CN100595211C - 血管生成素-2的特异结合剂 - Google Patents
血管生成素-2的特异结合剂 Download PDFInfo
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- CN100595211C CN100595211C CN02824877.5A CN02824877A CN100595211C CN 100595211 C CN100595211 C CN 100595211C CN 02824877 A CN02824877 A CN 02824877A CN 100595211 C CN100595211 C CN 100595211C
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Abstract
本发明公开了结合血管生成素-2的特异结合剂,如完全的人抗体。还公开了所述抗体的重链片段,轻链片段和CDRs,以及制备和使用所述抗体的方法。
Description
本申请要求2001年10月11日申请的美国临时申请登记号No.60/328,624的利益,该专利在此全文引作参考。
发明领域
本发明涉及识别血管生成素-2(Ang-2)并且与之结合的特异结合剂。更具体地说,本发明涉及特异性结合Ang-2的所述特异结合剂及其片段的制备,诊断用途,和治疗用途。
发明背景
血管发生,从存在的血管生成新的血管,对于很多生理和病理过程都是比需的。一般来说,血管发生由血管生成因子原和抗血管生成因子严格调节,但是在象癌症,眼新血管病,关节炎,和牛皮癣这样的疾病的情况下,该过程可能错误进行。Folkman,J.,Nat.Med.,1:27-31(1995)。
有很多种疾病已知与不受调节的或者不期望的血管发生相关。这样的疾病包括但不限于,眼新血管形成,例如视网膜病(包括糖尿病视网膜病),与年龄有关的斑变性,牛皮癣,成血管瘤(hemangioblastoma),血管瘤,动脉硬化,炎性疾病,例如类风湿性或风湿性炎症,尤其是关节炎(包括类风湿性关节炎),或者其他慢性炎症,例如慢性哮喘,动脉粥样硬化或者移植后动脉粥样硬化,子宫内膜异位,和瘤,例如所谓的实体瘤和液体(或血液)肿瘤(例如白血病和淋巴瘤)。与不期望的血管发生相关的其他疾病对于那些本领域技术人员是显而易见的。
虽然很多信号转导系统在血管发生的调节中涉及,但是表征得最充分并且最具内皮细胞选择性系统之一涉及Tie-2受体酪氨酸激酶(称作″Tie-2″或″Tie-2R″(也称作″ORK″);鼠Tie-2也称作″tek″)及其配体,血管生成素(Gale,N.W.和Yancopoulos,G.D.,Genes Dev.13:1055-1066[1999])。有四种已知的血管生成素;血管生成素-1(″Ang-1″)至血管生成素-4(″Ang-4″)。这些血管生成素也称作″Tie-2配体″.(Davis,S.,等,Cell,87:1161-1169[1996];Grosios,K.,等,Cytogenet Cell Genet,84:118-120[1999];Holash,J.,等,Investigative Ophthalmology & Visual Science,42:1617-1625[1999];Koblizek,T.I.,等,Current Biology,8:529-532[1998];Lin,P.,等,Proc Natl Acad Sci USA,95:8829-8834[1998];Maisonpierre,P.C.,等,Science,277:55-60[1997];Papapetropoulos,A.,等,Lab Invest,79:213-223[1999];Sato,T.N.,等,Nature,375:70-74[1998];Shyu,K.G.,等,Circulation,98:2081-2087[1998];Suri,C.,等,Cell,87:1171-1180[1996];Suri,C.,等,Science,282:468-471[1998];Valenzuela,D.M.,等,Proceedings of the NationalAcademy of Sciences of the USA,96:1904-1909[1999];Witzenbichler,B.,等,J Biol Chem,273:18514-18521[1998])。Ang-1与Tie-2结合刺激培养的内皮细胞中的受体磷酸化作用,发现Ang-2刺激和拮抗Tie-2受体磷酸化作用(Davis,S.,等,[1996],上文;Maisonpierre,P.C.,等,[1997],上文;Kim,I.,J.H.Kim,等,Oncogene 19(39):4549-4552(2000);Teichert-Kuliszewska,K.,P.C.Maisonpierre,等,Cardiovascular Research 49(3):659-70(2001))。
小鼠Tie-2和Ang-1敲除物的表型是类似的并且提示Ang-1-刺激的Tie-2磷酸化作用通过保持内皮细胞-支持细胞附着而介导子宫中发育血管的改变和稳定(Dumont,D.J.,等,Genes & Development,8:1897-1909[1994];Sato,T.N.,等,Nature,376:70-74[1995];Suri,C.,等,[1996],上文)。认为Ang-1在血管稳定中的作用在成年人中是保守的,而且广泛而基本性表达(Hanahan,D.,Science,277:48-50[1997];Zagzag,D.,等,ExperimentalNeurology,159:391-400[1999])。相反,Ang-2表达主要限于血管改造部位,认为在那里阻断Ang-1功能,从而诱导有益于血管发生的血管可塑性状态(Hanahan,D.,[1997],上文;Holash,J.,等,Science,284:1994-1998[1999];Maisonpierre,P.C.,等,[1997],上文)。
很多公开的研究支持证明病态血管-选择性Ang-2表达与血管发生有关。这些病理学情况包括,例如,牛皮癣,斑变性,和癌症(Bunone,G.,等,American Journal of Pathology,155:1967-1976[1999];Etoh,T.,等,Cancer Research,61:2145-2153[2001];Hangai,M.,等,Investigative Ophthalmology & Visual Science,42:1617-1625[2001];Holash,J.,等,[1999]上文;Kuroda,K.,等,Journalof Investigative Dermatology,116:713-720[2001];Otani,A.,等,Investigative Ophthalmology & Visual Science,40:1912-1920[1999];Stratmann,A.,等,American Journal ofPathology,153:1459-1466[1998];Tanaka,S.,等,J Clin Invest,103:34-345[1999];Yoshida,Y.,等,International Journalof Oncology,15:1221-1225[1999];Yuan,K.,等,Journal ofPeriodontal Research,35:165-171[2000];Zagzag,D.,等,[1999]上文)。这些研究大多数聚焦在癌症上,其中很多癌症类型表现出显示血管Ang-2表达。与在病理性血管发生中的表达相反,正常组织中Ang-2表达十分有限(Maisonpierre,P.C.,等,[1997],上文;Mezquita,J.,等,Biochemical and Biophysical ResearchCommunications,260:492-498[1999])。在正常成年人体内血管发生的三个主要部位是卵巢,胎盘,和子宫;这些是其中检测到Ang-2mRNA的正常(即,非癌)组织中主要组织。
一些功能研究提示Ang-2可能在肿瘤血管发生中涉及。Ahmad等(Cancer Res.,61:1255-1259[2001])描述Ang-2超量表达并且支持性证明这与小鼠异种移植模型中肿瘤生长增加有关。也参见Etoh等,上文,和Tanaka等,上文,其中给出支持Ang-2超量表达与肿瘤血管过多相关的数据。但是,相反,Yu等.(Am.J.Path.,158:563-570[2001])报道数据支持证明Lewis肺癌和TA3乳房癌细胞中Ang-2超量表达延长用相应的转染子注射的小鼠的存活。
在过去的几年中,很多出版物提出Ang-1,Ang-2和/或Tie-2可能是抗癌治疗的靶物。例如,美国专利Nos.6,166,185,5,650,490,和5,814,464各自公开了抗-Tie-2配体抗体和受体的概念。Lin等(Proc.Natl.Acad.Sci USA,95:8829-8834[1998])对小鼠注射腺病毒表达可溶Tie-2;声称可溶Tie-2减小小鼠产生的肿瘤的数目和大小。在最近的研究中,Lin等(J.Clin.Invest.,100:2072-2078[1997])对大鼠注射可溶形式的Tie-2;声称这种化合物减小大鼠的肿瘤大小。Siemeister等(Cancer Res.,59:3185-3189[1999])制备出表达Tie-2胞外结构域的人黑素瘤细胞系,对裸鼠注射这些细胞系,得出结论:声称可溶Tie-2导致肿瘤生长和肿瘤血管发生的″显著抑制″。从这个信息看,并且已知Ang-1和Ang-2都结合Tie-2,从这些研究不能清楚地看出i Ang-1,Ang-2,或Tie-2会是抗癌治疗的有吸引力的靶物。
提高这些分子的半寿期的一些肽与稳定的血浆蛋白例如I g恒定区的融合体描述于,例如,PCT公开WO 00/24782,2000年5月4日公开。
先前描述过提高分子半寿期的一种蛋白质或者其片段与一种稳定的血浆蛋白质例如Ig恒定区的融合体(例如,实施例,美国专利No.5,480,981;Zheng等,J.Immunol.,154:5590-5600,(1995);Fisher等,N.Engl.J.Med.,334:1697-1702,(1996);Van Zee,K.等,J.Immunol.,156:2221-2230,(1996);美国专利No.5,808,029,1998年9月15日公开;Capon等,Nature,337:525-531,(1989);Harvill等,Immunotech.,1:95-105,(1995);WO97/23614,1997年7月3日公开;PCT/US 97/23183,filed Dec.11,1997年12月11日申请;Linsley,J.Exp.Med.,174:561-569,(1991);WO 95/21258,1995年8月10日公开)。
有效的抗-Ang-2疗法可能使大量的癌症患者受益,因为大多数实体肿瘤需要新血管化生长直径超过1-2毫米。这样的疗法对其他与血管发生相关的疾病例如视网膜病,关节炎和牛皮癣有广泛的应用。
对于特异性识别并结合Ang-2的新的药物有着未开发的需求。这样的药物将有用于对与Ang-2活性相关的病态的诊断筛选和治疗干预。
因此,本发明的一个目的是提供调节Ang-2活性的Ang-2的特异结合剂。
发明概述
本发明提供一种包含重链和轻链的抗体,其中所述重链包含选自下组的重链可变区:526 HC(SEQ ID NO.1);528 HC(SEQ ID NO.3);531 HC(SEQ ID NO.5);533 HC(SEQ ID NO.7);535 HC(SEQ IDNO.9);536 HC(SEQ ID NO.11);537 HC(SEQ ID NO.13);540HC(SEQ ID NO.15);543 HC(SEQ ID NO.17);544 HC(SEQ ID NO.19);545 HC(SEQ ID NO.21);546 HC(SEQ ID NO.23);551 HC(SEQ IDNO.25);553 HC(SEQ ID NO.27);555 HC(SEQ ID NO.29);558HC(SEQ ID NO.31);559 HC(SEQ ID NO.33);565 HC(SEQ ID NO.35);F1-C6 HC(SEQ ID NO.37);FB1-A7 HC(SEQ ID NO.39);FD-B2HC(SEQ ID NO.41);FE-B7 HC(SEQ ID NO.43);FJ-G11 HC(SEQID NO.45);FK-E3 HC(SEQ ID NO.47);G1D4 HC(SEQ ID NO.49);GC1E8 HC(SEQ ID NO.51);H1C12 HC(SEQ ID NO.53);IA1-1E7HC(SEQ ID NO.55);IF-1C10 HC(SEQ ID NO.57);IK-2E2 HC(SEQID NO.59);IP-2C11 HC(SEQ ID NO.61);及其抗原结合片段;所述轻链包含选自下组的轻链可变区:526κ(SEQ ID NO.2);536κ(SEQID NO.12);543κ(SEQ ID NO.18);544κ(SEQ ID NO.20);551κ(SEQ ID NO.26);553κ(SEQ ID NO.28);555κ(SEQ ID NO.30);558κ(SEQ ID NO.32);565κ(SEQ ID NO.36);FE-B7κ(SEQ ID NO.44);FJ-G11κ(SEQ ID NO.46);FK-E3κ(SEQ ID NO.48);IA1-1E7κ(SEQ ID NO.56);IP-2C11κ(SEQ ID NO.62);528λ(SEQ ID NO.4);531λ(SEQ ID NO.6);533λ(SEQ ID NO.8);535λ(SEQ ID NO.10);537λ(SEQ ID NO.14);540λ(SEQ IDNO.16);545λ(SEQ ID NO.22);546λ(SEQ ID NO.24);559λ(SEQ ID NO.34);F1-C6λ(SEQ ID NO.38);FB1-A7λ(SEQ ID NO.40);FD-B2λ(SEQ ID NO.42);G1D4λ(SEQ ID NO.50);GC1E8λ(SEQ ID NO.52);H1C12λ(SEQ ID NO.54);IF-1C10λ(SEQ ID NO.58);IK-2E2λ(SEQ ID NO.60);及其抗原结合片段.
本发明还提供了包含至少一种选自下组的肽的特异结合剂:SEQ IDNO.1;SEQ ID NO.3;SEQ ID NO.5;SEQ ID NO.7;SEQ ID NO.9;SEQ ID NO.11;SEQ ID NO.13;SEQ ID NO.15;SEQ ID NO.17;SEQ ID NO.19;SEQ ID NO.21;SEQ ID NO.23;SEQ ID NO.25;SEQ ID NO.27;SEQ ID NO.29;SEQ ID NO.31;SEQ ID NO.33;SEQ ID NO.35;SEQ ID NO.37;SEQ ID NO.39;SEQ ID NO.41;SEQ ID NO.43;SEQ ID NO.45;SEQ ID NO.47;SEQ ID NO.49;SEQ ID NO.51;SEQ ID NO.53;SEQ ID NO.55;SEQ ID NO.57;SEQ ID NO.59;SEQ ID NO.61;SEQ ID NO.2;SEQ ID NO.12;SEQ ID NO.18;SEQ ID NO.20;SEQ ID NO.26;SEQ ID NO.28;SEQ ID NO.30;SEQ ID NO.32;SEQ ID NO.36;SEQ ID NO.44;SEQ ID NO.46;SEQ ID NO.48;SEQ ID NO.56;SEQ ID NO.62;SEQ ID NO.4;SEQ ID NO.6;SEQ ID NO.8;SEQ ID NO.10;SEQID NO.14;SEQ ID NO.16;SEQ ID NO.22;SEQ ID NO.24;SEQID NO.34;SEQ ID NO.38;SEQ ID NO.40;SEQ ID NO.42;SEQID NO.50;SEQ ID NO.52;SEQ ID NO.54;SEQ ID NO.58;和SEQ ID NO.60及其片段。
应该理解,特异结合剂可以是,例如抗体,如多克隆、单克隆、嵌合的、人源化或完全的人抗体。所述抗体也可以是单链抗体。本发明还涉及产生本发明的单克隆抗体的杂交瘤。
可以理解,本发明涉及如此处所描述的偶联物。该偶联物可以是,例如,本发明的特异结合剂(如抗体)。
本发明还涉及编码本发明的特异结合剂(如抗体)的核酸分子,以及包含所述核酸分子的载体,以及包含所述载体的宿主细胞。
此外,本发明提供了一种制备特异结合剂的方法,包括,(a)用至少一种编码权利要求1的特异结合剂转化宿主细胞;(b)在所述宿主细胞中表达核酸分子;和(c)分离所述特异结合剂。本发明进一步提供一种制备抗体的方法,包括:(a)用至少一种编码本发明抗体的核酸分子转化宿主细胞;(b)在所述宿主细胞中表达核酸分子;和(c)分离所述特异结合剂。
本发明还涉及抑制哺乳动物中不期望的血管发生的方法,包括施用治疗有效量的本发明的特异结合剂。本发明还提供治疗哺乳动物癌症的方法,包括施用治疗有效量的本发明的特异结合剂。
本发明还涉及抑制哺乳动物中不期望的血管发生的方法,包括施用治疗有效量的本发明的抗体。本发明还提供治疗哺乳动物癌症的方法,包括施用治疗有效量的本发明的抗体。
应该理解,本发明进一步涉及包含本发明的特异结合剂和药学可接受制剂的药物组合物。该药物组合物可以包含本发明的抗体和药学可接受制剂。
本发明提供了一种调节或抑制血管生成素-2活性的方法,包括施用一种或多种本发明的特异结合剂。本发明提供了一种调节或抑制血管生成素-2活性的方法,包括施用一种或多种本发明的抗体。
本发明还涉及调节哺乳动物血管渗透性或血浆渗漏中至少一项的方法,包括施用治疗有效量的本发明的特异结合剂。本发明还涉及治疗哺乳动物中以下病症中的至少一种的方法:眼新血管病,肥胖,成血管瘤,血管瘤,动脉硬化,炎性疾病,炎性紊乱,动脉粥样硬化,子宫内膜异位,肿瘤性疾病,骨相关疾病,或者牛皮癣,包括施用治疗有效量的本发明的特异结合剂。
此外,本发明涉及治疗哺乳动物癌症的方法,包括施用治疗有效量的本发明的特异结合剂和化疗药物。本领域技术人员应该理解,特异结合剂和化疗药物不需要同时施用。
本发明还涉及治疗哺乳动物癌症的方法,包括施用治疗有效量的本发明的抗体和化疗药物。特异结合剂和化疗药物不需要同时施用。
本发明还提供一种包含以下任意一种互补决定区1(CDR 1)的特异结合剂:526 HC(SEQ ID NO.1);528 HC(SEQ ID NO.3);531 HC(SEQ ID NO.5);533 HC(SEQ ID NO.7);535 HC(SEQ ID NO.9);536 HC(SEQ ID NO.11);537 HC(SEQ ID NO.13);540 HC(SEQID NO.15);543 HC(SEQ ID NO.17);544 HC(SEQ ID NO.19);545 HC(SEQ ID NO.21);546 HC(SEQ ID NO.23);551 HC(SEQID NO.25);553 HC(SEQ ID NO.27);555 HC(SEQ ID NO.29);558 HC(SEQ ID NO.31);559 HC(SEQ ID NO.33);565 HC(SEQID NO.35);F1-C6 HC(SEQ ID NO.37);FB1-A7 HC(SEQ ID NO.39);FD-B2 HC(SEQ ID NO.41);FE-B7 HC(SEQ ID NO.43);FJ-G11 HC(SEQ ID NO.45);FK-E3 HC(SEQ ID NO.47);G1D4 HC(SEQ ID NO.49);GC1E8 HC(SEQ ID NO.51);H1C12 HC(SEQ ID NO.53);IA1-1E7HC(SEQ ID NO.55);IF-1C10 HC(SEQ ID NO.57);IK-2E2 HC(SEQID NO.59);IP-2C11 HC(SEQ ID NO.61);526κ(SEQ ID NO.2);536κ(SEQ ID NO.12);543κ(SEQ ID NO.18);544κ(SEQ IDNO.20);551κ(SEQ ID NO.26);553κ(SEQ ID NO.28);555κ(SEQ ID NO.30);558κ(SEQ ID NO.32);565κ(SEQ ID NO.36);FE-B7κ(SEQ ID NO.44);F.J-G11κ(SEQ ID NO.46);FK-E3κ(SEQ ID NO.48);IA1-1E7κ(SEQ ID NO.56);IP-2C11κ(SEQID NO.62);528λ(SEQ ID NO.4);531λ(SEQ ID NO.6);533λ(SEQ ID NO.8);535λ(SEQ ID NO.10);537λ(SEQ ID NO.14);540λ(SEQ ID NO.16);545λ(SEQ ID NO.22);546λ(SEQ IDNO.24);559λ(SEQ ID NO.34);F1-C6λ(SEQ ID NO.38);FB1-A7λ(SEQ ID NO.40);FD-B2λ(SEQ ID NO.42);G1D4λ(SEQ ID NO.50);GC1E8λ(SEQ ID NO.52);H1C12λ(SEQ ID NO.54);IF-1C10λ(SEQ ID NO.58);和IK-2E2λ(SEQ ID NO.60)。
本发明还涉及一种包含以下任意一种互补决定区2(CDR2)的特异结合剂:526 HC(SEQ ID NO.1);528 HC(SEQ ID NO.3);531 HC(SEQ ID NO.5);533 HC(SEQ ID NO.7);535 HC(SEQ ID NO.9);536 HC(SEQ ID NO.11);537 HC(SEQ ID NO.13);540 HC(SEQID NO.15);543 HC(SEQ ID NO.17);544 HC(SEQ ID NO.19);545 HC(SEQ ID NO.21);546 HC(SEQ ID NO.23);551 HC(SEQID NO.25);553 HC(SEQ ID NO.27);555 HC(SEQ ID NO.29);558 HC(SEQ ID NO.31);559 HC(SEQ ID NO.33);565 HC(SEQID NO.35);F1-C6 HC(SEQ ID NO.37);FB1-A7 HC(SEQ ID NO.39);FD-B2 HC(SEQ ID NO.41);FE-B7 HC(SEQ ID NO.43);FJ-G11 HC(SEQ ID NO.45);FK-E3 HC(SEQ ID NO.47);G1D4 HC(SEQ ID NO.49);GC1E8 HC(SEQ ID NO.51);H1C12 HC(SEQ ID NO.53);IA1-1E7HC(SEQ ID NO.55);IF-1C10 HC(SEQ ID NO.57);IK-2E2 HC(SEQID NO.59);IP-2C11 HC(SEQ ID NO.61);526κ(SEQ ID NO.2);536κ(SEQ ID NO.12);543κ(SEQ ID NO.18);544κ(SEQ IDNO.20);551κ(SEQ ID NO.26);553κ(SEQ ID NO.28);555κ(SEQ ID NO.30);558κ(SEQ ID NO.32);565κ(SEQ ID NO.36);FE-B7κ(SEQ ID NO.44);FJ-G11κ(SEQ ID NO.46);FK-E3κ(SEQ ID NO.48);IA1-1E7κ(SEQ ID NO.56);IP-2C11κ(SEQID NO.62);528λ(SEQ ID NO.4);531λ(SEQ ID NO.6);533λ(SEQ ID NO.8);535λ(SEQ ID NO.10);537λ(SEQ ID NO.14);540λ(SEQ ID NO.16);545λ(SEQ ID NO.22);546λ(SEQ IDNO.24);559λ(SEQ ID NO.34);F1-C6λ(SEQ ID NO.38);FB1-A7λ(SEQ ID NO.40);FD-B2λ(SEQ ID NO.42);G1D4λ(SEQ ID NO.50);GC1E8λ(SEQ ID NO.52);H1C12λ(SEQ ID NO.54);IF-1C10λ(SEQ ID NO.58);和IK-2E2λ(SEQ ID NO.60)。
本发明还涉及一种包含以下任意一种互补决定区3(CDR3)的特异结合剂:526 HC(SEQ ID NO.1);528 HC(SEQ ID NO.3);531 HC(SEQ ID NO.5);533 HC(SEQ ID NO.7);535 HC(SEQ ID NO.9);536 HC(SEQ ID NO.11);537 HC(SEQ ID NO.13);540 HC(SEQID NO.15);543 HC(SEQ ID NO.17);544 HC(SEQ ID NO.19);545 HC(SEQ ID NO.21);546 HC(SEQ ID NO.23);551 HC(SEQID NO.25);553 HC(SEQ ID NO.27);555 HC(SEQ ID NO.29);558 HC(SEQ ID NO.31);559 HC(SEQ ID NO.33);565 HC(SEQID NO.35);F1-C6 HC(SEQ ID NO.37);FB1-A7 HC(SEQ ID NO.39);FD-B2 HC(SEQ ID NO.41);FE-B7 HC(SEQ ID NO.43);FJ-G11 HC(SEQ ID NO.45);FK-E3 HC(SEQ ID NO.47);G1D4 HC(SEQ ID NO.49);GC1E8 HC(SEQ ID NO.51);H1C12 HC(SEQ ID NO.53);IA1-1E7 HC(SEQ ID NO.55);IF-1C10 HC(SEQ ID NO.57);IK-2E2 HC(SEQ ID NO.59);IP-2C11 HC(SEQ ID NO.61);526κ(SEQ ID NO.2);536κ(SEQ ID NO.12);543κ(SEQ ID NO.18);544κ(SEQ IDNO.20);551κ(SEQ ID NO.26);553κ(SEQ ID NO.28);555κ(SEQ ID NO.30);558κ(SEQ ID NO.32);565κ(SEQ ID NO.36);FE-B7κ(SEQ ID NO.44);FJ-G11κ(SEQ ID NO.46);FK-E3κ(SEQ ID NO.48);IA1-1E7κ(SEQ ID NO.56);IP-2C11κ(SEQID NO.62);528λ(SEQ ID NO.4);531λ(SEQ ID NO.6);533λ(SEQ ID NO.8);535λ(SEQ ID NO.10);537λ(SEQ ID NO.14);540λ(SEQ ID NO.16);545λ(SEQ ID NO.22);546λ(SEQ IDNO.24);559λ(SEQ ID NO.34);F1-C6λ(SEQ ID NO.38);FB1-A7λ(SEQ ID NO.40);FD-B2λ(SEQ ID NO.42);G1D4λ(SEQ ID NO.50);GC1E8λ(SEQ ID NO.52);H1C12λ(SEQ ID NO.54);IF-1C10λ(SEQ ID NO.58);和IK-2E2λ(SEQ ID NO.60)。
本发明还提供一种编码本发明的特异结合剂的核酸分子。
此外,本发明涉及一种检测生物样品中血管生成素-2水平的方法,包括(a)使本发明的特异结合剂与样品接触,和(b)确定特异结合剂与样品的结合程度。本发明还涉及一种检测生物样品中血管生成素-2水平的方法,包括(a)使本发明的抗体与样品接触,和(b)确定抗体与样品的结合程度。
本发明还涉及抑制哺乳动物不期望的血管发生的方法,包括施用治疗有效量的这里描述的多肽或组合物。本发明还涉及调节哺乳动物血管发生的方法,包括施用治疗有效量的这里描述的多肽或组合物。本发明还涉及抑制哺乳动物中以不期望的血管发生为特征的肿瘤生长的方法,包括施用治疗有效量的这里描述的多肽或组合物。另外,本发明涉及治疗哺乳动物癌症的方法,包括施用治疗有效量的这里描述的多肽或组合物,和化疗药物。在优选的实施方案中,所述化疗药物是5-FU,CPT-11,和脱乙酰基紫杉醇(Taxotere)中的至少一种。但是要明白也能使用其他合适的化疗药物和其他癌症疗法。
可以明白本发明的特异结合剂能被用来治疗与失去控制的或不期望的血管发生相关的多种疾病。这样的疾病包括但不限于,眼新血管化,例如视网膜病(包括糖尿病视网膜病和与年龄相关的黄斑变性),牛皮癣,成血管瘤,血管瘤,动脉硬化,炎性疾病,例如类风湿性或风湿性炎症,特别是关节炎(包括类风湿性关节炎),或者其他慢性炎性紊乱,例如慢性哮喘,动脉或移植后动脉粥样硬化,子宫内膜异位,和肿瘤性疾病,例如所谓实体瘤和液体瘤(例如白血病)。通过施用特异结合剂能治疗的另外的疾病对于本领域技术人员是显而易见的。这样的另外的疾病包括但不限于肥胖,血管渗透,血浆渗漏,骨相关疾病,包括骨质疏松。因此,本发明进一步涉及治疗这些与失去控制或不期望的血管发生相关的疾病的方法。
本发明的其他实施方案通过这里提供的公开内容容易变成显而易见的。
附图简述
图1描述了用本发明的抗Ang-2抗体(克隆533,537或544),对照抗体,或者磷酸缓冲盐水(PBS)治疗的携带肿瘤的小鼠肿瘤体积(y-轴)对时间(x-轴)的曲线图。实施例中描述了详细情况。
图2A,2B,和2C描述分别在全长人Ang-2(hAng-2),hAng-2的N-末端,和hAng-2的C-末端,对于根据本发明的抗体TN8-Con4-C,L1-7-N,和12-9-3-C,以及对于对照抗体,Tie2-Fc,C2B8,或5B12的表位定位数据(O.D.370)。实施例中描述了详细情况。
发明详述
这里使用这部分的标题只是为了组织的目的,而不是为了在任何方面限制描述的主题。
对于重组DNA分子,蛋白质,和抗体制备,以及对于组织培养和细胞转化可以应用标准技术。酶促反应和纯化技术一般根据厂商说明进行或者根据现有技术通常公开的使用常规方法进行,例如Sambrook等(分子克隆:实验室手册“Molecular Cloning:A Laboratory Manual”冷泉港实验室出版社,冷泉港,N.Y.[1989])中给出的那些,或者根据这里描述的。除非提供具体的定义,这里描述的相关术语,试验方法和分析化学,合成有机化学,药学和药剂化学技术是本领域公知的和常规使用的。标准技术可以用于化学合成,化学分析,药物制备,制剂,和送递,和对患者的治疗。
定义
除非另外具体说明,贯穿说明书使用的术语如下定义。
术语″Ang-2″指美国专利No.6,166,185的图6中给出的多肽(″Tie-2配体-2″)或者其片段以及相关的多肽,包括等位变体,剪接变体,衍生物,取代,缺失,和/或插入变体,融合肽和多肽,和种间同系物或者其片段。Ang-2多肽可以包括或可以不包括另外的末端残基,例如,前导序列,引导序列,氨基末端甲硫氨酸,和赖氨酸残基,和/或标记或融合蛋白序列,取决于制备它的方法。
术语″生物活性″当与Ang-2或Ang-2特异结合剂相关联使用时指具有Ang-2或Ang-2特异结合剂的至少一种活性特征的肽或多肽。Ang-2的特异结合剂就Ang-2的至少一种生物活性来说可以具有激动剂,拮抗剂,或中和或阻断活性。
术语″特异结合剂″指一种分子,优选蛋白质分子,其以高于其它血管生成素的亲和力结合Ang-2(及这里定义的其变体和衍生物)。一种特异结合剂可以是一种蛋白质,肽,核酸,碳水化合物,脂质,或者优先与Ang-2结合的小分子量化合物。在优选的实施方案中,根据本发明的特异结合剂是以已知技术通过的抗体,如多克隆抗体,单克隆抗体(mAb),嵌合抗体,CDR嫁接的抗体,多特异性抗体,双特异性抗体,催化抗体,人源化抗体,人抗体,抗独特型(抗Id)抗体和可以以可溶或结合形式标记的抗体,及其片段、变体或衍生物,它们单独存在或与其它氨基酸序列组合。所述技术包括但并不限于酶促裂解,化学裂解,肽合成或重组技术。本发明的抗-Ang-2特异结合剂能结合Ang-2的部分,调节,例如,抑制或促进,Ang-2的生物活性和/或其他Ang-2-相关活性。
术语“多克隆抗体”是指识别并且结合相同抗原上的不同表位的抗体的异质混合物。可以从粗制血清制剂中获得多克隆抗体,或者可以使用例如抗原亲和层析或蛋白A/蛋白G亲和层析进行纯化。
术语“单克隆抗体”是指由相同的核酸分子编码的抗体集合,所述抗体任选由单个杂交瘤或其它细胞系产生,或由转基因哺乳动物产生,这样一般每种单克隆抗体将识别抗原上的相同表位。术语“单克隆”不限于用于制备抗体的特定方法,该术语也不限于在特定物种,如小鼠、大鼠等中产生的抗体。
术语“嵌合抗体”是指一种抗体,其中重链和/或轻链的一部分与来源于特定物种或属于特定抗体种类或亚类的抗体中的相应序列相同或同源,而所述链的其余部分与来源于另一物种或属于另一抗体种类或亚类的抗体中的相应序列相同或同源。也包括所述抗体的片段,它们显示出需要的生物活性(即,特异性结合Ang-2的能力)。见美国专利4,816,567和Morrison etal.,Proc Natl Acad Sci(USA),81:6851-6855[1985]。
术语“CDR嫁接的抗体”是指一种抗体,其中来自特定物种或同种型的一种抗体的CDR被重组插入相同或不同物种或同种型的另一种抗体的构架中。
术语“多特异性抗体”是指一种具有识别一种或多种抗原上的一个以上表位的可变区的抗体。该类型抗体的亚类是识别相同或不同抗原上的两种不同表位的“双特异性抗体”。
“催化”抗体是指这样的抗体,其中一种或多种细胞毒性的,或更普遍地说,一种或更具有生物活性的部分连接于与导向结合剂。
术语“人源化抗体”是指一种特定类型的CDR嫁接的抗体,其中抗体构架区来源于人,但是每个CDR被来源于另一物种的CDR,如鼠CDR取代。术语“CDR”在下文定义。
术语“完全的人”抗体是指其中CDR和构架区均来源于一种或多种人DNA分子的抗体。
术语“抗独特型”抗体是指任何特异性结合于识别抗原的另一种抗体的任何抗体。可以用此处描述的用于产生Ang-2特异性抗体的方法产生抗独特型抗体,只是这些抗体产生自例如用Ang-2特异性抗体或其Ang-2结合片段免疫动物,而不是Ang-2多肽自身或其片段。
这里使用的术语″变体″包括其中天然存在的(至少一种公知的)结合剂的氨基酸序列中的氨基酸残基被插入,缺失和/或取代的那些肽或多肽。本发明的变体包括如下所述的融合蛋白。
″衍生物″包括以不同于插入,缺失或取代的变体的一些方式化学修饰的那些结合剂。
″特异性结合Ang-2″指本发明的特异结合剂(例如抗体,或者其片段)识别并结合成熟的,全长或部分长度的人Ang-2多肽或者其直向同源物的能力,这样其亲和性(根据例如这里描述的亲和性ELISA或BIAcore测定确定)或者其中和能力(根据这里描述的例如,中和作用ELISA测定或类似测定来确定)至少是相同的任何其他血管生成素或其他肽或多肽的亲合力或中和能力的大小的10倍,但是任意地是50倍,100,250或500倍,或者甚至至少1000倍,其中抗体的肽部分第一次与人Pc部分融合用于在这样的测定中评价。
术语“抗原结合域”或“抗原结合区”是指含有与抗原相互作用并且在结合剂上赋予其对抗原的特异性和亲和力的特异结合剂氨基酸残基(或其它部分)的特异结合剂(如抗体分子)的部分。在抗体中,抗原结合域通常称作“互补决定区或CDR”。
术语″表位″指在一个或多个结合剂的抗原结合区能被特异结合剂例如抗体识别和结合的任何分子的部分。表位通常由化学活性表面分子基团例如氨基酸或糖基侧链组成,并且具有特异三维结构特征以及特异电荷特征。这里使用的表位可以是连续或不连续的。
术语″抑制和/或中和表位″是一种表位,当被特异结合剂例如抗体结合时,它导致体内,体外,或者原位包含这样的表位的分子,细胞,或生物体的生物活性的丧失(或者至少降低)。在本发明的上下文中,中和表位位于Ang-2的生物活性区或者与Ang-2的生物活性区有关。或者,术语″活性表位″是一种表位,当被本发明的特异结合剂例如抗体结合时,导致Ang-2的生物活性构象激活,或者至少维持。
术语″抗体片段″指肽或多肽,其包括完全完整抗体的部分。完全的抗体包含两个功能独立的部分或片段:称作“Fab”的抗原结合片段和称作“Fc”的羧基末端可结晶片段。Fab片段包括来自重链和轻链的第一恒定区(CH1和CL1)以及结合特异性抗体的来自重链和轻链的可变区。重链和轻链的每一个都包括三个互补决定区(CDRs)和分开各个CDRs的构架氨基酸残基。Fc区包括第二和第三重链恒定区(CH2和CH3)并且参与效应物功能如补体激活和吞噬细胞攻击。在一些抗体中,Fc和Fab区由抗体“铰链区”分开,并且,根据全长抗体如何被蛋白酶促裂解,饺链区可以与Fab或Fc片段缔合。例如,用木瓜蛋白酶裂解抗体,导致铰链区与得到的Fc片段缔合,而用胃蛋白酶裂解,提供了其中的铰链区与两个Fab片段同时缔合的片段。由于两个Fab片段实际上是在胃蛋白酶裂解之后共价连接的,得到的片段被称作F(ab′)2片段。
Fc结构域可以具有相对长的血清半寿期,而Fab的寿命短。[Caponetal.,Nature,337:525-31(1989)]。当作为融合蛋白的一部分表达时,Fc结构域可以赋予更长的半寿期或者带来诸如Fc受体结合、蛋白A结合、补体固定和可能甚至胎盘转移至与其融合的蛋白中的功能。Fc区可以是天然存在的Fc区,或者可以经改变而改进某些质量,如治疗质量或循环时间。
术语“可变区”或“可变结构域”是指抗体轻链和/或重链的一部分,一般包括重链中的大约氨基末端的120-130个氨基酸和轻链中的大约100-110个氨基末端氨基酸。可变区一般在氨基酸序列中,甚至在相同物种的抗体中广泛不同。抗体的可变区一般决定其特定抗原的每种特定抗体的结合和特异性。序列的可变性集中在那些称作互补决定区(CDRs)的区域中,而可变区中保守性更高的区域称作构架区(FR)。轻链和重链的CDRs在其中含有很大程度负责抗体与抗原的直接相互作用的氨基酸,而FRs中的氨基酸可以显著影响抗原结合/识别,如下文所讨论。
当涉及抗体时,根据恒定区的氨基酸序列,术语“轻链”集中指两种不同的类型,即κ或λ。
当涉及抗体时,根据重链恒定区的氨基酸序列,术语“重链”是指五种不同的类型,即α,δ,ε,γ和μ。重链和轻链的组合产生了五种公知的抗体类型,分别为IgA,IgD,IgE,IgG和IgM,包括四种公知的IgG亚类,命名为IgG1,IgG2,IgG3和IgG4。
当与象核酸分子,多肽,宿主细胞等这样的生物材料相关使用时,术语″天然存在的″指在自然界发现的没有被人改变的那些。
术语″分离的″当与Ang-2相关或与Ang-2的特异结合剂相关的使用时,指没有至少一种其天然环境中发现的污染多肽或化合物的化合物,优选基本上没有会干扰其治疗或诊断用途的污染哺乳动物多肽。
当术语″成熟″与Ang-2抗体或者其片段相关使用时,或者与Ang-2的其他蛋白质特异结合剂相关使用时,指没有前导序列或信号序列的肽或多肽。在例如在原核宿主细胞中表达本发明的结合剂时,″成熟″肽或多肽还可以包括另外的氨基酸残基(但是仍然没有前导序列),例如氨基末端甲硫氨酸,或者一个或多个甲硫氨酸和赖氨酸残基。可以使用用这种方法制备的肽或多肽,这些另外的氨基酸残基已经被去除或者没有被去除。
术语″有效量″和″治疗有效量″与Ang-2的特异结合剂相关使用时,指对于支持Ang-2的一种或几种生物活性水平可观察变化是有用的或必需的量。所述变化可以是Ang-2活性水平的提高或降低。优选地,所述变化是Ang-2活性水平的降低。
特异结合剂和抗体
此处使用的术语“特异结合剂”是指此处描述的具有识别和结合Ang-2的特异性的分子。适当的特异结合剂包括,但不限于,抗体及其衍生物,多肽和小分子。可以使用本领域公知的方法制备适当的特异结合剂。本发明的一种示例性的Ang-2多肽特异结合剂能够结合Ang-2的某一部分,并且优选调节Ang-2多肽的活性或功能。
特异性结合Ang-2多肽的抗体和抗体片段等特异结合剂在本发明的范围内。抗体可以是多克隆抗体,包括单特异性多克隆抗体,单克隆抗体,重组抗体,嵌合抗体,人源化抗体,如CDR嫁接的抗体,人抗体,单链抗体,催化抗体,多特异性和/或双特异性抗体,及其片段,变体和/或衍生物。
一般通过多次皮下或腹膜内注射添加或不添加佐剂的Ang-2多肽或其片段在动物(如兔、仓鼠、山羊、绵羊、马、猪、大鼠、沙鼠、豚鼠、小鼠或任何其它适当的哺乳动物,以及其它非哺乳动物物种)中产生针对Ang-2多肽的单克隆抗体。所述佐剂包括,但不限于弗氏完全和不完全佐剂,矿物凝胶如氢氧化铝,和表面活性物质如溶血卵磷脂、多元醇、聚阴离子、肽、油乳液、匙孔血蓝蛋白和二硝基苯酚。BCG(bacilliCalmette-Guerin)和Corynebacterium parvum是可能有用的人类佐剂。将抗原多肽与在要免疫的物种中具有免疫原性的载体蛋白,如匙孔血蓝蛋白,血清,白蛋白,牛血红蛋白或大豆胰蛋白酶抑制剂偶联可能是有用的。同样,聚集剂如明矾也可用于增强免疫应答。免疫后,对动物取血,测定抗Ang-2多抗体滴度,这可以使用“实施例”部分描述的测定法来确定。多克隆抗体可以在检测到它们的血清中利用,或者可以从血清中纯化,使用例如抗原亲和层析或蛋白A或G亲和性层析。
可以使用例如,但不限于传统的“杂交瘤”方法或更新的“噬菌体展示”技术产生针对Ang-2多肽的单克隆抗体。例如,可以按照Kohleretal.,Nature 256:495[1975];the human B-cell hybridomatechnique[Kosbor et al.,Immunol Today 4:72(1983);Coteetal.,Proc Natl Acad Sci(USA)80:2026-2030(1983);Brodeuret al.,Monoclonal Antibody Production Techniques andApplications,pp.51-63,Marcel Dekker,Inc.,New York,(1987)]and theEBV-hybridoma technique[Cole etal.,Monoclonal Antibodies and Cancer Therapy,Alan R Liss Inc,NewYork N.Y.,pp 77-96,(1985)]中描述的杂交瘤方法制备单克隆抗体。本发明还提供了产生与Ang-2多肽反应的单克隆抗体的杂交瘤细胞系。
当使用杂交瘤技术时,可以使用骨髓瘤细胞系。所述适用于生产杂交瘤的融合程序的细胞系优选不产生抗体,具有高融合效率,并且由于缺乏酶而使得它们不能在仅仅支持所需的融合细胞(杂交瘤)生长的某些选择性培养基中生长。例如,用于小鼠融合的细胞系为Sp-20,P3-X63/Ag8,P3-X63-Ag8.653,NSI/I.Ag 4 1,Sp210-Ag14,FO,NSO/U,MPC-11,MPC11-X45-GTG 1.7和S194/5XXO Bul,用于大鼠融合的细胞系为R210.RCY3,Y3-Ag 1.2.3,IR983F和4B210。其它适用于细胞融合的细胞系为U-266,GM1500-GRG2,LICR-LON-HMy2和UC729-6。考虑杂交瘤和其它产生单克隆抗体的细胞系为本发明的新组合物。
也可使用噬菌体展示技术从任何物种产生单克隆抗体。优选地,该技术用于产生完全的人抗体,其中编码单Fab或Fv抗体片段的多核苷酸在噬菌体颗粒的表面上表达。[Hoogenboom etal.,J Mol Biol227:381(1991);Marks etal.,J Mol Biol 222:581(1991);也见美国专利No.5,885,793]]。可以使用这里描述的结合测定“筛选”每个噬菌体,以鉴定那些具有Ang-2亲和性的抗体片段。因此,这些方法通过在丝状噬菌体的表面展示抗体片段所有组成成分而模拟免疫选择,并且随后通过它们与Ang-2的结合选择噬菌体。一种这样的方法描述于以Adams等的名义提交的PCT申请PCT/US98/17364,该申请描述了使用这样的方法分离MPL-和msk-受体的高亲和性和功能性激动抗体片段。在该方法中,按照以前的描述[Mullinax etal.,Proc Natl Acad Sci(USA)87:8095-8099(1990)],可以通过从外周血淋巴细胞克隆天然重排的人V基因而产生完全的人抗体所有组成成分的基因。
一旦鉴定了编码本发明的全长单克隆抗体的每条链或Fab或Fv片段的多核苷酸序列,可以采用公知的重组技术和本领域的常规实践,使用真核或原核宿主细胞表达单克隆抗体多核苷酸。或者,生产转基因动物,其中编码所需特异结合剂的多核苷酸被导入受体动物,例如,小鼠,兔,山羊或牛,采用的方式允许编码单克隆抗体或其它特异结合剂的多核苷酸分子表达。一方面,可以将编码单克隆抗体或其它特异结合剂的多核苷酸连接至哺乳动物特异性调节序列,并且嵌合多核苷酸可以被导入靶动物的生殖系。得到的转基因动物然后在其乳中产生需要的抗体[Pollock etal.,J Immunol Meth 231:147-157(1999);Little et al.,Immunol Today 8:364-370(2000)]。此外,通过用编码单克隆抗体或其它特异结合剂的多核苷酸转染适当植物,使用植物表达并且产生Ang-2特异结合剂如单克隆抗体。
在本发明的另一种实施方案中,来源于人之外的物种的单克隆或多克隆抗体或其片段可以是“人源化的”或“嵌合的”。对非人抗体进行人源化的方法是本领域公知的(见美国专利5,859,205,5,585,089,和5,693,762)。例如,人源化是利用本领域描述的方法[Jones etal.,Nature 321:522-525(1986);Riechmann etal.,Nature,332:323-327(1988);Verhoeyen etal.,Science 239:1534-1536(1988)],通过用人抗体的相应区域取代如啮齿动物的互补决定区(CDRs)的至少一部分而进行的。如此处所讨论和本领域所公知,本发明还提供了这些人抗体的变体和衍生物。
本发明还包括结合Ang-2多肽的完全的人抗体,及其片段、变体和/或衍生物。可以使用此处描述的噬菌体展示技术产生所述抗体。或者,可以使用在不产生内源性免疫球蛋白的情况下能够产生人抗体的所有组成成分的转基因动物(如小鼠)产生所述抗体。这可以通过用Ang-2抗原或其片段免疫动物而完成,其中Ang-2片段具有Ang-2独特的氨基酸序列。所述免疫原可以任选与载体偶联。见,例如,Jakobovits et al.,Proc Natl Acad Sci(USA),90:2551-2555(1993);Jakobovits et al.,Nature 362:255-258(1993);Bruggermann et al.,Year in Immuno,7:33(1993)。在一种方法中,所述转基因动物是通过使编码其中的重链和轻链免疫球蛋白的内源性基因座失去功能,并且将编码人重链和轻链蛋白的基因座插入其基因组而制备。然后将具有少于这些完整的修饰的部分修饰的动物进行杂交以获得具有所有所需的免疫系统修饰的动物。当施用免疫原时,这些转基因动物能够产生具有人可变区的抗体,包括人(而不是,例如鼠)的氨基酸序列,它们对于所需的抗原是免疫特异性的。见PCT申请PCT/US96/05928和PCT/US93/06926。其它方法描述于美国专利5,545,807,PCT申请PCT/US91/245,PCT/GB89/01207,以及EP546073B1和EP546073A1。也可以如此处所述,通过在宿主或者通过在此处所描述的杂交瘤细胞中表达重组DNA而产生人抗体。
转基因是通过很多不同的途径完成的。见,例如,Bruggeman et al.,Immunol Today 17:391-7(1996)。在一种方法中,构建一种微基因座,这样,人工使得种系构型中的基因片段彼此接近。由于大小限制(即一般小于30kb),得到的微基因座将含有有限数量的不同基因片段,但仍然能够产生抗体的大的所有组成成分。仅仅含有人DNA序列,包括启动子和增强子的微基因座在转基因小鼠中是完全有功能的。
当在转基因动物中需要更大数目的基因片段时,使用酵母人工染色体(YACs)。YACs可以从数十万碱基到1Mb,并且通过直接微量注射到卵中或者通过将YAC转移到胚胎干(ES)细胞系中而导入小鼠(或其它适当的动物)基因组。一般地,通过纯化DNA的脂转染或酵母原生质球融合而将YACs转移到ES细胞中,其中纯化的DNA携带于微团中,并且以类似于杂交瘤融合程序的方式进行融合。在DNA转移之后选择所需的ES细胞是通过在YAC上引入本领域公知的任何选择标记而完成的。
作为另一种选择,使用在细菌大肠杆菌宿主中扩增的噬菌体P1载体。尽管这些载体比YAC携带更少的插入的DNA,这些克隆容易以足够高的产率生长,以便允许直接微量注射到小鼠卵中。已经证明使用不同P1载体的混合物可以导致高水平的同源重组。
一旦已经使用本领域公知的任何检测循环抗体的血清水平的技术(如ELISA)鉴定了适当的转基因小鼠(或其它适当的动物),将转基因动物与其中的内源Ig基因座被破坏的小鼠杂交。该结果提供了其中基本上所有的B细胞都表达人抗体的后代。
作为另一种选择,用人Ig基因座置换完整的动物Ig基因座,其中得到的动物仅仅表达人抗体。在另一种方法中,用人基因座中的特定和相应区域置换动物基因座的部分。在某些情况下,从该程序得到的动物可以表达与完全的人抗体不同的嵌合抗体,这取决于小鼠Ig基因座中置换的性质。
也可以通过体外将人脾细胞(B或T细胞)暴露于抗原,然后在免疫受损的小鼠如SCID或nod/SCID中重建暴露的细胞而产生人抗体。见Brams et al.,J Immunol,160:2051-2058[1998];Carballidoet al.,Nat Med,6:103-106[2000]。在一种方法中,将人胎组织移植到SCID小鼠(SCID-hu)中,导致长期造血和人T细胞发育[McCuneetal.,Science 241:1532-1639(1988);Ifversen et al.,SemImmunol 8:243-248(1996)]。这些嵌合小鼠中的任何体液免疫应答完全依赖于这些动物中T细胞的共发育[Martensson etal.,Immunol83:1271-179(1994)]。在一种可选择的方法中,将人外周血淋巴细胞腹膜内(或其它方式)移植到SCID小鼠中[Mosier et al.,Nature 335:256-259(1988)]。当用激发剂,如葡萄球菌外毒素A(SEA)[Martensson et al.,Immunol 84:224-230(1995)],或抗人CD40单克隆抗体[Murphy etal.,Blood 86:1946-1953(1995)]处理移植细胞时,检测到了更高水平的B细胞产生。
或者,通过组装每个人VH片段和随机核苷酸的D片段以及人J片段从未重排的V基因片段产生完全合成的人重链所有组成成分[Hoogenboom etal.,J Mol Biol 227:381-388(1992)]。同样,通过组合每个人V片段和J片段构建轻链所有组成成分[Griffiths etal.,EMBO J 13:3245-3260(1994)]。将编码完整抗体(即重链和轻链)的核苷酸作为单链Fv片段连接,并且将该多核苷酸与编码丝状噬菌体小外被蛋白的核苷酸连接。当在噬菌体表面表达该融合蛋白时,通过使用固定抗原进行选择而鉴定编码特异性抗体的多核苷酸。
在另一种方法中,通过使一条链与噬菌体蛋白融合,并且将另一条链分泌到细菌周质中而将抗体片段组装为两个Fab片段[Hoogenboomet al.,Nucl Acids Res 19:4133-4137[1991];Barbas etal.,ProcNatl Acad Sci(USA)88:7978-7982(1991)]。
一般通过重组方法产生嵌合的、人源化的、CDR嫁接的和完全的人抗体或其片段。可以用此处描述的材料和方法将编码每种抗体的重链和轻链或其片段的多核苷酸分子导入宿主细胞并且进行表达。在一种优选实施方案中,所述抗体在哺乳动物宿主细胞,如CHO细胞中产生。所述产生的详细内容描述于下文。
特异结合剂的融合配偶体
在本发明的另一实施方案中,包含Ang-2抗体可变区,如具有此处描述的氨基酸序列的重链可变区或具有此处描述的氨基酸序列的轻链可变区的氨基酸序列的多核苷酸可以在N末端或C末端与人IgG的Fc区的一个或多个结构域融合。当与一种治疗蛋白,如Ang-2特异性抗体的Fab一起构建时,Fc结构域可以提供更长的半寿期,或者掺入Fc受体结合、蛋白A结合、补体固定以及可能甚至是胎盘转移等功能[Capon etal.,Nature,337:525-531(1989)]。
在一个例子中,可以使用本领域技术人员公知的方法,可以在抗Ang-2Fab或Fv片段等特异结合剂多肽(例如从噬菌体展示文库获得)的N末端或C末端融合抗体铰链区、CH2和CH3区。可以使用蛋白A或蛋白G亲和柱纯化得到的融合蛋白。已经发现融合于Fc区的肽和蛋白与未融合的对应物相比表现出显著更长的体内半寿期。同样,与Fc区的融合允许融合多肽的二聚化/多聚化。Fc区可以是天然存在的Fc区,或者可以经改变而改进某些质量,如治疗质量、循环时间、减少聚集问题等。本领域公知的其它例子包括以下这些,其中可以来自于人或其它物种或可以是合成的Fc区与CD30L的N末端融合以治疗霍奇金病、退行性淋巴瘤和T细胞白血病(美国专利5,480,981),Fc区与TNF受体融合以治疗脓毒性体克[Fisher etal.,N Engl J Med,334:1697-1702(1996)],Fc区与Cd4受体融合以治疗AIDS[Capon et al.,Nature,337:525-31(1989)]。
催化抗体是另一种类型的融合分子,并且包括一种或多种细胞毒性部分或更普遍的是一种或多种生物活性部分连接的抗体,所述抗体与特异结合剂连接。见,例如[Rader et al.,Chem Eur J 12:2091-2095(2000)]。该类型的细胞毒性剂改进抗体介导的细胞毒性,并且包括直接或间接刺激细胞死亡的细胞因子、放射性同位素、化疗药物(包括药物前体)、细菌毒素(如假单孢菌外毒素、白喉毒素等)、植物毒素(如蓖麻毒蛋白、gelonin等)、化学偶联物(如maytansinoid毒素,calechaemicin等)、放射性偶联物、酶偶联物(RNA酶偶联物、抗体定位的酶/药物前体治疗[ADEPT])等部分。一方面,细胞毒性剂可以通过将该试剂结合于抗体上的一种可选择的抗原识别位点而“连接”于双特异性或多特异性抗体的一种成分。作为一种选择,可以在将编码毒素的多核苷酸连接于编码结合剂的多核苷酸之后将蛋白毒素表达为与特异结合剂的融合蛋白。在另一种选择中,可以共价修饰特异结合剂以包括需要的细胞毒素。
所述融合蛋白的例子是免疫原性多肽、具有长循环半寿期的蛋白,如免疫球蛋白恒定区、标记蛋白、促进所需特异性结合剂多肽纯化的蛋白或多肽,以及促进多聚蛋白(如用于二聚体形成/稳定性的亮氨酸拉链基序)形成的多肽序列。
这种类型的插入性变体通常具有天然分子的所有或大部分,在N或C末端连接于第二种多肽的所有或一部分。例如,融合蛋白一般使用来自其它物种的前导序列,以便允许蛋白在异源宿主中的重组表达。另一种有用的融合蛋白包括添加免疫学活性结构域,如抗体表位,以便促进融合蛋白的纯化。在融合蛋白的结合处或其附近引入裂解位点将促进在纯化后去除外源性多肽。一种有用的融合包括连接功能性结构域如酶的活性位点、糖基化位点、细胞导向信号或跨膜区。
这种类型的插入变体一般具有在N-或C-末端与第二多肽的全部或部分连接的天然分子的全部或大部分。例如,融合蛋白一般使用来自其他物种的前导序列以允许在异源宿主中重组表达蛋白质。另一种有用的融合蛋白包括免疫活性结构域例如抗体表位的加入,以有利于融合蛋白的纯化。融合连接处或附近裂解位点所包含的会有利于在纯化之后去除外来多肽。其他有用的融合物包括功能结构域的连接,例如来自酶的活性位点,糖基化结构域,细胞定向信号或跨膜区。
有很多可以在本发明中使用的商售融合蛋白表达系统。特别有用的系统包括但不限于谷胱甘肽-S-转移酶(GST)系统(Pharmacia),麦芽糖结合蛋白系统(NEB,Beverley,Mass.),FLAG系统(IBI,New Haven,Conn.),和6xHis系统(Qiagen,Chatsworth,Calif.)。这些系统能产生只带有少数附加氨基酸的重组肽和/或抗体,这少数附加氨基酸不可能显著重组多肽抗原能力。例如,FLAG系统和6xHis系统只加入短序列,已知这两种系统免疫原性不好并且不会不利地影响多肽折叠成它的天然构象。另一种有用的N-末端融合体是蛋白质或肽的N-末端区Met-Lys二肽的融合体。这样的融合体可以产生蛋白质表达或活性的有利的提高。
一种特别有用的融合构建体可以是其中特异结合剂肽与半抗原融合以增强特异结合剂融合构建体的免疫原性的那种,所述特异结合剂融合构建体可以用于例如产生本发明的抗独特型抗体。所述融合构建体增加免疫原性是本领域技术人员公知的,例如,特异结合剂与辅助抗原如hsp70,或例如来自白喉毒素链的肽序列,或细胞因子如IL-2的融合体可以用于激发免疫应答。在另一种实施方案中,可以制备增强抗原结合剂组合物导向于特定位点或细胞。
也考虑其它融合构建体,它包括具有所需特性,如延长血清半寿期的IgG恒定区或用于导向的抗体或其片段的异源多肽。其他融合体系产生多肽杂合体,其中期望从期望的肽或抗体切除融合配偶体。在一个实施方案中,融合配偶体通过含有蛋白酶的特异识别序列的肽序列与重组抗体连接。合适的序列的例子是烟草Etch病毒蛋白酶(LifeTechnologies,Gaithersburg,Md.)或因子Xa(New EnglandBiolabs,Beverley,Mass.)识别的那些。
本发明还提供了融合多肽,其包括与截短的组织因子(tTF)组合的Ang-2抗体的可变区的全部或部分,如具有此处描述的氨基酸序列的重链可变区或具有此处描述的氨基酸序列的轻链可变区,TTF是由作为肿瘤血管凝固剂发挥作用的人血凝固-诱导蛋白质的截短形式构成的血管靶向剂,如美国专利Nos.:5,877,289;6,004,555;6,132,729;6,132,730;6,156,321;和欧洲专利No.EP 0988056所述。TTF与抗-Ang-2抗体或肽,或者其片段的融合有利于抗-Ang-2向靶细胞的送递。
特异结合剂的变体
本发明的特异性结合剂的变体包括插入,缺失,和/或取代变体。在本发明的一个方面,提供了插入变体,其中一个或多个氨基酸残基补充了特异结合剂氨基酸序列。插入可以位于氨基酸蛋白的一端或两端,或者可以位于特异结合剂氨基酸序列的内部区域。在一个末端或者两个末端有附加残基的插入变体能包括,例如,包括氨基酸标记或标记的融合蛋白和蛋白质。插入变体特异结合剂多肽,其中将一个或多个氨基酸残基添加到特异结合剂氨基酸序列,或其片段。
本发明的变体产物还包括成熟的特异结合剂产物。所述特异结合剂产物去除了前导序列或信号序列,得到的蛋白质与野生型Ang-2多肽相比有附加的氨基末端残基。附加的氨基末端残基可以来源于另一种蛋白,或可以包括一个或多个不能鉴定为来自于特定蛋白的残基。包括氨基酸位置-1有附加的甲硫氨酰残基的特异性结合剂(Met-1-特异结合剂),这些是在位置-2和-1有附加的甲硫氨酸和赖氨酸残基(Met-2-Lys-1-特异结合剂)的特异性结合剂产物。有附加的Met,Met-Lys,Lys残基(或一个或多个碱性残基,一般地)的变体特别用于在细菌宿主细胞中提高重组蛋白质生产。
本发明还包括使用特异表达系统产生的具有附加的额氨基酸残基的特异性结合剂。例如,使用表达作为谷胱甘肽-S-转移酶(GST)融合产物的一部分的期望的多肽的商售载体提供从期望的多肽裂解GST成分之后在氨基酸位置-1具有附加的甘氨酸残基的期望的多肽。也包括在其他载体系统表达得到的变体,包括其中一般在序列的羧基和/或氨基末端向氨基酸序列中插入聚组氨酸标记的那些。
插入变体还包括上文所述的融合蛋白,其中特异结合剂多肽的氨基和/或羧基末端与另一个多肽,其片段或者一般没有识别是任何特异蛋白质序列的一部分的氨基酸融合。
另一方面,本发明提供缺失变体,其中特异结合剂多肽中一个或多个氨基酸残基被去除。从特异结合剂多肽的一个或两个末端进行缺失,或者在抗体氨基酸序列中去除一个或多个残基。缺失变体必须包括特异结合剂多肽的所有的片段。
抗体片段包括结合于抗原多肽上的表位的抗体部分。所述片段的例子包括Fab和F(ab′)2片段,它们例如是通过全长抗体的酶促或化学裂解产生的。其它结合片段包括通过重组DNA技术,如含有编码抗体可变区的核酸序列的重组质粒的表达等产生的那些。本发明还包括Ang-2结合剂的多肽片段,其中所述片段维持了特异性结合Ang-2多肽的能力。此处也包括含有本发明的肽或多肽的至少5,10,15,20,25,30,35,40,45或50个连续氨基酸的片段。优选的多肽片段显示出本发明的抗原结合剂独特或特异的免疫学特性。可以通过本领域公知和常规实践的任何方法制备具有所需免疫学特性的本发明的片段。
另一方面,本发明提供本发明的特异结合剂的取代变体。一般认为取代变体与原来的多肽“相似”,或者与原来的多肽具有一定的“同一性百分比”,并且包括其中多肽的一个或多个氨基酸残基被去除并且由其它残基置换的多肽。一方面,取代作用性质是保守的,但是本发明包括也是不保守的取代作用。
通过公知的方法能容易地计算相关的多肽的同一性和相似性。这样的方法包括但不限于下面文献描述的那些:ComputationalMolecular Biology,Lesk,A.M.,编著,Oxford University Press,New York(1988);Biocomputing:Informatics and GenomeProjects,Smith,D.W.,编著,Academic Press,New York(1993);Computer Analysis of Sequence Data,Part 1,Griffin,A.M.,和Griffin,H.G.,编著,Humana Press,New Jersey(1994);Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press(1987);Sequence Analysis Primer,Gribskov,M.和Devereux,J.,编著,M.Stockton Press,New York(1991);和Carillo等,SIAM J.Applied Math.,48:1073(1988)。
设计测定两个多肽的相关性或同一性百分比的优选方法,得到测试序列之间的最大匹配。公众能够得到的计算机程序中描述了测定同一性的方法。测定两个序列之间的同一性的优选的计算机程序方法包括但不限于,GCG程序包,包括GAP(Devereux等,Nucl.Acid.Res.,12:387(1984);Genetics Computer Group,University ofWisconsin,Madison,WI,BLASTP,BLASTN,和FASTA(Altschul等,J.Mol.Biol.,215:403-410(1990))。公众从the NationalCenter for Biotechnology Information(NCBI)和其他来源(BLASTManual,Altschul等NCB/NLM/NIH Bethesda,Md.20894;Altschul等,上文(1990))能获得BLASTX程序。也可以使用公知的SmithWaterman算法来测定同一性。
用于将两个氨基酸序列比对的一些比对方案可以导致两个序列只有一个短的区匹配,这个小的比对区可以具有非常高的序列同一性,即使两个全长序列之间没有显著相关性。因此,在一些实施方案中,选择的比对方法(GAP程序)可以导致跨距至少是比较的靶多肽全长的10%对齐,即,比较至少400个氨基酸序列时至少40个连续的氨基酸,比较至少300至大约400个氨基酸序列时至少30个连续的氨基酸,比较至少300至大约400个氨基酸序列时至少30个连续的氨基酸,比较200至大约300个氨基酸序列时至少20个连续的氨基酸,比较大约100至200个氨基酸序列时至少10个连续的氨基酸。
例如,利用计算机算法GAP(Genetics Computer Group,University of Wisconsin,Madison,Wis.),将要测定序列同一性百分比的两个多肽对它们各个氨基酸进行最佳匹配比对(″匹配跨度″,根据算法确定)。在一些实施方案中,空位罚分(一般计算为3X平均对角线;″平均对角线″是使用的比较矩阵的对角线的平均值;″对角线″是特定比较矩阵分配给每一个完全氨基酸匹配的分数或数目)和空位延长罚分(它通常是空位罚分的1/10倍),并且与算法联合使用象PAM250或BLOSUM 62这样的比较矩阵。在一些实施方案中,算法还使用标准比较矩阵(关于PAM 250比较矩阵,参见Dayhoff等,Atlas ofProtein Sequence and Structure,5(3)(1978);关于BLOSUM 62比较矩阵,参见Heni koff等,Proc.Natl.Acad.Sci USA,89:10915-10919(1992))。
在一些实施方案中,多肽序列比较参数包括如下:
算法:Needleman等,J.Mol.Biol.,48:443-453(1970);
比较矩阵:上文Henikoff等(1992)的BLOSUM 62;
空位罚分:12
空位延长罚分:4
相似性阈值:0
使用上述参数的GAP程序是有用的。在一些实施方案中,使用GAP算法,上述参数对于多肽比较是默认参数(对于末端空位没有罚分)。
在一些实施方案中,对于多核苷酸分子序列(与氨基酸序列相对应)的参数包括如下:
算法:Needleman等,上文(1970);
比较矩阵:匹配=+10,错配=0
空位罚分:50
空位延长罚分:3
使用上述参数的GAP程序也是有用的。上述参数对于多核苷酸分子比较是默认参数。
其他例举的算法,空位罚分,空位延长罚分,比较矩阵,相似性阈值等也可以使用Program Manual,Wisconsin Package,第9版,1997年9月中提出的那些。进行的具体选择对于本领域技术人员来说是显而易见的并且取决于要进行的具体比较,例如DNA-与-DNA,蛋白质-与-蛋白质,蛋白质-与-DNA;另外,比较是否在给定序列对之间(其中一般优选GAP或BestFit)或者在一个序列和一个序列的大数据库之间(其中FASTA或BLASTA是优选的)。
如这里使用的,按常规使用20种常见氨基酸和它们的缩写。参见Immunology-A Synthesis(第二版,E.S.Golub和D.R.Gren,Eds.,Sinauer Associates,Sunderland,Mass.(1991)),这里为了所有的目的引作参考。
氨基酸可以具有L或D立体化学(除了Gly之外,其即不是L也不是D),并且本发明的多肽和成分可以包括立体化学的混合物。但是,L立体化性是优选的。本发明还提供了反向分子,其中氨基酸的氨基末端至羧基末端序列是反向的。例如,具有正常序列X1-X2-X3的分子的反向应该是X3-X2-X1.。本发明还提供了逆-反向分子,其中,如上所述,氨基酸的氨基末端至羧基末端序列是反向的,并且一般的″L″对映异构体的残基被改变为″D″立体异构型。
二十种常见氨基酸的立体异构体(例如,D-氨基酸),非天然氨基酸,例如[α]-,[α]-二取代氨基酸,N-烷基氨基酸,乳酸,和其他非常见氨基酸也是本发明的多肽的合适的成分。非常见氨基酸的例子包括但不限于:氨基脂肪酸,β-丙氨酸,β-氨基丙酸,氨基丁酸,哌啶酸,氨基癸酸,氨基庚酸,氨基异丁酸,氨基庚二酸,二氨基丁酸,锁链素,二氨基庚二酸,二氨基丙酸,N-乙基甘氨酸,N-乙基天冬酰胺,羟基赖氨酸,异-羟基赖氨酸,羟基脯氨酸,异锁链素,异-异亮氨酸,N-甲基甘氨酸,肌氨酸,N-甲基异亮氨酸,N-甲基缬氨酸,新缬氨酸,正亮氨酸,鸟氨酸,4-羟基脯氨酸,[γ]-羧基谷氨酸,[ε]-N,N,N-三甲基赖氨酸,[ε]-N-乙酰基赖氨酸,O-磷酸丝氨酸,N-乙酰基丝氨酸,N-甲酰基甲硫氨酸,3-甲基组氨酸,5-羟基赖氨酸,[σ]-N-甲基精氨酸,和其他相似氨基酸和氨基酸(例如,4-羟基脯氨酸)。
类似地,除非具体说明,单链多核苷酸序列的左手端是5′端;双链多核苷酸序列的左手方向指为5′方向。初始RNA转录本的5′至3′加入方向称作转录方向;和RNA具有相同序列并且是RNA转录本的5′至5′端的DNA链上的序列区称作″上游序列″;和RNA具有相同序列并且是RNA转录本的3′至3′端的DNA链上的序列区称作″下游序列″。
保守性氨基酸取代可以包括非天然存在的氨基酸残基,它们一般是通过化学肽合成,而不是通过在生物系统中合成而掺入的。这些包括肽模拟物和氨基酸部分的反向或插入形式。
天然存在的残基可以根据它们共同的侧链性质分为几类:
1)疏水性:Met,Ala,Val,Leu,Ile;
2)中性疏水性:Cys,Ser,Thr,Asn,Gln;
3)酸性:Asp,Glu;
4)碱性:His,Lys,Arg;
5)影响链取向的残基:Gly,Pro;和
6)芳香:Trp,Tyr,Phe。
例如,非保守性取代可以包括将这些类中的一个变化为另一类中的一个。所述取代的残基可以引入人抗体中与非人抗体同源的区域,或者引入分于的非同源区。
根据一些实施方案,进行这样的变化时,可以考虑氨基酸的亲水指数(hydropathic index)。以氨基酸的疏水性和电荷特征为基础对各种氨基酸指派亲水指数。它们是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸/胱氨酸(+2.5);蛋氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9);和精氨酸(-4.5)。
本领域知晓氨基酸亲水指数在对蛋白质带来相互影响的生物学功能中的重要性。Kyte等,J.Mol.Biol.,157:105-131(1982)。已知某些氨基酸可以被具有相似亲水指数或分数的另外的氨基酸取代而仍然保留相似的生物活性。在根据亲水指数进行变化中,在一些实施方案中,包括亲水指数在±2之内的氨基酸取代。在一些实施方案中,包括亲水指数在±1之内的那些,在一些实施方案中,包括亲水指数在±0.5之内的那些。
本领域还知晓,以亲水性为基础能有效地进行类似氨基酸的取代,特别是在由此产生的生物功能抗体或肽是为了在免疫实施方案中应用的情况下,本发明情况就是如此。在一些实施方案中,蛋白质最大局部平均素水性,这由其相邻氨基酸的亲水性支配,与它的免疫原性和抗原性相关,即,与蛋白质的生物学性质相关。
对这些氨基酸残基指定下面的亲水性值:精氨酸(+3.0);赖氨酸(+3.0);天冬氨酸(+3.0±1);谷氨酸(+3.0±1);丝氨酸(+0.3);天冬氨酸(+0.2);谷氨酰胺(+0.2);甘氨酸(0);苏氨酸(-0.4);脯氨酸(-0.5±1);丙氨酸(-0.5);组氨酸(-0.5);半胱氨酸(-1.0);蛋氨酸(-1.3);缬氨酸(-1.5);亮氨酸(-1.8);异亮氨酸(-1.8);酪氨酸(-2.3);苯丙氨酸(-2.5)和色氨酸(-3.4)在根据相似亲水性值进行改变中,在一些实施方案中,包括其亲水性值在±2之内的氨基酸取代。在一些实施方案中,包括亲水性值在±1之内的那些,在一些实施方案中,包括亲水性值在±0.5之内的那些。人们以亲水性为基础还可以鉴定主要氨基酸序列中的表位。这些区也称作″表位核心区″。
下面表1中给出例示的氨基酸取代作用。
表1
氨基酸取代作用
原残基 | 例示的取代作用 | 优选的取代作用 |
Ala | Val,Leu,Ile | Val |
Arg | Lys,Gln,Asn | Lys |
Asn | Gln,Glu,Asp | Gln |
Asp | Glu,Gln,Asp | Glu |
Cys | Ser,Ala | Ser |
Gln | Asn,Glu,Asp | Asn |
Glu | Asp,Gln,Asn | Asp |
Gly | Pro,Ala | Ala |
His | Asn,Gln,Lys,Arg | Arg |
Ile | Leu,Val,Met,Ala,Phe,正亮氨酸 | Leu |
Leu | 正亮氨酸Ile,Val,Met,Ala,Phe | Ile |
Lys | Arg,1,4二氨基-丁酸Gln,Asn | Arg |
Met | Leu,Phe,Ile | Leu |
Phe | Leu,Val,Ile,Ala,Tyr | Leu |
Pro | Ala | Gly |
Ser | Thr,Ala,Cys | Thr |
Thr | Ser | Ser |
Trp | Tyr,Phe | Tyr |
Tyr | Trp,Phe,Thr,Ser | Phe |
Val | Ile,Met,Leu,Phe,Ala,正亮氨酸 | Leu |
应用公知的技术,本领域技术人员能确定这里给出的多肽的合适的变体。在一些实施方案中,本领域技术人员通过定位据信对于活性不是重要的区而可以鉴定可以改变而不破坏活性的分子的合适的区。在一些实施方案中,人们能鉴定在相似肽或多肽中保守的分子的残基和部分。在一些实施方案中,即使对生物活性或者对结构是重要的区也可以进行保守性氨基酸取代而不破坏生物学活性或者不会不利地影响多肽结构。
另外,本领域技术人员能进行对相似多肽鉴定对于活性或结构重要的残基的结构-功能研究。考虑这样的比较,人们能预测蛋白质中相应于相似蛋白质中对于活性或结构重要的氨基酸残基的氨基酸残基的重要性。本领域技术人员可以选择对于这样预测的重要的氨基酸残基的化学类似氨基酸取代作用。
本领域技术人员还能分析与相似多肽中的结构相关的三维结构和氨基酸序列。考虑这样的信息,本领域技术人员可以对抗体预测有关其三维结构的氨基酸残基比对。在一些实施方案中,既然这样的残基可能在与其他分子的重要的相互作用中涉及,本领域技术人员可以选择不对预测在蛋白质表面上的氨基酸残基产生根本变化。此外,本领域技术人员可以获得在各个期望的氨基酸残基处包含单一氨基酸取代的试验变体。然后利用本领域技术人员公知的活性测定能对变体进行筛选。这样的变体可以被用来收集有关合适的变体的信息。例如,如果有人发现对特定氨基酸残基的改变导致活性破坏,不期望的降低,或者不适活性,可以避免有这样改变的变体。换句话说,根据从这样的常规实验收集的信息,本领域技术人员能容易地确定应该单独地或与其他突变组合地避免进一步的取代作用的氨基酸。
很多科学出版物致力于二级结构的判断。参见,Moult J.,Curr.Op.Biotech.,7(4):422-427(1996),Chou等,Biochemistry,13(2):222-245(1974);Chou等,Biochemistry,113(2):211-222(1974);Chou等,Adv.Enzymol.Relat.Areas Mol.Biol.,47:45-148(1978);Chou等,Ann.Rev.Biochem.,47:251-276和Chou等,Biophys.J.,26:367-384(1979)。此外,目前可获得辅助判断二级结构的计算机程序。一种二级结构判断方法是以同源性模型为基础的。例如,具有大于30%序列同一性的,或者大于40%相似性的两个多肽或蛋白质常常具有相似的结构拓扑学。近来蛋白质结构数据的增长(PDB)为二级结构提供了提高的可预测性,包括多肽或蛋白质结构中可能的折叠数目。参见Holm等,Nucl.Acid.Res.,27(1):244-247(1999)。有人提出(Brenner等,Curr.Op.Struct.Biol.,7(3):369-376(1997))一种给定多肽或蛋白质有有限数目的折叠,而且一旦明了关键的结构数目,结构预测将变得大大地更加精确。
确定二级结构的另外的方法包括″threading″(Jones,D.,Curr.Opin.Struct.Biol.,7(3):377-87(1997);Sippl等,Structure,4(1):15-19(1996)),″曲线分析″(Bowie等,Science,253:164-170(1991);Gribskov等,Meth.Enzym.,183:146-159(1990);Gribskov等,Proc.Nat.Acad.Sci.,84(13):4355-4358(1987)),和″改良键合″(参见Holm,上文(1999),和Brenner,上文(1997))。
在一些实施方案中,抗体变体包括糖基化变体,其中与原多肽的氨基酸序列相比,改变了糖基化位点的数目和/或类型。在某些实施方案中,蛋白变体包含比天然蛋白更多或更少的N-连接的糖基化位点。一种N-连接的糖基化位点特征在于序列:Asn-X-Ser或Asn-X-Thr,其中指定为X的氨基酸残基可以是除了脯氨酸之外的任何氨基酸残基。对构成该序列的氨基酸残基的取代或加入提供加入N-连接的糖链的可能的新的位点。或者,可以去除该序列的取代作用会去除已有的N-连接的糖链。还提供了N-连接的糖链的重排,其中一个或多个N-连接的糖基化位点(一般是天然存在的那些)被去除并且产生一个或多个新的N-连接的位点。其它优选的抗体变体包括半胱氨酸变体,其中与原氨基酸序列相比,缺失了一个或多个半胱氨酸残基,或者用另一种氨基酸(如丝氨酸)取代。当例如在分离不溶的包含体之后将抗体重新折叠为生物活性构象时,半胱氨酸变体可以是有用的。半胱氨酸变体一般比天然蛋白的半胱氨酸数目少,并且一般为偶数,以减少未配对半胱氨酸导致的相互作用。
根据某些实施方案,氨基酸取代:(1)减少对蛋白水解的易感性,(2)减少对氧化的易感性,(3)改变对形成蛋白复合物的结合亲和力,(4)改变结合亲和力,和/或(5)赋予或修饰所述多肽上的其它功能特性。根据某些实施方案,可以在天然存在的序列中(在某些实施方案中,在形成分子间接触的结构域外的多肽部分)进行单个或多个氨基酸取代(在某些实施方案中,保守氨基酸取代)。在某些实施方案中,保守氨基酸取代一般不会显著改变母体序列的结构特征)如取代氨基酸不应该破坏母体序列中的螺旋,或破坏作为母体序列特征的其它类型的二级结构。本领域公知的多肽二级和三级结构的例子描述于Proteins,Structures and Molecular Principles(Creighton,Ed.,W.H.Freeman and Company,New York(1984));Introduction to Protein Structure(C.Branden and J.Tooze,eds.,Garland Publishing,New York,N.Y.(1991));andThornton et at.Nature 354:105(1991)。
作为多肽或肽取代变体的本发明的特异结合剂分子中最多可以有大约10-12%的原始氨基酸序列被取代。对于抗体变体,重链可以有50,49,48,47,46,45,44,43,42,41,40,39,38,37,36,35,34,33,32,31,30,29,28,27,26,25,24,23,22,21,20,19,18,17,16,15,14,13,12,11,10,9,8,7,6,5,4,3,2,或1个氨基酸被取代,而轻链可以有25,24,23,22,21,20,19,18,17,16,15,14,13,12,11,10,9,8,7,6,5,4,3,2,或1个氨基酸被取代。
特异结合剂的衍生物
本发明还提供特异结合剂多肽的衍生物。衍生物包括具有不同于氨基酸残基的插入,缺失或取代的修饰的特异结合剂多肽。优选地,修饰作用性质是共价的,并且包括例如,与聚合物,脂质,其他有机和无机部分的化学键合。可以制备提高特异结合剂多肽的循环半寿期的本发明的衍生物,或者可以设计提高多肽对期望的细胞,组织,或器官的定向能力的本发明的衍生物。
本发明进一步包括衍生的结合剂,被共价修饰而包括一个或多个水溶性聚合物连接,例如聚乙二醇,聚氧乙二醇,或聚丙二醇,描述于美国专利Nos.:4,640,835;4,496,689;4,301,144;4,670,417;4,791,192;和4,179,337。本领域公知的其他有用的聚合物包括一甲氧基-聚乙二醇,葡聚糖,纤维素或者其他以碳水化合物为基础的聚合物,聚-(N-乙烯基吡咯烷酮)-聚乙二醇,丙二醇均聚物,a聚环氧丙烷/环氧乙烷共聚物,聚氧乙基化多元醇(例如,甘油)和聚乙烯醇,以及这些聚合物的混合物。特别优选的是用聚乙二醇(PEG)亚基共价修饰的特异结合剂产物。水溶性聚合物可以在特定位置例如在特异结合剂产物的氨基末端键合,或者与多肽的一个或多个侧链随机连接。2000年10月17日公布的Gonzales等人的美国专利No.6,133,426描述了用于提高对特异性结合剂,和对于人源化抗体的治疗能力的PEG的使用。
抗体诱变的靶位点
可以使用某些策略操作Ang-2-特异性抗体的固有性质,如抗体对其靶的亲和力。这些策略包括使用编码抗体的多核苷酸分子的位点特异性或随机诱变而产生抗体变体,然后进行设计用于回收表现出所需改变,如增加或降低的亲和力的抗体变体的筛选步骤。
诱变策略最常见的靶氨基酸残基是CDRs的氨基酸残基。如上文所述,这些区域含有实际上与Ang-2相互作用的残基和其它影响这些残基的空间排列的氨基酸。然而,也已经证明CDR区外的可变区的构架区中的氨基酸对抗体的抗原结合特性有显著贡献,并且可以作为操作所述特性的靶。见Hudson,Curr Opin Biotech,9:395-402(1999)及其中的参考文献。
可以通过将随机或定点诱变限制于CDRs中相当于容易在亲和力成熟过程中“超变“的区域的位点而产生更小和更有效筛选的抗体变体文库。见Chowdhury和Pastan,Nature Biotech,17:568-572[1999]及其中的参考文献。已知以此方式确定超变位点的DNA元件的类型包括直接和反向重复,某些共有序列,二级结构和回文序列。共有DNA序列包括四碱基序列嘌呤-G-嘧啶-A/T(即A或G-G-C或T-A或T)和丝氨酸密码子AGY(其中Y可以是C或T)。
因此,本发明的一种实施方案包括其目标为增加抗体对其靶的亲和力的诱变策略。这些策略包括诱变整个可变重链和轻链,仅仅诱变CDR区,诱变CDRs中的共有序列超变位点,诱变构架区,或这些方法的任意组合(在此上下文中的“诱变”可以是随机或定点的)。可以通过本领域技术人员公知的技术,如X线结晶学分辨所讨论的抗体和抗体-配体复合物的结构而完成对CDR区的确定描绘和包含抗体结合位点的残基的鉴定。基于所述抗体晶体结构的分析和表征的各种方法都是本领域技术人员公知的,并且尽管不能确定,也可以用于估计CDR区。所述常用方法的例子包括Kabat,Chothia,AbM和接触限定。
Kabat限定是基于序列变异性,并且是最常用的预测CDR区的限定。[Johnson and Wu,Nucleic Acids Res,28:214-8(2000)]。Chothia限定是基于结构环区的定位[Chothia et al.,J Mol Biol,196:901-17(1986);Chothia et al.,Nature,342:877-83(1989)]。AbM限定是Kabat和Chothia之间的折中。AbM是由OxfordMolecular Group生产的用于抗体结构模拟的完整程序组[Martin etal.,Proc Natl Acad Sci(USA)86:9268-9272(1989);Rees,etal.,ABMTM,a computer program for modeling variable regionsof antibodies,Oxford,UK;Oxford Molecular,Ltd.]。AbM程序组采用已知数据库和从头开始的方法的组合模拟来自一级测序的抗体三级结构。最近引入了称作接触限定的其它限定[MacCallum et al.,J Mol Biol,5:732-45(1996)]。该限定是基于可获得的复杂晶体结构的分析。
根据习惯,一般将重链中的CDR区称作H1,H2和H3并且按顺序编号,以便从氨基末端向羧基末端计数。轻链中的CDR区一般称作LI,L2和L3并且按顺序编号,以便从氨基末端向羧基末端计数。
根据Chothia和AbM限定,CDR-H1的长度为大约10-12个残基,并且一般起始于Cys之后4个残基,或者根据Kabat限定一般在5个残基之后。H1之后一般是Trp,一般是Trp-Val,但也可以是Trp-Ile,或Trp-Ala。根据AbM限定,H1的长度为大约10-12个残基,而Chothia限定排除了最后4个残基。
根据Kabat和AbM限定,CDR-H2一般起始于H1的末端后15个残基。在H2之前的残基一般是Leu-Glu-Trp-Ile-Gly,但也可以有多个变异。H2之后一般是氨基酸序列Lys/Arg-Leu/Ile/Val/Phe/Thr/Ala-Thr/Ser/Ile/Ala。根据Kabat限定,H2的长度为大约16-19个残基,而AbM定义预测长度一般为9-12个残基。
CDR-H3一般起始于H2末端后的33个残基,并且之前一般是氨基酸序列(典型为Cys-Ala-Arg)。H3后一般是氨基酸序列-Gly。H3的长度是3-25个残基。
CDR-L1一般起始于大约残基24,并且一般随后是Cys。CDR-L1之后的残基一般是Trp,并且一般以序列Trp-Tyr-Gln,Trp-Leu-Gln,Trp-Phe-Gln,或Trp-Tyr-Leu起始。CDR-L1的长度为大约10-17个残基。本发明的抗体的推定的CDR-L1精确符合该模式,Cys之后是15个氨基酸,然后是Trp-Tyr-Gln。
CDR-L2起始于L1末端后的大约16个残基。一般其后是残基Ile-Tyr,Val-Tyr,Ile-Lys或Ile-Phe。CDR-L2的长度为大约7个残基。
CDR-L3一般起始于L2末端后33个残基,其后一般是Cys。L3之后一般是氨基酸序列Phe-Gly-XXX-Gly。L3的长度为大约7-11个残基。
本领域已经描述过各种用于修饰抗体的方法。例如,美国专利5,530,101(属于Queen等,1996年6月25日)描述了制备人源化抗体的方法,其中人源化免疫球蛋白重链可变区构架区的序列与供体免疫球蛋白重链可变区构架区的序列具有65%-95%的同一性。除CDRs外,每个人源化免疫球蛋白链一般将含有来自于供体免疫球蛋白构架区的氨基酸,所述构架区例如能够与CDRs相互作用以影响结合亲和力,所述氨基酸例如是通过分子模拟预测的紧邻供体免疫球蛋白中的CDR或者约3埃内的一个或多个氨基酸。可以通过使用各种位置标准中的任意一个或全部而设计每一条重链和轻链。当组合至完整抗体中时,本发明的人源化免疫球蛋白对人基本没有免疫原性,并且保留与抗原,如含有表位的蛋白或其它化合物的供体免疫球蛋白基本相同的亲和力。也参见1997年12月2日授权的Queen等的美国专利5,693,761中的相关方法(″Polynucleotides encoding improved humanizedimmunoglobulins″),1997年12月2日授权的Queen等的美国专利5,693,762(″Humanized Immunoglobulins ″),以及1996年12月17日授权的Queen等的美国专利5,585,089(″HumanizedImmunoglobulins″)。
1996年10月15日授权的美国专利5,565,332(″Production ofchimeric antibodies-a combinatorial approach″)的一个实施例中描述了制备与母体抗体具有相似的结合特异性但具有增加的人类特征的抗体和抗体片段的生产方法。人源化抗体是通过链混排获得的,例如,使用噬菌体展示技术,并且将包含感兴趣抗原的特异性非人抗体的重链或轻链可变区的多肽与人互补(轻或重)链可变区的所有组成成分进行组合。鉴定了感兴趣抗原的特异性杂合配对物,并且将来自所选的配对物的人类链与人类互补可变区(轻或重)的所有组成成分进行组合。从得到的抗体多肽二聚物文库选自杂合体并且用于第二个人源化混排步骤。或者,如果该杂合体已经具有使其具有治疗价值的足够人类特征,则省略该第二步。也描述了进行修饰以增加人类特征的方法。也见Winter,FEBS Letts 430:92-92(1998)。
作为另一个例子,2000年4月25日授权的Carter等的美国专利6,054,297描述了通过用相应的人CDR氨基酸序列取代CDR氨基酸序列和/或用相应的人FR氨基酸序列取代FR氨基酸序列而制备人源化抗体的方法。
作为另一个例子,1998年6月16日授权的Studnicka等的美国专利5,766,886(″Modified antibody variable domains″)描述了用于鉴定抗体可变区的氨基酸残基的方法,所述可变区可以进行修饰而不减少抗原结合域的天然亲和力,同时减少其对异源物质的免疫原性,其中还描述了用于施用于异源物种的修饰的抗体可变区的制备方法。
如所讨论的内容,通过本领域公知的任何方法对抗体进行的修饰,一般设计为增加受体中对抗原的结合亲和力和/或减少抗体的免疫原性。在一种方法中,可以修饰人源化抗体以去除糖基化位点,从而增加抗体对其相关抗原的亲和力[Co et al.,Mol Immunol 30:1361-1367(1993)]。“重塑形”、“超嵌合化”和“veneering/resurfacing”等技术产生了具有更强治疗潜能的人源化抗体[Vaswami et al.,Annals of Allergy,Asthma,& Immunol81:105(1998);Roguska et al.,Prot Engineer 9:895-904(1996)]。也参见2000年月6日授权的Hardman等的美国专利6,072,035,其中描述了对抗体进行重新塑形的方法。尽管这些技术通过减少外源残基的数目而减少了抗体的免疫原性,它们不能防止重复施用抗体之后的抗独特型和抗异型反应。用于替代这些方法减少免疫原性的方法描述于Gilliland et al.,J Immunol 62(6):3663-71(1999)。
在许多情况下,对抗体进行人源化导致失去了抗原结合能力。因此优选“逆向突变”人源化抗体以包含原始(最常见是啮齿类)抗体中的一个或多个氨基酸残基,以便试图恢复抗体的结合亲和力。例如参见Saldanha et al.,Mol Immunol 36:709-19(1999)。
非肽特异结合剂类似物/蛋白质模拟物
此外,也包括提供稳定结构或减小生物降解性的肽的非肽特异结合剂类似物。在选择的抑制肽的基础上通过非肽部分置换一个或多个残基能制备肽模拟物类似物。优选地,非肽部分允许肽保留它的天然构象,或者稳定一种优选的,例如,生物活性构象,它保留识别和结合Ang-2的能力。一方面,得到的类似物/模拟物显示对Ang-2的提高的结合亲和力。Nachman等,Regul.Pept.57:359-370(1995)中描述了从肽制备非肽模拟物类似物的方法的一个例子,如果期望,例如通过本发明肽的糖基化作用,酰胺化作用,羧酸化作用,或磷酸化作用,或者通过产生酸加成盐,酰胺,酯,特别是C-末端酯,和N-酰基衍生物,能修饰本发明的特异结合剂肽。通过与其他部分形成共价或非共价复合物,也可以对特异结合剂肽加以修饰,产生肽衍生物。通过在N-或C-末端使化学部分与包括特异结合剂肽的氨基酸的侧链上的官能团连接能制备共价结合的复合物。
特别地,预见所述特异结合剂肽能与报道基团结合,包括但不限于放射性标记,荧光标记,酶(例如,催化测热反应或荧光反应),底物,固体基体,载体(例如,生物素或抗生物素蛋白)。因此,本发明提供一种包括抗体分子的分子,其中所述分子优选进一步包括选自放射性标记,荧光标记,酶,底物,固体基体,载体的报道基团。这样的标记是本领域技术人员公知的,例如,特别包括生物素标记。这样的标记的应用是本领域技术人员公知的,并且描述于,例如,美国专利Nos.3,817,837;3,850,752;3,996,345;和4,277,437。有用的其他标记包括但不限于放射性标记,荧光标记和化学发光标记。涉及使用这样的标记物的美国专利包括,例如美国专利Nos.3,817,837;3,850,752;3,939,350;和3,996,345。本发明的任何肽可以包括任何这些标记的一个,两个,或多个。
制备特异结合剂的方法
根据常规技术可以在溶液中或者在固相载体上合成作为蛋白的本发明的特异结合剂。固相肽合成目前的限制是85-100氨基酸长度。但是,化学合成技术通常可以用于化学连接一系列小肽以产生全长多肽。各种各样的自动合成仪是商业上可获得的并且可以根据公知的方法使用。参见,例如,Stewart和Young(上文);Tam等,J.Am.Chem.Soc.,105:6442,(1983);Merrifield,Science 232:341-347(1986);Barany和Merrifield,The Peptides,Gross and Meienhofer,编著,Academic Press,New York,1-284;Barany等,Int.J.Pep.ProteinRes.,30:705-739(1987);和美国专利No.5,424,398,各篇文献在此引作参考。
固相肽合成方法使用共聚(苯乙烯-二乙烯基苯),含有0.1-1.0mM胺/克聚合物。这些肽合成方法使用丁基氧羰基(t-BOC)或9-芴基甲氧羰基(FMOC)保护α-氨基.两种方法都涉及分步合成,从肽的C-末端开始每一步加上一个氨基酸(参见,Coligan等,Curr.Prot.Immunol.,Wiley Interscience,1991,第9单元)。完成化学合成时,可以将合成肽去保护,去除t-BOC或FMOC氨基保护基团并且降低的温度下用酸处理从聚合物上裂解下来(例如,液体HF-10%茴香醚在0℃下处理大约0.25至大约1小时)。蒸发溶剂之后,用1%乙酸溶液从聚合物萃取出肽,然后冻干,得到粗产物。一般通过象在Sephadex G-15上使用5%乙酸作为溶剂进行凝胶过滤这样的技术进行纯化。将过柱的合适的级分冻干得到同质肽或肽衍生物,然后用标准技术进行表征,象氨基酸分析,薄层色谱法,高效液相色谱法,紫外吸收光谱法,摩尔旋光,溶解性,并且通过固相埃德曼降解定量测定。
抗-Ang2-抗体、及其衍生物、变体和片段,以及其它基于蛋白的Ang-2结合剂的化学合成允许将非天然存在的氨基酸掺入试剂。
重组DNA技术是制备本发明的全长抗体和其他蛋白质特异性结合剂或者其片段的常规方法。可以将编码抗体或片段的cDNA分子插入表达载体,其接着可以被插入宿主细胞产生抗体或片段。可以理解编码所述抗体的cDNAs可以被修饰,以改变“原始”cDNA(从mRNA翻译),以便提供密码子简并或允许在各种宿主细胞中的密码子偏好使用。
一般情况下,应用这里实施例中描述的方法能获得编码肽的DNA分子。当需要获得与原始抗体分子相关的Fab分子或CDRs时,可以使用标准技术筛选适当的文库(噬菌体展示文库;淋巴细胞文库等),以鉴定和克隆相关Fabs/CDRs。用于所述筛选的探针可以是编码原始抗体Fab部分的全长或截短的Fab探针,针对原始抗体Fab部分的一个或多个CDRs的探针,或其它合适的探针。当采用DNA片段作为探针时,典型的杂交条件是Ausubel等(Current Protocols in Molecular Biology,Current Protocols Press[1994])中提出的那些。杂交之后,根据象探针大小,克隆的探针的期望的同源性,筛选的文库的类型,和筛选的克隆的数目这样的因素,在合适的严谨度下洗涤探针印迹。高严谨度筛选的例子是在50-65℃之间的温度下,0.1XSSC,和0.1%SDS。
可以使用各种各样的表达载体/宿主系统包含和表达编码本发明的特异结合剂多肽的多核苷酸分子。这些系统包括但不限于微生物,例如重组噬菌体,质粒或粘粒DNA表述载体转化的细菌;酵母表达载体转化的酵母;病毒表达载体(例如,杆状病毒)感染的昆虫细胞系统;病毒表达载体(例如,花椰菜花叶病毒,CaMV;烟草花叶病毒,TMV)转染的或者细菌表达载体(例如,Ti或pBR322质粒)转化的植物细胞体系;或者动物细胞体系。
重组特异结合剂蛋白质生产中有用的哺乳动物细胞包括但不限于VERO细胞,HeLa细胞,中国仓鼠卵巢(CHO)细胞系,COS细胞(例如COS-7),W138,BHK,HepG2,3T3,RIN,MDCK,A549,PC12,K562和293细胞,以及此处描述的杂交瘤细胞系。哺乳动物细胞系优选用于制备特异结合剂如抗体和抗体片段,它们一般被糖基化,并且其活性需要正确的重折叠。优选的哺乳动物细胞系包括CHO细胞、杂交瘤细胞和骨髓瘤细胞。
下文描述一些用于重组表达特异结合剂蛋白的示例性方法。
术语″表达载体″指用于从DNA(RNA)序列表达多肽的质粒,噬菌体,病毒或载体。一个表达载体可以包括转录单元,包括下面结构的组装(1)遗传元件或者在基因表达中具有调节作用的元件,例如启动子或增强子,(2)被转录到mRNA中并且翻译成蛋白质的编码结合剂的结构或序列,和(3)合适的转录起始和终止序列。要在酵母或真核表达系统中使用的结构单元优选包括使宿主细胞胞外分泌翻译的蛋白质的前导序列。或者,没有前导序列或转运序列表达重组蛋白质的情况下,可以包括氨基末端甲硫氨酰残基。这种残基可以或可以不接着从表达的重组蛋白裂解,提供肽终产物。
例如,使用商售表达系统,例如Pichia表达系统(Invitrogen,SanDiego,Calif.),根据生产商的说明,可以在酵母中重组表达肽。这种系统还依赖指导分泌的前-原-α序列,但是甲醇诱导时醇氧化酶(AOX1)启动子驱动插入片段的转录。
通过,例如,用来从细菌和哺乳动物细胞上清液纯化肽的方法,从酵母生长培养基纯化分泌的特异结合剂肽。
或者,可以将编码特异结合剂肽的cDNA克隆到杆状病毒表达载体pVL1393(PharMingen,San Diego,Calif.)中。可以根据生产商说明(PharMingen)使用这种载体在没有sF9蛋白质的培养基中感染Spodoptera frugiperda细胞,产生重组蛋白。使用肝素-琼脂糖凝胶柱(Pharmacia)纯化并浓缩特异结合剂蛋白。
或者,在昆虫系统中表达肽。用于蛋白质表述的昆虫系统是本领域技术人员公知的。在一个这样的系统中,苜蓿银纹夜蛾核型内多角体病毒(AcNPV)能被用作在草地夜蛾(Spodoptera frugiperda)细胞或粉纹夜蛾(Trichoplusia)幼虫中表达外源基因的载体。可以将特异结合剂肽编码序列克隆到病毒的不重要的区,例如多角体蛋白基因,并且置于多角体蛋白启动子的控制下。成功插入特异结合剂肽会使得多角体蛋白基因失活,并且产生没有外被蛋白外壳的重组蛋白。可以使用重组病毒感染草地夜蛾细胞或粉纹夜蛾幼虫,表达肽。Smith等,J.Virol.46:584(1983);Engelhard等,Proc.Nat.Acad.Sci.(USA)91:3224-7(1994)。
在另一个实施例中,通过PCR能扩增编码特异结合剂肽的DNA序列,并且克隆到合适的载体中,例如,pGEX-3X(Pharmacia)。设计pGEX载体产生包括谷胱甘肽-S-转移酶(GST)的载体编码的融合蛋白,和通过插入到载体克隆位点中的DNA片段编码的特异结合剂蛋白。能制备包括例如一个合适的酶切位点的PCR引物。仅使用有利于表达的融合部分或者另外不期望与感兴趣的肽连接,然后从融合蛋白的GST部分切割下来重组特异结合剂融合蛋白。pGEX-3X/特异结合剂肽构建体被转化到大肠杆菌XL-1Blue细胞(Stratagene,La Jolla Calif.)中,并且分离各个转化体并且培养。纯化各个转化体的质粒DNA,并且使用自动测序仪部分测序,证实以合适的方向编码核酸插入片段的期望的特异性结合剂的存在。
使用此处描述的重组系统表达编码抗-Ang-2抗体及其片段的多核苷酸可以导致产生抗体或其片段,所述抗体或其片段必须“重折叠”(正确产生各种二硫桥)而获得生物活性。所述抗体的典型重折叠程序见此处的实施例和下面的章节。
可以如下纯化特异结合剂,所述特异结合剂被制备成细菌中的不溶性包含体。离心破坏宿主细胞;在0.15M NaCl,10mM Tris,pH8,1mM EDTA中洗涤;并且在室温下用0.1毫克/毫升溶菌酶(Sigma,St.Louis,Mo.)处理15分钟。超声处理澄清溶胞产物,并且通过以12,000Xg离心10分钟沉积细胞碎屑。将含有特异结合剂的沉淀重新悬浮于50mMTris,pH 8,和10mM EDTA,用50%甘油分层,并且以6,000Xg离心30分钟。将沉淀重新悬浮于没有Mg++和Ca++的标准盐酸缓冲盐溶液(PBS)中。通过将重新悬浮的沉淀在变性SDS-PAGE(Sambrook等,上文)中分级分离而进一步纯化特异结合剂。凝胶在0.4M KCl中浸透,显现蛋白质,将其切下并且在没有SDS的凝胶展开缓冲液中电洗脱。如果在细菌中产生的GST/融合蛋白是可溶蛋白,可以利用GST PurificationModule(Pharmacia)将其纯化。
用于重组蛋白表达的哺乳动物宿主系统是本领域技术人员公知的。对于加工表达蛋白或者产生某些翻译后修饰的特定能力选择宿主细胞菌株,所述修饰在提供蛋白质活性中有用。这样的多肽修饰作用包括但不限于乙酰化作用,羧化作用,糖基化作用,磷酸化作用,脂质化作用和酰化作用。与象CHO这样的宿主细胞不同,HeLa,MDCK,293,W138等具有这样的翻译后活性的特定细胞机构和特征机理,并且可以选择来确保引入的外来蛋白质的正确修饰和加工。
可以利用很多种筛选系统来回收已经被转化重组产生蛋白质的细胞。这样的选择系统包括但不限于HSV胸腺嘧啶核苷激酶,次黄嘌呤-鸟嘌呤磷酸核糖转移酶和腺嘌呤磷酸核糖转移酶基因,分别在tk-,hgprt-或aprt-细胞中。还有,抗-代谢物抗性被用作下面筛选的基础:DHFR,它带来甲氨喋呤抗性;gpt,它带来霉酚酸抗性;neo,它带来氨基苷G418抗性并带来绿黄隆抗性;和hygro,它带来潮霉素抗性。可以使用的其他可选择基因包括trpB,它使得细胞利用吲哚代替色氨酸,或hisD,它使得细胞利用histinol代替组氨酸。给出用于鉴定转化体的可视指征的标记包括花色素苷,β-葡萄糖醛酸酶及其底物,GUS,和荧光素酶及其底物,荧光素。
特异性结合剂的纯化知重折叠
在某些情况下,本发明的特异性结合剂为了有生物活性可能需要″重折叠″并且被氧化为合适的三级结构并且产生二硫键。应用本领域公知的很多种方法能实现重折叠。这样的方法包括,例如,在离液剂的存在下将可溶性多肽试剂暴露给通常高于7的pH。离液剂的选择类似于胞函体增溶作用使用的选择,但是一般使用低浓度的离液剂。举例的离液剂是胍。在大多数情况下,重折叠/氧化溶液还含有还原剂加特定比例的其氧化形式,产生特定的氧化还原潜能,使得可能存在形成半胱氨酸桥的二硫化合物。一些常用的氧化还原对包括半胱氨酸/胱胺,谷胱甘肽/二硫双GSH,二氯化铜,二硫苏糖醇DTT/二噻烷DTT,和2-巯基乙醇(bME)/二硫-bME。在很多情况下,可以使用辅助溶剂提高重折叠效率。通常使用的辅助溶剂包括甘油,各种分子量的聚乙二醇,和胍。
期望纯化本发明的特异结合剂蛋白或其变体。蛋白质纯化技术是本领域公知的。这些技术在一个水平上包括多肽和非多肽级分的分级分离。将所述特异结合剂多肽与其他蛋白质分离之后,应用实现部分或完全纯化(或者纯化至均匀)的色谱法和电泳技术能进一步纯化感兴趣的多肽。特别适合制备本发明的特异结合剂的分析方法是离子交换色谱法,排阻层析;聚丙烯酰胺凝胶电泳;等电聚焦。纯化肽的特别有效的方法是快速蛋白质液相色谱法或HPLC。
本发明的一些方面涉及纯化,在特定实施方案中,涉及所编码特异结合剂蛋白或肽的大量纯化。这里使用的术语″纯化的特异结合剂蛋白或肽″,是意指与其他成分可分离的成分,其中将特异结合剂蛋白或肽纯化至相对其天然可获得状态的任何程度。因此纯化的特异结合剂蛋白或肽也称作从其天然存在的环境脱离的特异结合剂蛋白或肽。
一般,″纯化的″指经分级分离去除各种其他成分的特异结合剂组合物,所述组合物基本上保持其表达的生物活性。使用术语″基本上纯化″时,该概念指特异结合剂组合物,其中特异结合剂蛋白或肽形成组合物的主要成分,例如组合物中蛋白质构成大约50%,大约60%,大约70%,大约80%,大约90%,大约95%或更多。
从现有公开物来说,本领域技术人员公知很多用于定量特异结合剂的纯化的方法。这些包括,例如,测定活性级分特异结合活性,或者通过SDS/PAGE分析测定级分中特异结合剂的量。评定特异结合剂级分的纯度的优选的方法是计算级分的特异性结合活性,将它与开始的提取物的结合活性比较,这样计算出纯化度,这里通过″-纯化倍数″评价。用来表示结合活性的量的实际单位当然取决于选择进行纯化的特定分析技术和特异结合剂蛋白或肽是否显示可检测结合活性。
适合在结合剂蛋白纯化中使用的各种技术对于本领域技术人员是公知的。这些包括,例如,用硫酸铵沉淀,PEG,抗体(免疫沉淀)等或者通过热变性,接着离心;色谱步骤例如亲和色谱(例如,Protein-A-Sepharose),离子交换,凝胶过滤,反相,羟基磷灰石和亲和色谱;等电聚焦,凝胶电泳,以及这些和其他技术的组合。正如本领域公知的,相信进行各种纯化步骤的顺序是可以改变的,或者可以省略一些步骤,仍然得到制备基本上纯的特异性结合剂的合适的方法。
一般不要求本发明的特异结合剂总是以其最纯化的状态提供。事实上,想到在一些实施方案中比基本上纯稍差的特异结合剂产物具有用途。通过组合中较少的纯化步骤,或者通过使用不同形式的相同的一般纯化方案,可以实现部分纯化。例如,知道使用HPLC设备进行的阳离子交换柱色谱一般会导致比利用低压色谱系统的相同技术更大“倍数”的纯化作用。显示低度相对纯化的方法在特异结合剂的总回收中,或者在特异结合剂的结合活性的保持中有益。
已知特异结合剂的迁移随着SDS/PAGE的不同条件可以改变,有时改变显著[Capaldi等,Biochem.Biophys.Res.Comm.,76:425(1977)]。因此明白在不同的电泳条件下,纯化或部分纯化的特异性结合剂表达产物的表观分子量可以变化。
结合分析
免疫结合分析一般使用与分析物靶抗原特异性结合并且经常固定分析物靶抗原的捕获剂。捕获剂是与分析物特异性结合的部分。在本发明的一个实施方案中,捕获剂是特异性结合Ang-2的特异结合剂或者其片段。这些免疫结合分析是本领域公知的[Asai,编著Methods in CellBiology,Vol.37,Antibodies in Cell Biology,Academic Press,Inc.,New York(1993)]。
免疫结合分析常常使用标记试剂,它是捕获剂或抗原形成的结合的复合物存在的信号。标记试剂可以是包括结合的复合物的分子之一;即它可以是标记的特异性结合剂或者标记的抗特异性结合剂抗体。或者,标记试剂可以是第三分子,通常是另一种抗体,它结合结合的复合物。标记试剂可以是,例如,带有标记的抗特异性结合剂抗体。二抗,对结合的复合物是特异性的,可以没有标记,但是能被第四分子结合,第四分子对于二抗是其中一员的抗体物质是特异性的。例如,二抗可以被可检测部分修饰,例如生物素,它之后被第四分子结合,所述第四分子例如酶标记的链霉抗生物素蛋白。能特异性结合免疫球蛋白的恒定区的其他蛋白质,例如蛋白质A或蛋白质G也可以被用作标记试剂。这些结合蛋白质是链球菌细胞壁正常成分并且具有与各种物种的免疫球蛋白恒定区的强的非免疫原反应性。Akerstrom,J.Immunol.,135:2589-2542(1985);Chaubert,Mod.Pathol.,10:585-591(1997)。
在分析中,每一次混合试剂之后可能要求温育和/或洗涤步骤。温育步骤可以是大约5秒至几小时,优选大约5分钟至大约24小时。但是,温育时间取决于分析形式,分析物,溶液体积,浓度等。通常,在环境温度下进行分析,但是在一定温度范围内可以进行。
A.非竞争性结合鉴定法
免疫结合鉴定法可以是非竞争性类型。这些分析有一定量的直接测量的捕获分析物。例如,在优选的″夹心″鉴定法中,捕获试剂(抗体)可以直接结合固体底物,在那里被固定。这些固定化捕获试剂然后捕获(结合)分析样品中存在的抗原。这样被固定的蛋白质然后结合标记试剂,例如带有标记的二抗。在另一个优选的″夹心″鉴定法中,二抗没有标记,但是可以被对二抗从中衍生的物质的抗体特异性的标记抗体结合。二抗还可以被可检测部分例如生物素修饰,第三标记分子例如链霉抗生物生蛋白能特异性结合生物素。参见Harlow和Lane,Antibodies,A LaboratoryManual,Ch 14,Cold Spring Harbor Laboratory,NY(1988),这里引作参考。
B.竞争性结合鉴定法
免疫结合鉴定法可以是竞争性类型。通过测定样品中存在的分析物置换的或者从捕获试剂完全去除的加入的分析物的量,间接测定样品中存在的分析物的量。在一个优选的竞争性结合鉴定法中,向样品加入通常被标记的已知量的分析物,样品然后接触抗体(捕获试剂)。与抗体结合的标记分析物的量与样品中存在的分析物的浓度成反比(参见,Harlow和Lane,Antibodies,A Laboratory Manual,Ch 14,pp.579-583,上文)。
在另一个优选的竞争性结合鉴定法中,捕获试剂固定在固体底物上。通过测定蛋白质/抗体复合体中存在的蛋白质的量,或者通过测定保留的没有复合的蛋白质的量,可以测定与捕获试剂结合的蛋白质的量。通过提供标记蛋白质可以测定蛋白质的量。Harlow和Lane(上文)。
在另一个优选的竞争性结合鉴定法中,利用半抗原抑制作用。这里,已知的分析物固定在固体底物上。向样品加入已知量的抗体,并且样品接触固定的分析物。与固定的分析物结合的抗体的量与样品中存在的分析物的量成反比。通过测定抗体的固定级分或者溶液中保留的级分可以测定固定化抗体的量。测定可以是直接的,其中抗体被标记,或者通过接着加入标记部分而间接测定,所述标记部分如上所述特异性结合抗体。
C.竞争性结合鉴定法的应用
竞争性结合鉴定法可以用于交叉反应测定,允许技术人员测定本发明的特异结合剂识别的蛋白质或酶复合体是不是期望的蛋白质而不是交叉反应分子,或者测定融合蛋白是不是对抗原是特异性的而不结合不相关的抗原。在这种类型的鉴定法中,抗原可以固定到固体载体上并且向测试中加入未知蛋白质混合物,它会与特异结合剂与固定化蛋白质的结合相竞争。该竞争分子还结合与所述抗原不相关的一种或几种抗原。将蛋白质与特异结合剂和固定化抗原结合相竞争的能力与和固体载体固定化的相同蛋白质的结合相比较,测定蛋白质混合物的交叉反应。
D.其他结合鉴定法
本发明还提供Western印迹法,测定或定量分析样品中Ang-2的存在。所述技术一般包括以分子量为基础通过凝胶电泳分离样品蛋白质并且将蛋白质转移到合适的固体载体,例如硝基纤维素过滤器,尼龙过滤器,或衍生化尼龙过滤器。样品和特异性结合Ang-2的抗体或者其片段温育并且检测得到的复合体。这些抗体可以直接被标记或者接着被检测,使用特异性结合抗体的标记抗体。
实施例中阐述了检测破坏Ang-2与其受体结合的Ang-2特异结合剂的结合测定。
诊断分析
本发明的肽或者其片段用于特征在于表达Ang-2或亚基的症状或疾病的诊断,或者用于对用Ang-2的诱导物,其片段,Ang-2活性的激动剂或抑制剂治疗的患者监测的检定中。对于Ang-2的诊断鉴定包括使用特异结合剂和标记检测人体液或者细胞或组织提取物中的Ang-2的方法。本发明的特异结合剂可以在有或没有修饰作用下使用。在优选的诊断鉴定法中,通过连接,例如标记或报道分子,将特异结合剂标记。很多种标记和报道分子是公知的,其中的一些已经在这里描述。特别地,本发明用于人疾病的诊断。
本领域公知很多种使用对各种蛋白质特异的多克隆和单克隆抗体测定Ang-2蛋白质的方法。例子包括酶联免疫吸附测定(ELISA),放射免疫测定(RIA)和荧光激活细胞分类(FACS)。使用与Ang-2上两个不干扰表位反应的单克隆抗体的两个位点单克隆为基础的免疫测定是优选的。这些测定方法描述于,例如,Maddox等,J.Exp.Med.,158:1211(1983)。
为了提供诊断基础,通常确定人Ang-2表达的正常或标准值。在本领域公知的适合复合体形成的条件下,通过将来自正常受试者优选人的体液或细胞提取物与抗Ang-2的抗体混合,来实现测定。使用对照和疾病样品,通过比较特异结合剂与已知量的Ang-2蛋白质的结合能定量测定标准复合体形成的量。然后,将从正常样品获得的标准值与从可能受疾病影响的受试者的样品获得的值相比较。标准值和实验值之间的偏差表明对于疾病状态中的Ang-2的作用。
对于诊断应用,在一些实施方案中,本发明的特异结合剂或肽一般用可检测部分标记。可检测部分可以是任何能直接或间接产生可检测信号的那些。例如,可检测部分可以是放射性同位素,例如H,C,P,S,或I,荧光或化学发光化合物,例如荧光素异硫代氰酸酯,诺丹明,或荧光素;或者酶,例如碱性磷酸酶,[β]-半乳糖苷酶,或辣根过氧化物酶。Bayer等,Meth.Enz.,184:138-163,(1990)。
疾病
本发明提供用于治疗人疾病和病理状态的结合Ang-2的特异结合剂。可以与其他治疗药物结合使用调节Ang-2结合活性或者其他细胞活性的试剂,以增强它们的治疗效果或者降低可能的副作用。
一方面,本发明提供用于治疗特征在于细胞中不期望的或异常水平的Ang-2活性的疾病和症状的药物和方法。这些疾病包括癌症,和其他超增殖症状,例如增生,牛皮癣,接触性皮炎,免疫失调,和不孕症。
本发明还提供了治疗动物包括人的癌症的方法,包括对动物施用有效量的特异性结合剂,所述特异结合剂抑制或降低Ang-2活性。本发明进一步涉及抑制癌细胞生长的方法,包括生物系统中细胞增殖,侵入,和转移过程。所述方法包括使用本发明的化合物作为癌细胞生长抑制剂。优选地,应用所述方法对活体动物例如哺乳动物抑制或减小癌细胞生长,侵入,转移,或肿瘤发生。本发明的方法还容易适合在测试系统中使用,例如,分析癌细胞生长及其性质,以及鉴定影响癌细胞生长的化合物。
本发明的方法可治疗的癌症优选在哺乳动物中发生。哺乳动物包括,例如,人和其他灵长目,以及宠物或陪伴动物例如狗和猫,试验用动物例如大鼠,小鼠和兔,和农场动物例如马,猪,羊,和牛。
瘤或肿瘤包括其中细胞增殖失控且进行性的组织细胞的生长。一些这样的生长是良性的,但是其他称作恶性并且可能导致生物死亡。恶性肿瘤或癌与良性生长的区别在于,除了表现出进行性细胞增殖之外,它们可以侵犯周围的组织并且转移。此外,恶性肿瘤特征在于它们表现出较大分化损失(较大去分化),以及相对另一种和它们周围组织的它们的组织的较大损失。这种性质也称作″退行发育″。
本发明可治疗的肿瘤还包括实体瘤,即,癌和肉瘤。癌包括渗透(侵入)周围组织并且发生转移的得自上皮细胞的那些恶性肿瘤。腺癌是得自腺组织的癌,或者它形成可识别腺组积。另一个宽的分类或癌包括肉瘤,它们是包埋在纤丝或同质物质象胚胎缔结组织中的细胞。本发明还能治疗骨髓或淋巴系统癌症,包括白血病,淋巴瘤和一般不以肿瘤质存在而是分布在血管或淋巴网状系统中的其他癌症。
能接受本发明治疗的癌或肿瘤的类型包括,例如,ACTH-产生肿瘤,急性淋巴细胞白血病,急性非淋巴细胞白血病,肾上腺内皮癌,膀胱癌,脑癌,乳腺癌,子宫颈癌,慢性淋巴细胞白血病,慢性髓细胞白血病,结肠癌,皮肤T-细胞淋巴瘤,子宫内膜癌,食管癌,Ewing′s肉瘤,胆囊癌,毛状细胞白血病,头颈癌,霍奇金淋巴瘤,Kaposi′s肉瘤,肾癌,肝癌,肺癌(小细胞和非小细胞),恶性腹膜积液,恶性胸膜积液,黑素瘤,间皮瘤,多样骨髓瘤,神经胚细胞瘤,神经胶质瘤,非霍奇金淋巴瘤,骨肉瘤,卵巢癌,卵巢(胚细胞)癌,胰腺癌,阴茎癌,前列腺癌,视网膜母细胞瘤,皮肤癌,软组织肉瘤,鳞状细胞癌,胃癌,睾丸癌,甲状腺癌,滋养层肿瘤,子宫癌,阴道癌,阴户癌,和Wilms′肿瘤。
关于一些类型的实验确定的癌症的治疗,本发明在这里特别详细地描述。在这些详述的治疗中,使用现有技术标准体外和体内模型。这些方法能被用来鉴定预期在体内治疗方案中有效的药物。但是,明白本发明的方法不局限于这些肿瘤类型的治疗,而是延伸到源自任何器官系统的实体瘤。其侵入或转移与Ang-2表达或活性有关的癌症特别易于用本发明抑制或者甚至被诱导退化。
本发明还通过包括使用下面的本发明的化合物而实施,例如与另一种抗癌化疗药物例如任何常用化疗药物结合的特异结合剂。特异性结合剂与这样的其他药物结合能使化疗方案有增强的作用。熟练医师会想到很多种化疗法能结合本发明的方法。可以使用任何化疗药物,包括烷基化试剂,抗代谢物,激素和拮抗剂,放射性同位素,以及天然产物。例如,本发明的化合物能和抗生素一起给药,所述抗生素例如阿霉素和其他蒽环霉素类似物,氮芥例如环磷酰胺,嘧啶类似物例如5-氟尿嘧啶,顺铂,羟基脲,紫杉醇及其天然和合成衍生物,等。在另一个实施例中,在混合肿瘤情况下,例如乳腺癌,其中肿瘤包括促性激素依赖性和非促性激素依赖性细胞,该化合物可以和抑那通或果丝瑞宁(LH-RH的合成肽类似物)联合给药。其他抗肿瘤方案包括使用四环素化合物和另一种治疗用药程式,例如,手术,放射等,这里也称作″辅助抗肿瘤用药程式″。因此,本发明的方法可以使用这样的常规方案进行,好处是减小副作用并且增强药效。
本发明因此提供用于治疗多种癌症,包括实体瘤和白血病,的组合物和方法。可以治疗的癌症类型包括但不限于:乳腺癌,前列腺癌,和结肠癌;所有形式的肺支气管原癌;骨髓癌;黑素瘤;肝脏肿瘤;成神经细胞瘤;乳头状瘤;胺前体摄取与脱羧细胞瘤;迷芽瘤;腮原瘤;恶性癌综合症;癌心脏病;癌(例如,Walker癌,基细胞癌,basosquamous癌,Brown-Pearce癌,导管癌,Ehrlich肿瘤,Krebs 2癌,梅克尔细胞,粘蛋白,非小细胞肺癌,燕麦细胞,乳头状瘤,硬癌,细支气管癌,支气管原癌,鳞状细胞癌,和移行细胞癌);组织细胞性病;白血病;恶性组织细胞增多;Hodgkin′s病;免疫增殖小细胞肺癌;非霍金森淋巴瘤;浆细胞瘤;网状内皮组织增殖;黑素瘤;成软骨瘤;软骨瘤;软骨肉瘤;纤维瘤;纤维肉瘤;巨细胞肿瘤;组织细胞瘤;脂瘤;脂肉瘤;间皮瘤;粘液瘤;粘液肉瘤;骨瘤;骨肉瘤;脊索瘤;颅咽管瘤;无性细胞瘤;错构瘤;间叶瘤;中肾瘤;肌肉瘤;成釉细胞瘤;牙骨质瘤;牙瘤;畸胎瘤;胸腺瘤;tophoblastic肿瘤。此外,也可以治疗下面类型的癌症:腺瘤;胆管瘤;胆脂瘤;cyclindroma;囊腺癌;囊腺瘤;粒层细胞瘤;两性胚细胞瘤;肝细胞瘤;汗腺腺瘤;小岛细胞肿瘤;间质细胞肿瘤;乳头状瘤;塞尔托利氏细胞肿瘤;鞘细胞瘤;平滑肌瘤;平滑肌肉瘤;原粒细胞瘤;肌瘤;肌肉瘤;横纹肌瘤;横纹肌肉瘤;室管膜瘤;神经节瘤;神经胶质瘤;成神经管细胞瘤;脑膜瘤;神经鞘瘤;成神经细胞瘤;神经上皮瘤;神经纤维瘤;神经瘤;副神经节瘤;副神经节瘤nonchromaffin;血管角质瘤;嗜曙红细胞增多类淋巴管增生;血管瘤硬化;多发性血管瘤;血管球瘤;血管内皮瘤;血管瘤;血管外皮细胞瘤;血管肉瘤;淋巴管瘤;淋巴管肌瘤;淋巴管肉瘤;松果体瘤;癌肉瘤;软骨肉瘤;叶状囊性肉瘤;纤维肉瘤;血管肉瘤;平滑肌肉瘤;淋巴瘤性白血病;脂肉瘤;淋巴管肉瘤;肌肉瘤;粘液肉瘤;卵巢癌;横纹肌肉瘤;肉瘤;赘生物;nerofibromatosis;和子宫颈发育异常。
本发明的另一方面是使用本发明的材料和方法来防止和/或治疗任何皮肤超增殖症状,包括牛皮癣和接触性皮炎或者其他超增殖疾病。已经证明牛皮癣和接触性皮炎患者其身体病灶有升高的Ang-2活性[ogoshi等,J.Inv.Dermatol.,110:818-23(1998)]。优选地,与治疗表现这些临床症状人的其他药物联合使用对Ang-2特异性的特异性结合剂。利用各种各样的载体通过这里描述的给药途径和本领域技术人员公知的其他途径能送递特异性结合剂。
本发明的另一方面包括治疗各种其中涉及血管发生的视网膜病(包括糖尿病视网膜病和与年龄相关的黄斑变性),以及女性生殖道失调/疾病,例如子宫内膜异位,子宫纤维瘤,和与功能障碍血管增生相关的女性生殖周期期间其他这样的症状(包括子宫内膜微血管生长)。
本发明的另一方面涉及治疗异常血管生长,包括脑动静脉畸形(AVMs)胃肠粘膜损伤和修复,有消化系统溃疡病使患者胃十二指肠粘膜溃疡,包括中风导致的局部缺血,各种肝病中肺维管失调和非肝门高血压患者的肝门高血压。
本发明的另一方面是使用本发明提供的组合物和方法预防癌症。这样的试剂包括抗Ang-2特异结合剂。
药物组合物
Ang-2特异结合剂的药物组合物在本发明的范围内。含有抗体的药物组合物详细描述于,例如,2001年1月9日公布的Lam等人的美国专利No.6,171,586。这样的组合物含有治疗或预防有效量的特异性结合剂,例如与药学可接受试剂混合的这里描述的抗体,或者其片段,变体,衍生物或融合体。在优选的实施方案中,药物组合物含有与药学可接受试剂混合的部分或完全调节Ang-2的至少一种生物活性的拮抗剂特异性结合剂。典型地,所述特异性结合剂足够纯化,用于对动物施用。
药物组合物可以含有制剂材料,用于调整,保持或维持,例如,组合物的pH,克分子渗透压浓度,粘度,澄清度,颜色,等张性,气味,无菌,稳定性,溶解或释放速度,吸附或渗透。合适的制剂材料包括,但不限于,氨基酸(例如甘氨酸,谷氨酰胺,天冬酰胺,精氨酸或赖氨酸);抗菌剂;抗氧化剂(例如抗坏血酸,亚硫酸钠或亚硫酸氢钠);缓冲液(例如硼酸盐,碳酸氢盐,Tris-HCl,柠檬酸盐,磷酸盐,其他有机酸);膨胀剂(例如甘露糖醇或甘氨酸),螯合剂[例如乙二胺四乙酸(EDTA)];络合剂(例如咖啡因,聚乙烯吡咯烷酮,β-环糊精或羟丙基-β-环糊精);填料;单糖;二糖和其他碳水化合物(例如葡萄糖,甘露糖,或糊精);蛋白质(例如血清白蛋白,明胶或免疫球蛋白);着色剂;矫味剂和稀释剂;乳化剂;亲水聚合物(例如聚乙烯吡咯烷酮);低分子量多肽;成盐抗衡粒子(例如钠);防腐剂(例如氯化苄烷铵,苯甲酸,水杨酸,硫贡撒,苯乙醇,羟苯甲酯,羟苯丙酯,洗必太,山梨酸或过氧化氢);溶剂(例如甘油,丙二醇或聚乙二醇);糖醇(例如甘露糖醇或山梨糖醇);悬浮剂;表面活性剂或湿润剂(例如普流罗尼,PEG,脱水山梨糖醇酯,聚山梨酯类例如聚山梨酯20,聚山梨酯80,三硝基甲苯,氨丁三醇,卵磷脂,胆固醇,四丁酚醛);稳定增强剂(蔗糖或山梨醇);紧张性增强剂(例如碱金属卤化物(优选氯化钠或氯化钾,甘露糖醇,山梨糖醇);运送载体;稀释剂;赋形剂和/或药物佐剂(Remington′s Pharmaceutical Sciences,第18板,A.R.Gennaro,编著,Mack Publishing Company,1990)。
根据例如想用的给药途径,送递方式,和期望的剂量,本领域技术人员会确定最佳药物组合物。参见,例如,Remington′s PharmaceuticalSciences,上文。这样的组合物可以影响特异性结合剂的物理状态,稳定性,和体内释放速度,和体内清除速度。
药物组合物中的主要赋形剂和载体性质可以是含水的或非水的。例如,合适的赋形剂或载体可以是注射用水,生理盐水或人工脑脊髓液,可能补充有肠胃外给药组合物中常用的其他材料。中性缓冲盐水或者与血清白蛋白混合的盐水是另外的举例的赋形剂。其他例示的药物组合物含有大约pH 7.0-8.5的Tris缓冲液,或者大约pH 4.0-5.5的乙酸缓冲液,其可以进一步包括山梨糖醇或者合适的替代物。在本发明的一个实施方案中,可以通过将具有期望程度纯度的选择的组合物和任意的配药制剂(Remington′s Pharmaceutical Sciences,上文)混合成冻干块状物或水溶液而制备结合剂组合物储存。此外,利用合适的赋形剂例如蔗糖可以将结合剂产物配制成冻干剂。
可以选择用于肠胃外给药的药物组合物。或者,可以选择组合物用于吸入法或肠给药例如口服,耳给药,眼给药,直肠,或阴道给药。这样的药学可接受组合物的制备在本领域技术人员能力之内。
给药部位可接受的浓缩物中存在制剂成分。例如,使用缓冲液保持组合物为生理pH或者稍低的pH,一般在大约5至大约8的pH范围内。
当涉及肠胃外给药时,本发明中使用的治疗性组合物可以是无热源的药学可接受赋形剂中含有期望的特异性结合剂的肠胃外可接受水溶液。用于肠胃外注射的特别合适的赋形剂是无菌水,其中结合剂被配制成无菌的,等张的溶液,使当地防腐。而另一个制备涉及用一种提供产物缓蚀或持续性释放然后通过贮存注射送递的物质,例如可注射微球体,生物可降解颗粒,聚合物化合物(聚乳酸,聚乙醇酸),小球,或脂质体,将期望的分子制成制剂。也可以使用透明质酸,它在循环中有推广延长时间的作用。引入期望的分子的其他合适的方法包括可植入药物送递装置。
另一方面,可以在水溶液,优选生理可容缓冲液例如Hanks′溶液,ringer′s溶液,或者生理缓冲盐水中配制适合肠胃外给药的药物制剂。含水注射悬浮液可以含有提高悬浮液粘度的物质,例如羧甲基纤维素钠,山梨糖醇,或葡聚糖。另外,可以将活性化合物悬浮液制备成合适的油注射悬浮液。合适的亲油性溶剂或赋形剂包括脂肪油,例如芝麻油,或合成的脂肪酸酯,例如油酸乙醇,三甘油脂,或脂质体。非脂质聚阳离子氨基聚合物可以用于送药。任选地,悬浮液还可以含有合适的稳定剂或者提高化合物溶解度的试剂,制备出高浓缩溶液。
在另一个实施方案中,药物组合物可以配制成吸入法用药。例如,可以将结合剂配制成吸入用干粉末剂。也可以用用于气雾剂送药的抛射剂配制多肽或核酸分子吸入用溶液。在另一个实施方案中,可以喷洒溶液。PCT申请No.PCT/US94/001875中进一步描述了肺给药,它描述了肺给药化学修饰的蛋白质。
还涉及可以口服施用一些制剂。在本发明的一个实施方案中,使用或不使用象片剂和胶囊这样的固体剂型是常规使用的那些载体,能配制以这种方式给药的结合剂分子。例如,设计胶囊,当生物利用率最大并且系统之前降解最小时,在胃肠道的一点释放制剂的活性部分。可以含有附加试剂以有利于结合剂分子的吸收。也可以使用稀释剂,矫味剂,低熔点蜡,植物油,润滑剂,悬浮剂,片剂崩解剂,和粘合剂。
使用本领域技术人员公知的药学可接受载体也能将用于口服给药的药物组合物配制成适合口服给药的剂型。这样的载体使药物组合物被配制成患者摄食的片剂,丸剂,糖衣丸,胶囊,液体,凝胶,糖浆,浆液,悬浮液,等。
通过将活性化合物与固体赋形剂混合并且将得到的颗粒混合加工处理(任选地,在研磨之后),获得片剂或糖衣丸核心,能获得口服使用的药物制剂。如果期望,可以加入合适的辅助剂。合适的辅助剂包括碳水化合物或蛋白质,例如糖,包括乳糖,蔗糖,甘露糖醇,和山梨糖醇;来自玉米,小麦,稻,马铃薯,或其他植物的淀粉;纤维素,例如甲基纤维素,羟丙基甲基纤维素,或羧甲基纤维素钠;树胶,包括阿拉伯胶和黄芪胶;和蛋白质,例如明胶和胶原。如果期望,可以加入崩解剂或增溶剂,例如交联聚乙烯吡咯烷酮琼脂,和海藻酸或者其盐,例如藻酸盐。
糖衣丸心核可以与合适的包衣联合使用,所述合适的包衣是例如浓糖溶液,它还可以含有阿拉伯胶,滑石,聚乙烯吡咯烷酮,carbopol gel,聚乙二醇,和/或二氧化钛,漆溶液,和合适的有机溶剂或溶剂混合物。可以向片剂或糖丸剂包衣加入染料或颜料,用于产物识别或者表征活性化合物的量,即,剂量。
可以口服使用的药物制剂还可以包括明胶制成的适合推动的胶囊,以及明胶和包衣例如甘油或山梨糖醇制成的软密封胶囊。适合推动的胶囊可以含有与填料或粘合剂例如乳糖或淀粉,润滑剂,例如滑石或硬脂酸镁,和任选地,稳定剂混合的活性成分。在软胶囊中,活性化合物可以溶解于或悬浮于合适的液体中,例如脂肪油,液体,液体聚乙二醇,有或没有稳定剂。
另一种药物组合物可以含有与适合制备片剂的无毒赋形剂的混合物中有效量的结合剂。通过将片剂溶解于无菌水,或者其他合适的赋形剂中,可以制备单位剂量形式的溶液。合适的赋形剂包括但相比于,惰性稀释剂,例如碳酸钙,碳酸钠或碳酸氢钠,乳糖,或磷酸钙;或粘合试剂,例如淀粉,明胶,或阿拉伯胶;或润滑剂例如硬脂酸镁,硬脂酸,或滑石。
另外的药物组合物对于本领域技术人员是显然的,包括持续性释放或缓释送药制剂中含有结合剂分子的制剂。配制各种各样的其他持续性或缓释送药方式的技术,例如脂质体载体,生物可降解微粒或者大孔小球和贮存注射液,对于本领域技术人员也是公知的。参见,例如,PCT/US93/00829,它描述了用于送递药物组合物的大孔聚合物微粒的缓释。持续性释放制剂的另外的例子包括有形物品形式的半渗透聚合物基体,例如膜,或微胶囊。持续性释放基体可以包括聚酯类,水凝胶,聚较酯(美国专利No.3,773,919,EP 58,481),L-谷氨酸和γL-谷氨酸乙酯的共聚物[Sidman等,Biopolymers,22:547-556(1983)],聚(2-羟乙基-甲基丙烯酸酯)[Langer等,J.Biomed.Mater.Res.,15:167-277,(1981)]和[Langer等,Chem.Tech.,12:98-105(1982)],乙酸亚乙基乙烯酯(Langer等,上文)或聚-D(-)-3-羟基丁酸(EP 133,988)。持续性释放组合物还包括脂质体,通过本领域公知的几种方法制备。参见,例如,Eppstein等,Proc.Natl.Acad.Sci.(USA),82:3688-3692(1985);EP 36,676;EP 88,046;EP 143,949。
用于体内施用的药物组合物一般一定要灭菌。通过灭菌过滤膜灭菌过滤能实现这样。将组合物冻干,在冻干和重新配制之前或之后可以实施利用这种方法的灭菌。用于肠胃外给药的组合物可以以冻干形式或在溶液中储存。另外,一般将肠胃外组合物置于具有灭菌入口的容器内,例如,带有皮下注射针头可穿透的塞子的静脉溶液袋或小瓶。
一旦配制了药物组合物,可以在灭菌小瓶中贮溶液,悬浮液,凝胶,乳状液,固体,或脱水或冻干粉末剂。可以以待用形式或者在给药之前需要重新配置的形式(例如冻干的)贮存这样的制剂。
在具体的实施方案中,本发明涉及用于制备单剂量给药单位的试剂盒。试剂盒可以各自含有盛有干燥的蛋白质的第一容器和盛有含水制剂的第二容器两者。本发明范围内还包括包含单个或多个小室预装注射器(例如液体注射器和冻干剂注射器)的试剂盒。
治疗上使用的药物组合物的有效量取决于,例如,治疗背景和主体。本领域技术人员明白用于治疗的适当的剂量水平是不同的,部分取决于送递的分子,使用的结合剂分子的适应征,给药途径,和患者的大小(体重,体表面或器官大小)和状况(年龄和一般的健康情况)。因此,临床医师可以确定剂量并且改变给药途径,以获得最佳治疗效果。根据上面提到的因素,典型的剂量范围是大约0.1mg/kg至最多大约100mg/kg或者更多。在其他实施方案中,剂量范围可以是0.1mg/kg最多至100mg/kg;或者1mg/kg至最多大约100mg/kg;或者5mg/kg至最多大约100mg/kg。
对于任何化合物,开始时在细胞培养物或者动物模型例如小鼠,大鼠,兔,狗,猪,或猴中能估计治疗有效剂量。还可以使用动物模型来确定合适的浓度范围和给药途径。然后利用这样的信息来确定对人给药的有用的剂量和途径。
考虑与需要治疗的受试者相关的因素确定精确剂量。调节剂量和施用,提供足够水平的活性化合物或者保持期望的作用。可以考虑的因素包括病态的严重性,受者的一般健康,受者的年龄,体重和性别,该药的时间和次数,药物联合,反应灵敏性,对治疗的反应。根据特定制剂的半寿期和清除率,可以每3-4天,每周,或者每两周施用长效药物组合物。
给药次数取决于使用的制剂中结合剂分子的药物动力学参数。一般地,施用组合物,直到用量达到期望的作用。因此,可以用单剂量,或随时间多次给药(以相同或不同浓度/剂量),或者连续输液,可以施用组合物。合适剂量的进一步精确给药方案是常规制定的。通过使用适当的剂量-反应数据,可以确定合适的剂量。
药物组合物的给药途径与已知方法相一致,例如口服,通过静脉内,腹膜内,大脑内(薄壁组织内),脑室内,肌内,眼内,动脉内,肝门内,病灶内途径注射,骨髓内,鞘内,室内,经皮,皮下,腹膜内,鼻内,肠内,局部,舌下,尿道,阴道,或者直肠方式,通过持续性释放系统或者通过埋入装置。期望时,通过大丸剂注射,或者通过输液或者通过埋入装置连续施用组合物。
或者,另外,通过埋入其上已经吸收或者包在其中有期望的分子的膜,海绵状物质,或者其他合适的材料,可以局部施用组合物。当使用埋入装置时,可以将装置埋入任何合适的组织或器官,期望的分子的送递可以通过扩散,随时间释放的大丸剂,或者连续给药。
在某些情况下,期望以来自体内的方式使用药物组合物。在这样的情况下,使来自患者的细胞,组织,或器官接触药物组合物,其后接着将这些细胞,组织,和/或器官植回给患者。
在另外的情况下,本发明的结合剂例如特异结合剂能通过埋入利用这里描述的方法经基因工程处理表达和分泌多肽的细胞送递。这样的细胞可以是动物或人细胞,并且可以是自身的,异种的,或异基因的。任选地,细胞可以是无限增殖的。为了减小免疫应答机会,可以将细胞包在荚膜内,以避免周围组织渗透。密封材料是生物相容的半渗透聚合物外壳或膜,它允许蛋白质产物释放但是防止患者免疫系统或者周围组织的其他有害因子对细胞的破坏。
联合治疗
在Ang-2病理的治疗中,本发明的特异性结合剂可以与其他治疗法联合应用。这些其他疗法包括,例如放射疗法,化疗药物和其它生长因子。
化疗治疗可以使用抗肿瘤药物,包括,例如,烷基化试剂,包括:氮芥,例如双氯乙基甲胺,环磷酰胺,异磷酰胺,左旋溶肉瘤素和苯丁酸氮芥;亚硝基脲类,例如卡氨芥(BCNU),洛氮芥(CCNU),和司莫司汀(甲基-CCNU);氮丙啶/甲基三聚氰胺例如三亚乙基三聚氰胺(TEM),三胺硫磷,硫替哌(噻替哌),六甲基三聚氰胺(HMM,六甲蜜胺);磺酸烷基酯,例如白消安;三嗪类,例如这卡巴嗪(DTIC);抗代谢物,包括叶酸类似物,例如甲氨喋呤和曲美沙特,嘧啶类似物,例如5-氟尿嘧啶,氟去氧尿苷,吉西他滨,胞嘧啶阿拉伯糖苷(AraC,阿糖孢苷),5-氮杂胞苷,2,2′-二氟脱氧胞苷,嘌呤类似物,例如6-巯基嘌呤,6-硫代鸟嘌呤,硫唑嘌呤,2′-脱氧助间型霉素(喷司他丁),赤型羟基壬基腺嘌呤(EHNA),磷酸氟达拉滨,和2-氯脱氧腺苷(克拉屈滨,2-CdA);天然产物,包括抗有丝分裂药物,例如紫杉醇,长春花生物碱,包括长春碱(VLB),长春新碱,和长春烯碱,脱乙酰基紫杉醇,雌莫司汀,和盐酸雌莫司汀;ppipodophylotoxins例如依托泊苷和替尼泊苷;抗生素例如actimomycin D,柔毛霉素(柔红霉素),阿霉素,二羟蒽二酮,去甲柔毛霉素,博莱霉素,光辉霉素(普卡霉素),丝裂霉素C,和放线菌素;酶例如L-天冬酰胺酶;生物学反应修饰剂例如干扰素-α,IL-2,G-CSF和GM-CSF;各种药物例如铂复合物例如顺铂和卡铂,蒽二酮类例如二羟蒽二酮,取代的脲例如羟基脲,甲基肼衍生物包括N-甲基肼(MIH)和甲苄肼,肾上腺皮质抑制剂例如米托坦(o,p′-DDD)和安鲁米特;激素和拮抗剂包括肾上腺皮质激素甾族化合物拮抗剂例如强的松和等价物,地塞米松和安鲁米特;孕激素例如长效黄体酮,甲羟孕酮乙酸盐和甲地孕酮乙酸盐;雌激素例如己烯雌酚和乙炔基雌二醇等价物;抗雌激素例如他莫西芬;雄激素包括丙酸睾丸和氟甲睾酮/等价物;抗雄激素例如氟他胺,促性腺素释放激素类似物和抑那通;和非甾族抗雄激素例如氟他胺。
和生长因子的联合治疗包括细胞因子,淋巴因子,生长因子,或者其他造血因子,例如M-CSF,GM-CSF,TNF,IL-1,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-10,IL-11,IL-12,IL-13,IL-14,IL-15,IL-16,IL-17,IL-18,IFN,TNF0,TNF1,TNF2,G-CSF,Meg-CSF,GM-CSF,血小板生成素,干细胞因子,和红细胞生成素。其他成分包括已知的血小板生成素,例如Ang-1,-2,-4,-Y,和/或人Ang-样多肽,和/或血管内皮生长因子(VEGF)。生长因子包括血管生成素,骨形态发生蛋白-1,骨形态发生蛋白-2,骨形态发生蛋白-3,骨形态发生蛋白-4,骨形态发生蛋白-5,骨形态发生蛋白-6,骨形态发生蛋白-7,骨形态发生蛋白-8,骨形态发生蛋白-9,骨形态发生蛋白-10,骨形态发生蛋白-11,骨形态发生蛋白-12,骨形态发生蛋白-13,骨形态发生蛋白-14,骨形态发生蛋白-15,骨形态发生蛋白受体IA,骨形态发生蛋白受体IB,脑起源神经营养因子,睫状营养佳良因子,睫状神经营养因子受体,细胞因子-诱导的嗜中性白细胞趋化因子1,细胞因子-诱导的嗜中性白细胞趋化因子2,内皮细胞生长因子,内皮素1,表皮生长因子,来自上皮的嗜中性白细胞诱引剂,成纤维细胞生长因子4,成纤维细胞生长因子5,成纤维细胞生长因子6,成纤维细胞生长因子7,成纤维细胞生长因子8,成纤维细胞生长因子8b,成纤维细胞生长因子8c,成纤维细胞生长因子9,成纤维细胞生长因子10,酸性成纤维细胞生长因子,碱性成纤维细胞生长因子,得自神经胶质细胞系的嗜中性细胞因子受体-1,得自神经胶质细胞系的嗜中性细胞因子受体-2,生长相关蛋白质,生长相关蛋白质-1,生长相关蛋白质-2,生长相关蛋白质-3,肝素结合表皮生长因子,肝细胞生长因子,肝细胞生长因子受体,胰岛素-样生长因子I,胰岛素-样生长因子受体,胰岛素-样生长因子I I,胰岛素-样生长因子结合蛋白,角质形成细胞生长因子,白血病抑制因子,白血病抑制因子受体-1,神经生长因子,神经生长因子受体,神经营养蛋白-3,神经营养蛋白-4,胎盘生长因子,胎盘生长因子2,得自血小板的内皮细胞生长因子,得自血小板的生长因子,得自血小板的生长因子A链,得自血小板的生长因子AA,得自血小板的生长因子AB,得自血小板的生长因子B链,得自血小板的生长因子BB,得自血小板的生长因子受体-1,得自血小板的生长因子受体-2,pre-B细胞生长刺激因子,干细胞因子,干细胞因子受体,转化生长因子-1,转化生长因子-2,转化生长因子-1.2,转化生长因子-3,转化生长因子-5,潜伏型转化生长因子-1,转化生长因子-1结合蛋白I,转化生长因子-1结合蛋白II,转化生长因子-1结合蛋白III,肿瘤坏死因子受体I型,肿瘤坏死因子受体II,尿激酶型纤溶酶原激活剂受体,血管内皮生长因子,及其嵌合蛋白和生物学或免疫学活性片段。
免疫治疗
免疫治疗一般依赖定向并破坏癌细胞的免疫效应子细胞和分子的使用。免疫效应子可以是,例如,识别靶细胞表面上的一些标记的本发明的特异结合剂。单独的抗体可以用作治疗的效应子或者它可以补充其他细胞来实际实施细胞杀伤。抗体也可以偶联药物或毒素(化疗药物,放射性核素,蓖麻毒A链,霍乱毒素,百日咳毒素,等),因此可以只作为靶向试剂。
根据本发明,通过免疫疗法可以将Ang-2的突变形式靶向于本发明的抗体或抗体偶联物。特别考虑本发明的抗体组合物可以与结合Ang-2靶向治疗的治疗方法联合应用。
已经证明被动免疫疗法对于抗多种癌症特别有效。参见,例如,WO98/39027。
下面的实施例只是为了详细说明的目的,而不应该认为在任何方面限制本发明的范围。
实施例1
病理组织和正常组织中Ang-2表达
利用原位杂交检查正常和病理组织中Ang-2表达。通过逆转录酶-PCR从人或鼠胎儿肺cDNA扩增人(Genbank Accession Number:AF004327,核苷酸1274-1726)和鼠(Genbank Accession Number:AF004326,核苷酸1135-1588)Ang-2序列的片段,克隆到质粒pGEM-T中,并且通过测序证实。使用33P-UTP和RNA聚合酶从线性化质粒模板转录33P-标记反义RNA探针。甲醛固定化的石蜡包埋的组织块切成5微米,并且收集在带电载玻片上。原位杂交之前,组织用0.2M HCL,接着用蛋白酶K消化,并且用三乙醇胺和乙酸酐进行乙酰化作用。55℃下切片与放射性标记探针杂交过夜,然后进行RNA酶消化,并且在大约0.1XSSC在55℃下高严谨性洗涤,将载玻片浸入Kodak NTB2乳剂中,4℃下暴露2-3周,显影,并且复染色。在黑暗区和标准照明下检查切片,同时评价形态学和杂交信号。
结果表明正常产后人,Ang-2表达限于包含血管发生脉管系统的少数组织,例如卵巢,胎盘,和子宫。在正常成年人心脏,脑,肾,肝,肺,胰腺,脾,肌肉,扁桃体,胸腺,阑尾,淋巴结,胆囊,前列腺或睾丸和子宫中没有可检测的Ang-2表达。在五周大小的小鼠(而不是成年猴子或人),肾显示直小管中显著的Ang-2表达。为了确定这种表达是不是胚胎发育遗留的,使用鼠Ang-2探针和上述条件对最大一年龄大小的小鼠源的肾反复进行这项实验。在新生儿发育期发现Ang-2表达降低,但是一年龄小鼠的肾中仍然明显。
事实上对试验的所有肿瘤类型检查了Ang-2表达,包括,原发性人肿瘤,例如结肠癌(5例),乳房癌(10例),肺癌(8例),恶性胶质瘤(1例),转移性人肿瘤,例如乳房癌(2例),肺癌(2例),和卵巢癌(2例),已经转移到脑,和啮齿动物肿瘤模型例如C6(大鼠神经胶质瘤),HT29(人结肠癌),Colo-205(人结肠癌),HCT116(人结肠癌),A431(人表皮样瘤),A673(人横纹肌肉瘤),HT1080(人纤维肉瘤),PC-3(人前列腺癌),B16F10(鼠黑素瘤),MethA(鼠肉瘤),和Lewis肺癌。另外,对反应VEGF的生长到Matrigel栓中的新血管和早产视网膜病小鼠低氧症模型检查Ang-2表达。
实施例2
重组mAng-2蛋白和兔多克隆抗-Ang-2抗血清的产生
使用全长人Ang-2的PCR引物,通过PCR(Clontech AdvantagePCR Kit,Cat.# K1905-01)从鼠15日胚胎DNA文库(Marathon-Ready-cDNA,Cat.#;7459-1,Clonetech,Inc.)获得全长的,带组氨酸标记的Ang-2cDNA。使用FuGENE6转染试剂(Roche,Cat.#;1814443)将PCR产物连接至CMV启动子表达载体中,将得到的质粒转染到HT1080人纤维肉瘤细胞(得自ATCC)中。通过G418选择分离稳定的克隆。抗组氨酸标记和蛋白印迹筛选表达mAng-2-his的克隆。
从这些细胞的条件培养基(C.M.)纯化重组的mAng-2多肽。通过两步层析方法纯化含mAng-2-His的C.M.简言之,通过添加pH 9.5的Tris缓冲液将条件培养基滴定到约20mM的终浓度。此外,加入去污剂CHAPS至大约5mM的终浓度。然后将C.M.直接加至阴离子交换柱Q-sepharose ff(Pharmacia)。然后用含有大约50mM NaCl的大约10mM Tris pH 8.0洗涤柱。用含有大约350mM NaCl和大约5mMCHAPS的10mM Tris pH8.0以单个步骤洗脱重组的Ang-2-His。
将Q-sepharose柱的洗脱物调节至大约4mM咪唑,并且加至固定化的金属亲和柱(Ni-NTA superflow[Qiagen])。用含有大约5mMCHAPS和大约100mM咪唑的PBS洗脱结合的蛋白。然后将洗脱物浓缩至大约1.0mg/ml,然后用PBS透析,通过SDS-PAGE考马斯亮蓝染色测量mAng-2-His的纯度大于90%。
用大约0.2mg mAng-2/注射免疫兔,以产生抗体。用1∶1的大约1mL Hunter′s TiterMax(Sigma)和mAng-2注射兔。四周后,每只兔接受重复注射或加强;此后两周,接受下一次加强,在第7周,取出血清,评估对mAng-2的滴度。如果血清滴度高,连续6周每周取出50mL产物血液。然而,如果血清滴度低,对兔进行一次额外的加强,从第9周开始连续6周每周取出50mL产物血液。连续六周取血后,让兔休息6周。如果需要更多血清,最后一次取血后一个月对兔再进行一次加强。
使用中和ELISA(描述于下文),观察来自两只兔5254和5255的抗-mAng-2兔多克隆抗血清对mAng-2:Tie2相互作用的中和。
实施例3
评价Ang-2抗体的分子测定
进行分子测定(亲和力ELISA,中和作用ELISA,和BIAcore)评价结合Ang-2和相关家族成员的直接抗体,以及抗体对Ang-2:Tie-2相互作用的作用。下面详细描述这些体外和基于细胞的测定。
A.亲和力ELISA
为了最初筛选侯选抗-Ang-2抗体,使用纯化的人Ang-2(R&DSystems,Inc;目录号623-AN;Ang-2以2个截短型的混合物被提供)或鼠Ang-2多肽(如上所述制备)。为了证实结合测试,从用全长人Ang-2DNA转染的人293T细胞的条件培养基获得人Ang-2并且在含有大约50微克/毫升牛血清白蛋白(BSA)的无血清Dulbecco′s修饰的Eagle培养基(DMEM)中培养。
使用微量滴定板,向每个孔加入大约100微升/孔Ang-2,并且将板温育大约2小时,然后用含有大约0.1%Tween-20的磷酸缓冲盐水(PBS)将板冲洗四次。然后对于每孔用250微升的大约5%BSA的PBS溶液封闭各孔,板在室温下温育大约2小时。温育之后,弃除过量的封闭溶液,向孔中加入大约100微升的各种侯选抗-Ang-2抗体,稀释系列开始浓度是大约40毫微摩尔,然后在含有大约1%BSA的PBS中系列稀释4倍。培养板然后在室温下温育过夜。温育之后,用含有大约0.1%Tween-20的PBS冲洗平板。将冲洗又重复四次,然后向每孔加入在含有1%BSA的PBS中以1∶5000预先稀释的山羊抗-人IgG(Fc)-HRP(Pierce Chemical Co.,catalog #31416)大约100微升。培养板在室温下温育大约1小时。然后在含有大约0.1%Tween-20的PBS冲洗平板五次,然后每孔加入大约100微升的TMB(3,3′,5,5′-四甲基联苯胺液体底物体系;Sigma Chemical Company,St.Louis,Mo.,目录号T8665)底物,并且将培养板温育大约5-15分钟直到显示蓝色。然后在分光光度计上在大约370nm读取吸光度。
B.中和作用ELISA
根据对于亲和力ELISA所描述的制备结合了人Ang-2多肽的微量滴定板。在含有大约1%BSA和大约1nM Tie-2(以Tie-2-Fc分子提供,其中Tie-2部分只含有该分子的可溶性胞外部分;R&D Systems,目录号313-TI)的PBS溶液中以4倍稀释度从1000nM至0.2pM滴定侯选抗-Ang-2抗体。向各孔加入大约100微升的抗体/Tie-2溶液之后,培养板在室温下温育过夜,然后用含有大约0.1%Tween-20的PBS清洗五次。冲洗之后,每孔加入大约100微升的抗-Tie-2抗体(Pharmingen Inc.,catalog #557039),最终浓度达到大约1微克/毫升,培养板在室温下温育大约1小时。接着,以含有大约1%BSA的PBS中以1∶10,000的稀释度每孔加入大约100微升山羊抗-小鼠-IgG-HRP(Pierce Chemical CO.,catalog #31432)。培养板在室温下温育大约1小时,然后用含有大约0.1%Tween-20的PBS清洗五次。然后每孔加入大约100微升的TMB底物(如上所述),使得显色。然后在分光光度计上在大约370nm读取吸光度。
C.亲和力BIAcore
使用PBS和0.005%P20表面活性剂(Biacore,Inc.)作为洗脱缓冲液在2000(Biacore,Inc.,Piscataway,N.J.)上进行各种侯选Ang-2抗体的亲和力分析。使用Amine Coupling Kit(Biacore,Inc.)根据供应商建议的方法通过伯胺基团将重组蛋白质G(Repligen,Needham,Mass.)固定到研究级CM5传感器芯片(Biacore,Inc.)上。
通过首先将大约100Ru的各种侯选抗-Ang-2抗体捕获到固定的蛋白质G,然后以50微升/分钟的流速向结合的抗体表面注射各种浓度的(0-100nM)的huAng-2或mAng-2三分钟,进行结合分析。应用BIA求值3.1计算机程序(Biacore,Inc.)测定抗体结合动力学参数,包括ka(缔合作用速度常数),kd(离解作用速度常数)和KD(离解平衡常数)。离解平衡常数越低,表明抗体对Ang-2的亲和力越大。
实施例4
通过噬菌体展示产生完全的人Ang-2抗体
按照以下方案,通过对人Ang-2多肽(R and D Systems Inc.,catalog 623-AN)淘选Target Quest噬菌体展示Fab文库(TargetQuest,Inc.)而产生完全的人抗体。
通过两种方法将人Ang-2固定在聚苯乙烯磁珠表面:(1)4℃下以50ug/ml直接包被Ang-2过夜;和(2)通过山羊抗Ang-2抗体4℃下以50ug/ml间接捕获过夜。用PBS中的2%乳(MPBS)封闭珠表面。预选人Fab噬菌体文库,以去除与未包被的磁珠或山羊抗-Ang-2抗体反应的噬菌体克隆。然后在室温下用噬菌体文库温育Ang-2包被的磁珠过夜。噬菌体结合步骤之后,用含有大约0.1%Tween 20的MPBS洗涤表面6次,然后用含有大约0.1%Tween 20的PBS洗涤6次,然后用PBS洗涤两次。首先用大约100ug/ml人Tie2-Fc(R and D Systems,Minneapolis,MN),然后用大约100mM三乙醇胺洗脱结合的噬菌体。将洗脱的噬菌体感染至大肠杆菌TG1细胞,扩增,并且回收进行下一轮筛选。通过进行更严格的洗涤和减少输入噬菌体的数目在连续的轮次中增加选择压力。进行3轮选择后,鉴定18个独特的Ang-2结合Fab克隆,使用上文所述的ELISA亲和力测定进行检测,几乎所有的克隆都被识别为人Ang-2,小鼠Ang-2和大鼠Ang-2。这些噬菌体的大约10%也结合人Ang-1。按照下文所述将这些克隆转化为IgG1抗体。
为了获得其它独特的噬菌体,使用相同文库但略有不同的方案进行第二轮筛选。在此方案中,在大约4℃下在Nunc maxisorp免疫管中将人Ang-2铺于pH9.6的NaHCO3缓冲液中过夜。分别在1、2和3轮淘选中平铺约1.5,0.74和0.3ug/ml的Ang-2。用PBS中的大约2%乳(MPBS)封闭免疫管表面,然后在大约4ml 2%MPBS中用来自上文提到的相同噬菌体展示文库(Target Quest)的约2万亿个噬菌体颗粒(文库中的大约50拷贝的每种独特的噬菌体)温育。噬菌体温育步骤之后,用PBS加大约1%Tween 20洗涤表面20次,然后用PBS洗涤20次。用1uM hAng-2或1uM人Tie2(R and D Systems,如上文所述)洗脱结合的噬菌体。将洗脱的噬菌体感染至大肠杆菌TG1细胞(与噬菌体文库一起提供),扩增,并且回收进行下一轮筛选。通过PCR扩增与hAng-2或Tie2结合的所有噬菌体,鉴定16个独特的Ang-2结合Fab克隆,并且通过限制性消化分析这些克隆。对每个克隆的DNA进行测序。
用互补引物扩增每个噬菌体的每个重链可变区的编码序列。设计引物以在可变区的5’末端掺入HindIII位点,XbaI位点,Kozak序列和信号序列(翻译的肽为MDMRVPAQLLGLLLLWLRGARC;SEQ ID NO:69),而将BsmBI位点加在PCR产物的3’末端上。作为如何克隆重链的一个例子,用添加信号序列的最后7个氨基酸的引物2248-21(GTG GTT GAGAGG TGC CAG ATG TCA GGT CCA GCT GGT GCA G;SEQ ID NO:70)和将BsmBI位点加在可变区末端的2502-31(ATT ACG TCT CAC AGT TCGTTT GAT CTC CAC;SEQ ID NO:71)扩增克隆544的模板噬菌体DNA(Seq ID No.19)。使用将9个氨基酸加至信号肽(AQLLGLLLL;SEQ IDNO:73)的引物2148-98(CCG CTC AGC TCC TGG GGC TCC TGC TAT TGTGGT TGA GAG GTG CCA GAT;SEQ ID NO:72),然后使用2502-31,然后使用2489-36(CAG CAG AAG CTT CTA GAC CAC CAT GGA CAT GAGGGT CCC CGC TCA GCT CCT GGG;SEQ ID NO:74)和2502-31扩增得到的产物。引物2489-36从5′至3′添加HindIII位点,XbaI位点,Kozak序列和信号序列的前6个氨基酸。用XbaI和BsmBI消化PCR产物,然后克隆到含有人IgG1恒定区的哺乳动物表达载体中。该载体含有SV40启动子和DHFR选择。
来自每个噬菌体的轻链是κ或λ类型。对于每种轻链,设计互补引物,以便从从5′至3′添加HindIII位点,XbaI位点,Kozak序列和信号序列(如上文所述)。将具有无错误编码区的那些链克隆为全长产物。作为一个例子,用添加信号序列的最后7个氨基酸的引物2627-69(GTG GTT GAG AGG TGC CAG ATG TGA CAT TGT GAT GAC TCAGTC TCC;SEQ ID NO:75)和在终止密码子之后添加SalI位点的引物2458-54(CTT GTC GAC TTA TTA ACA CTC TCC CCT GTT G;SEQ ID NO:76)扩增作为全长编码区的噬菌体克隆536的轻链(Seq ID NO.11)。然后如前所述分别用与引物2458-54配对的额外的5’引物,2148-98和2489-36扩增PCR产物,完成信号序列和克隆位点的最终添加。将全长轻链作为XbaI-SalI片段克隆至上文所述的哺乳动物表达载体中。
与天然人恒定区序列相比,某些λ克隆在它们的恒定区中具有错误。为了纠正这些差异,用编码理想λ恒定区和噬菌体来源的可变区的DNA进行重叠PCR。这些克隆也克隆为如上文所述的XbaI-SalI片段。
当κ可变区与它们的恒定区独立进行克隆时,将BsmBI位点添加至PCR产物的3’末端。用XbaI和BsmBI消化PCR产物后,将κ链可变区克隆至含有人κ恒定区的表达载体中。
采用磷酸钙转染试剂盒(Invitrogen Corp.),一般根据制造商建议的程序将来自每个转化的噬菌体的成对轻链和重链构建体共转染至CHO细胞中。转染后14-16小时更换培养基,将细胞传代至组织培养皿中,用于按照制造商的推荐在大约48小时后进行选择。通过HT选择大约3周而分离转染的细胞,此时用胰蛋白酶消化转染的CHO细胞集落,并且合并至转染细胞的“合并物”中。
48小时后收集小规模条件培养基,并且使用抗人Fc抗体、抗人κ抗体或抗人λ抗体,通过蛋白印进分析抗体产生。然后使用标准组织培养无菌技术,在选择压力下传代选择的细胞群,直到获得足够的细胞,接种4个850cm2的滚瓶,每个滚瓶中接种2x107个存活细胞,并且使用DMSO制备冷冻的储备细胞系。接种后,将细胞维持在装有补加了谷氨酰胺和非必须氨基酸的含大约10%血清的DMEM培养基(Gibco/BRL,Inc)中。将细胞维持大约2-3天,直到达到约80%的细胞铺满度。此时将滚瓶中的培养基更换为补加了谷氨酰胺和非必须氨基酸的无血清培养基混合物(50%DMEM,50%F12,Gibco)。7天后收获条件培养基,添加新鲜的无血清培养基,用于一次或两次额外的收获。
采用标准程序,通过蛋白G亲和层析直接从条件培养基纯化抗体。采用低pH(约pH3)缓冲液完成从蛋白G柱的洗脱,此后用1M Tris,pH8.5中和洗脱的抗体蛋白,然后用10kD分子量截断离心浓缩器浓缩。然后将浓缩的抗体储液缓冲交换到PBS中。
产生了31种抗体,每一种由两条重链和两条轻链(κ或λ)组成,命名见下表2。
表2
抗体重链 | 抗体轻链 |
526HC<sup>*</sup> | 526kappa |
528HC<sup>*</sup> | 528lambda |
531HC<sup>*</sup> | 531lambda |
533HC<sup>*</sup> | 533lambda |
535HC<sup>*</sup> | 535lambda |
536HC<sup>*</sup> | 536kappa |
537HC<sup>*</sup> | 537lambda |
540HC<sup>*</sup> | 540lambda |
543HC<sup>*</sup> | 543kappa |
544HC<sup>*</sup> | 544kappa |
545HC<sup>*</sup> | 545lambda |
546HC<sup>*</sup> | 546lambda |
551HC<sup>*</sup> | 551kapPa |
553HC<sup>*</sup> | 553kappa |
555HC<sup>*</sup> | 555kappa |
558HC | 558kappa |
559HC | 559lambda |
565HC<sup>*</sup> | 565kappa |
F1-C6HC | F1-C6lambda |
表2(续)
FB1-A7HC | FB1-A7lambda |
FD-B2HC | FD-B2lambda |
FE-B7HC | FE-B7kappa |
FJ-G11HC | FJ-G11kappa |
FK-E3HC | FK-E3kappa |
G1D4HC<sup>*</sup> | G1D4lambda |
GC1E8HC | GC1E8lambda |
H1C12HC | H1C12lambda |
IA1-1E7HC | IA1-1E7kappa |
IF-1C10HC | IF-1C10lambda |
IK-2E2HC | IK-2E2lambda |
IP-2C11HC | IP-2C11kappa |
*按此处描述,测定与hAng-2,mAng-2,和hAng-1的结合。
以下四个表列出了从噬菌体转化至全长IgG1抗体的31个抗-Ang-2抗体的重链和轻链(κ和λ)的序列和SEQ ID Nos。用VBASE数据库,采用Kabat等在Sequences of Proteins of ImmunologicalInterest(NIH公开号91-3242;U.S.Dept.Health and HumanServices,5th ed.)中描述的技术预测单克隆抗体的互补决定区(CDRs)。将Fab区与数据库中具有最接近的种系序列(见:http://www.mrc-cpe.cam.ac.uk/imt-doc/restricted/ALIGNMENTS.html)的序列进行比对,然后肉眼比较所述序列。每个可变区(重链或轻链)的CDRs如表7所示。
表3
重链可变区
抗体HC | 序列 |
526HC(SEQ ID NO.1) | EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLDYDILTGPYAYWGQGTLVTVSS |
528HC(SEQ ID NO.3) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGVVGDFDWLSFFDYWGQGTLVTVSS |
531HC(SEQ ID NO.5) | EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPILGIANYAQKFQGRVTITADKSTNTAYMELTSLTSDDTAVYYCARDREDTAMVFNYWGQGTLVTVSS |
533HC(SEQ ID NO.7) | EVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLDYDILTGYGYWGQGTLVTVSS |
535HC(SEQ ID NO.9) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAAFSPFTETDAFDIWGQGTMVTVSS |
536HC(SEQ ID NO.11) | EVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLDYDILTGYGYWGQGTLVTVSS |
537HC(SEQ ID NO.13) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPILGIANYAQKFQGRVTITADKSTSTAYMELSGLGSEDTAVYYCARGSSDAAVAGMWGQGTLVTVSS |
540HC(SEQ ID NO.15) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPILGIANYAQKFQGRVTITADKFTSTAYMELSSLGSEDTAVYYCARAVPGTEDAFDIWGQGTMVTVSS |
543HC(SEQ ID NO.17) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARPYYDFWSGPGGMDVWGQGTTVTVSS |
544HC(SEQ ID NO.19) | QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARFESGYWGDAFDIWGQGTMVTVSS |
545HC(SEQ ID NO.21) | QVQLQESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGPVDFDYGDYAIDYWGQGTLVTVSS |
546HC(SEQ ID NO.23) | EVQLVDSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKETISFSTFSGYFDYWAQGTLVTVSS |
551HC(SEQ ID NO.25) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGYDFWSGYSLDAFDIWGQGTMVTVSS |
553HC(SEQ ID NO.27) | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYAMHWVRQAPGQRLEWMGWINAGNGNTKYSQKFQGRVTITRDTSASTAYMELSGLRSEDTAVYYCARGVDDYGGNSWAFDIWGQGTMVTVSS |
555HC(SEQ ID NO.29) | QVQLQESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSASDHYYDSSGYYSDAFDIWGQGTMVTVSS |
558HC(SEQ ID NO.31) | QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPGKGLEWIGEINHSGSTNFNPSLKSRITISVDTSNNQFSLKLSSVTAADTAAYYCARGHDWGMGIGGAAYDIWGQGTMVTVSS |
559HC(SEQ ID NO.33) | QVQLVQSGAEVKKPGASVKVSCKVSGYTLTESSMHWVRQAPGKGLEWMGGFDPEHGETTYAQKFQGRLTMTEDTSTDTAYMELSSLRSEDTAVYFCARGVQVTSGYHYFDHWGQGTLVTVSS |
565HC(SEQ ID NO.35) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTTTADESTSTAYMELSSLRSEDTAVYYCARSPIYYDILTGIDAFDIWGQGTMVTVSS |
F1-C6HC(SEQ ID NO.37) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARDPIPSGWYFDLWGRGTLVTVSS |
FB1-A7HC(SEQ ID NO.39) | QVQLVESGGGLVKPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREVGNYYDSSGYGYWGQGTLVTVSS |
FD-B2HC(SEQ ID NO.41) | QVQLQQSGPGLVKPSQTLSLTCAISGDTVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYSDYAVSLRGRITINLDTDTSKNQFSLQLNSVTPEDTAVYYCARDRGGYIDSWGQGTLVTVSS |
FE-B7HC(SEQ ID NO.43) | EVQLVESGGGLGQPGGSLRLSCAATGFSLDDYEMNWVRQAPGRGLEWVSYIIGSGKTIFYADSVKGRFTISRDNGKNSVYLQMNSLRAEDTAIYYCARGGGSAYYLNTSDIWGQGTMVTVSS |
FJ-G11HC(SEQ ID NO.45) | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDRGIAARSAYYYGMDVWGQGTTTVTVSS |
FK-E3HC(SEQ ID NO.47) | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDLNWVRQASGQGLEWMGWMNPTSGNTGYAQKFQGRITMTRNTSISTAYMELRSLRSDDTAVYYCARDPPSGGWEFDYWGQGTLVTVSS |
G1D4HC(SEQ ID NO.49) | QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSHAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTTTADESTSTAYMELSSLRSEDTAVYYCATSRLEWLLYLDYWGQGTLVTVSS |
GC1E8HC(SEQ ID NO.51) | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMEVRSLRSDDTAVYYCARGGSPYGGYAYPFDYWGQGTLVTVSS |
H1C12HC(SEQ ID NO.53) | EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLLDYDILTGYGYWGQGTLVTVSS |
IA1-1E7HC(SEQ ID NO.55) | QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPGKGLEWIGEINHSGSTNFNPSLKSRITISVDTSNNQFSLKLSSVTAADTAVYYCARGHDWGMGIGGAAYDIWGQGTMVTVSS |
IF-IC10HC(SEQ ID NO.57) | QVQLVESGGGLVQPGGSLRLSCAASGFTFFSTYAMTWVRQAPGKGLEWVSVIRSNGGTDYADFVKGRFTISRDNSKNTLYLQMNGLRAEDTAVYYCMTDYYWGQGTLVTVSS |
IK-2E2HC(SEQ ID NO.59) | EVQLLESGGGLVQPGGSLRLLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKETISFSTFSGYFDYWGQGTLVTVSS |
IP-2C11HC(SEQ ID NO.61) | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCAKEIAVAGTRYGMDVWGQGTTVTVSS |
表4
κ链可变区
抗体LC | 序列 |
526kappa(SEQ ID NO.2) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPPTFGGGTKVEIK |
536kappa(SEQ ID NO.12) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPPTFGQGTKLEIK |
543kappa(SEQ ID NO.18) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTGGGTKVEIK |
544kappa(SEQ ID NO.20) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLNWYLQKPGQSPQILIYLGSNRASGVPDRFSGSGSGTDFLKISRVEAEDVGVYYCMQGLQTPPTFGQGTKLEIK |
551kappa(SEQ ID NO.26) | DIVMTQSPLSLPVTPGEPASISCRSSQSLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIK |
553kappa(SEQ ID NO.28) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFTGSGSATDFTLRISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIK |
555kappa(SEQ ID NO.30) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLASNRASGVPDRFSGSGSGTDFTRISRVEAEDVGVYYCMQTLQIPITFGPGTKVDIK |
558kappa(SEQ ID NO.32) | EIVLTQSPGTLSLSPGERATLSCRASQSVSSSSLAWYQQKPGQAPRLLVYAASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSPRTFGQGTKVEIK |
565kappa(SEQ ID NO.36) | EIVLTQSPGTLSLSPGERATLSCRASQSVSSSSLAWYQQKPGQAPRLLVYAASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSPRTFGQGTKVEIK |
FE-B7kappa(SEQ ID NO.44) | DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSKGDNYLDWYLQKPGQSPQLLIYLGSHRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIK |
FJ-G11kappa(SEQ ID NO.46) | DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDDGKTYLDWYLQRPGQSPQLLMYTTSSRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATQFPYTFGQGTKLEIK |
FK-E3kappa(SEQ ID NO.48) | DIVMTQTPLSSTVTLGQPASISCRSSQSLVHEDGNTYLNWLHQRPGQPPRLLIYKISKRFSGVPDRFSGSGAGTDFTLKISRVEPEDVGVYYCMQSTRFPRTFGQGTKLEIK |
IA1-1E7kappa(SEQ ID NO.56) | EIVLTQSPATLSLSPGERATLSCRASQSVSSSFLAWYQQKAGQAPRLLIYDTSTRATGIADRFSGSGSGTDFTLTISRLEAEDSAVYYCQQYDFSPLTFGGGTKVEIK |
IP-2C11kappa(SEQ ID NO.62) | EIVLTQSPGTLSLSPGERATLSCRASQSISTFLAWYQQKPGQAPRLLIYDASNRATGIPGRFSGSGSGTDFTLTISNLEPEDFAVYYCQHRINWPLTFGGGTKVEIK |
表5
λ链可变区
抗体LC | 序列 |
528lambda(SEQ ID NO.4) | SYELTQPPSVSVSPGQTASITCSGDKLGYTYTSWFQQKPGQSPVLVIFQDFKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSTTAVVFGTGTKVTVL |
531lambda(SEQ ID NO.6) | QSVLTQPPSVSAAPGQKVTVSCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAFWVPGGGTKLTVL |
S33lambda(SEQ ID NO.8) | SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSHVVFGGGTKLTVL |
535lambda(SEQ ID NO.10) | QSVLTQPPSVSAAPGQKVTISCSGSNSNIGNNFVSWYQQLPGTAPKLLVYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAAEVVFGGGTKLTVL |
537lambda(SEQ ID NO.14) | QSVLTQPPSVSAAPGQDVTISCSGNNSNIGNNYVSWYQQVPGTAPKLLVYDNHKRPSGISDRFSGSKSDTSATLDITGLQPGDEADYYCGTWDTSLSANWVFGGGTKLTVL |
540lambda(SEQ ID NO.16) | QSVLTQPPSVSAAPGQKVTISCSGSSSNIGANYVSWYQQLPGTAPKLLIYNNNKRPSGIPDRFSGSKSDTSATLGITGLQTGDEADYYCGAWDSSLSASWVFGGGTKLTVL |
545lambda(SEQ ID NO.22) | QSVLTQPSSVSGAPGQRVTISCTGQSSNIGAGYDVHWYQQFPGRAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQPEDEADYYCQSYDSRLSGSVFGGGTKLTVL |
S46lambda(SEQ ID NO.24) | QSVLTQPSSVSEAPRQRVTISCSGSASNIGANGVSWYHQVPGKAPRLLLSHDGLVTSGVPDRLSVSKSGTSASLAISGLHSDDEGDYYCAVWDDSLNAVVFGGGTKLTVL |
559lambda(SEQ ID NO.34) | QSALTQPPSASGSPGQSITISCTGTNSDIGSYPFVSWYQRHPGKAPKLLIYDVSNRPSGVSDRFSGSKSGNTASLTISGLQAEDEGDYYCSSFTMNSFVIFGGGTKLTVL |
F1-C6lambda(SEQ ID NO.38) | QSVLTQPPSVSEAPRQRVTISCSGSSSNIGNNAVNWYQQLPGKAPKLLIYYDDLLPSGVSDRFSGSKSGTSASLAISGLRSEDEADYYCATWDDSLSGWVFGGGTKLTVL |
FB1-A7lambda(SEQ ID NO.40) | NFMLTQPHSVSESPGKTVTISCRSGGGIGSSFVHWFQQRPGSSPTTVIFDDNQRPTGVPDRFSAAIDTSSSSASLTISGLTAEDEADYYCQSSHSTAVVFGGGTKLTVL |
FD-B2lambda(SEQ ID NO.42) | NFMLTQPHSVSESPGKTVTISCTRSSGSIATNYVQWYQQRPGSSPATVIYEDNQRPSGVPDRFSGSIDTSSNSASLTISGLTTEDEADYFCQSYGDNNWVFGGGTKLTVL |
G1D4lambda(SEQ ID NO.50) | NFMLTQPHSVSESPGKTVIIPCTRSSGSIASNYVQWYQKRPGSAPSIVIYEDKQRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYNSRGVMFGGGTKLTVL |
GC1E8lambda(SEQ ID NO.52) | NFMLTQPHSVLESAGKTVTISCTRSSGSIASNYVQWYQQRPGTSPTNVIFEDNQRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEADYFCQSYDSNIWVFGGGTKLTVL |
H1C12lambda(SEQ ID NO.54) | QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQHLPGTAPKLLIYGNTNRPSGVPDRFSGSKSGTSASLAIAGLQAEDEADYYCQSYDSSLSGSLVFGGGTKLTVL |
IF-1C10lambda(SEQ ID NO.58) | NFMLTQPHSVSESPGKTVTISCTGSGGSIASNYVQWYQQRPGSAPTTVIYEDNQRPSGVPDRFSGSIDSSSNSASLISGLKTEDEADYYCQSYDSSTWVFGGGTKLTVL |
IK-2E2lambda(SEQ ID NO.60) | QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWFQQHPGKAPKLMIYKVNNRPSGLSNRFSGSQSGNTASLTISGLQAEDEADYYCSSYTSSSTLGFGGGTKLTVL |
表6
人恒定区(CR)
抗体CR | 序列 |
人lambda恒定区1(SEQ ID NO.63) | GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
人lambda恒定区2(SEQ ID NO.64) | GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
人lambda恒定区3(SEQ ID NO.65) | GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS |
人lambda恒定区7(SEQ ID NO.66) | GQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAECS |
人kappa恒定区(SEQ ID NO.67) | RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
人IgG1恒定区(SEQ ID NO.68) | ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
表7
Ang-2抗体的重链(HC)和轻链(LC)的互补决定区(CDRs)
CDR 1 | CDR2 | CDR 3 | |
抗体 | 残基 | 残基 | 残基 |
Ab 526HC | 26-36 | 50-66 | 96-113 |
Ab 526KC | 23-46 | 54-62 | 93-102 |
Ab 528HC | 26-36 | 50-66 | 96-113 |
Ab 528LC | 22-34 | 56-76 | 87-98 |
Ab 531HC | 26-36 | 50-66 | 96-110 |
Ab 531LC | 22-36 | 58-78 | 89-102 |
Ab 533HC | 26-36 | 50-66 | 96-112 |
Ab 533LC | 22-34 | 56-76 | 87-97 |
Ab 535HC | 26-36 | 50-66 | 96-111 |
Ab 535LC | 22-36 | 58-78 | 89-103 |
Ab 536HC | 26-36 | 50-66 | 96-112 |
Ab 536KC | 23-40 | 54-62 | 93-102 |
Ab 537HC | 26-36 | 50-66 | 96-109 |
Ab 537LC | 22-36 | 58-78 | 89-102 |
Ab 540HC | 26-36 | 50-66 | 96-110 |
Ab 540LC | 22-36 | 58-78 | 89-102 |
Ab 543HC | 26-36 | 50-66 | 96-113 |
Ab 543KC | 23-40 | 54-62 | 93-102 |
Ab 544HC | 26-36 | 50-66 | 96-111 |
Ab 544KC | 23-40 | 54-62 | 93-102 |
Ab 545HC | 26-36 | 50-66 | 96-113 |
Ab 545LC | 22-37 | 59-79 | 90-102 |
Ab 546HC | 26-36 | 50-66 | 96-113 |
Ab 546LC | 22-36 | 58-78 | 89-101 |
Ab 551HC | 26-36 | 50-66 | 96-114 |
Ab 551KC | 23-40 | 54-62 | 93-102 |
Ab 553HC | 26-36 | 50-66 | 96-113 |
Ab 553KC | 23-40 | 54-62 | 93-102 |
Ab 555HC | 26-36 | 50-66 | 96-118 |
Ab 555KC | 23-40 | 54-62 | 93-102 |
Ab 558HC | 26-36 | 50-65 | 95-113 |
Ab 558KC | 23-36 | 50-58 | 89-98 |
Ab 559HC | 26-36 | 50-66 | 96-112 |
Ab 559LC | 22-37 | 59-79 | 90-101 |
Ab 565HC | 26-36 | 50-66 | 96-115 |
Ab 565KC | 23-36 | 50-58 | 89-98 |
Ab F1-C6HC | 26-36 | 50-66 | 96-110 |
Ab F1-C6LC | 22-36 | 58-78 | 89-101 |
Ab FB1-A7HC | 26-36 | 50-66 | 96-112 |
Ab FB1-A7LC | 22-36 | 58-80 | 91-101 |
Ab FD-B2HC | 26-38 | 52-69 | 101-112 |
Ab FD-B2LC | 22-36 | 58-80 | 91-101 |
Ab FE-B7HC | 26-36 | 50-66 | 96-112 |
Ab FE-B7KC | 23-40 | 54-62 | 93-102 |
Ab FJ-G11HC | 26-36 | 50-66 | 96-115 |
Ab FJ-G11KC | 23-41 | 55-63 | 94-103 |
Ab FK-E3HC | 26-36 | 50-66 | 96-110 |
Ab FK-E3KC | 23-40 | 54-62 | 93-102 |
Ab G1D4HC | 26-36 | 50-66 | 96-110 |
Ab G1D4LC | 22-36 | 58-80 | 91-101 |
Ab GC1E8HC | 26-36 | 50-66 | 96-113 |
Ab GC1E8LC | 22-36 | 58-80 | 91-101 |
Ab H1C12HC | 26-36 | 50-66 | 96-112 |
Ab H1C12LC | 22-36 | 58-78 | 89-102 |
Ab IA1-1E7HC | 26-36 | 50-65 | 95-113 |
Ab IA1-1E7KC | 23-36 | 50-58 | 89-98 |
Ab IF-IC10HC | 26-37 | 51-66 | 96-102 |
Ab IF-1C10LC | 22-36 | 58-80 | 91-101 |
Ab IK-2E2HC | 26-36 | 50-66 | 96-113 |
Ab IK-2E2LC | 22-37 | 59-79 | 90-101 |
Ab IP-2C11HC | 26-36 | 50-66 | 96-112 |
Ab IP-2C11KC | 23-35 | 49-57 | 88-97 |
采用亲和和中和ELISA(如上文实施例3所述)以及BIAcore中和测定(如上文实施例3所述)检验17种抗体和阴性对照IgG1(称作asRDB1),以确定它们的亲和力、中和和特异性能力。结果见下表(表8),并且使用标准程序计算。
表8
Ang-2抗体EC50s和IC50s
采用上述BIAcore分析,评估两种抗体,克隆536和克隆545。按上述对于BIAcore测定的描述确定抗体结合,较低的KDS表示较高的亲和力,结果报道于下表9。
表9
hAng-2和mAng-2的抗体亲和力
实施例5
采用抗-Ang-2抗体的疗效研究
在小鼠中检验蛋白G纯化的兔抗Ang-2多克隆抗体的药代动力学。用多克隆抗-Ang-2兔抗体处理24只小鼠(1mg/小鼠)。在注射抗体后的以下时间点处死4只受治疗的动物:1小时,6小时,1天,3天,7天和14天。
结果表明,总的兔IgG在血清中具有大约19天的循环半衰期,而总IgG的抗-Ang-2IgG成分具有大约8天的半衰期。
为评估疗效,在异种移植后1,5,6,7,8,12,13,14,15,和18天后,腹膜内给予携带A431肿瘤异种移植物的小鼠(10只动物/组)10剂(每剂约10mg IgG/小鼠)蛋白G纯化的抗-mAng-2多克隆抗体。在第0,7,15和21天,测量体重,所述体重不受处理的影响。通过重复测量ANOVA,结果表明,与未免疫纯化的多克隆抗血清(10mg IgG/小鼠/剂)和载体(PBS)对照相比,抗-Ang-2多克隆抗体抑制A431肿瘤异种移植物大约50%的生长,p=0.008。
为检验完全的人单克隆抗-Ang-2抗体的体内效力,用抗Ang-2抗体克隆533,537或544,或PBS或人IgG1-κ阴性对照腹膜内处理携带A431肿瘤异种移植物的小鼠(10只动物/组)。第一剂给予大约420ug蛋白/小鼠,下三次给药时每次给予大约140ug蛋白/小鼠,下四次给药时每次给予大约55ug蛋白/小鼠,每只小鼠总共给予8剂。每周两次记录肿瘤体积和体重。研究末,处死动物,收集它们的血清用于通过ELISA测量抗体水平。从所有组收集肿瘤和正常组织。
如图1所示,抗-Ang-2处理组和对照组的肿瘤生长有显著差异。与对照组相比,所有三种抗-Ang-2处理都抑制肿瘤生长(在所有处理中,重复测量3种抗体的ANOVA,p<.005vs.hIgG1对照)。相反,对照组中的肿瘤以更高的速度继续生长)。
实施例6
表位定位
将全长(氨基酸1-495),N-末端(氨基酸1-254)和C-末端(氨基酸255-495)人Ang-2(hAng-2)蛋白质克隆到带有C-末端6xHis标记的CMV-驱动哺乳动物表达载体中。将三个得到的构建体加载体对照物瞬时表达到293T细胞中。然后从感染的细胞收集条件培养基,并且通过6xHis ELISA和蛋白质印迹估计培养基中Ang-2的表达水平。
根据下面的方案通过ELISA,通过它们结合人hAng-2的三种版本的能力,测定抗-Ang-2抗体和肽抗体的结合表位:每孔用100微升条件培养基包被高结合96-孔测定板,并且在37℃下温育1小时。吸出条件培养基,室温下每孔用200微升5%BSA的PBS溶液封闭平板1小时。然后吸出封闭溶液。以1微克/毫升1%BSA的PBS溶液每孔加入100微升抗体,肽抗体,或Tie2-Fc,并且室温下温育1小时。用200微升0.1%Tween的PBS溶液将孔洗涤四次。每孔加入100微升HRP-偶联的山羊抗-人IgG或山羊抗-小鼠IgG,并且室温下温育45分钟。然后用200微升0.1%Tween的PBS溶液将孔洗涤四次。然后每孔加入100微升TMB底物。在370nm下读取0.D.。
图2a,图2b,和图2c给出结果。
序列表
<110>AMGEN INC.
<120>血管生成素-2的特异结合剂
<130>A-722A
<140>未确定
<141>2002-10-11
<150>US 60/328,604
<151>2001-10-11
<160>76
<170>PatentIn Version 3.1
<210>1
<211>123
<212>PRT
<213>人
<400>1
Glu 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
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 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 Asp Leu Leu Asp Tyr Asp Ile Leu Thr Gly Pro Tyr Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>2
<211>112
<212>PRT
<213>人
<400>2
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210>3
<211>123
<212>PRT
<213>人
<400>3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Val Gly Asp Phe Asp Trp Leu Ser Phe Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>4
<211>107
<212>PRT
<213>人
<400>4
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Tyr Thr Tyr Thr
20 25 30
Ser Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Phe
35 40 45
Gln Asp Phe Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Thr Thr Ala Val
85 90 95
Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105
<210>5
<211>120
<212>PRT
<213>人
<400>5
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Glu Asp Thr Ala Met Val Phe Asn Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>6
<211>111
<212>PRT
<213>人
<400>6
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Val 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 Phe Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>7
<211>122
<212>PRT
<213>人
<400>7
Glu 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
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 Asp Leu Leu Asp Tyr Asp Ile Leu Thr Gly Tyr Gly Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>8
<211>106
<212>PRT
<213>人
<400>8
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Gln Tyr Ala
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Lys Asp Ser Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Asp Ser Ser His Val Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210>9
<211>121
<212>PRT
<213>人
<400>9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Phe Ser Pro Phe Thr Glu Thr Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>10
<211>112
<212>PRT
<213>人
<400>10
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 Asn Ser Asn Ile Gly Asn Asn
20 25 30
Phe Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Val 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 Ala Glu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>11
<211>122
<212>PRT
<213>人
<400>11
Glu 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
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 Asp Leu Leu Asp Tyr Asp Ile Leu Thr Gly Tyr Gly Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>12
<211>112
<212>PRT
<213>人
<400>12
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210>13
<211>119
<212>PRT
<213>人
<400>13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Gly Leu Gly Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Ser Asp Ala Ala Val Ala Gly Met Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>14
<211>111
<212>PRT
<213>人
<400>14
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Asp Val Thr Ile Ser Cys Ser Gly Asn Asn Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Val Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Val Tyr Asp Asn His Lys Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Asp Thr Ser Ala Thr Leu Asp Ile Thr Gly Leu Gln
65 70 75 80
Pro Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Thr Ser Leu
85 90 95
Ser Ala Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>15
<211>120
<212>PRT
<213>人
<400>15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Phe Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Gly Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Val Pro Gly Thr Glu Asp Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210>16
<211>111
<212>PRT
<213>人
<400>16
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 Ala 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 Asn Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Asp 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 Ala Trp Asp Ser Ser Leu
85 90 95
Ser Ala Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>17
<211>123
<212>PRT
<213>人
<400>17
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Tyr Tyr Asp Phe Trp Ser Gly Pro Gly Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210>18
<211>112
<212>PRT
<213>Homo sapiens
<400>18
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210>19
<211>121
<212>PRT
<213>人
<400>19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Glu Ser Gly Tyr Trp Gly Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>20
<211>112
<212>PRT
<213>人
<400>20
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Ile Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Leu Gln Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210>21
<211>123
<212>PRT
<213>人
<400>21
Gln Val Gln Leu Gln 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 Gly Pro Val Asp Phe Asp Tyr Gly Asp Tyr Ala Ile Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>22
<211>111
<212>PRT
<213>人
<400>22
Gln Ser Val Leu Thr Gln Pro Ser Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Gln Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Phe Pro Gly Arg 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 Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Arg
85 90 95
Leu Ser Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>23
<211>123
<212>PRT
<213>人
<400>23
Glu Val Gln Leu Val Asp 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 Glu Thr Ile Ser Phe Ser Thr Phe Ser Gly Tyr Phe Asp Tyr
100 105 110
Trp Ala Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>24
<211>110
<212>PRT
<213>人
<400>24
Gln Ser Val Leu Thr Gln Pro Ser Ser Val Ser Glu Ala Pro Arg Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ala Ser Asn Ile Gly Ala Asn
20 25 30
Gly Val Ser Trp Tyr His Gln Val Pro Gly Lys Ala Pro Arg Leu Leu
35 40 45
Leu Ser His Asp Gly Leu Val Thr Ser Gly Val Pro Asp Arg Leu Ser
50 55 60
Val Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His
65 70 75 80
Ser Asp Asp Glu Gly Asp Tyr Tyr Cys Ala Val Trp Asp Asp Ser Leu
85 90 95
Asn Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>25
<211>124
<212>PRT
<213>人
<400>25
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Asp Phe Trp Ser Gly Tyr Ser Leu Asp Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>26
<211>112
<212>PRT
<213>Homo sapiens
<400>26
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210>27
<211>123
<212>PRT
<213>人
<400>27
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Asp Asp Tyr Gly Gly Asn Ser Trp Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>28
<211>112
<212>PRT
<213>人
<400>28
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Ala Thr Asp Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210>29
<211>128
<212>PRT
<213>人
<400>29
Gln Val Gln Leu Gln 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 rrp 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 Ser Ala Ser Asp His Tyr Tyr Asp Ser Ser Gly Tyr Tyr Ser
100 105 110
Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210>30
<211>112
<212>PRT
<213>人
<400>30
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Ala Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Thr
85 90 95
Leu Gln Ile Pro Ile Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105 110
<210>31
<211>123
<212>PRT
<213>人
<400>31
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Sar Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Phe Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Asn Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ala Tyr Tyr Cys Ala
85 90 95
Arg Gly His Asp Trp Gly Met Gly Ile Gly Gly Ala Ala Tyr Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>32
<211>108
<212>PRT
<213>人
<400>32
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Val Tyr Ala Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210>33
<211>122
<212>PRT
<213>人
<400>33
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Ser
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Leu Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Val Gln Val Thr Ser Gly Tyr His Tyr Phe Asp His Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>34
<211>110
<212>PRT
<213>人
<400>34
Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Asn Ser Asp Ile Gly Ser Tyr
20 25 30
Pro Phe Val Ser Trp Tyr Gln Arg His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Gly Asp Tyr Tyr Cys Ser Ser Phe Thr Met Asn
85 90 95
Ser Phe Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>35
<211>125
<212>PRT
<213>人
<400>35
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Pro Ile Tyr Tyr Asp Ile Leu Thr Gly Ile Asp Ala Phe
100 105 110
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210>36
<211>108
<212>PRT
<213>人
<400>36
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Val Tyr Ala Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Pro
85 90 95
Arg Thr Phe Gly Gln GlyThr Lys Val Glu Ile Lys
100 105
<210>37
<211>120
<212>PRT
<213>人
<400>37
Gln ValGln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ile Pro Ser Gly Trp Tyr Phe Asp Leu Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>38
<211>110
<212>PRT
<213>人
<400>38
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 SerA la Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>39
<211>122
<212>PRT
<213>人
<400>39
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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 Glu Val Gly Asn Tyr Tyr Asp Ser 5er Gly Tyr Gly Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>40
<211>110
<212>PRT
<213>人
<400>40
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Gly Gly Gly Ile Gly Ser Ser
20 25 30
Phe Val His Trp Phe Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val
35 40 45
Ile Phe Asp Asp ASn Gln Arg Pro Thr Gly Val Pro Asp Arg Phe Ser
50 55 60
Ala Ala Ile Asp Thr Ser Ser Ser Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Thr Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ser His Ser
85 90 95
Thr Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>41
<211>122
<212>PRT
<213>人
<400>41
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Thr Val Ser Ser Asn
20 25 30
Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Ser Asp Tyr Ala
50 55 60
Val Ser Leu Arg Gly Arg Ile Thr Ile Asn Leu Asp Thr Asp Thr Ser
65 70 75 80
Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr
85 90 95
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Gly Tyr Ile Asp Ser Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>42
<211>110
<212>PRT
<213>人
<400>42
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Thr Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Ala Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Thr Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Thr Thr Glu Asp Glu Ala Asp Tyr Phe Cys Gln Ser Tyr Gly Asp
85 90 95
Asn Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>43
<211>122
<212>PRT
<213>人
<400>43
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Gly Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Ser Leu Asp Asp Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ile Gly Ser Gly Lys Thr Ile Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Lys Asn Ser Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Ser Ala Tyr Tyr Leu Asn Thr Ser Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>44
<211>112
<212>PRT
<213>人
<400>44
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Lys Gly Asp Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser His Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210>45
<211>125
<212>PRT
<213>人
<400>45
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Ile Ala Ala Arg Ser Ala Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210>46
<211>113
<212>PRT
<213>人
<400>46
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Asp Gly Lys Thr Tyr Leu Asp Trp Tyr Leu Gln Arg Pro Gly Gln
35 40 45
Ser Pro Gln Leu Leu Met Tyr Thr Thr Ser Ser Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys
65 70 75 80
Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
85 90 95
Ala Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210>47
<211>120
<212>PRT
<213>人
<400>47
Gln Val Gln Leu Val Gln Ser GTy Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Leu Asn Trp Val Arg Gln Ala Ser Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Thr Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Ile Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Pro Ser Gly Gly Trp Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>48
<211>112
<212>PRT
<213>人
<400>48
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Thr Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Glu
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Leu His Gln Arg Pro Gly Gln Pro
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Ile Ser Lys Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Pro Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser
85 90 95
Thr Arg Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210>49
<211>120
<212>PRT
<213>人
<400>49
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Arg Leu Glu Trp Leu Leu Tyr Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>50
<211>110
<212>PRT
<213>人
<400>50
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Ile Ile Pro Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Lys Arg Pro Gly Ser Ala Pro Ser Ile Val
35 40 45
Ile Tyr Glu Asp Lys Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asn Ser
85 90 95
Arg Gly Val Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>51
<211>123
<212>PRT
<213>人
<400>51
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Pro Tyr Gly Gly Tyr Ala Tyr Pro Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>52
<211>110
<212>PRT
<213>人
<400>52
Asn Phe Met Leu Thr Gln Pro His Ser Val Leu Glu Ser Ala Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Thr Ser Pro Thr Asn Val
35 40 45
Ile Phe Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Phe Cys Gln Ser Tyr Asp Ser
85 90 95
Asn Ile Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>53
<211>122
<212>PRT
<213>人
<400>53
Glu 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
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 Asp Leu Leu Asp Tyr Asp Ile Leu Thr Gly Tyr Gly Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>54
<211>111
<212>PRT
<213>人
<400>54
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 His Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly Asn Thr 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 Ala 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 Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>55
<211>123
<212>PRT
<213>人
<400>55
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Phe Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Asn Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly His Asp Trp Gly Met Gly Ile Gly Gly Ala Ala Tyr Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>56
<211>108
<212>PRT
<213>人
<400>56
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Phe Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Thr Ser Thr Arg Ala Thr Gly Ile Ala Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Ala Glu Asp Ser Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Phe Ser Pro
85 90 95
Leu Thr Phe Gly Gly GlyThr Lys Val Glu Ile Lys
100 105
<210>57
<211>112
<212>PRT
<213>人
<400>57
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 Ala Ala Ser Gly Phe Thr Phe Phe Ser Thr
20 25 30
Tyr Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Val Ile Arg Ser Asn Gly Gly Thr Asp Tyr Ala Asp Phe 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 Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Met Thr Asp Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210>58
<211>110
<212>PRT
<213>人
<400>58
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Gly Ser Gly Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>59
<211>123
<212>PRT
<213>人
<400>59
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 Glu Thr Ile Ser Phe Ser Thr Phe Ser Gly Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>60
<211>110
<212>PRT
<213>人
<400>60
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Phe Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Lys Val Asn Asn Arg Pro Ser Gly Leu Ser Asn Arg Phe
50 55 60
Ser Gly Ser Gln Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Leu Gly Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>61
<211>122
<212>PRT
<213>人
<400>61
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Ile Ala Val Ala Gly Thr Arg Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 102
<210>62
<211>107
<212>PRT
<213>人
<400>62
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Thr Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Gly Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ile Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210>63
<211>106
<212>PRT
<213>人
<400>63
Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210>64
<211>106
<212>PRT
<213>人
<400>64
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210>65
<211>106
<212>PRT
<213>人
<400>65
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210>66
<211>106
<212>PRT
<213>人
<400>66
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
35 40 45
Val Lys Val Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Ala Glu Cys Ser
100 105
<210>67
<211>107
<212>PRT
<213>人
<400>67
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210>68
<211>330
<212>PRT
<213>人
<400>68
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210>69
<211>22
<212>PRT
<213>人
<400>69
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210>70
<211>40
<212>DNA
<213>人
<400>70
gtggttgaga ggtgccagat gtcaggtcca gctggtgcag 40
<210>71
<211>30
<212>DNA
<213>人
<400>71
attacgtctc acagttcgtt tgatctccac 30
<210>72
<211>48
<212>DNA
<213>人
<400>72
ccgctcagct cctggggctc ctgctattgt ggttgagagg tgccagat 48
<210>73
<211>9
<212>PRT
<213>人
<400>73
Ala Gln Leu Leu Gly Leu Leu Leu Leu
1 5
<210>74
<211>54
<212>DNA
<213>人
<400>74
cagcagaagc ttctagacca ccatggacat gagggtcccc gctcagctcc tggg 54
<210>75
<211>45
<212>DNA
<213>人
<400>75
gtggttgaga ggtgccagat gtgacattgt gatgactcag tctcc 45
<210>76
<211>31
<212>DNA
<213>人
<400>76 31
cttgtcgact tattaacact ctcccctgtt g
Claims (25)
1.一种分离的抗体,包含:
(a)重链构架区、由SEQ ID NO.11的CDR1组成的重链CDR1区、由SEQ ID NO.11的CDR2组成的重链CDR2区,和由SEQ ID NO.11的CDR3组成的重链CDR3区;和
(b)轻链构架区、由SEQ ID NO.12的CDR1组成的轻链CDR1区、由SEQ ID NO.12的CDR2组成的轻链CDR2区,和由SEQ ID NO.12的CDR3组成的轻链CDR3区;
其中该抗体结合血管生成素-2(Ang-2)。
2.权利要求1的抗体,包含SEQ ID NO.11以及SEQ ID NO.12的CDR1、CDR2和CDR3。
3.权利要求1的抗体,包含SEQ ID NO.12以及SEQ ID NO.11的CDR1、CDR2和CDR3。
4.权利要求1的抗体及其抗原结合片段,包含重链和轻链,所述重链包含SEQ ID NO.11的重链可变区,所述轻链包含SEQ ID NO.12的轻链可变区。
5.权利要求1的抗体,包含重链可变区和轻链可变区,所述重链可变区包含SEQ ID NO.11的氨基酸序列或其抗原结合片段,其中所述抗原结合片段至少包含SEQ ID NO.11的CDR1、CDR2和CDR3,所述轻链可变区包含SEQ ID NO.12的氨基酸序列或其抗原结合片段,其中所述抗原结合片段至少包含SEQ ID NO.12的CDR1、CDR2和CDR3,其中该抗体结合血管生成素-2(Ang-2)。
6.权利要求1-5的任一项的抗体,其为多克隆、单克隆、嵌合、人源化或完全的人抗体。
7.权利要求6的抗体,其为单链抗体。
8.权利要求6或7的抗体,其中该抗体与选自报道基团、水溶性聚合物、Fc区和细胞毒性剂的分子共价结合。
9.一种药物组合物,包含权利要求6的抗体和药学可接受载体。
10.权利要求7的抗体,其是单链Fv抗体。
11.权利要求7的抗体,其是Fab抗体片段。
12.权利要求7的抗体,其是Fab’抗体片段。
13.权利要求7的抗体,其是(Fab’)2抗体片段。
14.编码权利要求1-13的任一项的抗体的核酸分子。
15.包含权利要求14的核酸分子的载体。
16.包含权利要求15的载体的分离的宿主细胞。
17.制备抗体的方法,包括
(a)用至少一种编码权利要求1-13的任一项的抗体的核酸分子转化宿主细胞;
(b)在所述宿主细胞中表达核酸分子;和
(c)分离所述抗体;
其中所述宿主细胞不是人细胞。
18.权利要求1-13的任一项的抗体在制备用于抑制不期望的血管发生的药物中的用途。
19.权利要求1-13的任一项的抗体在制备用于治疗癌症的药物中的用途。
20.一种药物组合物,包含权利要求1-13的任一项的抗体和药学可接受制剂。
21.权利要求1-13的任一项的抗体在制备用于调节或抑制血管生成素-2活性的药物中的用途。
22.权利要求1-13的任一项的抗体在制备用于调节血管渗透性或血浆渗漏的至少一种的药物中的用途。
23.权利要求1-13的任一项的抗体在制备用于治疗以下病症中的至少一种的药物中的用途:眼新血管病,肥胖,成血管瘤,血管瘤,动脉硬化,炎性疾病,炎性紊乱,动脉粥样硬化,子宫内膜异位,肿瘤性疾病,骨相关疾病,或者牛皮癣。
24.权利要求1-13的任一项的抗体和化疗药物在制备用于治疗癌症的药物中的用途。
25.检测生物样品中血管生成素-2的水平的方法,包括
(a)使权利要求1-13的任一项的抗体与所述样品接触;和
(b)确定抗体与所述样品的结合程度。
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PCT/US2002/032613 WO2003030833A2 (en) | 2001-10-11 | 2002-10-11 | Angiopoietin-2 specific binding agents |
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