly clinically (Carlin CS, Feldman SR, KruegerJG, Menter A, Krueger GG.J Am Acad Dermatol 2004; 50:859-66).For the result of other second ends of the final point, PASI 90 and making zero or minimum PGA for example, also with the first time efficacy analysis consistent and support it.

To replying of ABT-874 is fast.For the average percentage that the PASI score is improved, separate significantly as far back as the statistics that just occurred in the 1st week between the patient of placebo and ABT-874 treatment.During the test duration in 12-week, continuing to improve, even for the patient in ABT-874 200mg * 1 and 200mg * 4 dosage groups.

ABT-874 is well tolerable, and most AEs is slight.Although the patient of ABT-874-treatment obviously more likely experience at least may with the relevant AE of research medicine, most these AE are the AEs (injection site reaction, erythema, itch or stimulation) that are correlated with in the injection site.Between the AEs incidence of ABT-874 dosage that increases and increase, do not exist significantly relevant.It should be noted that and do not have cardiac muscle or cerebral infarction.

For the patient who accepts anti--IL-12/23 antibody, immune dependent event is interested especially.The most infectious AEs of normal report is nasopharyngitis, the infection of the upper respiratory tract, bronchitis and virus infections.During this test duration, there is not severe infections AEs report.2 routine malignant tumours during this research, have been diagnosed.In the patient of placebo treatment, diagnosed oophoroma, and in the patient of ABT-874-treatment, diagnosed non-melanoma skin cancer with optimum skin growth history.

In a word, ABT-874 is proved statistically and is obviously useful and well tolerable clinically in middle severe chronic psoriasis in plaques treatment patient.

Embodiment 5: the keeping of total man IL-12/-23 monoclone antibody ABT-874 replying in the treatment of middle severe psoriasis in plaques

Curative effect and the safety of assessment ABT-874 in 12-week, II phase, randomization check experiment and 36-week follow-up period.The purpose of following embodiment was to analyze during second 12 week that the II phase of hypodermic injection ABT-874 is studied in the treatment of severe psoriasis in plaques in this, and that replys after stopping to treat keeps.

1) week about once (eow), 100-mg ABT-874 continued for 12 weeks;

2) in the 0th week, 200-mg ABT-874, dose;

3) weekly, 200-mg ABT-874 continued for 4 weeks;

4) week about once, 200-mg ABT-874 continued for 12 weeks;

5) weekly, 200-mg ABT-874 continued for 12 weeks; Or

6) placebo.

First end of the final point is to reply at the 12nd week 〉=PASI75.That the patient who meets this first end of the final point enters 36-week is blind/treat the phase again.Stop using the treatment of research medicine, and during 36-week follow-up period in different time supervision patient PASI scores, comprise that PASI 50, PASI 75 and PASI90 reply.Assess keeping that PASI replys in whole 24 weeks.

In the 12nd week, in each group of 5 ABT-874 group, compare with placebo, have 〉=patient's of PASI75 percentage significantly higher (table 4) statistically.In the 24th week, PASI 75 respondents of quite big percentage have and keep at least 〉=PASI 50 scores of PASI 50 in the active treatment group.In addition, in the active treatment group PASI 75 respondents of quite big percentage also have keep at least 〉=the PASI score of PASI 75 and 〉=the PASI score (table 4 and Fig. 4 A-C) of PASI 90.During 24 weeks, the percentage of keeping the patient that PASI 75 replys in time in the past is depicted among Fig. 4 D.

The 24-week curative effect of table 4:ABT-874

	In the 12nd week, 〉=PASI 75	Keep 〉=PASI 50 replys: the 24th week is to the 12nd week	Keep 〉=PASI 75 replys: the 24th week is to the 12nd week	Keep 〉=PASI 90 replys: the 24th week is to the 12nd week
	In the 12nd week, 〉=PASI 75	Keep 〉=PASI 50 replys: the 24th week is to the 12nd week	Keep 〉=PASI 75 replys: the 24th week is to the 12nd week	Keep 〉=PASI 90 replys: the 24th week is to the 12nd week	Week about once, 100 mg continued for 12 weeks	??93％ ^*	??71％	??60％	??33％
200mg, dose	??63％ ^*	??68％	??23％	??7％	Week about once, 100 mg continued for 12 weeks	??93％ ^*	??71％	??60％	??33％
200mg, dose	??63％ ^*	??68％	??23％	??7％	Once in a week, 200-mg continued for 4 weeks	??90％ ^*	??82％	??60％	??23％
Week about once, 200-mg continued for 12 weeks	??93％ ^*	??89％	??73％	??53％	Once in a week, 200-mg continued for 4 weeks	??90％ ^*	??82％	??60％	??23％
Week about once, 200-mg continued for 12 weeks	??93％ ^*	??89％	??73％	??53％	Once in a week, 200-mg continued for 12 weeks	??90％ ^*	??85％	??83％	??57％
Placebo	??3％	??-	??7％	??7％	Once in a week, 200-mg continued for 12 weeks	??90％ ^*	??85％	??83％	??57％

^*P＜0.001 pair placebo, NRI.

In a word, ABT-874 is obviously more effective than placebo in middle severe psoriasis in plaques treatment.After stopping active treatment, in the 24th week, PASI 75 respondents of quite big percentage keep 〉=PASI 50, 〉=PASI 75 and 〉=the replying of PASI 90.

Equivalency range

Only use conventional test method, those skilled in the art just should confirm maybe can determine many equivalents of particular of the present invention described here.Such equivalent is defined as following claim and comprises.

Sequence table

<110>Abbott?Laboratories，et?al.

＜120〉be used for the treatment of psoriatic method

<130>BBI-276PC

<140>Not?yet?available

<141>Concurrently?Herewith

<150>60/880767

<151>2007-01-16

<150>60/904022

<151>2007-02-27

<150>60/925960

<151>2007-04-24

<150>60/961764

<151>2007-07-24

<150>60/997012

<151>2007-09-28

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＜223〉104 Xaa can be Tyr, Asn or

Thr

<400>7

Gln?Val?Gln?Leu?Val?Xaa?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Xaa

1???????????????5??????????????????10??????????????????15

Ser?Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Xaa?Tyr

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Asx

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?Xaa?Ser?Leu?Arg?Ala?Glu?Asp?Thr?Ala?Val?Tyr?Tyr?Cys

85??????????????????90??????????????????95

Xaa?Xaa?Xaa?Gly?Ser?Xaa?Asp?Xaa?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>8

<211>112

<212>PRT

＜213〉mankind

<220>

＜223〉can be Ser or Gln at 1 Xaa

<220>

＜223〉can be Tyr or Ser at 2 Xaa

<220>

＜223〉can be Thr or Ala at 13 Xaa

<220>

＜223〉23 and 91 Xaa can be Ser or

Thr

<220>

＜223〉can be Gly or Ser at 25 Xaa

<220>

＜223〉can be Arg or Ser at 26 Xaa

<220>

＜223〉can be Gly or Val at 30 Xaa

<220>

＜223〉can be Ser or Ala at 31 Xaa

<220>

＜223〉can be Lys or His at 35 Xaa

<220>

＜223〉can be Gly or Lys at 51 Xaa

<220>

＜223〉can be Gln or Asn at 54 Xaa

<220>

＜223〉can be Val or Leu at 79 Xaa

<220>

＜223〉can be Asp or Glu at 93 Xaa

<220>

＜223〉can be Ser, Arg or Lys at 94 Xaa

<220>

＜223〉can be Ser, Gly or Tyr at 95 Xaa

<220>

＜223〉can be Leu, Phe, Thr at 96 Xaa

Or Ser

<220>

＜223〉97 Xaa can be Arg, Ser, Thr,

Trp or His

<220>

＜223〉can be Gly or Pro at 98 Xaa

<220>

＜223〉can be Ser, Thr, Ala at 99 Xaa

Or Leu

<220>

＜223〉100 Xaa can be Arg, Ser, Met,

Thr or Leu

<220>

＜223〉101 Xaa can be Val, Ile, Thr,

Met or Leu

<220>

＜223〉can be Asn, Gly or Tyr at 32 Xaa

<220>

＜223〉can be Thr or Asp at 33 Xaa

<220>

＜223〉can be Asp or Ser at 53 Xaa

<400>8

Xaa?Xaa?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Xaa?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Xaa?Gly?Xaa?Xaa?Ser?Asn?Ile?Xaa?Xaa?Xaa

20??????????????????25??????????????????30

Xaa?Val?Xaa?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Xaa?Asn?Xaa?Xaa?Arg?Pro?Ser?Gly?Val?Pro?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Xaa?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Xaa?Tyr?Xaa?Xaa?Xaa?Xaa

85??????????????????90??????????????????95

Xaa?Xaa?Xaa?Xaa?Xaa?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>9

<211>6

<212>PRT

＜213〉mankind

<220>

＜223〉2 Xaa can be Gly, Val, Cys or

His

<220>

＜223〉can be Ser or Thr at 3 Xaa

<220>

＜223〉can be His, Thr, Val, Arg or Ile at 4 Xaa

<220>

＜223〉can be Asp or Ser at 5 Xaa

<220>

＜223〉6 Xaa can be Asn, Lys, Ala,

Thr, Ser, Phe, Trp or His

<400>9

His?Xaa?Xaa?Xaa?Xaa?Xaa

1???????????????5

<210>10

<211>12

<212>PRT

＜213〉mankind

<220>

＜223〉can be Asp or Ser at 4 Xaa

<220>

＜223〉represent any amino acid at 5 Xaa

<220>

＜223〉6 Xaa can be Gly, Asp, Gln,

Leu, Phe, Arg, His, Asn or Tyr

<400>10

Gln?Ser?Tyr?Xaa?Xaa?Xaa?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>11

<211>17

<212>PRT

＜213〉mankind

<220>

＜223〉can be Phe, Thr or Tyr at 1 Xaa

<220>

＜223〉can be Arg or Ala at 3 Xaa

<220>

＜223〉5 Xaa can be Asp, Ser, Glu or

Ala

<220>

＜223〉can be Gly or Arg at 6 Xaa

<220>

＜223〉represent any amino acid at 8 Xaa

<220>

＜223〉can be Tyr or Glu at 10 Xaa

<400>11

Xaa?Ile?Xaa?Tyr?Xaa?Xaa?Ser?Xaa?Lys?Xaa?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>12

<211>7

<212>PRT

＜213〉mankind

<220>

＜223〉1 Xaa can be Gly, Tyr, Ser,

Thr, Asn or Gln

<400>12

Xaa?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>13

<211>9

<212>PRT

＜213〉mankind

<220>

＜223〉represent any amino acid at 4 and 5 Xaa

<220>

＜223〉can be Tyr or His at 6 Xaa

<220>

＜223〉7 Xaa can be Gly, Met, Ala,

Asn or Ser

<400>13

Phe?Thr?Phe?Xaa?Xaa?Xaa?Xaa?Met?His

1???????????????5

<210>14

<211>13

<212>PRT

＜213〉mankind

<220>

＜223〉9 Xaa can be Ser, Cys, Arg,

Asn, Asp or Thr

<220>

＜223〉can be Asn, Met or Ile at 10 Xaa

<220>

＜223〉11 Xaa can be Thr, Tyr, Asp,

His, Lys or Pro

<400>14

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Xaa?Xaa?Xaa?Val?Lys

1???????????????5??????????????????10

<210>15

<211>114

<212>PRT

＜213〉mankind

<220>

＜223〉can be Ser or Glu at 30 Xaa

<220>

＜223〉can be Lys or Asn at 83 Xaa

<220>

＜223〉can be Gln or Glu at 5 Xaa

<400>15

Gln?Val?Gln?Val?Xaa?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg?Ser

1???????????????5??????????????????10??????????????????15

Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Xaa?Tyr?Gly

20??????????????????25??????????????????30

Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val?Ala

35??????????????????40??????????????????45

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

Gln?Met?Xaa?Ser?Leu?Arg?Ala?Glu?Asp?Thr?Ala?Val?Tyr?Tyr?Cys?Lys

85??????????????????90??????????????????95

Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr?Val

100?????????????????105?????????????????110

Ser?Ser

<210>16

<211>112

<212>PRT

＜213〉mankind

<220>

＜223〉can be Ser or Gln at 1 Xaa

<220>

＜223〉can be Tyr or Ser at 2 Xaa

<220>

＜223〉can be Thr or Ala at 13 Xaa

<220>

＜223〉can be Gly or Ser at 25 Xaa

<220>

＜223〉51 and 95 Xaa can be Gly or

Tyr

<220>

＜223〉can be Val or Leu at 79 Xaa

<400>16

Xaa?Xaa?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Xaa?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Xaa?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Xaa?Asn?Asp?Gln?Arg?Pro?Ser?Gly?Val?Pro?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Xaa?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Xaa?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>17

<211>6

<212>PRT

＜213〉mankind

<400>17

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>18

<211>12

<212>PRT

＜213〉mankind

<400>18

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>19

<211>17

<212>PRT

＜213〉mankind

<400>19

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>20

<211>7

<212>PRT

＜213〉mankind

<400>20

Gly?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>21

<211>9

<212>PRT

＜213〉mankind

<400>21

Phe?Thr?Phe?Ser?Ser?Tyr?Gly?Met?His

1???????????????5

<210>22

<211>13

<212>PRT

＜213〉mankind

<400>22

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>23

<211>115

<212>PRT

＜213〉mankind

<400>23

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>24

<211>112

<212>PRT

＜213〉mankind

<400>24

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Trp?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Gly?Asr?Asp?Gln?Arg?Pro?Ser?Gly?Val?Pro?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>25

<211>6

<212>PRT

＜213〉mankind

<400>25

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>26

<211>12

<212>PRT

＜213〉mankind

<400>26

Gln?Ser?Tyr?Asp?Arg?Tyr?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>27

<211>17

<212>PRT

＜213〉mankind

<400>27

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>28

<211>7

<212>PRT

＜213〉mankind

<400>28

Tyr?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>29

<211>9

<212>PRT

＜213〉mankind

<400>29

Phe?Thr?Phe?Ser?Ser?Tyr?Gly?Met?His

1???????????????5

<210>30

<211>13

<212>PRT

＜213〉mankind

<400>30

Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>31

<211>115

<212>PRT

＜213〉mankind

<400>31

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>32

<211>112

<212>PRT

＜213〉mankind

<400>32

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Tyr?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>33

<211>115

<212>PRT

＜213〉mankind

<400>33

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?Ser?Gly?Ser?Tyr?Asp?Tyr?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>34

<211>112

<212>PRT

＜213〉mankind

<400>34

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Arg?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>35

<211>115

<212>PRT

＜213〉mankind

<400>35

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?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?Lys?Ser?Gly?Ser?Tyr?Asp?Tyr?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>36

<211>112

<212>PRT

＜213〉mankind

<220>

＜223〉represent Gly or Tyr at 32 Xaa

<400>36

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Thr?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Ala?Xaa

20??????????????????25??????????????????30

Asp?Val?His?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Gly?Asn?Ser?Asn?Arg?Pro?Ser?Gly?Val?Pro?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Ser?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>37

<211>115

<212>PRT

＜213〉mankind

<400>37

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>38

<211>112

<212>PRT

＜213〉mankind

<400>38

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Arg?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>39

<211>115

<212>PRT

＜213〉mankind

<400>39

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?Ser?Gly?Ser?Tyr?Asp?Tyr?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>40

<211>112

<212>PRT

＜213〉mankind

<400>40

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>41

<211>115

<212>PRT

＜213〉mankind

<400>41

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?Ser?Gly?Ser?Tyr?Asp?Tyr?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>42

<211>112

<212>PRT

＜213〉mankind

<400>42

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Trp?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>43

<211>115

<212>PRT

＜213〉mankind

<400>43

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>44

<211>112

<212>PRT

＜213〉mankind

<400>44

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>45

<211>115

<212>PRT

＜213〉mankind

<400>45

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>46

<211>112

<212>PRT

＜213〉mankind

<400>46

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

1??????????????5???????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Trp?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>47

<211>115

<212>PRT

＜213〉mankind

<400>47

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>48

<211>112

<212>PRT

＜213〉mankind

<400>48

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Thr?Tyr?Asp?Lys?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Ser?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>49

<211>115

<212>PRT

＜213〉mankind

<400>49

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>50

<211>112

<212>PRT

＜213〉mankind

<400>50

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Thr?Tyr?Asp?Lys?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Ser?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>51

<211>115

<212>PRT

＜213〉mankind

<400>51

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?His?Gly?Ser?His?Asp?Thr?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>52

<211>112

<212>PRT

＜213〉mankind

<400>52

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Trp?Gly?Thr?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>53

<211>115

<212>PRT

＜213〉mankind

<400>53

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>54

<211>112

<212>PRT

＜213〉mankind

<400>54

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Val?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Arg?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>55

<211>115

<212>PRT

＜213〉mankind

<400>55

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>56

<211>112

<212>PRT

＜213〉mankind

<400>56

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Val?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Phe

85??????????????????90??????????????????95

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

100?????????????????105?????????????????110

<210>57

<211>115

<212>PRT

＜213〉mankind

<400>57

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>58

<211>112

<212>PRT

＜213〉mankind

<400>58

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Thr?Tyr?Asp?Lys?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Ser?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>59

<211>115

<212>PRT

＜213〉mankind

<400>59

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>60

<211>112

<212>PRT

＜213〉mankind

<400>60

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Glu?Arg?Gly?Phe

85??????????????????90??????????????????95

Thr?Gly?Ser?Met?Val?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>61

<211>115

<212>PRT

＜213〉mankind

<400>61

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>62

<211>112

<212>PRT

＜213〉mankind

<400>62

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Leu?Thr?Ile?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>63

<211>115

<212>PRT

＜213〉mankind

<400>63

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>64

<211>112

<212>PRT

＜213〉mankind

<400>64

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Ser

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Thr?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>65

<211>115

<212>PRT

＜213〉mankind

<400>65

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>66

<211>112

<212>PRT

＜213〉mankind

<400>66

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

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Leu?Thr?Met?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>67

<211>115

<212>PRT

＜213〉mankind

<400>67

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>68

<211>112

<212>PRT

＜213〉mankind

<400>68

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Leu?Thr?Met?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>69

<211>115

<212>PRT

＜213〉mankind

<400>69

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>70

<211>112

<212>PRT

＜213〉mankind

<400>70

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>71

<211>115

<212>PRT

＜213〉mankind

<400>71

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

Ser?Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Glu?Tyr

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>72

<211>112

<212>PRT

＜213〉mankind

<400>72

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>73

<211>115

<212>PRT

＜213〉mankind

<400>73

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>74

<211>112

<212>PRT

＜213〉mankind

<400>74

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Gly?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>75

<211>115

<212>PRT

＜213〉mankind

<400>75

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly?Thr?Met?Val?Thr

100?????????????????105?????????????????110

Val?Ser?Ser

115

<210>76

<211>112

<212>PRT

＜213〉mankind

<400>76

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Arg?Tyr?Thr

85??????????????????90??????????????????95

His?Pro?Ala?Leu?Leu?Phe?Gly?Thr?Gly?Thr?Lys?Val?Thr?Val?Leu?Gly

100?????????????????105?????????????????110

<210>77

<211>6

<212>PRT

＜213〉mankind

<400>77

Ser?Gly?Ser?Tyr?Asp?Tyr

1???????????????5

<210>78

<211>6

<212>PRT

＜213〉mankind

<400>78

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>79

<211>6

<212>PRT

＜213〉mankind

<400>79

His?Gly?Ser?Tyr?Asp?Tyr

1???????????????5

<210>80

<211>6

<212>PRT

＜213〉mankind

<400>80

Arg?Arg?Arg?Ser?Asn?Tyr

1???????????????5

<210>81

<211>6

<212>PRT

＜213〉mankind

<400>81

Ser?Gly?Ser?Ile?Asp?Tyr

1???????????????5

<210>82

<211>6

<212>PRT

＜213〉mankind

<400>82

His?Gly?Ser?His?Asp?Asp

1???????????????5

<210>83

<211>6

<212>PRT

＜213〉mankind

<400>83

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>84

<211>12

<212>PRT

＜213〉mankind

<400>84

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly

1???????????????5??????????????????10

<210>85

<211>12

<212>PRT

＜213〉mankind

<400>85

Ala?Lys?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly

1???????????????5??????????????????10

<210>86

<211>12

<212>PRT

＜213〉mankind

<400>86

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Ser?Gln?Gly

1???????????????5??????????????????10

<210>87

<211>12

<212>PRT

＜213〉mankind

<400>87

Thr?Thr?His?Gly?Ser?His?Asp?Thr?Trp?Gly?Gln?Gly

1???????????????5??????????????????10

<210>88

<211>12

<212>PRT

＜213〉mankind

<400>88

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?Gln?Gly

1???????????????5??????????????????10

<210>89

<211>12

<212>PRT

＜213〉mankind

<400>89

Lys?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Gly?His?Gly

1???????????????5??????????????????10

<210>90

<211>12

<212>PRT

＜213〉mankind

<400>90

Thr?Thr?His?Gly?Ser?His?Asp?Asn?Trp?Ser?Gln?Gly

1???????????????5??????????????????10

<210>91

<211>12

<212>PRT

＜213〉mankind

<400>91

Thr?Thr?His?Arg?Ser?His?Asn?Asn?Trp?Gly?Gln?Gly

1???????????????5??????????????????10

<210>92

<211>8

<212>PRT

＜213〉mankind

<400>92

Thr?Thr?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>93

<211>8

<212>PRT

＜213〉mankind

<400>93

Thr?Thr?His?Gly?Ser?His?Asp?Thr

1???????????????5

<210>94

<211>8

<212>PRT

＜213〉mankind

<400>94

Thr?Lys?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>95

<211>8

<212>PRT

＜213〉mankind

<400>95

Thr?Thr?Gln?Gly?Arg?His?Asp?Asn

1???????????????5

<210>96

<211>8

<212>PRT

＜213〉mankind

<400>96

Lys?Thr?Arg?Gly?Arg?His?Asp?Asn

1???????????????5

<210>97

<211>8

<212>PRT

＜213〉mankind

<400>97

Thr?Thr?His?Gly?Ser?His?Asp?Lys

1???????????????5

<210>98

<211>8

<212>PRT

＜213〉mankind

<400>98

Thr?Thr?His?Gly?Ser?His?Asp?Asp

1???????????????5

<210>99

<211>8

<212>PRT

＜213〉mankind

<400>99

Lys?Thr?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>100

<211>8

<212>PRT

＜213〉mankind

<400>100

Lys?Thr?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>101

<211>8

<212>PRT

＜213〉mankind

<400>101

Thr?Thr?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>102

<211>8

<212>PRT

＜213〉mankind

<400>102

Thr?Thr?Ser?Gly?Ser?Tyr?Asp?Tyr

1???????????????5

<210>103

<211>8

<212>PRT

＜213〉mankind

<400>103

Thr?Thr?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>104

<211>8

<212>PRT

＜213〉mankind

<400>104

Thr?Thr?His?Gly?Ser?Gln?Asp?Asn

1???????????????5

<210>105

<211>8

<212>PRT

＜213〉mankind

<400>105

Ala?Thr?His?Gly?Ser?Gln?Asp?Asn

1???????????????5

<210>106

<211>6

<212>PRT

＜213〉mankind

<400>106

His?Gly?Ser?Gln?Asp?Thr

1???????????????5

<210>107

<211>6

<212>PRT

＜213〉mankind

<400>107

Ser?Gly?Ser?Tyr?Asp?Tyr

1???????????????5

<210>108

<211>6

<212>PRT

＜213〉mankind

<400>108

His?Gly?Ser?Gln?Asp?Asn

1???????????????5

<210>109

<211>9

<212>PRT

＜213〉mankind

<400>109

Cys?Lys?Thr?His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>110

<211>12

<212>PRT

＜213〉mankind

<400>110

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Arg?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>111

<211>12

<212>PRT

＜213〉mankind

<400>111

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>112

<211>12

<212>PRT

＜213〉mankind

<400>112

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Arg?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>113

<211>12

<212>PRT

＜213〉mankind

<400>113

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>114

<211>12

<212>PRT

＜213〉mankind

<400>114

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Trp?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>115

<211>12

<212>PRT

＜213〉mankind

<400>115

Gln?Thr?Tyr?Asp?Ile?Ser?Glu?Ser?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>116

<211>12

<212>PRT

＜213〉mankind

<400>116

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>117

<211>12

<212>PRT

＜213〉mankind

<400>117

Gln?Thr?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>118

<211>12

<212>PRT

＜213〉mankind

<400>118

Gln?Thr?Tyr?Asp?Lys?Gly?Phe?Thr?Gly?Ser?Ser?Val

1???????????????5??????????????????10

<210>119

<211>12

<212>PRT

＜213〉mankind

<400>119

Gln?Ser?Tyr?Asp?Arg?Arg?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>120

<211>12

<212>PRT

＜213〉mankind

<400>120

Gln?Ser?Tyr?Asp?Trp?Asn?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>121

<211>12

<212>PRT

＜213〉mankind

<400>121

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>122

<211>12

<212>PRT

＜213〉mankind

<400>122

Gln?Ser?Tyr?Asp?Asn?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>123

<211>12

<212>PRT

＜213〉mankind

<400>123

Gln?Ser?Tyr?Asp?Asn?Ala?Val?Thr?Ala?Ser?Lys?Val

1???????????????5??????????????????10

<210>124

<211>12

<212>PRT

＜213〉mankind

<400>124

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>125

<211>12

<212>PRT

＜213〉mankind

<400>125

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Trp?Gly?Thr?Arg?Val

1???????????????5??????????????????10

<210>126

<211>12

<212>PRT

＜213〉mankind

<400>126

Gln?Ser?Tyr?Asp?Arg?Asp?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>127

<211>12

<212>PRT

＜213〉mankind

<400>127

Gln?Ser?Tyr?Glu?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>128

<211>12

<212>PRT

＜213〉mankind

<400>128

Gln?Ser?Tyr?Asp?Asn?Gly?Phe?Thr?Gly?Ala?Arg?Val

1???????????????5??????????????????10

<210>129

<211>12

<212>PRT

＜213〉mankind

<400>129

Gln?Ser?Tyr?Asp?Arg?Arg?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>130

<211>12

<212>PRT

＜213〉mankind

<400>130

Gln?Thr?Tyr?Asp?Lys?Gly?Phe?Thr?Gly?Ser?Ser?Val

1???????????????5??????????????????10

<210>131

<211>12

<212>PRT

＜213〉mankind

<400>131

Gln?Ser?Tyr?Asp?Arg?Asp?Phe?Thr?Gly?Thr?Arg?Val

1???????????????5??????????????????10

<210>132

<211>12

<212>PRT

＜213〉mankind

<400>132

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Tyr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>133

<211>12

<212>PRT

＜213〉mankind

<400>133

Gln?Thr?Tyr?Asp?Lys?Gly?Phe?Thr?Gly?Ser?Ser?Val

1???????????????5??????????????????10

<210>134

<211>12

<212>PRT

＜213〉mankind

<400>134

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ala?Arg?Val

1???????????????5??????????????????10

<210>135

<211>12

<212>PRT

＜213〉mankind

<400>135

Gln?Ser?Tyr?Glu?Arg?Gly?Phe?Thr?Gly?Ala?Arg?Val

1???????????????5??????????????????10

<210>136

<211>13

<212>PRT

＜213〉mankind

<400>136

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>137

<211>13

<212>PRT

＜213〉mankind

<400>137

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Phe?Lys?Val?Phe

1???????????????5??????????????????10

<210>138

<211>13

<212>PRT

＜213〉mankind

<400>138

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Val?Ser?Ala?Tyr?Val?Phe

1???????????????5??????????????????10

<210>139

<211>13

<212>PRT

＜213〉mankind

<400>139

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

1???????????????5??????????????????10

<210>140

<211>13

<212>PRT

＜213〉mankind

<400>140

Gln?Ser?Tyr?Asp?Arg?Gly?Tyr?Thr?Ala?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>141

<211>13

<212>PRT

＜213〉mankind

<400>141

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Lys?Val?Phe

1???????????????5??????????????????10

<210>142

<211>13

<212>PRT

＜213〉mankind

<400>142

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

1???????????????5??????????????????10

<210>143

<211>13

<212>PRT

＜213〉mankind

<400>143

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Tyr?Lys?Val?Phe

1???????????????5??????????????????10

<210>144

<211>13

<212>PRT

＜213〉mankind

<400>144

Gln?Ser?Tyr?Asp?Arg?Gly?Leu?Thr?Gly?Tyr?Arg?Leu?Phe

1???????????????5??????????????????10

<210>145

<211>13

<212>PRT

＜213〉mankind

<400>145

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Asp?Tyr?Lys?Val?Phe

1???????????????5??????????????????10

<210>146

<211>13

<212>PRT

＜213〉mankind

<400>146

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Pro?Arg?Leu?Phe

1???????????????5??????????????????10

<210>147

<211>13

<212>PRT

＜213〉mankind

<400>147

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

1???????????????5??????????????????10

<210>148

<211>13

<212>PRT

＜213〉mankind

<400>148

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ala?Arg?Val?Trp

1???????????????5??????????????????10

<210>149

<211>13

<212>PRT

＜213〉mankind

<400>149

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Tyr?Arg?Val?Phe

1???????????????5??????????????????10

<210>150

<211>13

<212>PRT

＜213〉mankind

<400>150

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Pro?Arg?Val?Phe

1???????????????5??????????????????10

<210>151

<211>13

<212>PRT

＜213〉mankind

<400>151

Gln?Ser?Tyr?Asp?Arg?Gly?Met?Thr?Ser?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>152

<211>13

<212>PRT

＜213〉mankind

<400>152

Gln?Ser?Tyr?Asp?Arg?Asp?Ser?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>153

<211>13

<212>PRT

＜213〉mankind

<400>153

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Arg?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>154

<211>13

<212>PRT

＜213〉mankind

<400>154

His?Ser?Tyr?Asp?Ser?Asp?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>155

<211>13

<212>PRT

＜213〉mankind

<400>155

His?Ser?Ser?Glu?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>156

<211>13

<212>PRT

＜213〉mankind

<400>156

His?Ser?Tyr?Asp?Asn?Arg?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>157

<211>13

<212>PRT

＜213〉mankind

<400>157

His?Ser?Tyr?Asp?Ser?Arg?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>158

<211>13

<212>PRT

＜213〉mankind

<400>158

Gln?Ser?Tyr?Asp?Ser?Glu?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>159

<211>13

<212>PRT

＜213〉mankind

<400>159

Gln?Ser?Tyr?Asp?Thr?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>160

<211>13

<212>PRT

＜213〉mankind

<400>160

His?Ser?Tyr?Asp?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>161

<211>13

<212>PRT

＜213〉mankind

<400>161

Gln?Ser?Tyr?Asp?Thr?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>162

<211>13

<212>PRT

＜213〉mankind

<400>162

His?Ser?Tyr?Asp?Thr?Lys?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>163

<211>13

<212>PRT

＜213〉mankind

<400>163

His?Ser?Ser?Asp?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>164

<211>13

<212>PRT

＜213〉mankind

<400>164

Gln?Ser?Tyr?Asp?Ser?Asp?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>165

<211>13

<212>PRT

＜213〉mankind

<400>165

His?Ser?Tyr?Glu?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>166

<211>13

<212>PRT

＜213〉mankind

<400>166

Gln?Ser?Tyr?Asp?Ala?Pro?Trp?Ser?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>167

<211>13

<212>PRT

＜213〉mankind

<400>167

Gln?Ser?Tyr?Asp?Ser?Asp?Phe?Thr?Gly?Ser?Lys?Val?Phe

1???????????????5??????????????????10

<210>168

<211>13

<212>PRT

＜213〉mankind

<400>168

His?Thr?Asn?Asp?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>169

<211>13

<212>PRT

＜213〉mankind

<400>169

His?Ser?Tyr?Asp?Thr?Arg?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>170

<211>13

<212>PRT

＜213〉mankind

<400>170

Gln?Ser?Tyr?Asp?Met?Arg?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>171

<211>13

<212>PRT

＜213〉mankind

<400>171

His?Ser?Ser?Asp?Ser?Asp?Ser?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>172

<211>13

<212>PRT

＜213〉mankind

<400>172

Gln?Ser?Tyr?Asn?Thr?Asp?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>173

<211>13

<212>PRT

＜213〉mankind

<400>173

Gln?Ser?Tyr?Asp?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>174

<211>13

<212>PRT

＜213〉mankind

<400>174

His?Ser?Tyr?Asp?Met?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>175

<211>13

<212>PRT

＜213〉mankind

<400>175

His?Ser?Tyr?Asp?Asn?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>176

<211>13

<212>PRT

＜213〉mankind

<400>176

His?Ser?His?Asp?Arg?Asp?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>177

<211>12

<212>PRT

＜213〉mankind

<400>177

Gln?Ser?Tyr?Asp?Ser?Ser?Leu?Arg?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>178

<211>13

<212>PRT

＜213〉mankind

<400>178

Gln?Ser?Tyr?Asp?Arg?Gly?Ile?His?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>179

<211>13

<212>PRT

＜213〉mankind

<400>179

Gln?Ser?Tyr?Asp?Ser?Gly?Phe?Pro?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>180

<211>13

<212>PRT

＜213〉mankind

<400>180

Gln?Ser?Tyr?Asp?Ile?Gly?Ser?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>181

<211>13

<212>PRT

＜213〉mankind

<400>181

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

1???????????????5??????????????????10

<210>182

<211>13

<212>PRT

＜213〉mankind

<400>182

Gln?Ser?Tyr?Asp?Ile?Gly?Met?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>183

<211>13

<212>PRT

＜213〉mankind

<400>183

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

1???????????????5??????????????????10

<210>184

<211>13

<212>PRT

＜213〉mankind

<400>184

Gln?Ser?Tyr?Asp?Ser?Gly?Val?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>185

<211>13

<212>PRT

＜213〉mankind

<400>185

Gln?Ser?Tyr?Asp?Arg?Gly?Leu?Thr?Ala?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>186

<211>13

<212>PRT

＜213〉mankind

<400>186

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

1???????????????5??????????????????10

<210>187

<211>13

<212>PRT

＜213〉mankind

<400>187

Gln?Ser?Tyr?Asp?Thr?Ala?Leu?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>188

<211>13

<212>PRT

＜213〉mankind

<400>188

Gln?Ser?Tyr?Asp?Ile?Arg?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>189

<211>13

<212>PRT

＜213〉mankind

<400>189

Gln?Ser?Tyr?Asp?Ile?Arg?Ser?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>190

<211>13

<212>PRT

＜213〉mankind

<400>190

Gln?Ser?Tyr?Asp?Asn?Arg?Leu?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>191

<211>13

<212>PRT

＜213〉mankind

<400>191

Gln?Ser?Tyr?Glu?Thr?Ser?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>192

<211>13

<212>PRT

＜213〉mankind

<400>192

Gln?Ser?Tyr?Asp?Ser?Ser?Ser?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>193

<211>13

<212>PRT

＜213〉mankind

<400>193

Gln?Ser?Tyr?Asp?Ser?Gly?Phe?Thr?Ala?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>194

<211>13

<212>PRT

＜213〉mankind

<400>194

Gln?Thr?Tyr?Asp?Lys?Gly?Phe?Thr?Gly?Ser?Ser?Val?Phe

1???????????????5??????????????????10

<210>195

<211>13

<212>PRT

＜213〉mankind

<400>195

Gln?Ser?Tyr?Asp?Asn?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>196

<211>13

<212>PRT

＜213〉mankind

<400>196

Gln?Ser?Tyr?Asp?Thr?Gly?Phe?Thr?Lys?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>197

<211>13

<212>PRT

＜213〉mankind

<400>197

Gln?Ser?Tyr?Asp?Ser?Asp?Val?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>198

<211>13

<212>PRT

＜213〉mankind

<400>198

Gln?Ser?Tyr?Asp?Ala?Gly?Phe?Thr?Gly?Ser?Arg?Val?Phe

1???????????????5??????????????????10

<210>199

<211>12

<212>PRT

＜213〉mankind

<400>199

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ser?Met?Leu

1???????????????5??????????????????10

<210>200

<211>12

<212>PRT

＜213〉mankind

<400>200

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Thr?Pro?Arg?Pro?Met

1???????????????5??????????????????10

<210>201

<211>12

<212>PRT

＜213〉mankind

<400>201

Gln?Ser?Tyr?Asp?Arg?Gly?Arg?Asn?Pro?Ala?Leu?Thr

1???????????????5??????????????????10

<210>202

<211>12

<212>PRT

＜213〉mankind

<400>202

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Trp?Leu?His

1???????????????5??????????????????10

<210>203

<211>12

<212>PRT

＜213〉mankind

<400>203

Gln?Ser?Tyr?Asp?Arg?Gly?Asn?Ser?Pro?Ala?Thr?Val

1???????????????5??????????????????10

<210>204

<211>12

<212>PRT

＜213〉mankind

<400>204

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Phe?Pro?Ser?Pro?Gln

1???????????????5??????????????????10

<210>205

<211>12

<212>PRT

＜213〉mankind

<400>205

Gln?Ser?Tyr?Asp?Arg?Gly?Leu?Asn?Pro?Ser?Ala?Thr

1???????????????5??????????????????10

<210>206

<211>12

<212>PRT

＜213〉mankind

<400>206

Gln?Ser?Tyr?Asp?Arg?Gly?Lys?Ser?Asn?Lys?Met?Leu

1???????????????5??????????????????10

<210>207

<211>12

<212>PRT

＜213〉mankind

<400>207

Gln?Ser?Tyr?Asp?Arg?Gly?His?Thr?Ala?His?Leu?Tyr

1???????????????5??????????????????10

<210>208

<211>12

<212>PRT

＜213〉mankind

<400>208

Gln?Ser?Tyr?Asp?Arg?Gly?Gln?Thr?Pro?Ser?Ile?Thr

1???????????????5??????????????????10

<210>209

<211>12

<212>PRT

＜213〉mankind

<400>209

Gln?Ser?Tyr?Asp?Arg?Gly?Tyr?Pro?Arg?Asn?Ile?Leu

1???????????????5??????????????????10

<210>210

<211>12

<212>PRT

＜213〉mankind

<400>210

Gln?Ser?Tyr?Asp?Arg?Gly?Ile?Thr?Pro?Gly?Leu?Ala

1???????????????5??????????????????10

<210>211

<211>12

<212>PRT

＜213〉mankind

<400>211

Gln?Ser?Tyr?Asp?Arg?Gly?Gln?Pro?His?Ala?Val?Leu

1???????????????5??????????????????10

<210>212

<211>12

<212>PRT

＜213〉mankind

<400>212

Gln?Ser?Tyr?Asp?Arg?Gly?Asn?Ser?Pro?Ile?Pro?Thr

1???????????????5??????????????????10

<210>213

<211>12

<212>PRT

＜213〉mankind

<400>213

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Pro?Asn?Asn?Ser?Phe

1???????????????5??????????????????10

<210>214

<211>12

<212>PRT

＜213〉mankind

<400>214

Gln?Ser?Tyr?Asp?Ser?Gly?Val?Asp?Pro?Gly?Pro?Tyr

1???????????????5??????????????????10

<210>215

<211>12

<212>PRT

＜213〉mankind

<400>215

Gln?Ser?Tyr?Asp?Arg?Gly?Arg?Pro?Arg?His?Ala?Leu

1???????????????5??????????????????10

<210>216

<211>12

<212>PRT

＜213〉mankind

<400>216

Gln?Ser?Tyr?Asp?Arg?Gly?Pro?Tyr?His?Pro?Ile?Arg

1???????????????5??????????????????10

<210>217

<211>12

<212>PRT

＜213〉mankind

<400>217

Gln?Ser?Tyr?Asp?Arg?Gly?Pro?His?Thr?Gln?Pro?Thr

1???????????????5??????????????????10

<210>218

<211>12

<212>PRT

＜213〉mankind

<400>218

Gln?Ser?Tyr?Asp?Arg?Gly?His?Asn?Asn?Phe?Ser?Pro

1???????????????5??????????????????10

<210>219

<211>12

<212>PRT

＜213〉mankind

<400>219

Gln?Ser?Tyr?Asp?Arg?Gly?Pro?Thr?His?Leu?Pro?His

1???????????????5??????????????????10

<210>220

<211>12

<212>PRT

＜213〉mankind

<400>220

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Pro?Ser?Tyr?Pro?Thr

1???????????????5??????????????????10

<210>221

<211>12

<212>PRT

＜213〉mankind

<400>221

Gln?Ser?Tyr?Asp?Ser?Gly?Thr?Ser?Asn?Leu?Leu?Pro

1???????????????5??????????????????10

<210>222

<211>12

<212>PRT

＜213〉mankind

<400>222

Gln?Ser?Tyr?Asp?Arg?Gly?Asp?Ser?Asn?His?Asp?Leu

1???????????????5??????????????????10

<210>223

<211>12

<212>PRT

＜213〉mankind

<400>223

Gln?Ser?Tyr?Asp?Arg?Gly?Leu?Pro?Arg?Leu?Thr?His

1???????????????5??????????????????10

<210>224

<211>12

<212>PRT

＜213〉mankind

<400>224

Gln?Ser?Tyr?Asp?Arg?Gly?Ile?Pro?Thr?Ser?Tyr?Leu

1???????????????5??????????????????10

<210>225

<211>12

<212>PRT

＜213〉mankind

<400>225

Gln?Ser?Tyr?Asp?Arg?Gly?Leu?Arg?Val?Gln?Ala?Pro

1???????????????5??????????????????10

<210>226

<211>12

<212>PRT

＜213〉mankind

<400>226

Gln?Ser?Tyr?Asp?Arg?Gly?Leu?Ser?Asp?Ser?Pro?Leu

1???????????????5??????????????????10

<210>227

<211>12

<212>PRT

＜213〉mankind

<400>227

Gln?Ser?Tyr?Asp?Ser?Gly?Ser?Leu?Arg?Arg?Ile?Leu

1???????????????5??????????????????10

<210>228

<211>12

<212>PRT

＜213〉mankind

<400>228

Gln?Ser?Tyr?Asp?Arg?Gly?Pro?Ala?Arg?Thr?Ser?Pro

1???????????????5??????????????????10

<210>229

<211>12

<212>PRT

＜213〉mankind

<400>229

Gln?Ser?Tyr?Asp?Arg?Gly?Arg?Ala?Ala?His?Pro?Gln

1???????????????5??????????????????10

<210>230

<211>12

<212>PRT

＜213〉mankind

<400>230

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Gln?Pro?Ala?Asx?Ile

1???????????????5??????????????????10

<210>231

<211>12

<212>PRT

＜213〉mankind

<400>231

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Thr?Met?Ile

1???????????????5??????????????????10

<210>232

<211>12

<212>PRT

＜213〉mankind

<400>232

Gln?Ser?Tyr?Asp?Arg?Gly?Arg?Ile?Pro?Ala?Asx?Thr

1???????????????5??????????????????10

<210>233

<211>12

<212>PRT

＜213〉mankind

<400>233

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Val?Pro?Ala

1???????????????5??????????????????10

<210>234

<211>12

<212>PRT

＜213〉mankind

<400>234

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?Asx?Pro?Ile?Pro?Ala

1???????????????5??????????????????10

<210>235

<211>12

<212>PRT

＜213〉mankind

<400>235

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Val?Pro?Ala

1???????????????5??????????????????10

<210>236

<211>12

<212>PRT

＜213〉mankind

<400>236

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Thr?Met?Tyr

1???????????????5??????????????????10

<210>237

<211>12

<212>PRT

＜213〉mankind

<400>237

Gln?Ser?Tyr?Asp?Arg?Gly?His?His?Tyr?Thr?Thr?Phe

1???????????????5??????????????????10

<210>238

<211>12

<212>PRT

＜213〉mankind

<400>238

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?His?Pro?Ala?Ala?Glu

1???????????????5??????????????????10

<210>239

<211>12

<212>PRT

＜213〉mankind

<400>239

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Ile?Pro?Ser?Ile?Glu

1???????????????5??????????????????10

<210>240

<211>12

<212>PRT

＜213〉mankind

<400>240

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?Ser?Pro?Ala?Ile?Met

1???????????????5??????????????????10

<210>241

<211>12

<212>PRT

＜213〉mankind

<400>241

Gln?Ser?Tyr?Asp?Arg?Gly?Ile?Trp?Pro?Asn?Leu?Asn

1???????????????5??????????????????10

<210>242

<211>12

<212>PRT

＜213〉mankind

<400>242

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Asn?Leu?Asn

1???????????????5??????????????????10

<210>243

<211>12

<212>PRT

＜213〉mankind

<400>243

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ser?Ile?Ser

1???????????????5??????????????????10

<210>244

<211>12

<212>PRT

＜213〉mankind

<400>244

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?Ala?Pro?Met?Ile?Asn

1???????????????5??????????????????10

<210>245

<211>12

<212>PRT

＜213〉mankind

<400>245

Gln?Ser?Tyr?Asp?Arg?Gly?His?His?Pro?Ala?Met?Ser

1???????????????5??????????????????10

<210>246

<211>12

<212>PRT

＜213〉mankind

<400>246

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ser?Ile?Thr

1???????????????5??????????????????10

<210>247

<211>12

<212>PRT

＜213〉mankind

<400>247

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Asp?Pro?Ala?Ile?Val

1???????????????5??????????????????10

<210>248

<211>12

<212>PRT

＜213〉mankind

<400>248

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>249

<211>12

<212>PRT

＜213〉mankind

<400>249

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?His?Pro?Ala?Leu?Thr

1???????????????5??????????????????10

<210>250

<211>12

<212>PRT

＜213〉mankind

<400>250

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Thr?Pro?Ala?Pro?Glu

1???????????????5??????????????????10

<210>251

<211>12

<212>PRT

＜213〉mankind

<400>251

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?His?Pro?Thr?Leu?Ile

1???????????????5??????????????????10

<210>252

<211>12

<212>PRT

＜213〉mankind

<400>252

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ser?Met?Leu

1???????????????5??????????????????10

<210>253

<211>12

<212>PRT

＜213〉mankind

<400>253

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Thr?Pro?Arg?Pro?Met

1???????????????5??????????????????10

<210>254

<211>12

<212>PRT

＜213〉mankind

<400>254

Gln?Ser?Tyr?Asp?Arg?Gly?Arg?Leu?Pro?Ala?Gln?Thr

1???????????????5??????????????????10

<210>255

<211>12

<212>PRT

＜213〉mankind

<400>255

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Leu?Thr?Ile

1???????????????5??????????????????10

<210>256

<211>12

<212>PRT

＜213〉mankind

<400>256

Gln?Ser?Tyr?Asp?Arg?Gly?Gln?Thr?Pro?Ser?Ile?Thr

1???????????????5??????????????????10

<210>257

<211>12

<212>PRT

＜213〉mankind

<400>257

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Phe?Gln?Met?Tyr

1???????????????5??????????????????10

<210>258

<211>12

<212>PRT

＜213〉mankind

<400>258

Gln?Ser?Tyr?Asp?Arg?Gly?Arg?Asn?Pro?Ala?Leu?Thr

1???????????????5??????????????????10

<210>259

<211>12

<212>PRT

＜213〉mankind

<400>259

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Leu?Thr?Met

1???????????????5??????????????????10

<210>260

<211>12

<212>PRT

＜213〉mankind

<400>260

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Leu?Thr?Met

1???????????????5??????????????????10

<210>261

<211>12

<212>PRT

＜213〉mankind

<400>261

Gln?Ser?Tyr?Asp?Ser?Gly?Tyr?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>262

<211>12

<212>PRT

＜213〉mankind

<400>262

Gln?Ser?Tyr?Asp?Ser?Gly?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>263

<211>12

<212>PRT

＜213〉mankind

<400>263

Gln?Ser?Tyr?Asp?Ser?Arg?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>264

<211>12

<212>PRT

＜213〉mankind

<400>264

Gln?Ser?Tyr?Pro?Asp?Gly?Thr?Pro?Ala?Ser?Arg?Val

1???????????????5??????????????????10

<210>265

<211>12

<212>PRT

＜213〉mankind

<400>265

Gln?Ser?Tyr?Ser?Thr?His?Met?Pro?Ile?Ser?Arg?Val

1???????????????5??????????????????10

<210>266

<211>12

<212>PRT

＜213〉mankind

<400>266

Gln?Ser?Tyr?Asp?Ser?Gly?Ser?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>267

<211>12

<212>PRT

＜213〉mankind

<400>267

Gln?Ser?Tyr?Pro?Asn?Ser?Tyr?Pro?Ile?Ser?Arg?Val

1???????????????5??????????????????10

<210>268

<211>10

<212>PRT

＜213〉mankind

<400>268

Gln?Ser?Tyr?Ile?Arg?Ala?Pro?Gln?Gln?Val

1???????????????5??????????????????10

<210>269

<211>12

<212>PRT

＜213〉mankind

<400>269

Gln?Ser?Tyr?Leu?Lys?Ser?Arg?Ala?Phe?Ser?Arg?Val

1???????????????5??????????????????10

<210>270

<211>12

<212>PRT

＜213〉mankind

<400>270

Gln?Ser?Tyr?Asp?Ser?Arg?Phe?Thr?Gly?Ser?Arg?Val

1???????????????5??????????????????10

<210>271

<211>12

<212>PRT

＜213〉mankind

<400>271

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>272

<211>12

<212>PRT

＜213〉mankind

<400>272

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>273

<211>12

<212>PRT

＜213〉mankind

<400>273

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Phe?Asp?Gly

1???????????????5??????????????????10

<210>274

<211>12

<212>PRT

＜213〉mankind

<400>274

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Ala?Pro?Ala?Leu?Ser

1???????????????5??????????????????10

<210>275

<211>12

<212>PRT

＜213〉mankind

<400>275

Gln?Ser?Tyr?Asp?Arg?Gly?Ser?Tyr?Pro?Ala?Leu?Arg

1???????????????5??????????????????10

<210>276

<211>12

<212>PRT

＜213〉mankind

<400>276

Gln?Ser?Tyr?Asp?Arg?Gly?Asn?Trp?Pro?Asn?Ser?Asn

1???????????????5??????????????????10

<210>277

<211>12

<212>PRT

＜213〉mankind

<400>277

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Ala?Pro?Ser?Leu?Leu

1???????????????5??????????????????10

<210>278

<211>12

<212>PRT

＜213〉mankind

<400>278

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>279

<211>12

<212>PRT

＜213〉mankind

<400>279

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?Thr?Pro?Arg?Ile?Arg

1???????????????5??????????????????10

<210>280

<211>12

<212>PRT

＜213〉mankind

<400>280

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>281

<211>12

<212>PRT

＜213〉mankind

<400>281

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>282

<211>12

<212>PRT

＜213〉mankind

<400>282

Gln?Ser?Tyr?Asp?Arg?Gly?Met?Ile?Pro?Ala?Leu?Thr

1???????????????5??????????????????10

<210>283

<211>12

<212>PRT

＜213〉mankind

<400>283

Gln?Ser?Tyr?Asp?Arg?Asn?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>284

<211>12

<212>PRT

＜213〉mankind

<400>284

Gln?Ser?Tyr?Asp?Arg?Phe?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>285

<211>12

<212>PRT

＜213〉mankind

<400>285

Gln?Ser?Tyr?Asp?Arg?Tyr?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>286

<211>12

<212>PRT

＜213〉mankind

<400>286

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>287

<211>12

<212>PRT

＜213〉mankind

<400>287

Gln?Ser?Tyr?Asp?Arg?Tyr?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>288

<211>9

<212>PRT

＜213〉mankind

<400>288

Phe?Thr?Phe?Glu?Ser?Tyr?Gly?Met?His

1???????????????5

<210>289

<211>9

<212>PRT

＜213〉mankind

<400>289

Phe?Thr?Phe?Ser?Ser?Tyr?Gly?Met?His

1???????????????5

<210>290

<211>9

<212>PRT

＜213〉mankind

<400>290

Phe?Thr?Phe?Tyr?Ser?Tyr?Gly?Met?His

1???????????????5

<210>291

<211>9

<212>PRT

＜213〉mankind

<400>291

Phe?Thr?Phe?His?Ser?Tyr?Gly?Met?His

1???????????????5

<210>292

<211>9

<212>PRT

＜213〉mankind

<400>292

Phe?Thr?Phe?Lys?Ser?Tyr?Gly?Met?His

1???????????????5

<210>293

<211>9

<212>PRT

＜213〉mankind

<400>293

Phe?Thr?Phe?Arg?Ser?Tyr?Gly?Met?His

1???????????????5

<210>294

<211>9

<212>PRT

＜213〉mankind

<400>294

Phe?Thr?Phe?Asn?Ser?Tyr?Gly?Met?His

1???????????????5

<210>295

<211>9

<212>PRT

＜213〉mankind

<400>295

Phe?Thr?Phe?Thr?Ser?Tyr?Gly?Met?His

1???????????????5

<210>296

<211>9

<212>PRT

＜213〉mankind

<400>296

Phe?Thr?Phe?Gly?Ser?Tyr?Gly?Met?His

1???????????????5

<210>297

<211>9

<212>PRT

＜213〉mankind

<400>297

Phe?Thr?Phe?Val?Ser?Tyr?Gly?Met?His

1???????????????5

<210>298

<211>9

<212>PRT

＜213〉mankind

<400>298

Phe?Thr?Phe?Ile?Ser?Tyr?Gly?Met?His

1???????????????5

<210>299

<211>9

<212>PRT

＜213〉mankind

<400>299

Phe?Thr?Phe?Trp?Ser?Tyr?Gly?Met?His

1???????????????5

<210>300

<211>9

<212>PRT

＜213〉mankind

<400>300

Phe?Thr?Phe?Ser?Glu?Tyr?Gly?Met?His

1???????????????5

<210>301

<211>9

<212>PRT

＜213〉mankind

<400>301

Phe?Thr?Phe?Ser?Cys?Tyr?Gly?Met?His

1???????????????5

<210>302

<211>9

<212>PRT

＜213〉mankind

<400>302

Phe?Thr?Phe?Ser?Ser?Tyr?Gly?Met?His

1???????????????5

<210>303

<211>9

<212>PRT

＜213〉mankind

<400>303

Phe?Thr?Phe?Ser?Tyr?Tyr?Gly?Met?His

1???????????????5

<210>304

<211>9

<212>PRT

＜213〉mankind

<400>304

Phe?Thr?Phe?Ser?His?Tyr?Gly?Met?His

1???????????????5

<210>305

<211>9

<212>PRT

＜213〉mankind

<400>305

Phe?Thr?Phe?Ser?Arg?Tyr?Gly?Met?His

1???????????????5

<210>306

<211>9

<212>PRT

＜213〉mankind

<400>306

Phe?Thr?Phe?Ser?Asn?Tyr?Gly?Met?His

1???????????????5

<210>307

<211>9

<212>PRT

＜213〉mankind

<400>307

Phe?Thr?Phe?Ser?Gln?Tyr?Gly?Met?His

1???????????????5

<210>308

<211>9

<212>PRT

＜213〉mankind

<400>308

Phe?Thr?Phe?Ser?Thr?Tyr?Gly?Met?His

1???????????????5

<210>309

<211>9

<212>PRT

＜213〉mankind

<400>309

Phe?Thr?Phe?Ser?Ala?Tyr?Gly?Met?His

1???????????????5

<210>310

<211>9

<212>PRT

＜213〉mankind

<400>310

Phe?Thr?Phe?Ser?Ile?Tyr?Gly?Met?His

1???????????????5

<210>311

<211>9

<212>PRT

＜213〉mankind

<400>311

Phe?Thr?Phe?Ser?Ser?Glu?Gly?Met?His

1???????????????5

<210>312

<211>9

<212>PRT

＜213〉mankind

<400>312

Phe?Thr?Phe?Ser?Ser?Cys?Gly?Met?His

1???????????????5

<210>313

<211>9

<212>PRT

＜213〉mankind

<400>313

Phe?Thr?Phe?Ser?Ser?Ser?Gly?Met?His

1???????????????5

<210>314

<211>9

<212>PRT

＜213〉mankind

<400>314

Phe?Thr?Phe?Ser?Ser?Tyr?Gly?Met?His

1???????????????5

<210>315

<211>9

<212>PRT

＜213〉mankind

<400>315

Phe?Thr?Phe?Ser?Ser?His?Gly?Met?His

1???????????????5

<210>316

<211>9

<212>PRT

＜213〉mankind

<400>316

Phe?Thr?Phe?Ser?Ser?Arg?Gly?Met?His

1???????????????5

<210>317

<211>9

<212>PRT

＜213〉mankind

<400>317

Phe?Thr?Phe?Ser?Ser?Asn?Gly?Met?His

1???????????????5

<210>318

<211>9

<212>PRT

＜213〉mankind

<400>318

Phe?Thr?Phe?Ser?Ser?Thr?Gly?Met?His

1???????????????5

<210>319

<211>9

<212>PRT

＜213〉mankind

<400>319

Phe?Thr?Phe?Ser?Ser?Ala?Gly?Met?His

1???????????????5

<210>320

<211>9

<212>PRT

＜213〉mankind

<400>320

Phe?Thr?Phe?Ser?Ser?Val?Gly?Met?His

1???????????????5

<210>321

<211>9

<212>PRT

＜213〉mankind

<400>321

Phe?Thr?Phe?Ser?Ser?Leu?Gly?Met?His

1???????????????5

<210>322

<211>9

<212>PRT

＜213〉mankind

<400>322

Phe?Thr?Phe?Ser?Ser?Ile?Gly?Met?His

1???????????????5

<210>323

<211>9

<212>PRT

＜213〉mankind

<400>323

Phe?Thr?Phe?Ser?Ser?Tyr?Asp?Met?His

1???????????????5

<210>324

<211>9

<212>PRT

＜213〉mankind

<400>324

Phe?Thr?Phe?Ser?Ser?Tyr?Glu?Met?His

1???????????????5

<210>325

<211>9

<212>PRT

＜213〉mankind

<400>325

Phe?Thr?Phe?Ser?Ser?Tyr?Cys?Met?His

1???????????????5

<210>326

<211>9

<212>PRT

＜213〉mankind

<400>326

Phe?Thr?Phe?Ser?Ser?Tyr?Ser?Met?His

1???????????????5

<210>327

<211>9

<212>PRT

＜213〉mankind

<400>327

Phe?Thr?Phe?Ser?Ser?Tyr?Tyr?Met?His

1???????????????5

<210>328

<211>9

<212>PRT

＜213〉mankind

<400>328

Phe?Thr?Phe?Ser?Ser?Tyr?Asn?Met?His

1???????????????5

<210>329

<211>9

<212>PRT

＜213〉mankind

<400>329

Phe?Thr?Phe?Ser?Ser?Tyr?Gly?Met?His

1???????????????5

<210>330

<211>9

<212>PRT

＜213〉mankind

<400>330

Phe?Thr?Phe?Ser?Ser?Tyr?Ala?Met?His

1???????????????5

<210>331

<211>9

<212>PRT

＜213〉mankind

<400>331

Phe?Thr?Phe?Ser?Ser?Tyr?Val?Met?His

1???????????????5

<210>332

<211>9

<212>PRT

＜213〉mankind

<400>332

Phe?Thr?Phe?Ser?Ser?Tyr?Met?Met?His

1???????????????5

<210>333

<211>9

<212>PRT

＜213〉mankind

<400>333

Phe?Thr?Phe?Ser?Ser?Tyr?Ile?Met?His

1???????????????5

<210>334

<211>9

<212>PRT

＜213〉mankind

<400>334

Phe?Thr?Phe?Ser?Ser?Tyr?Pro?Met?His

1???????????????5

<210>335

<211>17

<212>PRT

＜213〉mankind

<400>335

Glu?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>336

<211>17

<212>PRT

＜213〉mankind

<400>336

Cys?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>337

<211>17

<212>PRT

＜213〉mankind

<400>337

Tyr?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>338

<211>17

<212>PRT

＜213〉mankind

<400>338

His?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>339

<211>17

<212>PRT

＜213〉mankind

<400>339

Lys?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>340

<211>17

<212>PRT

＜213〉mankind

<400>340

Asn?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>341

<211>17

<212>PRT

＜213〉mankind

<400>341

Gln?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>342

<211>17

<212>PRT

＜213〉mankind

<400>342

Thr?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>343

<211>17

<212>PRT

＜213〉mankind

<400>343

Leu?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>344

<211>17

<212>PRT

＜213〉mankind

<400>344

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>345

<211>17

<212>PRT

＜213〉mankind

<400>345

Phe?Ile?Glu?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>346

<211>17

<212>PRT

＜213〉mankind

<400>346

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

1???????????????5??????????????????10??????????????????15

Gly

<210>347

<211>17

<212>PRT

＜213〉mankind

<400>347

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

1???????????????5??????????????????10??????????????????15

Gly

<210>348

<211>17

<212>PRT

＜213〉mankind

<400>348

Phe?Ile?His?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>349

<211>17

<212>PRT

＜213〉mankind

<400>349

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

1???????????????5??????????????????10??????????????????15

Gly

<210>350

<211>17

<212>PRT

＜213〉mankind

<400>350

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>351

<211>17

<212>PRT

＜213〉mankind

<400>351

Phe?Ile?Gln?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>352

<211>17

<212>PRT

＜213〉mankind

<400>352

Phe?Ile?Thr?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>353

<211>17

<212>PRT

＜213〉mankind

<400>353

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

1???????????????5??????????????????10??????????????????15

Gly

<210>354

<211>17

<212>PRT

＜213〉mankind

<400>354

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

1???????????????5??????????????????10??????????????????15

Gly

<210>355

<211>17

<212>PRT

＜213〉mankind

<400>355

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

1???????????????5??????????????????10??????????????????15

Gly

<210>356

<211>17

<212>PRT

＜213〉mankind

<400>356

Phe?Ile?Leu?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>357

<211>17

<212>PRT

＜213〉mankind

<400>357

Phe?Ile?Trp?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>358

<211>17

<212>PRT

＜213〉mankind

<400>358

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>359

<211>17

<212>PRT

＜213〉mankind

<400>359

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

1???????????????5??????????????????10??????????????????15

Gly

<210>360

<211>17

<212>PRT

＜213〉mankind

<400>360

Phe?Ile?Arg?Tyr?Ser?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>361

<211>17

<212>PRT

＜213〉mankind

<400>361

Phe?Ile?Arg?Tyr?Tyr?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>362

<211>17

<212>PRT

＜213〉mankind

<400>362

Phe?Ile?Arg?Tyr?Lys?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>363

<211>17

<212>PRT

＜213〉mankind

<400>363

Phe?Ile?Arg?Tyr?Arg?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>364

<211>17

<212>PRT

＜213〉mankind

<400>364

Phe?Ile?Arg?Tyr?Asn?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>365

<211>17

<212>PRT

＜213〉mankind

<400>365

Phe?Ile?Arg?Tyr?Gln?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>366

<211>17

<212>PRT

＜213〉mankind

<400>366

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

1???????????????5??????????????????10??????????????????15

Gly

<210>367

<211>17

<212>PRT

＜213〉mankind

<400>367

Phe?Ile?Arg?Tyr?Ala?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>368

<211>17

<212>PRT

＜213〉mankind

<400>368

Phe?Ile?Arg?Tyr?Val?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>369

<211>17

<212>PRT

＜213〉mankind

<400>369

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

1???????????????5??????????????????10??????????????????15

Gly

<210>370

<211>17

<212>PRT

＜213〉mankind

<400>370

Phe?Ile?Arg?Tyr?Ile?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>371

<211>17

<212>PRT

＜213〉mankind

<400>371

Phe?Ile?Arg?Tyr?Phe?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>372

<211>17

<212>PRT

＜213〉mankind

<400>372

Phe?Ile?Arg?Tyr?Asp?Asp?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>373

<211>17

<212>PRT

＜213〉mankind

<400>373

Phe?Ile?Arg?Tyr?Asp?Glu?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>374

<211>17

<212>PRT

＜213〉mankind

<400>374

Phe?Ile?Arg?Tyr?Asp?Ser?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>375

<211>17

<212>PRT

＜213〉mankind

<400>375

Phe?Ile?Arg?Tyr?Asp?Tyr?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>376

<211>17

<212>PRT

＜213〉mankind

<400>376

Phe?Ile?Arg?Tyr?Asp?Lys?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>377

<211>17

<212>PRT

＜213〉mankind

<400>377

Phe?Ile?Arg?Tyr?Asp?Arg?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>378

<211>17

<212>PRT

＜213〉mankind

<400>378

Phe?Ile?Arg?Tyr?Asp?Asn?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>379

<211>17

<212>PRT

＜213〉mankind

<400>379

Phe?Ile?Arg?Tyr?Asp?Gln?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>380

<211>17

<212>PRT

＜213〉mankind

<400>380

Phe?Ile?Arg?Tyr?Asp?Thr?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>381

<211>17

<212>PRT

＜213〉mankind

<400>381

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>382

<211>17

<212>PRT

＜213〉mankind

<400>382

Phe?Ile?Arg?Tyr?Asp?Val?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>383

<211>17

<212>PRT

＜213〉mankind

<400>383

Phe?Ile?Arg?Tyr?Asp?Phe?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>384

<211>17

<212>PRT

＜213〉mankind

<400>384

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Ser?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>385

<211>17

<212>PRT

＜213〉mankind

<400>385

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Tyr?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>386

<211>17

<212>PRT

＜213〉mankind

<400>386

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?His?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>387

<211>17

<212>PRT

＜213〉mankind

<400>387

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>388

<211>17

<212>PRT

＜213〉mankind

<400>388

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Thr?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>389

<211>17

<212>PRT

＜213〉mankind

<400>389

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Gly?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>390

<211>17

<212>PRT

＜213〉mankind

<400>390

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Met?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>391

<211>17

<212>PRT

＜213〉mankind

<400>391

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Leu?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>392

<211>17

<212>PRT

＜213〉mankind

<400>392

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Ile?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>393

<211>17

<212>PRT

＜213〉mankind

<400>393

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Pro?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>394

<211>17

<212>PRT

＜213〉mankind

<400>394

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Phe?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>395

<211>17

<212>PRT

＜213〉mankind

<400>395

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

1???????????????5??????????????????10??????????????????15

Gly

<210>396

<211>17

<212>PRT

＜213〉mankind

<400>396

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Ser?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>397

<211>17

<212>PRT

＜213〉mankind

<400>397

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>398

<211>17

<212>PRT

＜213〉mankind

<400>398

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Asn?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>399

<211>17

<212>PRT

＜213〉mankind

<400>399

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Val?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>400

<211>17

<212>PRT

＜213〉mankind

<400>400

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

1???????????????5??????????????????10??????????????????15

Gly

<210>401

<211>17

<212>PRT

＜213〉mankind

<400>401

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Ile?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>402

<211>17

<212>PRT

＜213〉mankind

<400>402

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Pro?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>403

<211>17

<212>PRT

＜213〉mankind

<400>403

Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Phe?Tyr?Ala?Asp?Ser?Val?Lys

1???????????????5??????????????????10??????????????????15

Gly

<210>404

<211>6

<212>PRT

＜213〉mankind

<400>404

Glu?Gly?Ser?His?Asp?Asn

1???????????????5

<210>405

<211>6

<212>PRT

＜213〉mankind

<400>405

Ser?Gly?Ser?His?Asp?Asn

1???????????????5

<210>406

<211>6

<212>PRT

＜213〉mankind

<400>406

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>407

<211>6

<212>PRT

＜213〉mankind

<400>407

Lys?Gly?Ser?His?Asp?Asn

1???????????????5

<210>408

<211>6

<212>PRT

＜213〉mankind

<400>408

Gln?Gly?Ser?His?Asp?Asn

1???????????????5

<210>409

<211>6

<212>PRT

＜213〉mankind

<400>409

Thr?Gly?Ser?His?Asp?Asn

15

<210>410

<211>6

<212>PRT

＜213〉mankind

<400>410

Ala?Gly?Ser?His?Asp?Asn

15

<210>411

<211>6

<212>PRT

＜213〉mankind

<400>411

Leu?Gly?Ser?His?Asp?Asn

15

<210>412

<211>6

<212>PRT

＜213〉mankind

<400>412

Pro??Gly?Ser?His?Asp?Asn

15

<210>413

<211>6

<212>PRT

＜213〉mankind

<400>413

Phe?Gly?Ser?His?Asp?Asn

15

<210>414

<211>6

<212>PRT

＜213〉mankind

<400>414

His?Asp?Ser?His?Asp?Asn

15

<210>415

<211>6

<212>PRT

＜213〉mankind

<400>415

His?Cys?Ser?His?Asp?Asn

15

<210>416

<211>6

<212>PRT

＜213〉mankind

<400>416

His?His?Ser?His?Asp?Asn

15

<210>417

<211>6

<212>PRT

＜213〉mankind

<400>417

His?Arg?Ser?His?Asp?Asn

15

<210>418

<211>6

<212>PRT

＜213〉mankind

<400>418

His?Thr?Ser?His?Asp?Asn

15

<210>419

<211>6

<212>PRT

＜213〉mankind

<400>419

His?Gly?Ser?His?Asp?Asn

15

<210>420

<211>6

<212>PRT

＜213〉mankind

<400>420

His?Val?Ser?His?Asp?Asn

1???????????????5

<210>421

<211>6

<212>PRT

＜213〉mankind

<400>421

His?Met?Ser?His?Asp?Asn

1???????????????5

<210>422

<211>6

<212>PRT

＜213〉mankind

<400>422

His?Leu?Ser?His?Asp?Asn

1???????????????5

<210>423

<211>6

<212>PRT

＜213〉mankind

<400>423

His?Ile?Ser?His?Asp?Asn

1???????????????5

<210>424

<211>6

<212>PRT

＜213〉mankind

<400>424

His?Pro?Ser?His?Asp?Asn

1???????????????5

<210>425

<211>6

<212>PRT

＜213〉mankind

<400>425

His?Trp?Ser?His?Asp?Asn

1???????????????5

<210>426

<211>6

<212>PRT

＜213〉mankind

<400>426

His?Gly?Asp?His?Asp?Asn

1???????????????5

<210>427

<211>6

<212>PRT

＜213〉mankind

<400>427

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>428

<211>6

<212>PRT

＜213〉mankind

<400>428

His?Gly?Tyr?His?Asp?Asn

1???????????????5

<210>429

<211>6

<212>PRT

＜213〉mankind

<400>429

His?Gly?His?His?Asp?Asn

1???????????????5

<210>430

<211>6

<212>PRT

＜213〉mankind

<400>430

His?Gly?Arg?His?Asp?Asn

1???????????????5

<210>431

<211>6

<212>PRT

＜213〉mankind

<400>431

His?Gly?Asn?His?Asp?Asn

1???????????????5

<210>432

<211>6

<212>PRT

＜213〉mankind

<400>432

His?Gly?Thr?His?Asp?Asn

1???????????????5

<210>433

<211>6

<212>PRT

＜213〉mankind

<400>433

His?Gly?Gly?His?Asp?Asn

1???????????????5

<210>434

<211>6

<212>PRT

＜213〉mankind

<400>434

His?Gly?Ala?His?Asp?Asn

1???????????????5

<210>435

<211>6

<212>PRT

＜213〉mankind

<400>435

His?Gly?Ile?His?Asp?Asn

1???????????????5

<210>436

<211>6

<212>PRT

＜213〉mankind

<400>436

His?Gly?Pro?His?Asp?Asn

1???????????????5

<210>437

<211>6

<212>PRT

＜213〉mankind

<400>437

His?Gly?Trp?His?Asp?Asn

1???????????????5

<210>438

<211>6

<212>PRT

＜213〉mankind

<400>438

His?Gly?Phe?His?Asp?Asn

1???????????????5

<210>439

<211>6

<212>PRT

＜213〉mankind

<400>439

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>440

<211>6

<212>PRT

＜213〉mankind

<400>440

His?Gly?Ser?Arg?Asp?Asn

1???????????????5

<210>441

<211>6

<212>PRT

＜213〉mankind

<400>441

His?Gly?Ser?Thr?Asp?Asn

1???????????????5

<210>442

<211>6

<212>PRT

＜213〉mankind

<400>442

His?Gly?Ser?Ala?Asp?Asn

1???????????????5

<210>443

<211>6

<212>PRT

＜213〉mankind

<400>443

His?Gly?Ser?Val?Asp?Asn

1???????????????5

<210>444

<211>6

<212>PRT

＜213〉mankind

<400>444

His?Gly?Ser?Leu?Asp?Asn

1???????????????5

<210>445

<211>6

<212>PRT

＜213〉mankind

<400>445

His?Gly?Ser?Ile?Asp?Asn

1???????????????5

<210>446

<211>6

<212>PRT

＜213〉mankind

<400>446

His?Gly?Ser?Phe?Asp?Asn

1???????????????5

<210>447

<211>6

<212>PRT

＜213〉mankind

<400>447

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>448

<211>6

<212>PRT

＜213〉mankind

<400>448

His?Gly?Ser?His?Ser?Asn

1???????????????5

<210>449

<211>6

<212>PRT

＜213〉mankind

<400>449

His?Gly?Ser?His?Tyr?Asn

1???????????????5

<210>450

<211>6

<212>PRT

＜213〉mankind

<400>450

His?Gly?Ser?His?His?Asn

1???????????????5

<210>451

<211>6

<212>PRT

＜213〉mankind

<400>451

His?Gly?Ser?His?Arg?Asn

1???????????????5

<210>452

<211>6

<212>PRT

＜213〉mankind

<400>452

His?Gly?Ser?His?Asn?Asn

1???????????????5

<210>453

<211>6

<212>PRT

＜213〉mankind

<400>453

His?Gly?Ser?His?Gly?Asn

1???????????????5

<210>454

<211>6

<212>PRT

＜213〉mankind

<400>454

His?Gly?Ser?His?Ala?Asn

1???????????????5

<210>455

<211>6

<212>PRT

＜213〉mankind

<400>455

His?Gly?Ser?His?Val?Asn

1???????????????5

<210>456

<211>6

<212>PRT

＜213〉mankind

<400>456

His?Gly?Ser?His?Ile?Asn

1???????????????5

<210>457

<211>6

<212>PRT

＜213〉mankind

<400>457

His?Gly?Ser?His?Asp?Ser

1???????????????5

<210>458

<211>6

<212>PRT

＜213〉mankind

<400>458

His?Gly?Ser?His?Asp?His

1???????????????5

<210>459

<211>6

<212>PRT

＜213〉mankind

<400>459

His?Gly?Ser?His?Asp?Lys

1???????????????5

<210>460

<211>6

<212>PRT

＜213〉mankind

<400>460

His?Gly?Ser?His?Asp?Arg

1???????????????5

<210>461

<211>6

<212>PRT

＜213〉mankind

<400>461

His?Gly?Ser?His?Asp?Asn

1???????????????5

<210>462

<211>6

<212>PRT

＜213〉mankind

<400>462

His?Gly?Ser?His?Asp?Thr

1???????????????5

<210>463

<211>6

<212>PRT

＜213〉mankind

<400>463

His?Gly?Ser?His?Asp?Gly

1???????????????5

<210>464

<211>6

<212>PRT

＜213〉mankind

<400>464

His?Gly?Ser?His?Asp?Ala

1???????????????5

<210>465

<211>6

<212>PRT

＜213〉mankind

<400>465

His?Gly?Ser?His?Asp?Leu

1???????????????5

<210>466

<211>6

<212>PRT

＜213〉mankind

<400>466

His?Gly?Ser?His?Asp?Ile

1???????????????5

<210>467

<211>6

<212>PRT

＜213〉mankind

<400>467

His?Gly?Ser?His?Asp?Pro

1???????????????5

<210>468

<211>6

<212>PRT

＜213〉mankind

<400>468

His?Gly?Ser?His?Asp?Trp

1???????????????5

<210>469

<211>6

<212>PRT

＜213〉mankind

<400>469

His?Gly?Ser?His?Asp?Phe

1???????????????5

<210>470

<211>13

<212>PRT

＜213〉mankind

<400>470

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Asp?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>471

<211>13

<212>PRT

＜213〉mankind

<400>471

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Cys?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>472

<211>13

<212>PRT

＜213〉mankind

<400>472

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>473

<211>13

<212>PRT

＜213〉mankind

<400>473

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Tyr?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>474

<211>13

<212>PRT

＜213〉mankind

<400>474

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Lys?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>475

<211>13

<212>PRT

＜213〉mankind

<400>475

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Arg?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>476

<211>13

<212>PRT

＜213〉mankind

<400>476

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Asn?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>477

<211>13

<212>PRT

＜213〉mankind

<400>477

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Thr?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>478

<211>13

<212>PRT

＜213〉mankind

<400>478

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Pro?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>479

<211>13

<212>PRT

＜213〉mankind

<400>479

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asp?Thr?Val?Lys

1???????????????5??????????????????10

<210>480

<211>13

<212>PRT

＜213〉mankind

<400>480

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Glu?Thr?Val?Lys

1???????????????5??????????????????10

<210>481

<211>13

<212>PRT

＜213〉mankind

<400>481

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Ser?Thr?Val?Lys

1???????????????5??????????????????10

<210>482

<211>13

<212>PRT

＜213〉mankind

<400>482

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Tyr?Thr?Val?Lys

1???????????????5??????????????????10

<210>483

<211>13

<212>PRT

＜213〉mankind

<400>483

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?His?Thr?Val?Lys

1???????????????5??????????????????10

<210>484

<211>13

<212>PRT

＜213〉mankind

<400>484

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Lys?Thr?Val?Lys

1???????????????5??????????????????10

<210>485

<211>13

<212>PRT

＜213〉mankind

<400>485

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>486

<211>13

<212>PRT

＜213〉mankind

<400>486

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Gln?Thr?Val?Lys

1???????????????5??????????????????10

<210>487

<211>13

<212>PRT

＜213〉mankind

<400>487

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Thr?Thr?Val?Lys

1???????????????5??????????????????10

<210>488

<211>13

<212>PRT

＜213〉mankind

<400>488

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Gly?Thr?Val?Lys

1??????????????5??????????????????10

<210>489

<211>13

<212>PRT

＜213〉mankind

<400>489

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Met?Thr?Val?Lys

1???????????????5??????????????????10

<210>490

<211>13

<212>PRT

＜213〉mankind

<400>490

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Ile?Thr?Val?Lys

1???????????????5??????????????????10

<210>491

<211>13

<212>PRT

＜213〉mankind

<400>491

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Asp?Val?Lys

1???????????????5??????????????????10

<210>492

<211>13

<212>PRT

＜213〉mankind

<400>492

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Cys?Val?Lys

1???????????????5??????????????????10

<210>493

<211>13

<212>PRT

＜213〉mankind

<400>493

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Ser?Val?Lys

1???????????????5??????????????????10

<210>494

<211>13

<212>PRT

＜213〉mankind

<400>494

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Tyr?Val?Lys

1???????????????5??????????????????10

<210>495

<211>13

<212>PRT

＜213〉mankind

<400>495

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?His?Val?Lys

1???????????????5??????????????????10

<210>496

<211>13

<212>PRT

＜213〉mankind

<400>496

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Lys?Val?Lys

1???????????????5??????????????????10

<210>497

<211>13

<212>PRT

＜213〉mankind

<400>497

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Arg?Val?Lys

1???????????????5??????????????????10

<210>498

<211>13

<212>PRT

＜213〉mankind

<400>498

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Asn?Val?Lys

1???????????????5??????????????????10

<210>499

<211>13

<212>PRT

＜213〉mankind

<400>499

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Gln?Val?Lys

1???????????????5??????????????????10

<210>500

<211>13

<212>PRT

＜213〉mankind

<400>500

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Thr?Val?Lys

1???????????????5??????????????????10

<210>501

<211>13

<212>PRT

＜213〉mankind

<400>501

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Ala?Val?Lys

1???????????????5??????????????????10

<210>502

<211>13

<212>PRT

＜213〉mankind

<400>502

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Val?Val?Lys

1???????????????5??????????????????10

<210>503

<211>13

<212>PRT

＜213〉mankind

<400>503

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Leu?Val?Lys

1???????????????5??????????????????10

<210>504

<211>13

<212>PRT

＜213〉mankind

<400>504

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Ile?Val?Lys

1???????????????5??????????????????10

<210>505

<211>13

<212>PRT

＜213〉mankind

<400>505

Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn?Pro?Val?Lys

1???????????????5??????????????????10

<210>506

<211>7

<212>PRT

＜213〉mankind

<400>506

Asp?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>507

<211>7

<212>PRT

＜213〉mankind

<400>507

Glu?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>508

<211>7

<212>PRT

＜213〉mankind

<400>508

Cys?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>509

<211>7

<212>PRT

＜213〉mankind

<400>509

Ser?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>510

<211>7

<212>PRT

＜213〉mankind

<400>510

Tyr?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>511

<211>7

<212>PRT

＜213〉mankind

<400>511

His?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>512

<211>7

<212>PRT

＜213〉mankind

<400>512

Lys?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>513

<211>7

<212>PRT

＜213〉mankind

<400>513

Arg?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>514

<211>7

<212>PRT

＜213〉mankind

<400>514

Asn?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>515

<211>7

<212>PRT

＜213〉mankind

<400>515

Gln?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>516

<211>7

<212>PRT

＜213〉mankind

<400>516

Thr?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>517

<211>7

<212>PRT

＜213〉mankind

<400>517

Gly?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>518

<211>7

<212>PRT

＜213〉mankind

<400>518

Ala?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>519

<211>7

<212>PRT

＜213〉mankind

<400>519

Val?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>520

<211>7

<212>PRT

＜213〉mankind

<400>520

Met?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>521

<211>7

<212>PRT

＜213〉mankind

<400>521

Leu?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>522

<211>7

<212>PRT

＜213〉mankind

<400>522

Ile?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>523

<211>7

<212>PRT

＜213〉mankind

<400>523

Pro?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>524

<211>7

<212>PRT

＜213〉mankind

<400>524

Trp?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>525

<211>7

<212>PRT

＜213〉mankind

<400>525

Phe?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>526

<211>7

<212>PRT

＜213〉mankind

<400>526

Gly?Asn?Asp?Ser?Arg?Pro?Ser

1???????????????5

<210>527

<211>7

<212>PRT

＜213〉mankind

<400>527

Gly?Asn?Asp?Tyr?Arg?Pro?Ser

1???????????????5

<210>528

<211>7

<212>PRT

＜213〉mankind

<400>528

Gly?Asn?Asp?Arg?Arg?Pro?Ser

1???????????????5

<210>529

<211>7

<212>PRT

＜213〉mankind

<400>529

Gly?Asn?Asp?Gln?Arg?Pro?Ser

1???????????????5

<210>530

<211>7

<212>PRT

＜213〉mankind

<400>530

Gly?Asn?Asp?Thr?Arg?Pro?Ser

1???????????????5

<210>531

<211>7

<212>PRT

＜213〉mankind

<400>531

Gly?Asn?Asp?Ala?Arg?Pro?Ser

1???????????????5

<210>532

<211>7

<212>PRT

＜213〉mankind

<400>532

Gly?Asn?Asp?Ile?Arg?Pro?Ser

1???????????????5

<210>533

<211>7

<212>PRT

＜213〉mankind

<400>533

Gly?Asn?Asp?Pro?Arg?Pro?Ser

1???????????????5

<210>534

<211>12

<212>PRT

＜213〉mankind

<400>534

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>535

<211>12

<212>PRT

＜213〉mankind

<400>535

Gln?Ser?Tyr?Cys?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>536

<211>12

<212>PRT

＜213〉mankind

<400>536

Gln?Ser?Tyr?Ser?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>537

<211>12

<212>PRT

＜213〉mankind

<400>537

Gln?Ser?Tyr?Tyr?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>538

<211>12

<212>PRT

＜213〉mankind

<400>538

Gln?Ser?Tyr?Asn?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>539

<211>12

<212>PRT

＜213〉mankind

<400>539

Gln?Ser?Tyr?Gln?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>540

<211>12

<212>PRT

＜213〉mankind

<400>540

Gln?Ser?Tyr?Thr?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>541

<211>12

<212>PRT

＜213〉mankind

<400>541

Gln?Ser?Tyr?Gly?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>542

<211>12

<212>PRT

＜213〉mankind

<400>542

Gln?Ser?Tyr?Ala?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>543

<211>12

<212>PRT

＜213〉mankind

<400>543

Gln?Ser?Tyr?Leu?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>544

<211>12

<212>PRT

＜213〉mankind

<400>544

Gln?Ser?Tyr?Ile?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>545

<211>12

<212>PRT

＜213〉mankind

<400>545

Gln?Ser?Tyr?Trp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>546

<211>12

<212>PRT

＜213〉mankind

<400>546

Gln?Ser?Tyr?Phe?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>547

<211>12

<212>PRT

＜213〉mankind

<400>547

Gln?Ser?Tyr?Asp?Asp?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>548

<211>12

<212>PRT

＜213〉mankind

<400>548

Gln?Ser?Tyr?Asp?Cys?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>549

<211>12

<212>PRT

＜213〉mankind

<400>549

Gln?Ser?Tyr?Asp?Ser?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>550

<211>12

<212>PRT

＜213〉mankind

<400>550

Gln?Ser?Tyr?Asp?Tyr?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>551

<211>12

<212>PRT

＜213〉mankind

<400>551

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>552

<211>12

<212>PRT

＜213〉mankind

<400>552

Gln?Ser?Tyr?Asp?Asn?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>553

<211>12

<212>PRT

＜213〉mankind

<400>553

Gln?Ser?Tyr?Asp?Gln?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>554

<211>12

<212>PRT

＜213〉mankind

<400>554

Gln?Ser?Tyr?Asp?Thr?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>555

<211>12

<212>PRT

＜213〉mankind

<400>555

Gln?Ser?Tyr?Asp?Gly?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>556

<211>12

<212>PRT

＜213〉mankind

<400>556

Gln?Ser?Tyr?Asp?Ala?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>557

<211>12

<212>PRT

＜213〉mankind

<400>557

Gln?Ser?Tyr?Asp?Val?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>558

<211>12

<212>PRT

＜213〉mankind

<400>558

Gln?Ser?Tyr?Asp?Met?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>559

<211>12

<212>PRT

＜213〉mankind

<400>559

Gln?Ser?Tyr?Asp?Leu?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>560

<211>12

<212>PRT

＜213〉mankind

<400>560

Gln?Ser?Tyr?Asp?Ile?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>561

<211>12

<212>PRT

＜213〉mankind

<400>561

Gln?Ser?Tyr?Asp?Pro?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>562

<211>12

<212>PRT

＜213〉mankind

<400>562

Gln?Ser?Tyr?Asp?Trp?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>563

<211>12

<212>PRT

＜213〉mankind

<400>563

Gln?Ser?Tyr?Asp?Arg?Asp?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>564

<211>12

<212>PRT

＜213〉mankind

<400>564

Gln?Ser?Tyr?Asp?Arg?Cys?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>565

<211>12

<212>PRT

＜213〉mankind

<400>565

Gln?Ser?Tyr?Asp?Arg?Ser?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>566

<211>12

<212>PRT

＜213〉mankind

<400>566

Gln?Ser?Tyr?Asp?Arg?Tyr?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>567

<211>12

<212>PRT

＜213〉mankind

<400>567

Gln?Ser?Tyr?Asp?Arg?His?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>568

<211>12

<212>PRT

＜213〉mankind

<400>568

Gln?Ser?Tyr?Asp?Arg?Arg?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>569

<211>12

<212>PRT

＜213〉mankind

<400>569

Gln?Ser?Tyr?Asp?Arg?Asn?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>570

<211>12

<212>PRT

＜213〉mankind

<400>570

Gln?Ser?Tyr?Asp?Arg?Gln?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>571

<211>12

<212>PRT

＜213〉mankind

<400>571

Gln?Ser?Tyr?Asp?Arg?Thr?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>572

<211>12

<212>PRT

＜213〉mankind

<400>572

Gln?Ser?Tyr?Asp?Arg?Gly?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>573

<211>12

<212>PRT

＜213〉mankind

<400>573

Gln?Ser?Tyr?Asp?Arg?Ala?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>574

<211>12

<212>PRT

＜213〉mankind

<400>574

Gln?Ser?Tyr?Asp?Arg?Val?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>575

<211>12

<212>PRT

＜213〉mankind

<400>575

Gln?Ser?Tyr?Asp?Arg?Leu?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>576

<211>12

<212>PRT

＜213〉mankind

<400>576

Gln?Ser?Tyr?Asp?Arg?Ile?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>577

<211>12

<212>PRT

＜213〉mankind

<400>577

Gln?Ser?Tyr?Asp?Arg?Pro?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>578

<211>12

<212>PRT

＜213〉mankind

<400>578

Gln?Ser?Tyr?Asp?Arg?Trp?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>579

<211>12

<212>PRT

＜213〉mankind

<400>579

Gln?Ser?Tyr?Asp?Arg?Phe?Thr?His?Pro?Ala?Leu?Leu

1???????????????5??????????????????10

<210>580

<211>48

<212>DNA

＜213〉synthetic construction

＜223〉16 to 34 nucleotide can be made randomization nucleotide represent 12% of sequence by any nucleotide substitution

<400>580

tgtcccttgg?ccccagtagt?catagctccc?actggtcgta?cagtaata?????????48

<210>581

<211>35

<212>DNA

＜213〉synthetic construction

<400>581

gacacctcga?tcagcggata?acaatttcac?acagg??????????????????????35

<210>582

<211>15

<212>DNA

＜213〉synthetic construction

<400>582

tggggccaag?ggaca????????????????????????????????????????????15

<210>583

<211>45

<212>DNA

＜213〉synthetic construction

<400>583

attcgtccta?taccgttcta?ctttgtcgtc?tttccagacg?ttagt???????????45

<210>584

<211>18

<212>DNA

＜213〉synthetic construction

<400>584

attcgtccta?taccgttc?????????????????????????????????????????18

<210>585

<211>66

<212>DNA

＜213〉synthetic construction

＜223〉28 to 42 nucleotide can be made randomization nucleotide represent 12% of sequence by any nucleotide substitution

<400>585

ggtcccagtt?ccgaagaccc?tcgaacccct?caggctgctg?tcatatgact?ggcagtaata????60

gtcagc???????????????????????????????????????????????????????????????66

<210>586

<211>15

<212>DNA

＜213〉synthetic construction

<400>586

tggggccaag?ggaca????????????????????????????????????????????15

<210>587

<211>24

<212>DNA

＜213〉synthetic construction

<400>587

tgaagagacg?gtgaccattg?tccc??????????????????????????????24

<210>588

<211>16

<212>DNA

＜213〉synthetic construction

<400>588

gacacctcga?tcagcg???????????????????????????????????????16

<210>589

<211>48

<212>DNA

＜213〉synthetic construction

<400>589

gagtcattct?cgacttgcgg?ccgcacctag?gacggtcagc?ttggtccc????48

<210>590

<211>12

<212>PRT

＜213〉mankind

<400>590

Gln?Ser?Tyr?Asp?Arg?Gly?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>591

<211>12

<212>PRT

＜213〉mankind

<220>

＜223〉Xaa is by the random cipher coding of NNS sequence, and N is any nucleotide, and S is deoxidation cytimidine or deoxidation guanidine

<400>591

Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Phe?Thr?Gly?Ser?Met?Val

1???????????????5??????????????????10

<210>592

<211>12

<212>PRT

＜213〉mankind

<220>

<400>592

Gln?Ser?Tyr?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Ser?Met?Val

1???????????????5??????????????????10

<210>593

<211>12

<212>PRT

＜213〉mankind

<220>

<400>593

Gln?Ser?Tyr?Asp?Arg?Gly?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa

1???????????????5??????????????????10

<210>594

<211>100

<212>PRT

＜213〉mankind

<400>594

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?His

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Gly?Arg?Thr?Arg?Asn?Lys?Ala?Asn?Ser?Tyr?Thr?Thr?Glu?Tyr?Ala?Ala

50??????????????????55??????????????????60

Ser?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Ser

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Ala?Arg

100

<210>595

<211>100

<212>PRT

＜213〉mankind

<400>595

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?His

20??????????????????25??????????????????30

Tyr?Met?Ser?Trp?Val?Arg?Gln?Ala?Gln?Gly?Lys?Gly?Leu?Glu?Leu?Val

35??????????????????40??????????????????45

Gly?Leu?Ile?Arg?Asn?Lys?Ala?Asn?Ser?Tyr?Thr?Thr?Glu?Tyr?Ala?Ala

50??????????????????55??????????????????60

Ser?Val?Lys?Gly?Arg?Leu?Thr?Ile?Ser?Arg?Glu?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Ser?Ser?Leu?Lys?Thr?Glu?Asp?Leu?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Ala?Arg

100

<210>596

<211>100

<212>PRT

＜213〉mankind

<400>596

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?His

20??????????????????25??????????????????30

Tyr?Met?Ser?Trp?Val?Arg?Gln?Ala?Gln?Gly?Lys?Gly?Leu?Glu?Leu?Val

35??????????????????40??????????????????45

Gly?Leu?Ile?Arg?Asn?Lys?Ala?Asn?Ser?Tyr?Thr?Thr?Glu?Tyr?Ala?Ala

50??????????????????55??????????????????60

Ser?Val?Lys?Gly?Arg?Leu?Thr?Ile?Ser?Arg?Glu?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Met?Tyr?Leu?Gln?Met?Ser?Asn?Leu?Lys?Thr?Glu?Asp?Leu?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Ala?Arg

100

<210>597

<211>100

<212>PRT

＜213〉mankind

<400>597

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Tyr?Met?Ser?Trp?Val?Arg?Gln?Ala?Gln?Gly?Lys?Gly?Leu?Glu?Leu?Val

35??????????????????40??????????????????45

Gly?Leu?Ile?Arg?Asn?Lys?Ala?Asn?Ser?Tyr?Thr?Thr?Glu?Tyr?Ala?Ala

50??????????????????55??????????????????60

Ser?Val?Lys?Gly?Arg?Leu?Thr?Ile?Ser?Arg?Glu?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Ser?Ser?Leu?Lys?Thr?Glu?Asp?Leu?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Ala?Arg

100

<210>598

<211>98

<212>PRT

＜213〉mankind

<400>598

Glu?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Leu?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ser?Gly?Ile?Ser?Trp?Asn?Ser?Gly?Ser?Ile?Gly?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Ala?Lys

<210>599

<211>98

<212>PRT

＜213〉mankind

<400>599

Glu?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Arg?Pro?Gly?Gly

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Ala?Arg

<210>600

<211>98

<212>PRT

＜213〉mankind

<400>600

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Leu?Ile?Ser?Trp?Asp?Gly?Gly?Ser?Thr?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Ala?Lys

<210>601

<211>98

<212>PRT

＜213〉mankind

<400>601

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

<210>602

<211>98

<212>PRT

＜213〉mankind

<400>602

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

<210>603

<211>100

<212>PRT

＜213〉mankind

<400>603

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

1???????????????5??????????????????10??????????????????15

Ser?Leu?Lys?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Gly?Ser

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Ser?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Gly?Arg?Ile?Arg?Ser?Lys?Ala?Asn?Ser?Tyr?Ala?Thr?Ala?Tyr?Ala?Ala

50??????????????????55??????????????????60

Ser?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Ala?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Arg

100

<210>604

<211>100

<212>PRT

＜213〉mankind

<400>604

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Gly?Arg?Ile?Lys?Ser?Lys?Thr?Asp?Gly?Gly?Thr?Thr?Asp?Tyr?Ala?Ala

50??????????????????55??????????????????60

Pro?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Thr

100

<210>605

<211>100

<212>PRT

＜213〉mankind

<400>605

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Gly?Arg?Ile?Glu?Ser?Lys?Thr?Asp?Gly?Gly?Thr?Thr?Asp?Tyr?Ala?Ala

50??????????????????55??????????????????60

Pro?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Thr

100

<210>606

<211>100

<212>PRT

＜213〉mankind

<400>606

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Gly?Arg?Ile?Lys?Ser?Lys?Thr?Asp?Gly?Gly?Thr?Thr?Asp?Tyr?Ala?Ala

50??????????????????55??????????????????60

Pro?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Thr

100

<210>607

<211>100

<212>PRT

＜213〉mankind

<400>607

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Pro?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Thr

100

<210>608

<211>100

<212>PRT

＜213〉mankind

<400>608

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Trp?Met?Asn?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Gly?Arg?Ile?Lys?Ser?Lys?Thr?Asp?Gly?Gly?Thr?Thr?Asp?Tyr?Ala?Ala

50??????????????????55??????????????????60

Pro?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Thr

100

<210>609

<211>100

<212>PRT

＜213〉mankind

<400>609

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Gly?Arg?Ile?Lys?Ser?Lys?Thr?Asp?Gly?Gly?Thr?Thr?Asp?Tyr?Ala?Ala

50??????????????????55??????????????????60

Pro?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Asn?Thr

65??????????????????70??????????????????75??????????????????80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Lys?Thr?Glu?Asp?Thr?Ala?Val?Tyr

85??????????????????90??????????????????95

Tyr?Cys?Thr?Thr

100

<210>610

<211>98

<212>PRT

＜213〉mankind

<400>610

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?Pro?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Asn?His

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Val?Lys

<210>611

<211>98

<212>PRT

＜213〉mankind

<400>611

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?Asn?His

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

Val?Lys

<210>612

<211>98

<212>PRT

＜213〉mankind

<400>612

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?Asn?Ser

20??????????????????25??????????????????30

Asp?Met?Asn?Trp?Val?His?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ser?Gly?Val?Ser?Trp?Asn?Gly?Ser?Arg?Thr?His?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Val?Arg

<210>613

<211>98

<212>PRT

＜213〉mankind

<400>613

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?Asn?Ser

20??????????????????25??????????????????30

Asp?Met?Asn?Trp?Ala?Arg?Lys?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ser?Gly?Val?Ser?Trp?Asn?Gly?Ser?Arg?Thr?His?Tyr?Val?Asp?Ser?Val

50??????????????????55??????????????????60

Lys?Arg?Arg?Phe?Ile?Ile?Ser?Arg?Asp?Asn?Ser?Arg?Asn?Ser?Leu?Tyr

65??????????????????70??????????????????75??????????????????80

Leu?Gln?Lys?Asn?Arg?Arg?Arg?Ala?Glu?Asp?Met?Ala?Val?Tyr?Tyr?Cys

85??????????????????90??????????????????95

Val?Arg

<210>614

<211>98

<212>PRT

＜213〉mankind

<400>614

Thr?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Leu?Val?Glu?Pro?Gly?Gly

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Gly?Val?Ser?Trp?Asn?Gly?Ser?Arg?Thr?His?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Val?Arg

<210>615

<211>97

<212>PRT

＜213〉mankind

<400>615

Glu?Val?His?Leu?Val?Glu?Ser?Gly?Gly?Gly?Leu?Val?Gln?Pro?Gly?Gly

1???????????????5??????????????????10??????????????????15

Ala?Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Asn?Tyr

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ala?Asn?Gly?Thr?Ala?Gly?Asp?Thr?Tyr?Tyr?Pro?Gly?Ser?Val?Lys

50??????????????????55??????????????????60

Gly?Arg?Phe?Thr?Ile?Ser?Arg?Glu?Asn?Ala?Lys?Asn?Ser?Leu?Tyr?Leu

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Arg

<210>616

<211>97

<212>PRT

＜213〉mankind

<400>616

Glu?Val?Gln?Leu?Val?Glu?Thr?Gly?Gly?Gly?Leu?Ile?Gln?Pro?Gly?Gly

1???????????????5??????????????????10??????????????????15

Ser?Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Val?Ser?Ser?Asn

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Val?Ile?Tyr?Ser?Gly?Gly?Ser?Thr?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Arg

<210>617

<211>97

<212>PRT

＜213〉mankind

<400>617

Glu?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Leu?Val?His?Pro?Gly?Gly

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ser?Ala?Ile?Gly?Thr?Gly?Gly?Gly?Thr?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Arg

<210>618

<211>97

<212>PRT

＜213〉mankind

<400>618

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ser?Ala?Ile?Gly?Thr?Gly?Gly?Gly?Thr?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Arg

<210>619

<211>98

<212>PRT

＜213〉mankind

<400>619

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Ala?Lys

<210>620

<211>98

<212>PRT

＜213〉mankind

<400>620

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?Ser?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Ser?Tyr

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Val?Lys

<210>621

<211>98

<212>PRT

＜213〉mankind

<400>621

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?Ser?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Ser?Tyr

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Val?Lys

<210>622

<211>98

<212>PRT

＜213〉mankind

<400>622

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ala?Ile?Ser?Ser?Asn?Gly?Gly?Ser?Thr?Tyr?Tyr?Ala?Asn?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?Gly?Ser?Leu?Arg?Ala?Glu?Asp?Met?Ala?Val?Tyr?Tyr?Cys

85??????????????????90??????????????????95

Ala?Arg

<210>623

<211>98

<212>PRT

＜213〉mankind

<400>623

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ala?Ile?Ser?Gly?Ser?Gly?Gly?Ser?Thr?Tyr?Tyr?Gly?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?Lys

<210>624

<211>98

<212>PRT

＜213〉mankind

<400>624

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

<210>625

<211>98

<212>PRT

＜213〉mankind

<400>625

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>626

<211>98

<212>PRT

＜213〉mankind

<400>626

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

85??????????????????90??????????????????95

Ala?Arg

<210>627

<211>98

<212>PRT

＜213〉mankind

<400>627

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>628

<211>98

<212>PRT

＜213〉mankind

<400>628

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>629

<211>98

<212>PRT

＜213〉mankind

<400>629

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>630

<211>98

<212>PRT

＜213〉mankind

<400>630

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>631

<211>98

<212>PRT

＜213〉mankind

<400>631

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>632

<211>98

<212>PRT

＜213〉mankind

<400>632

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>633

<211>98

<212>PRT

＜213〉mankind

<400>633

Gln?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?Ser?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Ser?Tyr

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Val?Lys

<210>634

<211>98

<212>PRT

＜213〉mankind

<400>634

Gln?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?Ser?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Ser?Tyr

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Ala?Arg

<210>635

<211>98

<212>PRT

＜213〉mankind

<400>635

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

Lys?Gly?Arg?Phe?Ala?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

<210>636

<211>98

<212>PRT

＜213〉mankind

<400>636

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>637

<211>98

<212>PRT

＜213〉mankind

<400>637

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Ala?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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?Lys

<210>638

<211>97

<212>PRT

＜213〉mankind

<400>638

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ala?Ile?Gly?Thr?Ala?Gly?Asp?Thr?Tyr?Tyr?Pro?Gly?Ser?Val?Lys

50??????????????????55??????????????????60

Gly?Arg?Phe?Thr?Ile?Ser?Arg?Glu?Asn?Ala?Lys?Asn?Ser?Leu?Tyr?Leu

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Arg

<210>639

<211>98

<212>PRT

＜213〉mankind

<400>639

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Glu?Met?Asn?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

<210>640

<211>98

<212>PRT

＜213〉mankind

<400>640

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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?Leu?Arg?Ala?Arg?Leu?Cys?Ile?Thr?Val

85??????????????????90??????????????????95

Arg?Glu

<210>641

<211>98

<212>PRT

＜213〉mankind

<400>641

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>642

<211>98

<212>PRT

＜213〉mankind

<400>642

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>643

<211>98

<212>PRT

＜213〉mankind

<400>643

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>644

<211>98

<212>PRT

＜213〉mankind

<400>644

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>645

<211>98

<212>PRT

＜213〉mankind

<400>645

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asn?Ser?Lys?Asn?Arg?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

<210>646

<211>98

<212>PRT

＜213〉mankind

<400>646

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>647

<211>98

<212>PRT

＜213〉mankind

<400>647

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Trp?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>648

<211>98

<212>PRT

＜213〉mankind

<400>648

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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?Gly?Thr?Ala?Val?Tyr?Tyr?Cys

85??????????????????90??????????????????95

Ala?Arg

<210>649

<211>98

<212>PRT

＜213〉mankind

<400>649

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

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

<210>650

<211>98

<212>PRT

＜213〉mankind

<400>650

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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?Lys

<210>651

<211>98

<212>PRT

＜213〉mankind

<400>651

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Trp?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>652

<211>98

<212>PRT

＜213〉mankind

<400>652

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Trp?Tyr?Asp?Gly?Ser?Asn?Lys?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?Lys

<210>653

<211>95

<212>PRT

＜213〉mankind

<400>653

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala??Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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?Arg?Lys

85??????????????????90??????????????????95

<210>654

<211>98

<212>PRT

＜213〉mankind

<400>654

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Ser?Tyr?Asp?Gly?Ser?Asn?Lys?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

<210>655

<211>98

<212>PRT

＜213〉mankind

<400>655

Gln?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Val?Ile?Trp?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Ala

50??????????????????55??????????????????60

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

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

<210>656

<211>98

<212>PRT

＜213〉mankind

<400>656

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Tyr?Ile?Ser?Ser?Ser?Ser?Ser?Thr?Ile?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Ala?Arg

<210>657

<211>98

<212>PRT

＜213〉mankind

<400>657

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ser?Ile?Ser?Ser?Ser?Ser?Ser?Tyr?Ile?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

<210>658

<211>97

<212>PRT

＜213〉mankind

<400>658

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ser?Ile?Ser?Ser?Ser?Ser?Tyr?Ile?Tyr?Tyr?Ala?Asp?Ser?Val?Lys

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Arg

<210>659

<211>98

<212>PRT

＜213〉mankind

<400>659

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Ser?Ile?Ser?Ser?Ser?Ser?Ser?Tyr?Ile?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

<210>660

<211>98

<212>PRT

＜213〉mankind

<400>660

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ser?Tyr?Ile?Ser?Ser?Ser?Ser?Ser?Thr?Ile?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

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

<210>661

<211>97

<212>PRT

＜213〉mankind

<400>661

Glu?Asp?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Leu?Val?Gln?Pro?Gly?Gly

1???????????????5??????????????????10??????????????????15

Ser?Leu?Arg?Pro?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Ala?Phe?Ser?Ser?Tyr

20??????????????????25??????????????????30

Val?Leu?His?Trp?Val?Arg?Arg?Ala?Pro?Gly?Lys?Gly?Pro?Glu?Trp?Val

35??????????????????40??????????????????45

Ser?Ala?Ile?Gly?Thr?Gly?Gly?Asp?Thr?Tyr?Tyr?Ala?Asp?Ser?Val?Met

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

Gln?Met?Asn?Ser?Leu?Ile?Ala?Glu?Asp?Met?Ala?Val?Tyr?Tyr?Cys?Ala

85??????????????????90??????????????????95

Arg

<210>662

<211>98

<212>PRT

＜213〉mankind

<400>662

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Trp?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Val?Trp?Val

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

<210>663

<211>98

<212>PRT

＜213〉mankind

<400>663

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Trp?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Val?Trp?Val

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

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

<210>664

<211>98

<212>PRT

＜213〉mankind

<400>664

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ala?Asn?Ile?Lys?Gln?Asp?Gly?Ser?Glu?Lys?Tyr?Tyr?Val?Asp?Ser?Val

50??????????????????55??????????????????60

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

<210>665

<211>98

<212>PRT

＜213〉mankind

<400>665

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Trp?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Val?Trp?Val

35??????????????????40??????????????????45

Ser?Arg?Ile?Asn?Ser?Asp?Gly?Ser?Ser?Thr?Ser?Tyr?Ala?Asp?Ser?Met

50??????????????????55??????????????????60

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

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Thr?Arg

<210>666

<211>98

<212>PRT

＜213〉mankind

<400>666

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

1???????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

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

35??????????????????40??????????????????45

Ala?Asn?Ile?Lys?Gln?Asp?Gly?Ser?Glu?Lys?Tyr?Tyr?Val?Asp?Ser?Val

50??????????????????55??????????????????60

Lys?Gly?Arg?Phe?ThrIle?Ser?Arg?Asp?Asn?Ala?Lys?Asn?Ser?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

<210>667

<211>98

<212>PRT

＜213〉mankind

<400>667

Gln?Val?Gln?Leu?Val?Gln?Ser?Gly?Gly?Gly?Val?Val?Gln?Pro?Gly?Arg

1?????????????????5??????????????????10??????????????????15

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

20??????????????????25??????????????????30

Gly?Met?His?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35??????????????????40??????????????????45

Ala?Phe?Ile?Arg?Tyr?Asp?Gly?Ser?Asn?Lys?Tyr?Tyr?Ala?Asp?Ser?Val

50??????????????????55??????????????????60

Lys?Gly?Arg?Phe?ThrIle?Ser?Arg?Asp?Asn?Ser?Lys?Asn?Thr?Leu?Tyr

65??????????????????70??????????????????75??????????????????80

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

85??????????????????90??????????????????95

Thr?Thr

<210>668

<211>98

<212>PRT

＜213〉mankind

<400>668

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Ala?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Lys?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Asn?Asn

20??????????????????25??????????????????30

Tyr?Val?Ser?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Asp?Asn?Asn?Lys?Arg?Pro?Ser?Gly?Ile?Pro?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Thr?Leu?Gly?Ile?Thr?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Thr?Gly?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gly?Thr?Trp?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Ser?Ala

<210>669

<211>98

<212>PRT

＜213〉mankind

<400>669

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val??Ser?Ala?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Lys?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Ser?Ser?Asp?Met?Gly?Asn?Tyr

20??????????????????25??????????????????30

Ala?Val?Ser?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Glu?Asn?Asn?Lys?Arg?Pro?Ser?Gly?Ile?Pro?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Thr?Leu?GlyIle?Thr?Gly?Leu?Trp

65??????????????????70??????????????????75??????????????????80

Pro?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Leu?Ala?Trp?Asp?Thr?Ser?Pro

85??????????????????90??????????????????95

Arg?Ala

<210>670

<211>98

<212>PRT

＜213〉mankind

<400>670

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Ala?Ser?Gly?Thr?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys??Ser?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Asn?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala??Pro??Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Ser?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ser?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Ala?Ala?Trp?Asp?Asp?Ser?Leu

85??????????????????90??????????????????95

Asn?Gly

<210>671

<211>98

<212>PRT

＜213〉mankind

<400>671

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Ala?Ser?Gly?Thr?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Ser?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Tyr?Val?Tyr?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Ser?Gly?Leu?Arg

65??????????????????70??????????????????75??????????????????80

Ser?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Ala?Ala?Trp?Asp?Asp?Ser?Leu

85??????????????????90??????????????????95

Ser?Gly

<210>672

<211>98

<212>PRT

＜213〉mankind

<400>672

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Glu?Ala?Pro?Arg?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys??Ser?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Asn?Asn

20??????????????????25??????????????????30

Ala?Val?Asn?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Lys?Ala??Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

Ile?Tyr?Tyr?Asp?Asp?Leu?Leu?Pro?Ser?Gly?Val?Ser?Asp?Arg?Phe?Ser

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Ser?Gly?Leu?Gln

65??????????????????70??????????????????75??????????????????80

Ser?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Ala?Ala?Trp?Asp?Asp?Ser?Leu

85??????????????????90??????????????????95

Asn?Gly

<210>673

<211>99

<212>PRT

＜213〉mankind

<400>673

Gln?Ser?Val?Leu?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1?????????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Thr?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Ala?Gly

20??????????????????25??????????????????30

Tyr?Val?Val?His?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu

35??????????????????40??????????????????45

Leu?Ile?Tyr?Gly?Asn?Ser?Asn?Arg?Pro?Ser?Gly?Val?Pro?Asp?Gln?Phe

50??????????????????55??????????????????60

Ser?Gly?Ser?Lys??Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala??Ile?Thr?Gly?Leu

65??????????????????70??????????????????75??????????????????80

Gln?Ser?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Lys?Ala?Trp?Asp?Asn?Ser

85??????????????????90??????????????????95

Leu?Asn?Ala

<210>674

<211>99

<212>PRT

＜213〉mankind

<400>674

Gln?Ser?Val?Val?Thr?Gln?Pro?Pro?Ser?Val?Ser?Gly?Ala?Pro?Gly?Gln

1???????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys?Thr?Gly?Ser?Ser?Ser?Asn?Ile?Gly?Ala?Gly

20??????????????????25??????????????????30

Tyr?Asp?Val?His?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Ser?Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Leu

65??????????????????70??????????????????75??????????????????80

Gln?Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser

85??????????????????90??????????????????95

Leu?Ser?Gly

<210>675

<211>98

<212>PRT

＜213〉mankind

<400>675

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

1????????????????5??????????????????10??????????????????15

Arg?Val?Thr?Ile?Ser?Cys??Ser?Gly?Gly?Arg?Ser?Asn?Ile?Gly?Ser?Asn

20??????????????????25??????????????????30

Thr?Val?Lys?Trp?Tyr?Gln?Gln?Leu?Pro?Gly?Thr?Ala?Pro?Lys?Leu?Leu

35??????????????????40??????????????????45

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

50??????????????????55??????????????????60

Gly?Ser?Lys?Ser?Gly?Thr?Ser?Ala?Ser?Leu?Ala?Ile?Thr?Gly?Val?Gln

65??????????????????70??????????????????75??????????????????80

Ala?Glu?Asp?Glu?Ala?Asp?Tyr?Tyr?Cys?Gln?Ser?Tyr?Asp?Ser?Ser?Leu

85??????????????????90??????????????????95

Arg?Gly

BBI-276PC

1

BBI-276PC

Claims

1. treat psoriatic method in the individuality for one kind, described method comprises step:

(i) individuality of chronic psoriasis is suffered from selection; With

(ii) give antibody or its antigen-binding portion thereof of a physical efficiency in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23;

Thereby the chronic psoriasis in the treatment individuality.

2. the process of claim 1 wherein the psoriasis clinical diagnosis that described individuality has had 6 months at least.

3. the process of claim 1 wherein that described individuality suffered from least 2 months stable psoriasis in plaques.

4. treat psoriatic method in the individuality for one kind, described method comprises step:

(i) select do not have the individuality that is selected from following situation: experience systematicness or biology to resist-the IL-12 treatment before; Non-psoriasis in plaques; Before treatment, can not stop local at least 2 weeks of curing psoriasis; At least 2 weeks of UV-B phototherapy before treatment; At least 4 weeks of psoralen-ultraviolet phototherapy before treatment; At least 4 weeks of systemic treatment before treatment; At least 12 weeks of biological therapy before treatment; In therapeutic process, need to take in oral or injectable corticoid; Sb.'s illness took a turn for the worse to need the asthma of being in hospital before screening in the period of 10; The infection of severe infections or hazards; Malignant tumour history except that the basal-cell carcinoma that success is treated; With to containing the main immune response history of immunoglobulin G medicine; With

Thereby the psoriasis in the treatment individuality.

5. treat psoriatic method in the individuality for one kind, described method comprises step:

(i) be chosen in the individuality of not inoculating the live virus agent in 1 month; With

Thereby the psoriasis in the treatment individuality.

6. treat psoriatic method in the individuality for one kind, described method comprises step:

(i) give antibody or its antigen-binding portion thereof of a physical efficiency in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23,

(ii) the monitoring individuality is selected from the following laboratory result of significant abnormal clinically: aspartate transaminase or the alanine aminotransferase＞5 times normal value upper limit; Serum total bilirubin＞3 times normal value the upper limit; Serum creatinine＞3 times normal value the upper limit; Cretinephosphokinase＞5 times normal value the upper limit; Haemoglobin＜8g/dL; White blood cell count(WBC)＜2 * 10 ⁹/ L; And platelet count＜75 * 10 ⁹/ L;

(iii) stop to give wherein to detect individual antibody or its antigen-binding portion thereof of significant abnormal laboratory result clinically;

Thereby the psoriasis in the treatment individuality.

7. each method of claim 1-6 wherein whenever biweekly gives antibody or its antigen-binding portion thereof.

8. each method of claim 1-6 wherein gives antibody or its antigen-binding portion thereof once in a week.

9. each method of claim 1-6, wherein the dosage with about 200mg gives antibody or its antigen-binding portion thereof.

10. each method of claim 1-6, wherein the dosage with about 100mg gives antibody or its antigen-binding portion thereof.

11. each method of claim 1-6, wherein when p40 subunit during in conjunction with the p35 subunit of IL-12, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.

12. each method of claim 1-6, wherein when p40 subunit during in conjunction with the p19 subunit of IL-23, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.

13. each method of claim 1-6, wherein when the p40 subunit in conjunction with the p35 subunit of IL-12 and when p40 subunit during in conjunction with the p19 subunit of IL-23, antibody or its antigen-binding portion thereof can be in conjunction with the epi-positions of this p40 subunit.

14. each method of claim 1-3, wherein chronic psoriasis is chronic psoriasis in plaques.

15. each method of claim 4-6, wherein psoriasis is a chronic psoriasis.

16. the method for claim 15, wherein chronic psoriasis is chronic psoriasis in plaques.

17. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually keep after giving antibody or its antigen-binding portion thereof for the first time at least that PASI 90 replys one period duration, thus the psoriasis in the treatment individuality.

18. the method for claim 17, wherein the duration was at least about for 12 weeks.

19. the method for claim 17 wherein whenever biweekly gives antibody or its antigen-binding portion thereof.

20. the method for claim 17 wherein gives antibody or its antigen-binding portion thereof once in a week.

21. the method for claim 17 wherein gives antibody with single dose.

22. the method for claim 17, wherein the dosage with about 200mg gives antibody or its antigen-binding portion thereof.

23. the method for claim 17, wherein the dosage with about 100mg gives antibody or its antigen-binding portion thereof.

24. the method for claim 17, wherein psoriasis is a chronic psoriasis.

25. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individual keeping after giving antibody or its antigen-binding portion thereof for the first time made zero or minimum one period duration of PGA grade, thus the psoriasis in the treatment individuality.

26. the method for claim 25, wherein the duration was at least about for 12 weeks.

27. the method for claim 25 wherein whenever biweekly gives antibody or its antigen-binding portion thereof.

28. the method for claim 25 wherein gives antibody or its antigen-binding portion thereof once in a week.

29. the method for claim 25 wherein gives antibody or its antigen-binding portion thereof with single dose.

30. the method for claim 25, wherein the dosage with about 200mg gives antibody or its antigen-binding portion thereof.

31. the method for claim 25, wherein the dosage with about 100mg gives antibody or its antigen-binding portion thereof.

32. the method for claim 25, wherein psoriasis is a chronic psoriasis.

33. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individuality is giving antibody or its antigen-binding portion thereof for the first time after about 8 weeks show the PASI scores of improving, thus the psoriasis in the treatment individuality.

34. the method for claim 33, wherein individuality is giving antibody or its antigen-binding portion thereof for the first time after about 4 weeks show the PASI scores of improving.

35. the method for claim 33, wherein individuality is giving antibody or its antigen-binding portion thereof for the first time after about 2 weeks show the PASI scores of improving.

36. the method for claim 33, wherein individuality is giving antibody or its antigen-binding portion thereof for the first time after about 1 week shows the PASI score of improving.

37. the method for claim 33 wherein whenever biweekly gives antibody or its antigen-binding portion thereof.

38. the method for claim 33 wherein gives antibody or its antigen-binding portion thereof once in a week.

39. the method for claim 33 wherein gives antibody or its antigen-binding portion thereof with single dose.

40. the method for claim 33, wherein the dosage with about 200mg gives antibody or its antigen-binding portion thereof.

41. the method for claim 33, wherein the dosage with about 100mg gives antibody or its antigen-binding portion thereof.

42. the method for claim 33, wherein psoriasis is a chronic psoriasis.

43. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually keep after giving antibody or its antigen-binding portion thereof for the first time at least that PASI 100 replys one period duration, thus the psoriasis in the treatment individuality.

44. the method for claim 43, wherein the duration was at least about for 12 weeks.

45. the method for claim 43 wherein whenever biweekly gives antibody or its antigen-binding portion thereof.

46. the method for claim 43 wherein gives antibody or its antigen-binding portion thereof once in a week.

47. the method for claim 43, wherein the dosage with about 200mg gives antibody or its antigen-binding portion thereof.

48. the method for claim 43, wherein psoriasis is a chronic psoriasis.

49. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually after stopping to give antibody or its antigen-binding portion thereof, keep at least that PASI 50 replys one period duration, thus the psoriasis in the treatment individuality.

50. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually after stopping to give antibody or its antigen-binding portion thereof, keep at least that PASI 75 replys one period duration, thus the psoriasis in the treatment individuality.

51. psoriatic method in the treatment individuality, described method comprises and gives physical efficiency antibody or its antigen-binding portion thereof in conjunction with the epi-position of the p40 subunit of IL-12 and/or IL-23, wherein individually after stopping to give antibody or its antigen-binding portion thereof, keep at least that PASI 90 replys one period duration, thus the psoriasis in the treatment individuality.

52. each method of claim 49-51, wherein the duration was at least about for 12 weeks.

53. each method of claim 49-51 wherein gives antibody at least about 12 weeks.

54. each method of claim 49-51 wherein whenever biweekly gives antibody or its antigen-binding portion thereof.

55. each method of claim 49-51 wherein gives antibody or its antigen-binding portion thereof once in a week.

56. each method of claim 49-51 wherein gives antibody or its antigen-binding portion thereof with single dose.

57. each method of claim 49-51, wherein the dosage with about 200mg gives antibody or its antigen-binding portion thereof.

58. each method of claim 49-51, wherein the dosage with about 100mg gives antibody or its antigen-binding portion thereof.

59. each method of claim 49-51, wherein psoriasis is a chronic psoriasis.

60. psoriatic method in the treatment individuality, described method comprise with the antibody of every relieve pain individuality biweekly at people IL-12 and human IL-2 3, thereby treatment psoriasis.