CN102617708A - 诱导t细胞死亡的表位 - Google Patents
诱导t细胞死亡的表位 Download PDFInfo
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Abstract
本发明涉及诱导T细胞死亡的表位,具体地,涉及诱导细胞死亡的表位和含有所述表位的多肽。还公开了诱导活化的T细胞死亡的化合物、制备针对所述表位的抗体的方法、鉴定与所述表位结合的化合物的方法、诱导活化的T细胞死亡的方法和含有所述化合物的药物组合物。
Description
本申请是申请日为2005年05月11日,申请号为200580023402.2(国际申请号为PCT/US2005/016441),名称为“诱导T细胞死亡的表位”的发明专利申请的分案申请。
相关的申请
本申请要求2004年5月11日提交的美国临时申请系列号60/570,161的优先权,作为参考将其内容完整地在此引入。
背景
在治疗自体免疫疾病、移植排斥、过敏性疾病和T细胞来源的癌症中控制不需要的免疫应答是关键的。通过免疫抑制或通过免疫耐受性的诱导可以限制过度侵袭性的T细胞的活性。细胞凋亡被认为涉及维持免疫系统的适当功能和除去不需要的细胞,例如过度侵袭性的T细胞(Kabelitz等(1993)Immunol Today 14,338-340;和Raff(1992)Nature 356,397-399)。
概述
本发明涉及诱导T细胞死亡的表位。这些表位可用于,尤其是,选择结合这些表位的化合物。这样的化合物在治疗涉及过度侵袭性T细胞的疾病中是有用的。这种疾病的实例包括自体免疫疾病、移植排斥、过敏性疾病和T细胞来源的癌症。
在一个方面,本发明的特征是分离的表位的三维构象。在活化的T细胞上的所述表位与配体的结合诱导细胞的死亡。这种表位被表示为:
(1)X1-X2-X3-X4-X5(SEQ ID NO:1),其中
X1是Tyr、Trp、His或Met;
X2是Asp;
X3是Ser、Phe、Pro、Glu或His;
X4是在动物中天然产生的任何氨基酸;以及
X5是Pro、Tyr、His或Trp;
(2)X6-X7-X8-X9-X10(SEQ ID NO:2),其中
X6是Asp;
X7是Tyr、Met、Asn、Trp或Phe;
X8是Phe或Leu;
X9是Pro;以及
X10是Glu;或者
(3)X11-X12-X13-X14(SEQ ID NO:3),其中
X11是Pro;
X12是Met;
X13是Glu或Ser;以及
X14是Ile。
任何如上所述的表位可以是,例如,多肽、两个多肽的相互作用区域、糖(carbohydrate)部分、糖蛋白,或它们的任何构象的、功能的等同物。
在另一个方面,本发明的特征是含有X1-X2-X3-X4-X5、X6-X7-X8-X9-X10,或X11-X12-X13-X14的分离的多肽。在活化的T细胞上的所述多肽与配体的结合诱导该细胞的死亡。在一个实施方案中,所述多肽含有4到400个氨基酸(例如,4和400之间的任何整数,包括4和400)。例如,所述多肽可以是X1-X2-X3-X4-X5(SEQ ID NO:1)、X6-X7-X8-X9-X10(SEQ ID NO:2)、X11-X12-X13-X14(SEQ ID NO:3)、或SEQ ID NO:4、6-18和20-22的任何一个。
“分离的表位”或“分离的多肽”是指基本上不含天然相关的分子的表位或多肽,即,它是至少75%(例如,75%和100%之间的任何数,包括75%和100%)的干重纯度的。可以通过任何适当的标准方法,例如,通过柱层析、聚丙烯酰胺凝胶电泳或HPLC分析来测定纯度。本发明的分离的表位或多肽可以从天然来源纯化、通过重组DNA技术或通过化学方法来制备。
在另一个方面,本发明的特征是与上述表位之一结合的新的化合物。所述化合物可以是任何类型的分子,包括抗体,例如单克隆抗体。本发明的化合物可以用于检测本发明的表位和用于诱导活化的T细胞的死亡。
制备抗体的方法也处在本发明的范围内。所述方法包括向受试者施用有效量的上述表位(例如,多肽)之一。所述抗体可以用于检测本发明的表位或用于诱导活化的T细胞的死亡。
本发明特征还在于鉴定诱导活化的T细胞死亡的候选化合物(例如,单克隆抗体)的方法。所述方法涉及用测试化合物接触本发明的表位并测定所述测试化合物是否与表位结合。如果测试化合物与表位结合,它就是诱导活化的T细胞死亡的候选物。
本发明进一步的特征在于通过用本发明的化合物接触活化的T细胞来诱导活化的T细胞死亡的方法。
在另一个方面,本发明特征在于药物组合物,其含有药学上可接受的载体和(1)本发明的表位,例如多肽,或(2)与所述表位结合的化合物。
本发明提供了用于治疗涉及过度侵袭性T细胞的疾病的组合物和方法,所述疾病例如自体免疫疾病、移植排斥、过敏性疾病和T细胞来源的癌症。在以下附随的说明中将阐述本发明的一个或多个实施方案的细节。根据详细的说明,本发明的其他特征、目的和益处将更为明显。
本发明还涉及如下方面:
1.由X1-X2-X3-X4-X5表示的分离的表位的三维构象,其中在活化的T细胞上的所述表位与配体的结合诱导所述细胞的死亡,和
X1是Tyr、Trp、His或Met;
X2是Asp;
X3是Ser、Phe、Pro、Glu或His;
X4是任何氨基酸;和
X5是Pro、Tyr、His或Trp。
2.包含X1-X2-X3-X4-X5的分离的多肽,其中在活化的T细胞上的所述多肽与配体的结合诱导所述细胞的死亡,和
X1是Tyr、Trp、His或Met;
X2是Asp;
X3是Ser、Phe、Pro、Glu或His;
X4是任何氨基酸;和
X5是Pro、Tyr、His或Trp。
3.项2的多肽,其中所述多肽长度是5到1500个氨基酸。
4.项3的多肽,其中所述多肽长度是5到150个氨基酸。
5.项4的多肽,其中所述多肽长度是5到15个氨基酸。
6.项2的多肽,其中所述多肽选自SEQ ID NO:4和6-13。
7.项2的多肽,其中所述多肽是X1-X2-X3-X4-X5。
8.抗体,其与具有项1的三维构象的表位结合并且诱导活化的T细胞死亡。
9.项8的抗体,其中所述抗体是单克隆的。
10.制备抗体的方法,所述方法包括向受试者施用有效量的具有项1的三维构象的表位。
11.鉴定诱导活化的T细胞的死亡的候选化合物的方法,所述方法包括使化合物与具有项1的三维构象的表位接触,其中所述化合物与所述表位的结合表明所述化合物是诱导活化的T细胞死亡的候选物。
12.项11的方法,其中所述化合物是抗体。
13.项12的方法,其中所述化合物是单克隆抗体。
14.诱导活化的T细胞的死亡的方法,所述方法包括使活化的T细胞与项8的抗体接触。
15.药物组合物,包括具有项1的三维构象的表位和药学上可接受的载体。
16.药物组合物,包含项2的多肽和药学上可接受的载体。
17.药物组合物,包含项8的化合物和药学上可接受的载体。
18.由X6-X7-X8-X9-X10表示的分离的表位的三维构象,其中在活化的T细胞上的所述表位与配体的结合诱导所述细胞的死亡,和
X6是Asp;
X7是Tyr、Met、Asn、Trp或Phe;
X8是Phe或Leu;
X9是Pro;和
X10是Glu。
19.包含X6-X7-X8-X9-X10的分离的多肽,其中在活化的T细胞上的所述多肽与配体的结合诱导所述细胞的死亡,和
X6是Asp;
X7是Tyr、Met、Asn、Trp或Phe;
X8是Phe或Leu;
X9是Pro;和
X10是Glu。
20.项19的多肽,其中所述多肽长度是5到1500个氨基酸。
21.项20的多肽,其中所述多肽长度是5到150个氨基酸。
22.项21的多肽,其中所述多肽长度是5到15个氨基酸。
23.项19的多肽,其中所述多肽选自SEQ ID NO:14-18。
24.项19的多肽,其中所述多肽是X6-X7-X8-X9-X10。
25.抗体,其与具有项18的三维构象的表位结合并且诱导活化的T细胞死亡。
26.项25的抗体,其中所述抗体是单克隆的。
27.制备抗体的方法,所述方法包括向受试者施用有效量的具有项18的三维构象的表位。
28.鉴定诱导活化的T细胞的死亡的候选化合物的方法,所述方法包括使化合物与具有项18的三维构象的表位接触,其中所述化合物与所述表位的结合表明所述化合物是诱导活化的T细胞死亡的候选物。
29.项28的方法,其中所述化合物是抗体。
30.项29的方法,其中所述化合物是单克隆抗体。
31.诱导活化的T细胞的死亡的方法,所述方法包括使活化的T细胞与项25的抗体接触。
32.药物组合物,包括具有项18的三维构象的表位和药学上可接受的载体。
33.药物组合物,包含项19的多肽和药学上可接受的载体。
34.药物组合物,包含项25的抗体和药学上可接受的载体。
35.由X11-X12-X13-X14表示的分离的表位的三维构象,其中在活化的T细胞上的所述表位与配体的结合诱导所述细胞的死亡,和
X11是Pro;
X12是Met;
X13是Glu或Ser;和
X14是Ile。
36.包含X11-X12-X13-X14的分离的多肽,其中在活化的T细胞上的所述多肽与配体的结合诱导所述细胞的死亡,和
X11是Pro;
X12是Met;
X13是Glu或Ser;和
X14是Ile。
37.项36的多肽,其中所述多肽长度是4到1500个氨基酸。
38.项37的多肽,其中所述多肽长度是4到150个氨基酸。
39.项38的多肽,其中所述多肽长度是4到15个氨基酸。
40.项36的多肽,其中所述多肽选自SEQ ID NO:20-22。
41.项36的多肽,其中所述多肽是X11-X12-X13-X14。
42.抗体,其与具有项35的三维构象的表位结合并且诱导活化的T细胞死亡。
43.项44的抗体,其中所述抗体是单克隆的。
44.制备抗体的方法,所述方法包括向受试者施用有效量的具有项35的三维构象的表位。
45.鉴定诱导活化的T细胞的死亡的候选化合物的方法,所述方法包括使化合物与具有项35的三维构象的表位接触,其中所述化合物与所述表位的结合表明所述化合物是诱导活化的T细胞死亡的候选物。
46.项45的方法,其中所述化合物是抗体。
47.项46的方法,其中所述化合物是单克隆抗体。
48.诱导活化的T细胞死亡的方法,所述方法包括使活化的T细胞与项42的抗体接触。
49.药物组合物,包括具有项35的三维构象的表位和药学上可接受的载体。
50.药物组合物,包含项36的多肽和药学上可接受的载体。
51.药物组合物,包含项42的抗体和药学上可接受的载体。
详细说明
本发明基于出乎意料的发现,通过新的诱导T细胞死亡的表位的接合,T细胞可以被诱导经历细胞凋亡和被耗尽。对于治疗与过度的或不需要的T细胞介导的免疫应答或T细胞增殖相关的病症,耗尽活化的T细胞是特别有用的。例如,耗尽活化的T细胞可以引起降低或消除与自体免疫疾病、移植排斥、过敏性疾病或T细胞来源的癌症相关的不需要的T细胞活性或增殖。
因此,本发明的特征是分离的表位的三维构象。在活化的T细胞上配体与表位的结合诱导细胞的死亡。所述表位由X1-X2-X3-X4-X5、X6-X7-X8-X9-X10或X11-X12-X13-X14表示。例如,使用如Duggan等,(1995)J Med Chem.38:3332-41和Toogood(2002)J Med Chem.45:1543-57中描述的计算机模拟程序,可以确定X1-X2-X3-X4-X5、X6-X7-X8-X9-X10或X11-X12-X13-X14的三维构象。构象、功能等效物的表位可以根据X1-X2-X3-X4-X5、X6-X7-X8-X9-X10或X11-X12-X13-X14的三维构象来设计,使用本领域已知的方法来制备,并通过例如以下实施例中描述的方法来测试它们涉及诱导活化的T细胞死亡的能力。参见,例如,Barbas等(2001)Phage display.A laboratory manual.CSHLPress;Parmley等(1998)Gene 73,305-318;Scott等(1990)Science 249,386-390;美国专利申请No.20030049252Al;WO 03/013603Al;Osborne(1996)Curr Opin Immunol 8:245-248;Lin等(1997)J.Immunol.158,598-603;Zhang等(1995)Nature 377,348-350;Lai等(1995)Eur J Immunol 25,3243-3248;Mollereau等(1996)J Immunol 156,3184-3190;和Gribben等(1995)Proc Natl Acad Sci USA 92,811-815。
如在此使用的,“活化的T细胞”是比未活化的T细胞具有更高的扩增频率、速率或幅度的T细胞。细胞的“死亡”包括程序化的细胞死亡,即,细胞凋亡。当用药物处理的细胞群体展现出比未处理的细胞群体更高的死亡率时,该药物“诱导细胞死亡”。例如,根据annexin V染色和FACS分析测定的,当用单克隆抗体m128-9F9、m152-15A7或m166-43B6处理时,与未处理的细胞相比,经历了细胞凋亡的体外活化的T细胞的百分比是约两倍(参见以下实施例)。
本发明特征还在于含有X1-X2-X3-X4-X5、X6-X7-X8-X9-X10或X11-X12-X13-X14的分离的多肽。所述多肽可用于鉴定诱导活化的T细胞死亡的化合物。这种化合物与活化的T细胞表面上表达的多肽的结合诱导细胞死亡。进一步的,通过与细胞表面多肽竞争内源性的诱导死亡的配体,游离多肽(即,不在细胞表面上表达的那些)可以抑制不需要的细胞的死亡。所述多肽的长度或序列可以根据这些用途来变化。本发明的多肽可以作为,例如,分离的T细胞表面蛋白、合成多肽或重组多肽来获得。为了制备重组多肽,可以将编码它的核酸与编码融合伙伴(partner)的另一个核酸连接,所述融合伙伴例如,谷胱甘肽-S-转移酶(GST)、6x-His表位标记或M13基因3蛋白。产生的融合核酸在适合的宿主细胞中表达可以通过标准方法分离的融合蛋白。可以进一步处理分离的融合蛋白,例如通过酶消化,来除去融合伙伴并获得本发明的重组多肽。
本发明的表位或本发明的多肽可用于在动物(用于制备抗体)或人(用于治疗疾病)中产生抗体。在动物中制备单克隆和多克隆抗体及其片段的方法是本领域已知的。参见,例如,Harlow和Lane,(1988)Antibodies:ALaboratory Manual,Cold Spring Harbor Laboratory,New York。术语“抗体”包括完整的分子及其片段,例如Fab、F(ab′)2、Fv、scFv(单链抗体)和dAb(结构域抗体;Ward,等(1989)Nature,341,544)。这些抗体可用于检测表位,例如,鉴定与表位结合的化合物(见下文)。能诱导活化的T细胞死亡的抗体对于治疗诸如自体免疫疾病、移植排斥、过敏性疾病或T细胞来源的癌症的疾病也是有用的。一般地,本发明的表位,例如,多肽,可以与载体蛋白,例如KLH偶联,与佐剂混合,并注入到宿主动物中。然后可以通过肽亲和层析来纯化该动物中产生的抗体。通常采用的宿主动物包括兔、小鼠、豚鼠和大鼠。可用于提高免疫应答的各种佐剂取决于宿主物种,包括弗氏佐剂(完全的和不完全的),矿物凝胶例如氢氧化铝,表面活性物质例如溶血卵磷脂,普卢兰尼克多元醇类(pluronic polyol),聚阴离子,肽,油乳剂,钥孔血蓝素,和二硝基酚。有用的人佐剂包括BCG(卡介苗(bacille Calmette-Guerin))和Corynebacterium parvum。
抗体分子的异质性群体(heterogeneous populations)多克隆抗体存在于被免疫受试者的血清中。针对特定抗原的抗体匀质群体单克隆抗体可以使用标准杂交瘤技术来制备(参见,例如,Kohler等(1975)Nature 256,495;Kohler等(1976)Eur J Immunol 6,511;Kohler等(1976)Eur J Immunol 6,292;和Hammerling等(1981)Monoclonal Antibodies and T Cell Hybridomas,Elsevier,N.Y.)。特别地,可以通过为了在培养物中通过连续细胞系产生抗体分子的任何技术来获得单克隆抗体,例如在Kohler等(1975)Nature 256,495和美国专利No.4,376,110中描述的;人B细胞杂交瘤技术(Kosbor等(1983)ImmunolToday 4,72;Cole等(1983)Proc.Natl.Acad.Sci.USA 80,2026,和EBV杂交瘤技术(Cole等(1983)Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,Inc.,pp.77-96)。这样的抗体可以是任何免疫球蛋白类型,包括IgG、IgM、IgE、IgA、IgD,和它们的任何亚类。可以体外或体内地培养产生本发明的单克隆抗体的杂交瘤。在体内生产高滴度单克隆抗体的能力使之成为特别有用的制备方法。
此外,可以使用为了产生“嵌合抗体”而开发的技术。参见,例如,Morrison等(1984)Proc Natl Acad Sci USA 81,6851;Neuberger等(1984)Nature 312,604;和Takeda等(1984)Nature 314:452。嵌合抗体是一种分子,其中不同的部分来自不同的动物物种,例如,具有来自鼠单克隆抗体的可变区和人免疫球蛋白恒定区的那些抗体。或者,可以修改为了制备单链抗体而描述的技术(美国专利No.4,946,778和4,704,692)来制备单链Fv抗体的噬菌体库。通过经由氨基酸桥连接Fv区的重链和轻链片段来形成单链抗体。此外,可以通过已知的技术来产生抗体片段。例如,这种片段包括但不限于,可通过抗体分子的胃蛋白酶消化而产生的F(ab′)2片段,以及可通过还原F(ab′)2片段的二硫键产生的Fab片段。
抗体也可以通过本领域已知的方法来人源化。例如,具有期望的结合特异性的单克隆抗体可以被商业地人源化(Scotgene,Scotland;and OxfordMolecular,Palo Alto,Calif.)。完全人的抗体,例如在转基因动物中表达的那些,处在本发明的范围之内(参见,例如,Green等(1994)Nature Genetics 7,13;和美国专利No.5,545,806和5,569,825)。
本发明进一步特征在于与本发明的表位结合并诱导活化的T细胞死亡的新化合物。例如,可以根据表位的三维构象,使用计算机模拟程序来设计这种化合物,并使用本领域已知方法来合成。也可以通过如下所述的库筛选来鉴定该化合物。
测试化合物可以使用本领域已知的组合库方法中的许多方法的任何一种来获得,这些库包括:肽文库、类肽文库(具有肽的功能性、但带有对酶降解有抗性的新的非肽骨架的分子的库)、空间可定址的(spatially addressable)平行固相或液相库、通过去褶合或亲和层析选择获得的合成库、“一珠一化合物”的库、和抗体库。参见,例如,Zuckermann等(1994)J Med Chem 37,2678-85;Lam(1997)Anticancer Drug Des 12,145;Lam等(1991)Nature 354,82;Houghten等(1991)Nature 354,84;和Songyang等(1993)Cell 72,767。
用于分子库合成的方法的实例可在本领域中找到,例如:DeWitt等(1993)PNAS USA 90,6909;Erb等(1994)PNAS USA 91,11422;Zuckermann等(1994)J Med Chem 37,2678;Cho等(1993)Science 261,1303;Carrell等(1994)Angew Chem Int Ed Engl 33,2059;Carell等(1994)Angew Chem Int EdEngl 33,2061;和Gallop等(1994)J Med Chem 37,1233。
化合物的库可以存在于溶液中(例如,Houghten(1992)Biotechniques 13,412-421)、或珠子(Lam(1991)Nature 354,82-84)、芯片(Fodor(1993)Nature 364,555-556)、细菌(美国专利No.5,223,409)、芽孢(美国专利No.5,223,409)、质粒(Cull等(1992)PNAS USA,89,1865-1869)或噬菌体(Scott和Smith(1990)Science 249,386-390;Devlin(1990)Science 249,404-406;Cwirla等(1990)PNAS USA 87,6378-6382;Felici(1991)J Mol Biol 222,301-310;和美国专利No.5,223,409)上。
为了鉴别诱导活化的T细胞死亡的候选化合物,用本发明的表位接触测试化合物,评估所述化合物与表位的结合。如果测试化合物与表位结合,它就是诱导活化的T细胞死亡的候选物。
按各种方法进行筛选分析。例如,一种方法包括将表位(或含有表位的分子,例如,多肽或融合蛋白)或测试化合物锚定在固相上,并在反应结束时检测固相上形成的表位-测试化合物复合物。实际上,微量滴定板可以方便地用作固相。可以通过非共价的或共价的连接来固定锚定元件。非共价连接可以仅通过用锚定元件(anchor component)的溶液包被固体表面并使平板干燥来实现。或者,特异于锚定元件的固定化抗体(例如,单克隆抗体)可用来将锚定元件固定到固体表面。将非锚定元件添加到包被有锚定元件的固体表面。在反应完成后,在一定条件下除去非锚定元件的未结合部分(例如,通过洗涤),从而任何形成的复合物仍保持固定在固体表面上。可以按多种方式完成这些复合物的检测。当非锚定元件被预先标记时,检测到固定到固体表面上的标记指示了复合物形成。当非锚定元件没有预先标记时,可使用间接标记来检测表面上形成的复合物,例如,使用特异于非锚定元件的抗体(该抗体随后可以用例如标记的抗Ig抗体直接标记或间接标记)。
或者,可以在液相中进行反应。例如,使用特异于表位(或含有表位的分子)或测试化合物的固定化抗体,来从未结合的元件(component)中分离复合物。然后,例如使用特异于其他元件的标记的抗体来检测复合物。
通过使用以下实施例中描述的方法或本领域已知的任何其他方法来确定化合物诱导活化的T细胞死亡的能力,可以验证候选化合物。验证的化合物可用于诱导活化的T细胞的死亡,和用于治疗诸如自体免疫疾病、移植排斥、过敏性疾病或T细胞来源的癌症的疾病。
本发明提供了诱导活化的T细胞死亡的方法,例如,通过在体外使活化的T细胞与本发明的化合物接触,或通过向有需要的受试者施用有效量的本发明的化合物。需要治疗的受试者可被鉴定为患有以过度或不需要的T细胞介导的免疫应答为特征的病症或存在该风险,例如,患有自体免疫疾病、移植排斥、过敏性疾病或T细胞来源的癌症的患者。这种方法可以单独地或者与其他药物或治疗共同地进行。
术语“治疗”被定义为向受试者施用组合物,目的是治愈、减轻、解除、矫正、防止或改善失调、失调的症状、继发于失调的疾病状态或趋于失调的倾向。“有效量”是能够在治疗的受试者中产生医学上期望的结果,例如上述结果的组合物的量。
要治疗的示例性疾病包括但不限于糖尿病、关节炎(包括类风湿性关节炎、青少年类风湿性关节炎、骨关节炎和牛皮癣关节炎)、多发性硬化、脑脊髓炎、重症肌无力、全身性红斑狼疮、自体免疫甲状腺炎、皮炎(包括特异反应性皮炎和湿疹性皮炎)、牛皮癣、Sjogren氏综合症、Crohn氏病、口疮性溃疡、虹膜炎、结膜炎、角膜结膜炎、I型糖尿病、炎症性肠疾病、溃疡性结肠炎、哮喘、过敏性哮喘、皮肤红斑狼疮(cutaneous lupuserythematosus)、硬皮症、阴道炎、直肠炎、药疹、麻风病翻转反应、麻风的结节性红斑、自体免疫葡萄膜炎、变态反应性脑脊髓炎、急性坏死出血性脑病、自发性的双侧渐进性感觉神经性的听力丧失、再生障碍性贫血、纯红细胞贫血、自发性血小板减少、多软骨炎、Wegener氏肉芽肿病、慢性活动性肝炎、Stevens-Johnson综合症、自发性口炎性腹泻、扁平苔癣、Graves氏病、结节病、原发性胆汁肝硬变、后葡萄膜炎(uveitis posterior)、间隙肺部纤维化、移植物抗宿主病、移植的情况(包括使用异源或异种组织的移植)例如骨髓移植、肝脏移植、或任何器官或组织的移植、变态反应例如特异反应性过敏、AIDS和T细胞瘤例如白血病或淋巴瘤。
在体内途径中,治疗组合物(例如,含有本发明的表位、本发明的多肽或本发明的化合物的组合物)被施用给受试者。一般地,表位、多肽或化合物被悬浮在药学上可接受的载体(例如,生理盐水)中,并口服地、或通过静脉内输注、或皮下、肌肉内、鞘内、腹膜内、直肠内、阴道内、鼻内、胃内、气管内或肺内地注射或植入来施用。
所需的剂量取决于给药途径的选择;配方的性质;受试者的疾病的性质;受试者的大小、体重、表面积、年龄和性别;施用的其他药物;以及主治医师的判断。适合的剂量在0.01-100.0mg/kg的范围内。考虑到可用组合物的变化和各种给药途径的不同效率,所需剂量的广泛变化是预期的。例如,预计口服施用比静脉内注射需要更高的剂量。这些剂量水平的变化可以使用本领域充分了解的、用于优化的经验性规则来调整。将组合物封装在适合的递送载体中(例如,聚合的微粒或可植入装置)可以提高给药的效率,特别是对于口服给药。
含有药学上可接受的载体和有效量的本发明的化合物的药物组合物也处在本发明的范围内。该药物组合物可用于治疗如上所述的疾病。药学上可接受的载体包括溶剂、分散介质、包衣、抗菌剂和抗真菌剂,以及等渗剂和吸收延迟剂。
本发明的药物组合物可以使用常规方法被配制为用于不同给药途径的剂型。例如,它可以被配置为用于口服施用的胶囊、软明胶胶囊剂(gel seal)或片剂。胶囊可以含有任何标准的药学上可接受的材料,例如明胶或纤维素。片剂可以根据常规程序通过压缩组合物与固体载体和润滑剂的混合物来配制。固体载体的实例包括淀粉和糖膨润土(sugar bentonite)。组合物也可以以含有粘合剂,例如乳糖或甘露醇、常规填料和制片剂的硬壳片剂或胶囊剂的形式来施用。可以通过胃肠外途径施用药物组合物。胃肠外剂型的实例包括活性剂的水溶液、等渗盐水或5%葡萄糖,或其他公知的药学上可接受的赋形剂。环糊精或其他增溶剂是熟悉本领域的人员公知的,可以用作用于治疗剂给药的药物赋形剂。
可以在体外和体内评估本发明的组合物的效力。参见,例如,以下的实施例。简要地,可以在体外测试该组合物诱导活化的T细胞死亡的能力。对于体内研究,可以将组合物注射到动物(例如,小鼠模型)中,然后获取它的治疗效果。根据该结果,可以确定合适的剂量范围和给药途径。
以下的具体实施例被认为仅仅是说明性的,无论如何不是对所公开的其余部分的限定。不需进一步的详细描述,相信本领域的技术人员可以根据在此的说明将本发明利用到最大程度。此处引用的全部出版物作为参考将它们完全地引入。
制备小鼠脾细胞悬液
将小鼠脾脏浸泡在8ml的Hank′s平衡盐溶液(HBSS)中,用无菌盖玻片轻轻地切碎,转移到15ml离心管(Costar),在200x g下离心5分钟。弃去上清液,通过轻敲管壁将细胞团粒重悬浮在残余的缓冲液中。通过添加1ml的RBC裂解缓冲液(0.6M NH4Cl,0.17M Tris-base,pH 7.65)裂解污染红细胞(RBC),随后在室温下孵育2min,用9ml的HBSS快速中止。将细胞在200x g沉淀5分钟,洗涤两次,重悬浮在RPMI培养基中。用血细胞计(CambridgeScientific Inc.)和台盼蓝排斥测定混合物中细胞的浓度和存活力。
制备抗T细胞、诱导凋亡的单克隆抗体
通过用Concanovalin A活化的人T细胞免疫小鼠来产生诱导T细胞凋亡的单克隆抗体,并筛选它们结合活化人T细胞以及随后诱导T细胞的细胞凋亡的能力。根据Kohler和Milstein((1976)Euro J Immunol 6,511-519)的公知的细胞融合方法产生分泌期望抗体的杂交瘤来制备单克隆抗体。根据这些方法产生的三个杂交瘤分泌单克隆抗体,分别称为m128-9F9、m152-15A7和m166-43B6,其能在体外诱导T细胞的细胞凋亡。
将每个杂交瘤的浓缩的培养物上清液在20000x g旋转10分钟,用结合缓冲液(0.1M醋酸钠,pH 5.0)以1∶1的比例稀释上清液。用3-5ml的结合缓冲液洗涤蛋白G柱(约1ml床体积(bed volum))三次。将澄清的培养物上清液加载到蛋白G柱上,收集流通物并再加载到柱上。然后用6-10ml结合缓冲液洗涤柱,用5ml洗脱缓冲液(0.1M甘氨酸-HCl,pH 2.8)从柱上洗脱结合的抗体。每个级分含有1ml洗脱的抗体,通过将每1ml级分与50微升1M的Tris-HCl、pH 7.5混合来将洗脱的级分调节到中性pH值。集中含有抗体的级分,相对2升PBS、pH 7.4透析三次,每次透析三小时。根据Bradford描述的方法使用Bio-Rad蛋白质分析(BIO-RAD,Hercules,CA)来测定抗体样品中的蛋白浓度。
通过单克隆抗体诱导活化人T细胞的死亡
将活化的T细胞(参见上面)重悬浮在含有5ng/ml的IL-2的RPMI培养基中至5x 105细胞/ml的终浓度,并用对照Ig、m128-9F9、m152-15A7或m166-43B6处理。
公知的是诱导T细胞死亡的抗体能够用做治疗剂来治疗T细胞相关的疾病,例如移植排斥、自体免疫疾病和过敏症。针对人T细胞产生了三种单克隆抗体,检查了这些单克隆抗体诱导活化人T细胞的细胞凋亡的能力。将含有由杂交瘤细胞系m128-9F9、m152-15A7或m166-43B6分泌的单克隆抗体的培养物上清液分别与未活化的人T细胞(第0天)或体外活化的人T细胞(第7天)孵育6小时。孵育后细胞用annexin V染色,进行FACS分析。设门于(gated)CD3阳性细胞以确定体外活化的人T细胞或静息人T细胞的计数。凋亡的细胞是annexin V染色阳性的。表1概述了在所有扫描的T细胞中凋亡的T细胞的百分比。出人意料地,由杂交瘤细胞系m128-9179、m152-15A7和m166-43B6分泌的单克隆抗体诱导了体外活化的人T细胞的死亡但不影响未活化的人T细胞。这种诱导活化的T细胞的细胞凋亡而不影响静息T细胞的能力是细胞凋亡途径的独特特征,并且是靶向T细胞介导的疾病的治疗试剂的支配性特征。
表1凋亡的T细胞的百分比
未处理的 | 抗myc | m128-9F9 | 未处理的 | 抗myc | m152-15A7 | m166-43B6 | |
第0天 | 4.17 | 6.67 | 5.82 | 18.18 | 15.52 | 5.23 | 6.57 |
第7天 | 12.63 | 13.36 | 28.71 | 24.18 | 23.08 | 51.66 | 49.44 |
诱导T细胞死亡的表位的鉴定
为了鉴定由单克隆抗体m128-9F9、m152-15A7和m166-43B6识别的诱导死亡的表位,将这些单克隆抗体用于在多肽文库(Ph.D.-12TM噬菌体展示肽文库试剂盒(Phage Display Peptide Library Kit),New England Biolabs,Inc.)中筛选共有结合序列。所述库含有与406-aa M13基因3蛋白连接的各种12-mer肽。96孔微量滴定板用0.1M NaHCO3(pH 8.6)包被缓冲液中10μg/ml浓度的50μl/孔的抗体在4℃包被过夜。洗涤之后,通过与含有0.1MNaHCO3(pH 8.6)、5mg/ml BSA、0.02%NaN3的封闭缓冲液(150μl/孔)在4℃孵育至少一小时来封闭平板。然后将平板与各种浓度的来自如上所述多肽文库的融合蛋白在室温下孵育一小时。在用含TBS的0.5%Tween洗涤之后,用含0.2M Glycine-HCl(pH 2.2)的1mg/ml BSA缓冲液洗脱结合的融合蛋白,用1M Tris-HCl(pH 9.1)中和。然后测定洗脱的融合蛋白的氨基酸序列。
由单克隆抗体m128-9F9结合的多肽序列显示如下:
获得了X1-X2-X3-X4-X5的共有多肽序列,其中X1=Y/W/H/M、X2=D、X3=S/F/P/E/H、X4=任何氨基酸,和X5=P/Y/H/W。
由单克隆抗体m166-43B6结合的多肽序列显示如下:
获得了X6-X7-X8-X9-X10的共有多肽序列,其中X6=D、X7=Y/M/N/W/F、X8=F或L、X9=P、和X10=E。
由单克隆抗体m152-15A7结合的多肽序列显示如下:
YTPMPMEISHSA SEQ ID NO:20
MNDKYIPMSISA SEQ ID NO:21
KIPHKTLVPMEI SEQ ID NO:22
TDSAAMEIQTTQ SEQ ID NO:23
获得了X11-X12-X13-X14的共有多肽序列,其中X11=P/A、X12=M、X13=E/S、和X14=I。
由单克隆抗体识别的诱导T细胞死亡的表位的ELISA分析
为了鉴定由如上所述单克隆抗体识别的诱导死亡的表位的特异性,进行了夹心ELISA。将含表位多肽的连续稀释物(从0.0017fmol到17fmol)与预先包被在ELISA平板上的单克隆抗体m128-9F9、m152-15A7或m166-43B6孵育,来测定它们的结合亲和性。
96孔微量滴定板用浓度1μg/ml的50μl/孔的抗体在4℃包被过夜。通过与含0.25%BSA的PBS溶液(150μl/孔)在37℃孵育1小时来封闭平板。然后将平板在室温下与含有各种多肽的融合蛋白孵育2小时。用含0.05%Tween 20的PBS(PBST)洗涤4次之后,然后将平板与2μg/ml特异于融合伙伴(fusion partner)的抗体在室温下孵育1.5小时。孵育之后,用PBST洗涤平板4次。然后将50μl的1比3000稀释的、与碱性磷酸酶(AP)缀合的特异的山羊抗融合伙伴抗体添加到每个孔中,在37℃孵育平板1小时。通过添加50μl的AP底物溶液(1AP底物片溶于5ml底物缓冲液)来进行酶反应。结果证明了所有选择的多肽特异性地结合用于进行选择的、它们的相应的抗体。
其他实施方案
在本说明书中公开的所有特征可以按任何组合来组合。在本说明中公开的每个特征可以由服务于相同、等同或类似目的的可选择特征来替代。因而,除非是特意地声明了,所公开的每个特征仅仅是普通系列的同等物或类似特征的一个实例。
根据以上的说明,本领域技术人员可以容易地确定本发明的基本特征而不背离本发明的精神和范围,可以进行本发明的各种变化和修改来使其适应各种用途和状况。因而,其他实施方案也处在本发明的范围之内。
Claims (10)
1.由X1-X2-X3-X4-X5表示的分离的表位的三维构象,其中在活化的T细胞上的所述表位与配体的结合诱导所述细胞的死亡,和
X1是Tyr、Trp、His或Met;
X2是Asp;
X3是Ser、Phe、Pro、Glu或His;
X4是任何氨基酸;和
X5是Pro、Tyr、His或Trp。
2.包含X1-X2-X3-X4-X5的分离的多肽,其中在活化的T细胞上的所述多肽与配体的结合诱导所述细胞的死亡,和
X1是Tyr、Trp、His或Met;
X2是Asp;
X3是Ser、Phe、Pro、Glu或His;
X4是任何氨基酸;和
X5是Pro、Tyr、His或Trp。
3.权利要求2的多肽,其中所述多肽长度是5到1500个氨基酸。
4.权利要求3的多肽,其中所述多肽长度是5到150个氨基酸。
5.权利要求4的多肽,其中所述多肽长度是5到15个氨基酸。
6.权利要求2的多肽,其中所述多肽选自SEQ ID NO:4和6-13。
7.权利要求2的多肽,其中所述多肽是X1-X2-X3-X4-X5。
8.抗体,其与具有权利要求1的三维构象的表位结合并且诱导活化的T细胞死亡。
9.权利要求8的抗体,其中所述抗体是单克隆的。
10.制备抗体的方法,所述方法包括向受试者施用有效量的具有权利要求1的三维构象的表位。
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EP (2) | EP1751300B1 (zh) |
JP (3) | JP5710854B2 (zh) |
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CA (1) | CA2565872C (zh) |
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US7744888B2 (en) | 2001-08-03 | 2010-06-29 | Abgenomics Cooperatief U.A. | Methods of modulating T cell or natural killer cell activity with anti-P-selectin glycoprotein ligand 1 antibodies |
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UA105492C2 (uk) | 2004-05-11 | 2014-05-26 | Абдженомікс Коеператіеф У.А. | Спосіб одержання антитіла для викликання смерті активованих т-клітин, спосіб визначення прийнятної сполуки для викликання смерті активованих т-клітин та фармацевтична композиція |
WO2009093251A2 (en) * | 2008-01-24 | 2009-07-30 | Gavish-Galilee Bio Applications Ltd | Reovirus vaccine based on sigma c protein sequence |
AU2012271845B2 (en) | 2011-06-13 | 2017-07-27 | Altrubio Inc. | Anti-PSGL-1 antibodies and uses thereof |
ES2880731T3 (es) | 2016-01-08 | 2021-11-25 | Altrubio Inc | Anticuerpos anti-PSGL-1 tetravalentes y usos de los mismos |
CN111201038A (zh) | 2017-01-11 | 2020-05-26 | 戊瑞治疗有限公司 | Psgl-1拮抗剂及其用途 |
KR20190128198A (ko) | 2017-03-14 | 2019-11-15 | 파이브 프라임 테라퓨틱스, 인크. | 산성 pH에서 VISTA에 결합하는 항체 |
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