CN1652820A - 使用ctla-4抗体的治疗方法 - Google Patents
使用ctla-4抗体的治疗方法 Download PDFInfo
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- CN1652820A CN1652820A CNA038108593A CN03810859A CN1652820A CN 1652820 A CN1652820 A CN 1652820A CN A038108593 A CNA038108593 A CN A038108593A CN 03810859 A CN03810859 A CN 03810859A CN 1652820 A CN1652820 A CN 1652820A
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Abstract
本发明提供了使用抗人CTLA-4的人序列抗体的治疗方法。尤其是提供了癌症治疗方法。
Description
本申请根据35U.S.C.§119(e)要求2002年4月12日提交的美国临时专利申请序号60/372,284和2002年5月17日提交的美国临时专利申请序号60/381,274的优先权。此处将这些临时申请的全部内容引入作为参考。
发明领域
本发明一般涉及分子免疫学和人类疾病的治疗。具体地,本发明涉及使用抗人CTLA-4抗体的新的治疗方法。
背景技术
脊椎动物免疫系统需要多种信号以实现最优的免疫活化(见,例如,Janeway,Cold Spring Harbor Symp.Quant.Biol.1989;54:1-14;PaulWilliam E.,ed.Raven Press,N.Y.,Fundamental Immunology,第4版(1998),尤其是12和13章,411-478页)。T淋巴细胞(T细胞)和抗原呈递细胞(APC)的相互作用是免疫应答所必需的。在免疫应答过程中T细胞和APC上存在的许多粘着分子的水平增加(Springer等,A.Rev.Immunol.1987;5:223-252;Shaw和Shimuzu,Current Opinion in Immunology,1988Eds.Kindt和Long,1:92-97;和Hemler,Immunology Today 1988;9:109-113)。这些分子的水平增加可能有助于解释为什么活化的APC比静息的APC对刺激抗原特异性T细胞增殖更有效(Kaiuchi等,J.Immunol.1983;131:109-114;Kreiger等,J.Immunol.1985;135:2937-2945;McKenzie,J.Immunol.1988;141:2907-2911;和Hawrylowicz和Unanue,J.Immunol..1988;141:4083-4088)。
T细胞免疫应答是一个复杂过程,其包括细胞-细胞相互作用(Springer等,A.Rev.Immunol.1987;5:223-252),尤其是T细胞和辅助细胞如APC之间的相互作用,和可溶性免疫介质(细胞因子或淋巴因子)的产生(Dinarello,New Engl.J.Med 1987;317:940-945;Sallusto,J.Exp.Med.1997;179:1109-1118)。该应答被几种T细胞表面受体,包括T细胞受体复合物(Weiss,Ann.Rev.Immunol.1986;4:593-619)和其他“辅助”表面分子所调节(Allison,Curr.Opin.Immunol.1994;6:414-419;Springer,1987,如前引文)。这些辅助分子中的许多是由细胞表面上的单克隆抗体反应性定义的天然细胞表面分化(CD)抗原(McMichael,Ed.,Leukocyte Typing III,Oxford Univ.Press,Oxford,N.Y.,1987)。
T辅助细胞(Th)抗原应答需要APC提供的信号。第一个信号由T细胞受体复合物(Weiss,J.Clin.Invest.1990,86:1015)与APC上II类主要组织相容性复合物(MHC)分子背景中呈递的抗原的相互作用启动(Allen,Immunol.Today 1987;8:270)。该抗原特异性信号并不足以产生完全应答,在缺乏第二信号时实际上可能导致克隆失活或无反应性(Schwartz,Science1990;248:1349)。在许多实验系统中已阐明了对MHC提供的第二“共刺激”信号的需要(Schwartz,如上引文;Weaver和Unanue,Immunol.Today1990;11:49)。该第二信号的分子性质还不完全清楚,但已经清楚在一些情况下可溶性分子如白介素(IL)-1(Weaver和Unanue,如前引文)和参与胞间粘附的膜受体(Springer,Nature 1990;346:425)可提供共刺激信号。
CD28抗原——免疫球蛋白超家族的一种同二聚体糖蛋白(Aruffo和Seed,Proc.Natl.Acad.Sci.1987;84:8573-8577)——是一种在大多数成熟人T细胞上发现的辅助分子(Damle等,J.Immunol.1983;131:2296-2300)。现今的证据表明该分子在与T细胞受体复合物启动的T细胞活化途径不同的替代T细胞活化途径中起作用(June等,Mol.Cell.Biol.1987;7:4472-4481)。与CD28抗原有反应性的单克隆抗体(Mab)可提高由各种多克隆刺激物启动的T细胞应答(June等的综论,如前引文)。这些刺激作用可能由于Mab诱导的细胞因子产生(Thompson等,Proc.Natl.Acad.Sci1989;86:1333-1337;和Lindsten等,Science 1989;244:339-343)作为mRNA稳定性增加的结果(Lindsten等,1989,如前引文)而出现。抗CD28mAb也可具有抑制作用,即,它们可以阻断自体的混合淋巴细胞反应(Damle等,Proc.Natl.Acad.Sci.1981;78:5096-6001)和抗原特异性T细胞克隆活化(Lesslauer等,Eur.J.Immunol.1986;16:1289-1296)。
CTLA-4是一种T细胞表面分子,其最初通过鼠的溶细胞性T细胞cDNA文库的示差筛选鉴定(Brunet等,Nature 328:267-270(1987))。CTLA-4也是免疫球蛋白(Ig)超家族的一员;CTLA-4含有单个胞外Ig结构域。CTLA-4转录物已经在具有细胞毒活性的T细胞群体中发现,提示CTLA-4可能在溶细胞反应中发挥功能(Brunet等,如前引文;Brunet等,Immunol.Rev.103-21-36(1988))。研究人员已报导了对CTLA-4的人类对应物(Dariavach等,Eur.J.immunol.18:1901-1905(1988))的基因克隆和作图,其作图定位在与CD28相同的染色体区域(2q33-34)(Lafage-Pochitaloff等,Immunogenetics 31:198-201(1990))。该人CTLA-4 DNA和编码CD28蛋白的DNA的序列比较揭示了序列的显著同源性,在近膜区和胞质区具有最大的同源性(Brunet等,1988,如前引文;Dariavach等,1988,如前引文)。
公认CTLA-4可以对抗CD28活性并可以抑制T细胞活化(Krummel,J.Exp.Med.1995;182:459-465;Krummel等,Int′l Immunol.1996;8:519-523;Chambers等,Immunity.1997;7:885-895)。CTLA-4缺陷小鼠患有大面积淋巴组织增生(Chambers等,同上引文)。据报导CTLA-4的阻断可以增加体外(Walunas等,Immunity.1994;1:405-413)和体内(Kearney,J.Immunol.1995;155:1032-1036)T细胞应答,加剧抗肿瘤免疫(Leach,Science 1996;271:1734-1736),和增加诱导的自身免疫疾病(Luhder,J Exp.Med.1998;187:427-432)。据报导CTLA-4对T细胞免疫应答的最初特征还具有可选的或额外的影响(Chambers,Curr.Opin.Immunol.1997;9:396-404;Bluestone,J.Immunol.1997;158:1989-1993;Thompson,Immunity 1997;7:445-450)。这和所观察到的一些自身免疫患者具有抗CTLA-4自身抗体的现象相一致。可能阻断CTLA-4的自身抗体在这些患者中起着致病的作用(Matsui,J.Immunol.1999;162:4328-4335)。
非人CTLA-4抗体已经在上面讨论的各种研究中使用。此外,抗人CTLA-4的人抗体已经被描述为许多疾病状况的免疫刺激调节剂,如治疗和防止病毒和细菌感染和用于治疗癌症(例如,PCT出版物WO01/14424和PCT出版物WO00/37504)。美国专利号5,855,887公开了通过组合T细胞与CTLA-4阻断剂增加哺乳动物T细胞对抗原刺激的应答。美国专利号5,811,097公开了一种通过使用CTLA-4阻断剂减少非-T细胞肿瘤生长的方法。美国专利申请号09/644,668和09/948,939公开了人CTLA-4抗体,在此处将其引入作为参考。
本说明书中该部分和其他部分中对参考文献的引用和讨论仅仅用于阐明本发明而不是承认这些参考文献是此处描述的发明的“现有技术”。
发明概述
本发明提供了使用抗CTLA-4抗体促进或加强再次免疫应合或记忆免疫应答的方法。抗CTLA-4抗体显示出能够增加已经具有针对病原体的保护性抗原,例如,癌抗原或来自感染物的抗原的免疫性的受试者中的保护性免疫的幅度。导致这种先前免疫的可能原因有天然暴露于,例如,切除后的肿瘤的癌细胞或已减退或抑制的感染剂感染。可检查这些患者以得到这种暴露的证据,即,患者是否具有对病原体的保护性抗原的免疫性。备选地,患者可能已经接受过针对该病原体的接种免疫,在这种情况下可以认为或检验到存在免疫性。
在一个实施方案中,本发明的CTLA-4抗体可以用于恶性肿瘤的治疗,其中患者以前已经接受过癌症疫苗或者显示出对肿瘤具有一定水平的天然保护性免疫。这些抗体可以作为单一的药剂使用或者与一种或多种其他疗法,如化疗、放射疗法、细胞因子、趋化因子和其他生物信号分子、肿瘤特异性疫苗、自体和同种异体干细胞拯救因子(例如,以提高移植物抗肿瘤效果)、其他治疗性抗体、分子定向疗法、抗血管生成疗法、具有治疗目的的感染剂(如使肿瘤局限化的细菌)和基因疗法相组合。这些抗体可以以单剂量或多剂量形式施用。这些抗体可以在辅助治疗或新辅助治疗(neoadiuvant therapy)中单独使用或者与上面提到的疗法联合使用。
使用抗CTLA-4抗体的治疗可以用于激活接受过癌症疫苗治疗的患者体内先已存在的记忆应答。因此,可选择经疫苗治疗的患者以进一步用抗CTLA-4抗体治疗从而进一步诱导或增强免疫应答。
在一个实施方案中,抗原是癌抗原并且患者先前已经用抗癌疫苗治疗。癌抗原可以是例如,黑素瘤抗原或前列腺癌抗原。在另一个实施方案中,抗原为病毒抗原并且患者先前已经用病毒疫苗治疗。病毒抗原可以是例如,肝炎抗原。在一个实施方案中,患者为人。在一个优选的实施方案中,抗CTLA-4抗体是人抗-CTLA4抗体。本发明的一种优选的人抗-CTLA4抗体是10D1,但是本发明的方法可以使用任何人CTLA-4抗体。在其它的实施方案中,抗CTLA-4抗体是重组抗体如嵌合的或人源化的(例如,CDR-嫁接的)抗CTLA-4抗体。
本发明的抗体也可以用于控制由感染性生物体,包括但不限于,细菌、分枝杆菌、螺旋菌、真菌、病毒、寄生生物和朊病毒,引起的致病性感染。抗体可以作为单一药剂使用或者与一种或多种其它药剂,如抗生素、疫苗、抗体、细胞因子、受体抑制剂和毒力阻断剂(virulence blocking agent)组合使用。抗体可以以单剂量或多剂量形式使用。
本发明的治疗方法(其被设计以刺激再次或记忆免疫应答)可能尤其有利于治疗可能有高度危险出现疾病并发症的免疫抑制患者。这些免疫抑制患者的实例包括逆转录病毒感染,包括HIV感染的患者、先生性、遗传性自身免疫或药理学诱导的免疫缺陷患者、包括糖尿病和老年患者,以及具有伤口、创伤或严重烧伤的患者。
通过施用抗CTLA4抗体刺激免疫应答的本发明方法也可以用于急性接触抗原的情况(如暴露于生物恐怖剂,如炭疽或天花,其中被暴露的患者已经事先接种过抗该物质的疫苗)或代替加强免疫接种。
本发明也阐明了患者可以用抗CTLA4进行长期治疗而不会出现有害的副作用如非特异性T细胞活化,如自身免疫。
抗CTLA4的血浆浓度可以保持在检测水平以上至少1、2、3、4或5个月或者更长,而不会出现不期望的免疫学结果。在一个优选的实施方案中,本发明提供了诱导或增强患者中抗原免疫应答的方法,包括对患者施用抗CTLA4抗体使抗CTLA4抗体的血浆浓度保持在可检测水平以上至少1、2、3、4或5个月。在一个实施方案中,抗CTLA4抗体被多次施用从而使得血浆浓度保持在可检测水平之上至少1、2、3、4或5个月。在另一个实施方案中,抗CTLA4抗体以一定量和时间间隔施用从而患者中抗CTLA4抗体的血浆浓度持续至少1、2、3、4或5个月为至少2μg/ml。在另一个实施方案中,施用抗CTLA4抗体的量和时间间隔使得患者体内抗CTLA4抗体的血浆浓度为至少5μg/ml并持续至少1、2、3、4或5个月。在另一个实施方案中,抗CTLA4抗体的施用量和施用时间间隔使得患者中抗CTLA4抗体的血浆浓度为至少10μg/ml并持续至少1、2、3、4或5个月。在一个优选的实施方案中,被长期用抗CTLA4抗体治疗的患者患有恶性肿瘤,如黑素瘤或前列腺癌。在另一个优选的实施方案中,除了利用抗CTLA4抗体治疗外患者已经,或者正在接受疫苗治疗。
本发明的另一方面涉及使用与细胞毒性剂相连的抗CTLA4抗体的方法。细胞毒性剂的实例包括细胞毒性药物(例如,阿霉素、刺孢霉素,等等)和放射性同位素。这种与细胞毒性剂相连的抗CTLA4抗体可用于耗竭CTLA4+细胞。可被耗竭的CTLA4+细胞的实例包括CTLA4+恶性肿瘤和在T细胞介导的自身免疫疾病中表达CTLA4的抗原特异性活化T细胞。因此,在另一个实施方案中,本发明提供了治疗患有CTLA4+T细胞恶性肿瘤的患者的方法,包括:向患者施用与细胞毒性剂相连的抗CTLA4抗体从而治疗患者的T细胞恶性肿瘤。在另一个实施方案中,本发明提供了治疗患者的T细胞介导的自身免疫疾病的方法,包括:向患者施用与细胞毒性剂相连的抗CTLA4抗体从而治疗患者的T细胞介导的自身免疫疾病。
在一个优选的实施方案中,本发明的抗CTLA4抗体为在WO01/14424中公开的人单克隆抗体10D1。
本文引用的所有出版物、图、GenBank Accession参考(序列)、ATCC保藏物、专利和专利申请为所有目的在这里特别地被并入作为参考,就像它们中的每一个被单独表示并入一样。
附图简述
图1显示了用黑素瘤疫苗和抗CTLA4抗体10D1治疗的动物中黑素瘤-特异性抗体应答。通过流式细胞计数法测量了来自治疗的动物的合并血浆中的抗体反应性。
图2显示了灵长类动物的持续给药过程中抗CTLA4抗体10D1的药物动力学图谱。在第0、28、56、84和140天施用抗体并通过ELISA分析10D1的血浆浓度。显示了6个治疗的动物的平均值+/-SEM。
图3显示了在第0天用单剂10D1治疗的前列腺癌患者中抗CTLA-4抗体10D1的药物动力学图谱。显示了血浆浓度(μg/ml)。显示了14个治疗的患者的平均值+/-SEM。
图4显示了在第0天用抗CTLA4抗体输注后各个时间点处两名人类患者中前列腺特异性抗原(PSA)水平(ng/ml)。
发明详述
本发明提供了用于促进或加强再次免疫应答或记忆免疫应答以及用于进行更有效的癌症治疗的基于CTLA-4抗体的新方法。此外,公开了抗CTLA-4抗体的优选的血浆浓度。本发明的方法提供了治疗癌症、感染和对免疫应答有响应的其他疾病或病症的手段。
本发明部分基于在癌症的免疫治疗中临床试验人序列抗CTLA-4抗体时得到的如下观察结果。试验证明了抗CTLA抗体在以前接触过肿瘤抗原的受试者的治疗中的有效性。此外,显示了一次或多次给药后抗CTLA4抗体的可检测的血浆水平的持续性。
A.
对先已用癌症疫苗接种的患者的临床试验
患有晚期黑素瘤或晚期卵巢癌的9名患者参与研究,其中他们静脉内接受3mg/kg CTLA-4单克隆抗体10D1(Medarex)。患者以前接受过早期黑素瘤治疗,这些治疗包括免疫治疗(三名患者接受α-干扰素,一名患者接受与QS-21混合的GM2神经节苷脂疫苗)、手术(4名患者)、放射(2名患者)、化疗(3名患者)和蛋白酶体抑制剂(1名患者)。两名卵巢癌患者以前接受过多次化疗。此外,所有患者都参与I期疫苗研究。三个黑素瘤患者和两个卵巢癌患者用经工程化而分泌GM-CSF的自体细胞免疫。这些患者之一还接受了MUC-1疫苗。三个黑素瘤患者用工程化后表达gp100和MART-1的自体树突细胞免疫。一个黑素瘤患者接种gp100肽和高剂量IL-2。
以前用GM-CSF分泌性肿瘤细胞接种的三个黑素瘤患者在用10D1治疗后具有广泛的肿瘤坏死。从所有三个患者切除的组织的组织病理学显示出严重破坏的肿瘤血管以及肿瘤附近的淋巴细胞和粒细胞浸润。一个患者在用10D1治疗后3月纵隔肿块被完全切除。以前用黑素瘤抗原接种的四个患者在肿瘤附近出现淋巴细胞浸润,但是没有肿瘤坏死。卵巢癌患者没有经历切除或活组织检查,但是两个患者在10D1治疗后CA-125(卵巢癌的肿瘤标记)血液水平都发生有利的改变。
B.
对自然暴露于肿瘤抗原的患者的检查
具有IV期黑素瘤的14名患者在一个或多个治疗周期中接受抗CTLA4抗体10D1,并用两种gp100肽接种。所有患者以前都经历过对原发性肿瘤的手术。六名患者以前进行过化疗。11名患者以前进行过免疫治疗。通过计算机轴向断层造影(CT)和磁共振(MR)成像测量临床应答。一名患者(其先前经历过手术和化疗)在5个治疗周期后肺、脑和皮下肿瘤完全消退。另两名患者是部分应答者。两名患者是“混合型”非应答者,因为一些损害缩小而其他损害尺寸增加。因为没有进行组织活检,混合型非应答者中损害的变大可能不是由于癌症引起。例如,一名患者(3号患者)的几处肺损害出现消退但是纵隔淋巴结增大。来自肺的淋巴管将淋巴液排到纵隔淋巴结中(Schwartz,等,Principle of Surgery,1984,第4版,p.661);淋巴结可以因淋巴结流域(drainage basin)内组织发炎而变大。可能3号患者是完全应答者,其淋巴结变大是由于炎症而不是由于癌症所致。
基于上面讨论的结果,本发明提供了抗CTLA-4抗体的许多有利的用途。如在以前经历过免疫或暴露的癌症患者中所证实的,这些抗体提供了再次或记忆免疫刺激。从而,抗CTLA-4抗体可用作加强剂,其特别可以用于免疫受损的患者。免疫系统抑制可有许多原因导致,这些原因包括但不限于疾病(包括像HIV等免疫缺陷疾病)、衰老、增加的肿瘤负担、癌症治疗(例如,化疗和放疗),以及其他原因。因此,抗CTLA-4抗体治疗适应于增强免疫受损个体的免疫力。
C.
用CTLA-4抗体和黑素瘤疫苗对猴的试验
单独用黑素瘤疫苗或者用黑素瘤疫苗与抗CTLA4抗体10D1在第0、28、56、84和140天处理恒河猴。抗CTLA4抗体和疫苗的组合使用比只使用疫苗导致显著更大的抗黑素瘤细胞的抗体应答。此外,T细胞增殖研究表明用抗CTLA4抗体和疫苗治疗导致CD8+和CD4+细胞的抗原特异性增殖。抗CTLA-4抗体的血浆水平在整个160天期间保持在可检测水平之上。平均血浆浓度在6个月研究中保持高于20μg/ml。
该研究表明在灵长类动物中抗CTLA4抗体的长期给药是安全的并且可检测的血浆水平可以保持6个月以上。
D.
用抗CTLA-4抗体对晚期黑素瘤患者的试验
患有晚期黑素瘤的17名患者被静脉内以3mg/kg施用单剂抗CTLA4抗体10D1。9名患者以前进行过免疫治疗,6名以前接受过放射治疗,5名以前接受过化疗。抗CTLA4抗体的血浆水平长达4个月保持在可检测水平。在以前进行过免疫接种的患者中,2名患者有部分应答,包括三个软组织肿块消退和肺部肿块减小大于50%。
该研究表明在单剂抗CTLA4抗体后人类患者中血浆水平可以保持高于可检测水平长达4个月。此外,在以前接种疫苗的患者中见到的肺部肿块的减小表明CTLA4抗体可激活针对肿瘤的预先存在的记忆应答。
E.
用抗CTLA-4抗体对晚期前列腺癌患者的试验
14名患有晚期前列腺癌的患者被静脉内以3.0mg/kg施用单剂人单克隆抗CTLA4抗体10D1。抗CTLA-4抗体的血浆水平存在长达4个月。观察到前列腺特异抗原(PSA)的减少和症状减轻。除皮疹和搔痒症(它们是可逆的)外,没有不利的免疫影响。
在下面及实施例中更详细地解释本发明的这些和其他益处。
除非指出,术语“患者”或“受试者”可互换使用并且指哺乳动物如人类患者和非人灵长类动物,以及实验动物如兔、大鼠和小鼠及其他动物。动物包括所有脊椎动物,例如,哺乳动物和非哺乳动物,如绵羊、狗、母牛、鸡、两栖动物,和爬行动物。
术语“治疗”包括施用本发明的化合物或药剂以预防或延缓疾病的症状、并发症或生物化学标记的出现,减轻症状或阻止或抑制疾病、病症或失调(例如,自身免疫疾病)的进一步发展。治疗可以是预防性的(以预防或延缓疾病的发作,或预防其临床或亚临床症状的表现)或可以是治疗性抑制或减轻疾病表现后的症状。
术语“晚期癌症”指不再局限于原发性肿瘤位置的癌症,或者根据美国癌症联合委员会(American Joint Committee on Cancer,AJCC)定为III或IV期的癌症。
通常,短语“良好耐受的”指健康状况上没有出现治疗引起的并会影响治疗决定的不利改变。
如此处所用的术语“淋巴细胞”具有本领域中的通常意义,指血液、淋巴和淋巴组织中存在的任何单个核、非吞噬性白细胞,即,B和T淋巴细胞。
短语“T淋巴细胞亚群”或“T细胞亚群”指以表达特定细胞表面标记为特征的T淋巴细胞或T细胞(见Barclay,A.N.等(eds.),1997,TheLeukocyte Antigen Facts Book,第二版,Academic Press,伦敦,英国)。关于T细胞,术语“稳定”指T细胞亚群的频率或百分数不随着药剂的施用过程或持续时间而变。
术语“细胞毒性T淋巴细胞相关抗原4”、“CTLA-4”、“CTLA4”、“CTLA-4抗原”和“CD152”(见,例如,Murata(1999)Am.J.Pathol.155:453-460)可互换使用,包括人CTLA-4的变体、同种型、物种同源物,和与CTLA-4具有至少一个共同表位的类似物(见,例如,Balzano(1992)Int.J.Cancer Suppl.7:28-32)。CTLA-4的全序列见GenBank记录号L15006。
术语“表位”指能够特异结合抗体的蛋白质决定簇。表位通常由分子的化学活性表面簇如氨基酸或糖侧链组成并通常具有特定三维结构特征以及特定电荷特征。构象性和非构象性表位的区别在于存在变性溶剂时丧失与前者但不是与后者的结合。
完整“抗体”包括通过二硫键相互连接的至少两条重(H)链和两条轻(L)链。每条重链由重链可变区(此处简写为HCVR或VH)和重链恒定区组成。重链恒定区由三个结构域:CH1、CH2和CH3组成。每条轻链由轻链可变区(此处简写为LCVR或VL)和轻链恒定区组成。轻链恒定区由一个结构域CL组成。VH和VL区可进一步细分成叫做互补决定区(CDR)的高变区,其散布于叫做构架区(FR)的更保守的区域中。每个VH和VL由三个CDR和四个FR组成,从氨基端到羧基端以下面的顺序排列:FRl,CDR1,FR2,CDR2,FR3,CDR3,FR4。重链和轻链的可变区含有与抗原相互作用的结合域。抗体的恒定区可介导免疫球蛋白与宿主组织或因子的结合,这些组织或因子包括免疫系统的各种细胞(例如,效应细胞)和经典补体系统的第一组分(Clq)。术语抗体包括保持结合CTLA-4的能力的完整抗体的抗原结合部分。结合的实例包括(i)Fab片段——由VL、VH、CL、和CH1结构域组成的单价片段;(ii)F(ab’)2片段——含有在铰链区通过二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1结构域组成的Fd片段;(iv)由抗体的单个臂的VL和VH结构域组成的Fv片段;(v)dAb片段(Ward等,(1989)Nature 341:544-546),其由VH结构域组成;和(vi)分离的互补决定区(CDR)。此外,虽然Fv片段的两个结构域VL和VH由单独的基因编码,但是它们可以连接在一起——这可使用重组方法,通过合成的接头使它们成为单个蛋白链而实现,其中VL和VH区配对形成单价分子(称作单链Fv(scFv);见,例如,Bird等(1988)Science 242:423-426;和Huston等(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这种单链抗体被包括到术语“抗体”中。可通过重组技术或完整抗体的酶促或化学切割制备片段。
术语“人序列抗体”包括具有来自人种系免疫球蛋白序列的可变区和恒定区(如果存在)的抗体。本发明的人序列抗体可包括不是由人种系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机或定点诱变或通过体内体细胞突变导入的突变)。这种抗体可在非人转基因动物中产生,即,如在PCT公开号WO01/14424和WO00/37504中所描述的。然而,术语“人序列抗体”,如此处所用的,不旨在包括如下抗体,在该抗体中来自另一哺乳动物物种(如小鼠)种系的CDR序列被嫁接到人构架序列上(即,人源化抗体)。
术语“单克隆抗体”或“单克隆抗体组合物”指具有单分子组成的抗体分子制品。单克隆抗体组合物显示出对特定表位的单一结合特异性和亲和性。因此,术语“人单克隆抗体”指具有来自人种系免疫球蛋白序列的可变区和恒定区(如果存在)的显示出单一结合特异性的抗体。在一个实施方案中,人单克隆抗体通过杂交瘤产生,该杂交瘤包括与永生化细胞融合的B细胞,该B细胞来自转基因非人动物,如转基因小鼠,具有包含人重链转基因和轻链转基因的基因组。
术语“多克隆抗体”指具有1种以上(两种或多种)不同的人CTLA-4抗体的制品。这种制品含有结合多种不同表位的抗体。
CTLA-4抗体可结合人CTLA-4上的表位以抑制CTLA-4与人B7相应受体的相互作用。因为人CTLA-4与人B7的相互作用会转导一种信号导致具有人CTLA-4受体的T细胞失活,所以对此相互作用的拮抗将有效诱导、提高或延长具有人CTLA-4受体的T细胞的活化,从而延长或提高免疫应答。优选的抗CTLA-4抗体在例如,美国专利号5,811,097、5,855,887、6,051,227、PCT公开号WO01/14424和WO00/37504;以及美国公开号2002/0039581A1中描述。适于在本发明中使用的这些和其他抗体可以根据本领域中熟知的方法和/或在此处引用的参考文献中描述的方法制备。在优选的实施方案中,本发明中使用的抗CTLA-4抗体为“人抗体”——即,从人分离的抗体——或者它们为“人序列抗体”(定义如上)。例如,国际专利公开号WO01/14424描述了从用人抗体基因修饰的转基因小鼠分离人序列抗CTLA-4抗体的方法。因此,这些抗体虽然分离自非人动物,但是具有相应于人抗体序列的氨基酸序列(包括恒定区和可变区序列)。一种尤其优选的抗体(其用于实施例中,下文)在此处称作抗体10D1。该人序列抗体以前已经被描述过并且在例如,WO01/14424中被全面表征。
短语“免疫细胞应答”指免疫系统细胞对外部或内部刺激物(例如,抗原、细胞因子、趋化因子,和其他细胞)的应答,该应答在免疫细胞中产生生化变化,导致免疫细胞迁移、杀死靶细胞、吞噬作用、产生抗体及免疫应答的其他可溶性效应物,等等。
术语“T淋巴细胞应答”和“T淋巴细胞活性”在此处可互换使用,指依赖于T淋巴细胞的免疫应答组分(即,T淋巴细胞增殖和/或分化成辅助细胞、细胞毒性杀伤细胞或抑制性T淋巴细胞,辅助T淋巴细胞为B淋巴细胞提供导致或防止抗体产生的信号,细胞毒性T淋巴细胞杀伤特异靶细胞,以及释放调节其他免疫细胞的功能的可溶性因子如细胞因子)。
术语“免疫应答”指淋巴细胞、抗原呈递细胞、吞噬细胞、粒细胞,和上面的细胞或肝脏产生的可溶性大分子(包括抗体、细胞因子和补体)的协同作用,其导致选择性损害、破坏、或消除侵入人体的病原体、感染病原体的细胞或组织、癌细胞、或者,对于自身免疫或病理炎症而言,正常的人细胞或组织。
免疫应答的各组成要素可以体外通过本领域普通技术人员熟知的各种方法检测。例如,(1)细胞毒性T淋巴细胞可与放射性标记的靶细胞孵育并且通过放射活性的释放检测这些靶细胞的裂解,(2)辅助T淋巴细胞可与抗原和抗原呈递细胞孵育并通过标准方法测量细胞因子的合成和分泌(Windhagen A;等,1995,Immunity 2(4):373-80),(3)抗原呈递细胞可与完整蛋白抗原孵育并通过T淋巴细胞活化试验或生物物理方法检测抗原在MHC上的呈递(Harding等,1989,Proc.Natl.Acad.Sci.,86:4230-4),(4)肥大细胞可与和它们的Fc-ε受体交联的试剂孵育并通过酶免疫分析测量组胺的释放(Siraganian,等,1983,TIPS 4:432-437)。
类似地,模式生物(例如,小鼠)或人类患者中的免疫应答产物也可以通过本领域中普通技术人员熟知的各种方法检测。例如,(1)应答疫苗接种引起的抗体产生可容易地通过临床实验室中现今使用的标准方法,如ELISA检测;(2)免疫细胞向炎症部位的迁移可通过擦伤皮肤表面并安置无菌容器以捕获擦伤部位上迁移的细胞来检测(Peters等,1988,Blood 72:1310-5);(3)应答有丝分裂原引起的外周血单个核细胞增殖或混合淋巴细胞反应可使用3H-胸苷测量;(4)PBMC中粒细胞、巨噬细胞和其他吞噬细胞的吞噬能力可通过将PMBC与标记的颗粒一起置于孔中来测量(Peters等,1988);和(5)免疫系统细胞的分化可通过将PBMC用抗CD分子如CD4和CD8的抗体标记并测量表达这些标记物的PBMC的分数来确定。
为了方便起见,免疫应答通常在本发明中描述为“初次”或“再次”免疫应答。初次免疫应答(其也被描述为“保护性”免疫应答)指因初次接触特定抗原(例如,最初“免疫作用”)而在个体中产生的免疫应答。这种免疫作用可以例如,由于天然接触抗原引起(例如,因初次感染显示或呈递抗原的某种病原体引起)或由个体中某个肿瘤(例如,切除的肿瘤)的癌细胞呈递的抗原引起。备选地,免疫作用也可以通过向个体接种含有抗原的疫苗而出现。例如,疫苗可以是抗特定病原体(例如,抗病毒、细菌或寄生虫)的疫苗或者其可以是含有来自癌细胞的一种或多种抗原的癌症疫苗。
初次免疫应答可随着时间变弱或减弱并且甚至可能消失或者至少减弱至不能被检测到。因此,本发明也涉及“再次”免疫应答,其在此处也被描述为“记忆免疫应答”。术语“再次免疫应答”指初次免疫应答已经产生后在个体中引起的免疫应答。从而,可以通过引发再次免疫应答以,例如增强已经变弱或减弱的现有免疫应答,或者使已经消失或者不再能被检测到的先前免疫应答重新产生。可以通过施用来引起再次免疫应答的药剂以后被称为“加强剂”,因为该药剂可以说是“加强”了初次免疫应答。
作为实例,但是不是限制,再次免疫应答可通过向个体再次导入引起初次免疫应答的抗原而产生(例如,通过重新施用疫苗)。然而,对抗原的再次免疫应答也可以通过施用可能不含有实际抗原的其他药剂引起。例如,本发明提供了通过对个体施用抗CTLA-4抗体来加强再次免疫应答的方法。在这些方法中,实际抗原不需要与抗CTLA-4抗体一起施用,并且含有抗CTLA-4抗体的组合物也不必含有该抗原。再次或记忆免疫应答可以是体液(抗体)应答或细胞应答。再次或记忆体液应答在对抗原首次呈递时产生的记忆性B细胞进行刺激时发生。迟发型超敏(DTH)反应是一种由CD4+细胞介导的细胞再次或记忆免疫应答。对抗原的首次暴露造成免疫系统被致敏,而再次暴露导致DTH。
如此处所用的,短语“细胞表面受体”包括能够接收信号并跨细胞质膜传送这种信号的分子和分子复合体。本发明的“细胞表面受体”的实例是T细胞受体(TCR)或CTLA-4的B7配体。
术语“非特异性T细胞活化”指不依赖于T细胞的抗原特异性而对T细胞的刺激。
如此处所用的,术语“效应细胞”指参与免疫应答的效应阶段(与免疫系统的认知和活化阶段相对的阶段)的免疫细胞。示例性免疫细胞包括骨髓或淋巴来源的细胞,例如,淋巴细胞(例如,B细胞和T细胞,包括溶细胞性T细胞(CTL))、杀伤细胞、天然杀伤细胞、巨噬细胞、单核细胞、嗜酸性粒细胞、嗜中性粒细胞、多形核细胞、粒细胞、肥大细胞和嗜碱性粒细胞。效应细胞表达特异Fc受体并执行特定免疫功能。效应细胞可诱导依赖抗体的细胞介导的细胞毒性(ADCC),例如,嗜中性粒细胞能够诱导ADCC。例如,表达FcαR的单核细胞、巨噬细胞、嗜中性粒细胞、嗜酸性粒细胞和淋巴细胞参与靶细胞的特异杀伤和向免疫系统的其他组分呈递抗原,或者与呈递抗原的细胞结合。效应细胞也可以吞噬靶抗原,靶细胞或微生物。
“靶细胞”指可被组合物(例如,本发明的人序列抗体或人单克隆抗体,本发明的双特异性或多特异性分子)靶定的受试者(例如,人或动物)中的任何不想要的细胞。靶细胞可以是表达或过表达人CTLA-4的细胞。表达人CTLA-4的细胞可以包括肿瘤细胞,例如淋巴瘤。
本发明还包括修饰的抗体。术语“修饰的抗体”包括已经通过例如部分抗体的缺失、加入或置换修饰的抗体,如单克隆抗体、嵌合抗体,和人源化抗体。例如,可通过缺失恒定区并将其替代为旨在增加抗体的半衰期,例如血清半衰期、稳定性或亲和性的恒定区来修饰抗体。
本发明的抗体缀合物可用于修饰给定的生物学应答或创造生物学应答(例如,募集效应细胞)。药物部分不应理解为限于经典化学治疗剂。例如,药物部分可以是具有期望的生物学活性的蛋白质或多肽。这种蛋白质可包括,例如,酶活性毒素,或其活性片段,如相思豆毒蛋白、蓖麻毒素A、假单胞菌外毒素、或白喉毒素;蛋白质,如肿瘤坏死因子或α干扰素;或生物反应调节物,如,淋巴因子、白介素-1(“IL-1”)、白介素-2(“IL-2”)、白介素-6(“IL-6”)、粒细胞巨噬细胞集落刺激因子(“GM-CSF”)、粒细胞集落刺激因子(“G-CSF”),或者其他生长因子。
缀合这种治疗部分到抗体的技术是熟知的,见例如,Arnon等,″癌症治疗中用于药物的免疫定向的单克隆抗体″,Monoclonal Antibodies AndCancer Therapy,Reisfeld等(编辑),243-56页(Alan R.Liss,Inc.1985);Hellstrom等,″药物递送抗体″,Controlled Drug Delivery(第二版),Robinson等(编辑),623-53页(Marcel Dekker,Inc.1987);Thorpe,“癌症治疗中细胞毒性剂的抗体载体:综述”,Monoclonal Antibodies′84:Biological And Clinical Applications,Pinchera等(编辑),475-506页(1985);“对癌症治疗中放射性标记抗体的治疗性用途的分析、结果和前景展望”,Monoclonal Antibodies For Cancer Detection And Therapy,Baldwin等(编辑),303-16页(Academic Press 1985),和Thorpe等,“抗体-毒素缀合物的制备和细胞毒性性质”,Immunol.Rev.,62:119-58(1982)。
癌症治疗
通过抗体对CTLA-4的阻断可增强患者体内对癌细胞的记忆或再次免疫应答。抗CTLA-4的抗体可以与免疫原性剂组合使用或单独使用以刺激免疫,这些免疫原性剂如癌细胞、纯化的肿瘤抗原(包括重组蛋白、肽和糖分子)、细胞和用编码免疫刺激细胞因子和细胞表面抗原如B7的基因转染的细胞(见,例如,Hurwitz,A.等(1998)Proc.Natl.Acad.Sci U.S.A.1998;95:10067-10071)。
当按照接种疫苗方案时CTLA-4阻断是有效的。已经设计了许多抗肿瘤免疫接种的实验策略(见Rosenberg,S.,2000,Development of CancerVaccines,ASCO Educational Book Spring:60-62;Logothetis,C.,2000,ASCO Educational Book Spring:300-302;Khayat,D.2000,ASCOEducational Book Spring:414-428;Foon,K.2000,ASCO EducationalBook Spring:730-738;还见Restifo,N.和Sznol,M.,Cancer Vaccines,Ch.61,pp.3023-3043,DeVita,V.等(编辑),1997,
Cancer:Principles and Practice of Oncology,第五版)。在这些策略之一中,使用自体或同种异体肿瘤细胞制备疫苗。当肿瘤细胞经转导表达GM-CSF时这些细胞疫苗显示出最有效。GM-CSF已经被证实为肿瘤接种中抗原呈递的有力激活剂(Dranoff等Proc.Natl.Acad.Sci U.S.A.1993;90:3539-43)。
通过抗CTLA-4的阻断作用加强GMCSF-修饰的肿瘤细胞疫苗可以提高许多实验室肿瘤模型如乳腺癌(Hurwitz等,1998,如前引文)、原发性前列腺癌(Hurwitz等,Cancer Research 2000;60:2444-8)和黑素瘤(vanElsas等J.Exp.Med.1999,190:355-66)中疫苗的功效。在这些实例中,已经使得非免疫原性肿瘤,如B16黑素瘤,变得易于被免疫系统破坏。肿瘤细胞疫苗也可以被修饰以表达其他免疫激活剂,如IL2,和共刺激分子,等等。
对各种肿瘤中基因表达和大规模基因表达模式的研究已经导致对所谓的“肿瘤特异性抗原”的定义(Rosenberg,Immunity 1999;10:281-7)。在许多情况中,这些肿瘤特异性抗原为在肿瘤和肿瘤所来源的细胞中表达的分化抗原,例如黑素细胞抗原gp100、MAGE抗原、Trp-2。更重要的,这些抗原中的许多可能被证实是宿主中发现的肿瘤特异性T细胞的靶标。CTLA-4阻断剂可作为加强剂与基于发现在肿瘤中表达的蛋白和/或肽的重组版本的疫苗联合使用,以加强对这些蛋白的再次或记忆免疫应答。这些蛋白通常被免疫系统认作自身抗原并因此对免疫系统产生耐受。肿瘤抗原也可以包括蛋白质端粒酶,该酶是染色体端粒合成所必需的并且在超过85%的人类癌症中和仅仅有限数目的体细胞组织中表达(Kim等,Science1994;266:2011-2013)。这些体细胞组织可通过各种方法躲避免疫攻击。肿瘤抗原也可以是因改变蛋白质序列或在两种不相关序列间造成融合蛋白(如,费城染色体中的bcr-abl)的体细胞突变而在癌细胞中表达的“新生抗原”,或者是来自B细胞肿瘤的独特型。其他肿瘤疫苗可包括来自人类癌症所涉及的病毒的蛋白,这些病毒如人乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV)。可以与CTLA-4阻断剂联合使用的另一种肿瘤特异性抗原为从肿瘤组织自身分离的纯化的热休克蛋白(HSP)。这些热休克蛋白含有来自肿瘤细胞的蛋白质的片段,并且这些HSP在向抗原呈递细胞递送以引起肿瘤免疫方面非常有效(Suot和Srivastava,Science 1995;269:1585-1588;Tamura等,Science 1997,278:117-120)。
树突细胞(DC)是可用于引发抗原特异性应答的有力抗原呈递细胞。DC可离体产生并可以用各种蛋白质和肽抗原以及肿瘤细胞提取物加载(Nestle等,Nature Medicine1998;4:328-332)。DC也可以通过遗传方法转导以表达这些肿瘤抗原。为了免疫目的,DC也已经直接与肿瘤细胞融合(Kugler等,Nature Medicine 2000;6:332-336)。作为接种疫苗的一种方法,可通过CTLA-4阻断有效地加强DC免疫以激活更强的抗肿瘤应答。
可以与CTLA-4阻断剂组合的另一类黑素瘤疫苗是从黑素瘤细胞系裂解物及免疫学佐剂制备的疫苗,如MELACINE疫苗——来自两种人黑素瘤细胞系的裂解物加DETOXTM免疫学佐剂的混合物。疫苗治疗可用抗CTLA4加强,并使用或不使用额外的化疗治疗。
CTLA-4阻断也可用于加强通过标准癌症治疗诱导的免疫。在这些情况中,可能可以减小施用的化疗剂的剂量(Mokyr等,Cancer Research,1998;58:5301-5304)。CTLA-4阻断剂和化疗组合使用的科学基础是细胞死亡(其是多数化疗化合物的细胞毒性作用的结果)将导致抗原呈递途径中肿瘤抗原的水平增加。从而,CTLA-4可增强由化疗释放的肿瘤细胞引发的免疫应答。此外,CTLA-4的免疫刺激活性可用于克服化疗的免疫抑制效果。可与抗CTLA-4治疗组合的化疗剂的实例包括,但不限于,阿地白介素、六甲聚腈胺、阿米斯丁、天冬酰胺酶、博来霉素、卡培他滨、卡铂、卡氮芥、克拉屈滨、西沙比利、顺氯氨铂、环磷酰胺、阿糖胞苷、达卡巴嗪(DTIC)、放线菌素D、多西紫杉、阿霉素、屈大麻酚、重组人类红细胞生成素α、依托泊苷、非格司亭、氟达拉滨、氟尿嘧啶、吉西他滨、格雷西隆、羟基脲、去甲柔毛霉素、异环磷酰胺、α干扰素、伊立替康、达克普隆、左旋四咪唑、甲酰四氢叶酸、甲地孕酮、巯基乙磺酸钠、氨甲蝶呤、甲氧氯普胺、丝裂霉素、邻氯苯对氯苯二氯乙烷、二羟蒽二酮、奥美拉唑、奥丹西隆、紫杉醇(泰索)、匹鲁卡品、甲哌氯丙嗪(prochloroperazine)、利妥希玛、他莫西芬、红豆杉醇、盐酸托扑替堪、司徒曼布、长春碱、长春新碱和去甲长春花碱。对于前列腺癌治疗,可与抗CTLA-4组合的优选的化疗剂是紫杉醇(Taxol)。对于黑素瘤癌症治疗,可与抗CTLA-4组合的优选的化疗剂是达卡巴嗪(DTIC)。
可通过细胞死亡来致敏免疫系统的其他组合治疗为放射、手术和激素剥夺(hormone deprivation)(Kwon,E.等Proc.Natl.Acad.Sci U.S.A.1999;96(26):15074-9)。这些方案均在宿主中造成肿瘤抗原来源。例如,手术时对肿瘤的任何操作都可以极大地增加血液中的癌细胞数目(Schwartz,等,Principle of Surgery 1984.第四版,338页)。血管生成抑制剂也可以与CTLA-4阻断剂组合。血管生成的抑制导致肿瘤细胞死亡,而这可使肿瘤抗原流入宿主抗原呈递途径。所有这些导致肿瘤释放和可以被CTLA-4阻断加强的可能的免疫系统致敏。
感染性疾病
本发明的其他方法用于治疗曾暴露于特定毒素或病原体的患者。类似于如上讨论的本发明方法在肿瘤中的应用,抗体介导的CTLA-4阻断可单独使用,或者作为佐剂与疫苗组合,以刺激对病原体、毒素和自身抗原的再次或记忆免疫应答。CTLA-4阻断已经显示出在巴西日本圆线虫(Nippostrongylus brasiliensis)(McCoy,K.等(1997)186(2);183-187)和杜氏利什曼原虫(Leishmania donovani)(Murphy,M.等(1988)J.Immunol.161:4153-4160)感染的急性期有效。该治疗方法对其尤其有用的病原体的实例包括现今对其没有有效疫苗的病原体,或常规疫苗对其不完全有效的病原体。这些病原体包括,但不限于HIV、肝炎病毒(A、B、&C)、流感病毒、疱疹病毒、贾第虫、疟原虫、利什曼原虫、金黄色葡萄球菌(Staphylococcus aureus)和绿脓杆菌(Pseudomonas aeruginosa)。CTLA-4阻断尤其可以用于加强针对诸如HIV等因素导致的已建立感染的免疫性,这些因素在感染过程中呈现变化的抗原。这些新的表位在抗人CTLA-4施用时被识别为外来的,从而激起不会被通过CTLA-4的负信号抑制的强烈T细胞应答。
可通过本发明方法治疗的导致感染的病原性病毒的一些实例包括肝炎病毒(A、B或C)、疱疹病毒(例如,VZV、HSV-1、HAV-6、HSV-II、和CMV、Epstein Barr病毒)、腺病毒、流感病毒、黄病毒、艾可病毒、鼻病毒、柯萨奇病毒、cornovirus、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、痘苗病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒和虫媒脑炎病毒。
可通过本发明的方法治疗的导致感染的病原性细菌的一些实例包括衣原体、立克次氏体细菌、分枝杆菌、葡萄球菌、链球菌、肺炎球菌、脑膜炎球菌、Conococci和克雷白氏杆菌、变形杆菌、沙雷氏菌、假单胞菌、军团菌、白喉菌、沙门氏菌、芽孢杆菌、霍乱菌、破伤风菌、肉毒杆菌、炭疽杆菌、鼠疫细菌、钩端螺旋体、和Lyme氏疏螺旋体病细菌。
可通过本发明的方法治疗的导致感染的病原性真菌的一些实例包括假丝酵母(Candida)(白假丝酵母(C.albicans)、克鲁斯氏假丝酵母(C.krusei)、光滑假丝酵母(C.glabrata)、热带假丝酵母(C.tropicalis)、等)、新型隐球酵母(Ctyptococcus neoformans)、曲霉(Aspergillus)(烟曲霉(A.fumigatus)、黑曲霉(A.niger)、等)、毛霉菌目(Mucorales)(毛霉((Mucor)、犁头霉(Absidia)、根霉(Rhizophus))、Sporothrixschenkii、皮炎芽生菌(Blastomyces dermatitidis)、巴西芽生菌(Paracoccidioides brasiliensis)、粗球孢菌(Coccidioides immitis)和英膜组织胞浆菌(Histoplasma capsulatum)。
可通过本发明的方法治疗的导致感染的病原性寄生虫的一些实例包括溶组织内阿米巴(Entamoebahistolytica)、结肠小袋虫(Balantidium coli)、福氏耐格里阿米巴(Naegleria fowleri)、棘阿米巴属种(Acanthamoebasp.)、兰伯贾第虫(Giardia lambia)、隐孢子虫属种(Cryptosporidiumsp.)、卡氏肺孢子虫(Pneumocystis carinii)、间日疟原虫(Plasmodiumvivax)、微小巴贝虫(Babesia microti)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、杜氏利什曼原虫(Leishmania donovani)、鼠弓形体(Toxoplasma gondi)、巴西日本圆线虫(Nippostrongylusbrasiliensis)。
促进有益的“自身免疫”反应
抗CTLA-4抗体引起和增大自身免疫反应的能力已经在许多实验系统中记载(EAE-实验室自身免疫脑脊髓炎:MS的一种鼠模型(Perrin等,JImmunol 1996;157:1333-1336);糖尿病(Luhder等,1998,如前引文)。实际上,通过使用肿瘤细胞和肽疫苗诱导抗肿瘤应答揭示了许多抗肿瘤应答涉及抗自身反应(在抗CTLA-4+GM-CSF修饰的B16黑素瘤中观察到的褪色(Van Elsas等,如前引文);在Trp-2接种的小鼠中的褪色(Overwijk等,Proc.Natl.Acad.Sci.U.S.A.1999 96:2982-2987);TRAMP肿瘤细胞疫苗引起的自身免疫前列腺炎(Hurwitz 2000,如前引文),在人临床试验中观察到的黑素瘤肽抗原接种和白斑(Rosenberg和White,J ImmunotherEmphasis Tumor Immunol 1996;19:81-4)。
因此,可以考虑使用抗CTLA-4加强作用与各种自身蛋白联合以设计接种方案从而有效产生抗这些自身蛋白的免疫应答用于治疗疾病。例如,阿尔茨海默氏病涉及在脑中以淀粉样沉积物形式不适当积累Aβ肽;抗淀粉状蛋白的抗体应答能够清除这些淀粉样沉积物(Schenk等,Nature 1999;400:173-177)。
其他自身蛋白也可用作靶标,如IgE(用于治疗过敏和哮喘),TNF(用于治疗类风湿性关节炎)。最后,可通过使用抗CTLA-4抗体诱导针对各种激素的抗体应答。对生殖激素的中和抗体应答可用于避孕。对特定肿瘤生长所需的激素和其他可溶性因子的中和性抗体应答也可以被考虑作为可能的免疫接种目标。
与上述使用抗CTLA-4抗体的方法相类似的方法可用于诱导治疗性自身免疫应答以治疗患者体内其他自身抗原,如淀粉样沉积物,包括阿尔茨海默氏病中的Aβ、细胞因子如TNFα和IgE的不适当积累。
实施例
本发明也通过下面的实施例进行描述。然而,本说明书中这些和其他实施例的使用仅仅是阐明性的而决不是对本发明或任何示例性术语的范围和意义的限制。同样,本发明不被此处描述的任何特定优选的实施方案所限制。实际上,本发明的许多修改和变化在本领域技术人员读过本说明书后是显而易见的,并且可以实施这些修改和变化而不背离本发明的精神和范围。因此本发明仅仅被所附权利要求以及这些权利要求的等价方案的完整范围所限制。
实施例1:抗CTLA-4治疗增强恒河猴中对黑素瘤细胞疫苗的再次抗体和T细胞应答
在恒河猴(得自Primate Products,Miami,Florida)中检查本发明的人抗CTLA-4抗体增强对黑素瘤细胞疫苗的抗体和T细胞应答的能力。每组6只猴子(3只雄性,3只雌性)的试验组用1)单独的黑素瘤细胞疫苗(SK-mel-3——经转染表达GM-CSF的人黑素瘤肿瘤细胞系)或2)SK-mel-3和在WO01/14424中描述的抗CTLA-4抗体10D1处理。完整细胞疫苗将允许在该动物模型中研究针对各种正常组织的自身免疫反应,尽管此细胞疫苗来源于人。
为了制备疫苗,使SK-mel细胞生长到汇合并收获。将细胞用丝裂霉素C处理,洗涤几次并以1×107/ml重悬于盐水中。以体积1.3ml/kg以10mg/kg剂量静脉内施用抗体。SK-mel-3细胞以固定量(5×106个细胞/只动物以0.5ml/只动物)皮下施用。针对每种疫苗制剂检验内毒素(<2EU/ml)和48小时后的GM-CSF的产生(2-8ng/ml/106个细胞)。在第0、28、56、84和140天施用适宜抗体和/或疫苗。在第13、41、69和97天使用细胞流式计数法评价对黑素瘤细胞疫苗的抗体应答。猴子的健康状况每周两次评价并每周记录体重。
血液学、药物动力学分析和功能性分析在研究开始前进行并在整个研究中周期性地进行。完整的宏观和微观病理学检查在第167天进行。
检查用黑素瘤疫苗和抗CTLA-4抗体处理的动物中抗体应答的特异性。在处理的第41天从用SK-mel-3疫苗和mAb 10D1处理的6只恒河猴得到血浆并合并。将血浆以1∶1000稀释并通过细胞流式计数法检测对各种黑素瘤和非黑素瘤细胞系的反应性。结果如图1所示,其表明猴子中的抗体应答对人黑素瘤细胞系比对人非黑素瘤细胞系和非人细胞系显示出更大的特异性。
在第140天使用额外剂量后评价长期给药对用抗体和/和疫苗治疗的猴子的影响。在研究过程中直到第160天在各个时间点用重组CTLA-4通过ELISA监控抗CTLA-4抗体的血浆浓度。相对于标准曲线分析样品稀释液,确定10D1血浆浓度。在长期给药过程中10D1的血浆浓度的数据如图2所示,其中给出了6个治疗的动物的平均+/-SEM。结果表明抗CTLA-4抗体的血浆水平在整个160天的期间保持在可检测的水平之上,提示在整个治疗期间都保持了CTLA4阻断。被处理的猴子中mAb 10D1的平均血浆浓度在输注后那天达到175到315μg/ml的峰值,并在6个月研究中保持高于20μg/ml。临床化学、笼边观察(Cage-side observation)和完整的组织学分析没有揭示与抗体或疫苗施用相关的任何显著变化。长期给药除了在两只猴子的疫苗注射部位导致轻微刺激外没有导致治疗相关的病理,尽管CTLA-4阻断具有建立自身反应性抗黑素细胞应答的潜在能力。这些猴没有出现针对10D1 mAb的可检测的抗体应答,并且在研究持继期中保持高水平活性循环抗体。而且,该抗CTLA-4抗体的长期给药与治疗的功效相关并且未伴随有害副作用(例如非特异性T细胞活化)。从而,本实验阐明灵长类动物可有效地用抗CTLA-4抗体长期治疗从而使血浆浓度保持在可检测水平之上至少1、2、3、4或5个月或甚至更长时间而没有严重副作用。
实施例2:从人类迟发型超敏反应(DHT)实验得到的抗原特异性T细
胞增殖证据
具有切除的III期(2名患者)或IV期(17名患者)黑素瘤的19名患者接受CTLA-4抗体10D1的递增给药(0.3,1和3mg/kg),并注射gp100/酪氨酸酶/MART-1肽疫苗和不完全弗氏佐剂。酪氨酸酶368-376(370D)、MART-126-35(27L)和gp100 209-217(210M)肽都与野生型相比有一个氨基酸修饰以增加HLA结合。疫苗以1mg/剂/肽在12个月内施用8次。通过DTH反应性测量的免疫应答表明9名患者中4名对gp100应答,9名患者中的2名对MART-1应答。ELISPOT分析表明在使用新鲜CD8 T细胞试验的16名患者中4名有免疫应答。
实施例3:Mab 10D1黑素瘤的I期临床试验(MDXCTLA4-02)的结果
MDXCTLA4-02是I期公开、多中心临床试验,用于在患有进行性、不可切除的恶性黑素瘤的17名患者中评价Mab 10D1的安全性和药物动力学。中值年龄为59岁(范围29-79)。9名患者以前曾接受过免疫治疗,6名接受过放射,5名接受过化疗。所有患者经90分钟静脉内接受单剂3mg/kg10D1,然后被跟踪评价毒性、药物动力学、循环T细胞活化和临床结果。完成了所有输注,仅仅有轻微的不利事件。7名患者出现轻微的、可逆的皮疹或搔痒。抗体的血浆水平持续1到4个月。活化的外周T细胞没有显著增加并且除了轻微皮疹没有临床自身免疫的迹象。两名患者出现三个软组织肿块消褪和肺部肿块减小超过50%的部分应答。此外,肺部肿块减小超过50%的患者是以前用黑素瘤疫苗治疗的患者,这提示抗CTLA-4抗体治疗能够活化对此肿瘤的预先存在的记忆应答。该研究的结果表明抗CTLA-4治疗具有良好耐受性以及明显的免疫学和抗肿瘤活性迹象。
抗体治疗后在各个时间点通过流式细胞计数法分析用10D1治疗的患者中的淋巴细胞亚群。结果总结在下面的表1中。
表1:在用3.0mg/Kg MAb 10D1治疗的黑素瘤癌症受试者中淋巴细胞亚群的流式细胞计数法分析
亚群 | 基线 | 24小时 | 7天 | 14天 | 21天 | 28天 |
CD3 | 72.9±3.6 | 68.9±4.1 | 75.1±3.6 | 73.2±4.3 | 74.7±3.9 | 74.2±4.2 |
CD4 | 48.8±3.0 | 44.3±3.6 | 49.3±3.6 | 50.5±3.8 | 49.2±4.3 | 50.8±4.5 |
CD8 | 22.3±2.5 | 25.3±3.0 | 26.2±2.5 | 21.9±1.8 | 26.3±2.9 | 23.7±2.7 |
CD19 | 12.2±2.5 | 12.7±3.0 | 8.7±2.2 | 11.3±2.9 | 9.4±2.2 | 9.4±2.1 |
CD4+CD25 | 65.8±3.4 | 64.9±4.0 | 60.8±3.4 | 61.7±3.0 | 58.3±3.0 | 60.9±2.9 |
CD8+CD25 | 14.4±1.7 | 13.4±1.8 | 13.1±1.9 | 11.9±1.6 | 10.9±1.3 | 13.7±2.1 |
CD4+HLA-DR | 11.8±1.3 | 12.4±1.7 | 19.7±3.5 | 20.9±1.9 | 18.4±1.2 | 17.1±1.6 |
CD8+HLA-DR | 13.6±2.2 | 17.9±2.8 | 17.7±2.9 | 17.5±2.3 | 20.2±2.9 | 17.5±2.6 |
CD4+45RO | 23.7±3.4 | 22.9±3.7 | 19.4±3.4 | 17.9±3.8 | 17.3±3.7 | 19.2±3.8 |
CD8+45RO | 40.5±3.5 | 39.1±3.8 | 37.6±4.1 | 35.5±4.9 | 35.1±5.0 | 35.7±4.3 |
类似于在前列腺癌患者中观察到的结果(见下面的实施例6),在黑素瘤研究中的结果表明10D1治疗导致CD4/HLA-DR+亚群随时间大约增加50%。其他淋巴细胞亚群随时间保持基本恒定。如上所述,当评价抗CTLA4抗体时抗CTLA4抗体治疗随时间增加CD4/HLA-DR+亚群的能力可用作选择性特征(即,可评价一组抗CTLA4抗体增加CD4/HLA-DR+亚群的能力并且可以选择能够随时间增加该亚群的抗CTLA-4抗体)。此外,可以在用抗CTLA-4处理的受试者中随时间监控淋巴细胞亚群,尤其是CD4/HLA-DR+亚群,作为抗体有效性的一个标记。
实施例4:在先已免疫接种的黑素瘤和卵巢癌患者中进行抗CTLA-4
抗体阻断的人类研究
对9名以前接受过免疫的晚期癌症患者施用抗CTLA-4抗体10D1。患者1-6通过I期临床MDXCTLA4-02入选,其合格标准为手术不可切除的III期或IV期黑素瘤、疾病发展、至少12周的预期寿命、足够的终器功能、稳定的止痛治疗,和至少60%的卡尔诺夫斯基活动状况。患者如果患有另一种恶性肿瘤(除了治疗的非黑素瘤皮肤癌或表面膀胱癌外)、自身免疫疾病、活性感染、卡那霉素超敏反应;或者如果使用过皮质类固醇,那么他们将被排除。患者7-9通过用于患有转移性黑素瘤、转移性卵巢癌、转移性非小细胞肺癌或急性髓性白血病的患者的I期试验而入选。
4名患者以前曾进行过早期黑素瘤治疗(3名患者接受α干扰素,一名患者接受与QS-21混合的GM2神经节苷脂疫苗,一名患者接受放疗)。对转移性黑素瘤的以前的非免疫治疗包括手术(4名患者)、放射(2名患者)、化疗(3名患者)和蛋白酶体抑制剂(一名患者)。两名卵巢癌患者在研究前整个3到4年中接受过对复发疾病的多次化疗。
所有患者在进入本研究前参加过对转移性疾病的I期疫苗研究。三名黑素瘤和两名卵巢癌患者用辐射过的自体肿瘤细胞免疫,该细胞通过腺病毒介导的基因转移被改造而分泌GM-CSF。这些患者之一(8号患者)还接受了MUC-1疫苗。3名黑素瘤患者用通过腺病毒介导的基因转移而被工程化以表达gp100和MART-1的自体树突细胞免疫。1名黑素瘤患者用修饰的gp100肽和高剂量白介素-2接种。
最初,以10ml生理盐水中的0.2mg测试剂量在10分钟内静脉内施用10D1以鉴定潜在的超敏反应。然后在90分钟内静脉内递送剩余的3mg/kg10D1剂量。抗体施用后,患者经历临床、实验室和射线照片评估,每天都进行,连续3天,然后每周进行,连续4周,然后是每月进行。
1名患者具有急性超敏反应,表现为输注过程中轻微的低血压和恶心。该反应容易地被抗组胺所控制并且输注平安地完成。5名患者在输注后持续2到7天出现短暂的I/II级全身性症状,包括肌痛、关节痛、厌食、疲劳、鼻塞和咳嗽。1名患者持续几个月出现间歇复发的症状。1名患者表现出短暂的III级肝功能异常。
以前用辐射过的自体GM-CSF分泌性肿瘤细胞接种的三名黑素瘤患者在用10D1治疗后出现广泛肿瘤坏死。1号患者在入选本研究时具有中枢神经系统、肺、腹部和软组织转移瘤。10D1施用后1个月,1号患者的神经学状况显示出临床改变,并且皮下损伤剧烈发炎。1号患者6天后死亡。尸体解剖时,注意到脑、硬膜外和内脏转移瘤显著的出血性肿瘤坏死。组织病理学检查显示伴随着出血的广泛肿瘤破坏(至少90%)。肿瘤血管被严重破坏,导致广泛的局部缺血性坏死。在每个损伤中剩余边缘存活的肿瘤细胞,伴随着粒细胞和淋巴细胞反应。
2号患者在10D1输注后1个月开始出现复发的II级全身性症状。纵隔损伤的活组织检查显示具有淋巴细胞和粒细胞浸润的广泛肿瘤坏死。免疫组织化学表明存在CD8+和CD4+T细胞以及产生免疫球蛋白的CD20+B淋巴细胞。纵隔损伤在2个月后被完全切除。对损伤的病理学分析表明密集的纤维样变性、广泛的坏死和正在进行的淋巴细胞和粒细胞应答。也观察到以堵塞的血管壁中周围淋巴浸润为特征的血管病。肿瘤坏死和血管损伤在空间上相关。
7号患者在10D1输注后3周在大的皮下损伤中发生炎症。该损伤在输注后2个月被切除。对该损伤的病理学检查表明广泛的肿瘤坏死和纤维样变性、显著的血管病和淋巴细胞与粒细胞浸润。
在以前用限定的黑素瘤抗原免疫的4名黑素瘤患者中观察到较不显著的抗肿瘤效果。3号患者在输注后7个月切除正扩大的纵隔损伤。病理学分析显示无肿瘤坏死的密集淋巴细胞浸润。免疫组织化学表明存在CD8+细胞,但是无CD4+和CD20+细胞。4号患者具有类似的CD4+细胞浸润但是在淋巴结转移瘤中没有肿瘤坏死,转移瘤在抗体输注后2个月被切除。5号患者在皮下损伤中没有出现淋巴浸润和肿瘤坏死,该损伤在抗体输注后2个月被切除。6号患者没有进行活组织检查,他的肿瘤继续发展。
抗体输注导致2名卵巢癌患者中CA-125水平的变化。CA-125从卵巢癌细胞的表面脱落并且是疾病状态的有用标记(Jacobs,I.(1994)Gyn.Oncol.55:S22-27)。对于8号患者,从抗体输注后2个月开始,CA-125值减少43%(230到132)。该应答没有保持但是10D1的第二次输注使CA-125水平稳定了2个月。9号患者在抗体输注后1个月具有稳定的CA-125值,伴随着腹水减少。9号患者在输注前具有快速上升的CA-125。
在4名患者中注意到持续1-2个月的低效价自身抗体(抗核抗体、抗甲状腺球蛋白抗体、类风湿因子)。没有自身免疫疾病的临床迹象。
所有黑素瘤患者在抗体输注后3天到3周之间在躯干和四肢上出现无症状I级网状和红斑状皮疹。7名患者进行皮肤活检。活检的7名患者中的5名在表面真皮中有延伸到表皮内的显著的血管周围T细胞浸润。与垂死的黑素细胞并列出现CD4+和CD8+T细胞。没有临床上明显的白斑。在1名患者中注意到轻度的视网膜病灶性色素减退,但是没有影响视敏度。一名卵巢癌患者在输注后2周在脸和躯干上发生红斑皮疹。皮肤活检表明表面真皮中血管周的T细胞浸润但是无针对黑素细胞的反应性。
10D1诱导循环性嗜中性粒细胞的显著增加,并且嗜中性粒细胞浸润和肿瘤坏死相关。
结果表明单剂10D1抗CTLA-4抗体输注可以具有显著的抗肿瘤效果并且可被安全地施用于人类患者。低效价自身抗体的产生表明该治疗可以,至少部分地,损害系统耐受性,但是没有观察到自身免疫疾病的临床迹象。
实施例5:对患有黑素瘤的患者施用抗CTLA-4抗体10D1和肽疫苗的研究
具有进行性IV期黑素瘤的14名患者接受抗CTLA-4抗体10D1,并用两种HLA-A*0201-限制性gp100肽进行免疫接种治疗。患者的特征总结在下面的表2中。
表2
患者 | 年龄/性别 | 疾病位点 | 先前治疗1 | 治疗周期数2 | 应答3(月) | I/II级毒性 | III/IV级毒性 |
1 | 52/M | 肺 | I,S | 2 | PR(10+) | 小肠结肠炎,皮炎 | |
2 | 40/F | 锁骨上淋巴结 | C,I,S | 1 | NR | 白斑 | 皮炎 |
3 | 39/M | 肺,纵隔皮下 | S | 6 | NR(混合的) | ||
4 | 55/F | 皮肤,皮下 | I,S | 1 | NR | 肺部浸润 | |
5 | 67/M | 肝脏,腹膜后腔,皮下 | C,I,R,S | 4 | NR | ANA+4 | |
6 | 59/M | 肺,皮下 | I,S | 4 | NR | 白斑 | |
7 | 48/M | 肺,脑,肾上腺,皮下 | C,I,S | 2 | NR | ||
8 | 48/M | 肺,肝脏,肾上腺,肠系膜,皮下 | C,I,S | 2 | NR | ||
9 | 53/M | 纵隔,肠系膜,皮肤 | I,R,S | 2 | NR | ||
10 | 62/M | 肺,肺门 | C,I,S | 2 | NR(混合的) | ||
11 | 54/M | 肺,脑,皮下 | C,S | 5 | CR(7+) | 垂体炎 | |
12 | 43/M | 膈下,肌肉,皮下 | I,S | 3 | NR | ANA+ | 肝炎 |
13 | 49/F | 肺,皮下 | C,I,S | 4 | PR(6+) | 皮炎 | |
14 | 63/M | 肺,骨盆淋巴结 | S | 4 | NR |
1C=化疗,I=免疫治疗,R=放疗,S=手术。
2一个治疗周期由CTLA-4抗体的一次输注和用gp100:209-217(210M)和gp100:280-288(288V)肽的一次接种组成。
3NR=无应答,PR=部分应答,CR=完全应答。
4ANA=抗核抗体。
所有患者都是卡尔诺夫斯基活动状况≥60%的HLA*0201+。6名患者有内脏转移瘤。患者没有自身免疫或免疫缺陷疾病的迹象。所有患者以前都对他们的原发性损伤进行过手术。6名患者先前进行过化疗。11名患者先前进行过免疫治疗,包括α干扰素(患者2、5-8、10、12和13)、低剂量IL-2(患者2、5和13)、高剂量静脉内IL-2(患者4、7和8)、全细胞黑素瘤疫苗(患者1、2和6)、NY-ESO-I肽疫苗(患者4和5),和GM-CSF(患者9)。患者先前未用gp100免疫并且在治疗前的3周内没有进行系统性治疗。
治疗周期每3周进行一次,其组成为:90分钟静脉内施用3mg/kg抗CTLA-4抗体10D1,接着在一肢皮下注射在不完全弗氏佐剂(IFA)中乳化的1mg gp100:209-217(210M)肽(IMDQVPFSV)并在另一肢皮下注射IFA中乳化的1mg gp100:280-288(288V)肽(YLEPGPVTV)(由国家癌症研究所癌症治疗评价系统提供合成的肽)。患者在治疗前和每两个治疗周期后3周采血。外周血单个核细胞(PBMC)通过Ficoll-Hypaque分离方法分离并用10%二甲亚砜在热失活的人AB血清中冷藏之后在-180℃保藏备用。患者接受1到6个治疗周期(表2)。
通过胸、腹和骨盆的计算机轴向X线断层造影(CT)和脑的磁共振成像(MRI)评价临床应答。这些成像研究在开始治疗的4周内然后在每两个治疗周期后进行。按需要使用额外的放射学研究以估计疾病位置。计算治疗前和治疗后每个患者中肿瘤的最长直径的总和(世界卫生组织RECIST标准)。部分应答定义为持续至少一个月所有可评价的转移瘤的最长直径的总和减少至少30%,但是小于100%,并且没有新的或增大的肿瘤。完全应答定义为持续至少一个月所有可评价的转移瘤的最长直径的总和减少100%,并且没有新的肿瘤。无应答定义为非部分或完全应答的应答。
评价患者的自身免疫应答。患者在治疗前和开始治疗后3个月接受眼科检查。所有患者在甲状腺球蛋白Ab、类风湿因子和抗核抗体的研究开始前进行阴性血清血液检验。在研究过程中每3周测量人抗人(抗独特型)Ab、红细胞沉降速率、抗核Ab、促甲状腺素和游离T4水平。
使用标准ELISA用CTLA-4-Ig包被的微量滴定孔(R&D Systems,Minneapolis,Minnesota)确定10D1的血浆浓度。在板上孵育血浆样品的稀释液。结合的抗CTLA-4抗体用碱性磷酸酶标记的山羊抗人IgG F(ab)-特异性探针检测,该探针用底物p-NPP显影。
一种12天的体外致敏试验(其比ELISPOT或四聚体分析(tetramerassay)更灵敏)被用于估计所有11名患者(可得到PBMC用于检验)的免疫学反应性(Rosenberg,S.A.等,Nat.Med.1998;4:321-327)。将冷藏的PBMC融化并在含有10%热失活的人AB血清和1μM天然gp100:209-217或gp100:280-288肽和300IU/ml IL-2的基于Iscove的完全培养基中培养。在培养开始后11到13天收获细胞并将细胞与肿瘤细胞或肽脉冲的T2细胞共孵育过夜。上清液中释放的γ干扰素(IFN-γ)使用商业ELISA测定法(Pierce-Endogen,Rockford,Illinois)测量。所有的11名患者在1到4个治疗周期后显示出成功的抗天然gp100:209-217肽的免疫性。6名患者对天然gp100:280-288肽具有成功的免疫性。
在Fc-受体封闭和用抗体(BD Biosciences,San Diego,California)或四聚体(Beckman Coulter Immunomics,San Diego,California)染色后进行流式细胞计数法分析。比较两个治疗周期之前和之后9名患者的PBMC上表面标记物的表达。HLA-DR(活化标记物)表达在治疗后CD3+CD4+细胞(P=0.0004;成对t-检验)和CD3+CD4+(可能CD8+)细胞(P=0.04)上显著增加。CD3+CD4+细胞在治疗后也显示出CD45RO(一种记忆细胞标记物)表达的显著增加(P=0.04)。表达CD69、CD25和CTLA-4的细胞群体的百分数没有改变。
1、11和13号患者是应答者(表15)。1号患者在两个治疗周期后唯一的肺损伤缩小。13号患者在2个治疗周期后唯一的肺损伤缩小且皮下损伤完全消除。11号患者有31个肺损伤、2个皮下损伤和1个脑损伤。脑损伤在2个治疗周期后从0.5cm长大到约1.0cm。再3个治疗周期后,11号患者的所有损伤均完全消除,包括脑损伤。
3号患者具有混合的应答,其中4个治疗周期后一些肺损伤消除但是纵隔淋巴结变大。10号患者在2个治疗周期后肺门损伤和几个其他肺损伤显著缩小,但是其他肺损伤变大。
I/II级不利事件包括腹泻(3、5和14号患者)、皮肤皮疹(14号患者)、肺浸润和轻微的胸膜炎性胸痛(4号患者)和白斑(2和6号患者)。
6名患者出现7种III/IV级不利事件,包括皮炎(1、2和13号患者)、结肠炎/小肠结肠炎(1和9号患者)、垂体炎(垂体发炎)(11号患者)和肝炎(12号患者)。在停止治疗和施用维持性治疗和/或类固醇治疗后所有患者都恢复。没有复发或随后的自身免疫事件。
自身免疫筛检血液检查是正常的,除了5号和12号患者产生了抗核抗体。
该研究阐明了在接受抗CTLA-4抗体10D1和两种肽疫苗的患者中转移性黑素瘤退化的客观证据。
实施例6:在前列腺癌中的MAb 10D1的I期人类临床试验
(MDXCTLA4-01)
MDXCTLA4-01是在患有进行性、转移性、激素不应性前列腺癌的患者中对抗细胞毒性T淋巴细胞相关抗原-4的单克隆抗体(抗CTLA-4)10D1(Mab 10D1)的公开研究。治疗为单剂MAb 10D1,其通过输注以3.0mg/kg的剂量静脉内施用。组织学诊断为原发性前列腺腺癌和进行性转移性前列腺瘤的患者在雄激素剥夺和至少一种全身性非激素治疗后经筛选参与本研究。入选标准为:进行性可测量的疾病、进行性PSA,PSA>5ng/ml,睾酮<50ng/dl,原发性生殖腺雄激素抑制,预期寿命>12周和卡尔诺夫斯基活动状况≥60%。
由于试验中监控患者免疫状态的重要性和监控抗CTLA-4抗体对T细胞活化的全身性影响的特定目标,该研究的进入标准包括CD4和CD8 T细胞的最小水平分别为≥500/ml和≥500/ml。然而,在研究的最初积累过程中观察到尽管CD4和CD8 T细胞明显存在,但是前列腺癌患者的T细胞数目显著减少。基于上面的进入标准,许多患者在开时就被排除。所观察的T细胞数目的明显减少是在前列腺癌患者中以前未曾记录的观察资料,这可能和这些患者中涉及癌症疫苗接种的治疗相关。在这些观测后,修改入选标准以包括CD4和CD8数分别为≥300/ml和≥200/ml的患者。
受试者经历体检、ECG、胸部X光照片、诊断成像和用于血液学、生化和免疫功能评价的血液采样。每月进行电话访问直到治疗后6个月以收集和记录疾病进展后关于部分不利事件的信息,这些不利事件包括自身免疫不利事件。监控PSA(下降、下降持续时间、上升、达到上升的时间)和疾病应答(完全的、部分的、稳定的、进行性的)。临输注前、输注过程中、输注后最多2个月评价MAb 10D1的血浆浓度。
具有HRPC的14名患者入选。中值年龄为69岁(范围是56-79)。7名患者以前接受过化疗。所有患者经90分钟静脉内接受单剂3mg/kg 10D1然后跟踪以检查毒性、药物动力学、循环T细胞活化和临床结果。所有输注按计划完成,只有轻微的输注相关不利事件(AE)。应答口服类固醇治疗有轻微的可逆皮疹或搔痒。没有其他3级或更大的与10D1相关的AE。药物动力学图谱如图3所示,该图以μg/ml给出血浆浓度。显示了关于14名患者(n=14)的平均值+/-SEM。图3中显示的结果表明抗体的血浆水平长达3个月保持可检测并且额外的监测发现血浆水平可持续甚至4个月保持可检测。活化的外周T细胞没有显著增加,并且没有观察到临床自身免疫。7名未进行过化疗的患者中的2名患者具有持续3个月和5个月的PSA应答(一致标准(consensus criteria)),一名症状改善。其他患者经历PSA曲线斜率的显著变化。将患者再次用第二剂10D1(3mg/kg)治疗并且在再次治疗时,以前应答的患者再次经历PSA减少而无显著AE。该治疗被良好耐受,并且有免疫学和抗肿瘤活性的明显迹象。从而,该研究表明人类患者可以用抗CTLA-4抗体治疗使抗体的血浆水平保持在可检测水平之上1、2、3或甚至4个月而没有有害副作用。
抗体治疗后在各个时间点通过流式细胞计数法分析用10D1治疗的患者中的淋巴细胞亚群。结果在表3中总结(术语以平均值+/-SEM给出)。
表3:在用3.0mg/Kg MAb 10D1治疗的前列腺癌症受试者中淋巴细胞亚群的流式细胞分析。
亚群 | 基线 | 24小时 | 7天 | 14天 | 21天 | 28天 |
CD3 | 71.7±3.45 | 75.6±3.53 | 77.6±2.45 | 78.5±2.49 | 75.6±2.42 | 76.0±2.70 |
CD4 | 40.3±3.49 | 38.7±3.36 | 44.0±3.20 | 38.7±3.36 | 42.9±2.98 | 44.5±3.05 |
CD8 | 30.5±3.91 | 35.6±4.54 | 32.6±4.43 | 30.8±4.14 | 31.5±4.28 | 30.7±4.32 |
CD19 | 7.6±1.24 | 5.7±1.27 | 6.4±1.24 | 6.2±0.98 | 6.7±1.27 | 6.8±1.15 |
CD4+CD25 | 69.2±3.47 | 65.0±3.38 | 66.0±3.28 | 63.7±3.09 | 65.6±2.97 | 64.5±3.25 |
CD8+CD25 | 14.0±2.54 | 11.2±1.56 | 13.8±2.91 | 15.4±2.56 | 14.3±2.68 | 13.3±2.92 |
CD4+HLA-DR | 11.3±2.78 | 11.4±3.12 | 14.2±2.49 | 17.1±3.33 | 17.3±3.32 | 17.4±3.81 |
CD8+HLA-DR | 20.4±3.44 | 21.5±3.64 | 19.8±3.87 | 20.6±4.28 | 21.8±3.82 | 20.7±4.66 |
CD4+45RO | 68.0±4.98 | 72.4±4.37 | 76.1±4.19 | 76.0±3.58 | 76.8±3.93 | 76.9±4.10 |
CD8+45RO | 41.9±6.00 | 44.8±5.83 | 48.7±6.04 | 48.4±5.20 | 50.7±5.64 | 50.7±5.43 |
结果表明10D1治疗导致CD4/HLA-DR+亚群随时间增加约50%。其他淋巴细胞亚群随时间基本保持恒定。
为了评价是否施用MAb 10D1可诱导不期望的非特异性T细胞活化,针对下面每一标记通过流式细胞计数法分析来自前列腺癌受试者的外周血淋巴细胞:CD4、CD8、CD25、CD44、CD69和HLA-DR。对于迄今处理的每个前列腺癌受试者,未观察到治疗过程中这些标记的频率有显著变化。该分析的一个实例在表4中给出,表4显示了在两名受试者中MAb10D1施用前、施用过程中和之后CD4、CD25、CD69阳性细胞和CD8、CD25、CD69阳性细胞的频率。这些数据表明MAb 10D1不导致非特异性T细胞活化。
表4.在用3.0mg/Kg MAb 10D1治疗的前列腺癌受试者中T细胞活化标记的流式细胞计数法分析。
患者编号 | 时间点 | CD(4+25+69)% | CD(8+25+69)% |
3 | 入选时 | 1.7 | 0.8 |
3 | -30分钟(输注前) | 2.6 | 0.8 |
3 | 40分钟 | 2.5 | 0.7 |
3 | 130分钟 | 1.9 | 0.9 |
3 | 145分钟 | 1.7 | 0.5 |
3 | 160分钟 | 1.7 | 1 |
3 | 190分钟 | 1.5 | 1.5 |
3 | 250分钟 | 2.1 | 1.2 |
3 | 370分钟 | 1.3 | 0.9 |
3 | 24小时 | 1.6 | 1.6 |
3 | 48小时 | 2.7 | 3 |
3 | 72小时 | 0.9 | 0.5 |
3 | 7天 | 0.9 | 0.1 |
3 | 14天 | 0.4 | 0.5 |
3 | 21天 | 2.3 | 1.9 |
4 | 入选时 | 1.4 | 0.8 |
4 | -30分钟(输注前) | 0.5 | 0.3 |
4 | 40分钟 | 0.3 | 0.1 |
4 | 130分钟 | 0.3 | 0.1 |
4 | 145分钟 | 0.4 | 0.2 |
4 | 160分钟 | 0.2 | 0.2 |
4 | 190分钟 | 0.8 | 0.3 |
4 | 250分钟 | 0.1 | 0 |
4 | 370分钟 | 0.3 | 0.1 |
4 | 24小时 | 0.2 | 0.3 |
4 | 48小时 | 0.4 | 0.6 |
4 | 72小时 | 0.8 | 0.3 |
4 | 7天 | 1 | 0.7 |
4 | 14天 | 1.1 | 0.8 |
来自MDXCTLA4-01临床试验的结果已经表明输注是可耐受的,仅仅有微小反应。观察到抗体的延长的血浆半衰期,抗体保留在血浆中约3到4个月。观察到免疫效果的明显证据而无显著非特异性T细胞活化。在用抗CTLA-4抗体治疗的前列腺癌患者中观察到症状减轻和前列腺特异抗原(PSA)水平下降。PSA水平降低的代表性结果在图4中显示,其显示了第0天输注3mg/kg抗CTLA-4抗体后各个时间点两名患者的PSA水平(ng/ml)(一个用实心圆代表,另一个通过空心圆代表)。结果表明PSA水平在抗体输注后减少并在治疗后持续受抑制约3-4个月,这和血浆中抗CTLA-4抗体的存在相关。也观察到一些其他小的免疫效果,包括免疫介导的皮疹和搔痒、短暂的阳性自身抗体血清转变、在黑素瘤患者中黑色素的色素改变和肿瘤位置的炎症反应。除了皮疹和搔痒,所有潜在的不利免疫效果都是亚临床的。总之,现在从抗CTLA-4抗体治疗的人类临床试验得到的结果表明该抗体被良好耐受并在接受者中刺激免疫效应。
引用的参考文献
在本发明的说明书中引用和讨论了许多参考文献,包括专利、专利申请和各种出版物。对这些参考文献的引用和/或讨论仅仅用于阐明本发明的说明书而不是承认这些文献是此处描述的发明的“现有技术”。在本说明书中引用和讨论的所有参考文献在此处被完整地并入作为参考,就像每篇参考文献被单独并入作为参考一样。
Claims (31)
1.加强患者体内对抗原的再次免疫应答的方法,该方法包括向已经产生对该抗原的初次免疫应答的患者施用有效量的抗CTLA-4抗体,该抗CTLA-4抗体的有效量将足以增强与该抗原接触时患者体内针对该抗原的再次免疫应答。
2.权利要求1的方法,其中抗原是癌抗原并且患者以前已经用抗癌疫苗治疗过。
3.权利要求2的方法,其中癌抗原是黑素瘤抗原。
4.权利要求2的方法,其中癌是黑素瘤并且患者已经用含有NY-ESO-1肽的抗黑素瘤疫苗治疗过。
5.权利要求2的方法,其中癌是黑素瘤并且抗癌疫苗含有选自gp100和MART-1的抗原。
6.权利要求2的方法,其中癌抗原是前列腺癌抗原。
7.权利要求1的方法,其还包括在施用抗CTLA-4抗体前检测患者对所述抗原的免疫性,和仅仅向显示出对所述抗原具有免疫性的患者施用抗CTLA-4抗体。
8.权利要求7的方法,其中抗原是癌抗原。
9.权利要求7的方法,其中抗原是病毒抗原。
10.权利要求7的方法,其中抗原是细菌抗原。
11.权利要求1的方法,其中抗原为病毒抗原并且患者以前已经用病毒疫苗治疗过。
12.权利要求1的方法,其中病毒抗原为肝炎抗原。
13.权利要求1的方法,其中患者为人。
14.权利要求1的方法,其中抗CTLA-4抗体为人抗CTLA-4抗体。
15.权利要求1的方法,其中抗CTLA-4抗体为人源化抗CTLA-4抗体。
16.权利要求1的方法,其中抗CTLA-4抗体为人序列抗CTLA-4抗体。
17.诱导或增强患者体内对抗原的免疫应答的方法,其包括向患者施用抗CTLA-4抗体从而使抗CTLA-4抗体的血浆浓度保持在可检测水平之上至少4个月。
18.权利要求17的方法,其中抗CTLA-4抗体被多次施用从而使得血浆浓度保持在可检测水平之上至少4个月。
19.权利要求17的方法,其中抗CTLA-4抗体的施用量和施用时间间隔使患者中抗CTLA-4抗体的血浆浓度持续至少4个月为至少2μg/ml。
20.权利要求17的方法,其中抗CTLA-4抗体的施用量和施用时间间隔使患者中抗CTLA-4抗体的血浆浓度至少持续4个月为至少5μg/ml。
21.权利要求17的方法,其中抗CTLA-4抗体的施用量和施用时间间隔使患者中抗CTLA-4抗体的血浆浓度持续至少4个月为至少10μg/ml。
22.权利要求17的方法,其中患者为人。
23.权利要求17的方法,其中抗CTLA-4抗体为人抗CTLA-4抗体。
24.权利要求17的方法,其中抗CTLA-4抗体为人源化抗CTLA-4抗体。
25.权利要求17的方法,其中抗CTLA-4抗体为人序列抗CTLA-4抗体。
26.治疗患者的CTLA4+T细胞恶性肿瘤的方法,包括向患者施用与细胞毒性剂连接的抗CTLA-4抗体从而治疗患者的T细胞恶性肿瘤。
27.权利要求26的方法,其中细胞毒性剂为细胞毒性药物。
28.权利要求26的方法,其中细胞毒性剂为放射性同位素。
29.治疗患者的T细胞介导的自身免疫疾病的方法,包括:向患者施用与细胞毒性剂连接的抗CTLA-4抗体从而治疗患者的T细胞介导的自身免疫疾病。
30.权利要求29的方法,其中细胞毒性剂为细胞毒性药物。
31.权利要求29的方法,其中细胞毒性剂为放射性同位素。
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102449481A (zh) * | 2009-05-29 | 2012-05-09 | 德克萨斯大学系统董事会 | 用于分离和处理自身免疫性t细胞的拟肽配体 |
CN102449481B (zh) * | 2009-05-29 | 2016-05-25 | 德克萨斯大学系统董事会 | 用于分离和处理自身免疫性t细胞的类肽配体 |
CN102822200A (zh) * | 2009-07-20 | 2012-12-12 | 百时美施贵宝公司 | 对增殖性疾病进行协同性治疗的抗ctla-4抗体与各种治疗方案的组合 |
CN103547595A (zh) * | 2011-03-09 | 2014-01-29 | 安迪拓普有限公司 | 人源化ctla-4抗体 |
CN108271359A (zh) * | 2015-02-13 | 2018-07-10 | 索伦托治疗有限公司 | 结合ctla4的抗体治疗剂 |
CN108003238A (zh) * | 2017-11-30 | 2018-05-08 | 常州费洛斯药业科技有限公司 | 一种能特异识别ctla-4的全人源单克隆抗体或抗体片段及其方法和用途 |
CN108003238B (zh) * | 2017-11-30 | 2021-02-02 | 常州费洛斯药业科技有限公司 | 一种能特异识别ctla-4的全人源单克隆抗体或抗体片段及其方法和用途 |
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AU2008255203B2 (en) | 2011-03-10 |
SI1503794T1 (sl) | 2012-09-28 |
EP1503794A1 (en) | 2005-02-09 |
ATE552849T1 (de) | 2012-04-15 |
US20090117037A1 (en) | 2009-05-07 |
JP2005529873A (ja) | 2005-10-06 |
CA2481207C (en) | 2015-06-30 |
EP1503794B1 (en) | 2012-04-11 |
US7452535B2 (en) | 2008-11-18 |
ES2384168T3 (es) | 2012-07-02 |
DK1503794T3 (da) | 2012-07-23 |
CY1113243T1 (el) | 2016-04-13 |
US8142778B2 (en) | 2012-03-27 |
AU2008255203A1 (en) | 2009-01-08 |
WO2003086459A1 (en) | 2003-10-23 |
MXPA04010013A (es) | 2004-12-13 |
HUS1200022I1 (hu) | 2012-11-28 |
ES2384168T9 (es) | 2013-01-16 |
NZ536420A (en) | 2008-04-30 |
PT1503794E (pt) | 2012-06-21 |
IL164287A (en) | 2013-07-31 |
US20040005318A1 (en) | 2004-01-08 |
EP1503794B9 (en) | 2012-09-19 |
AU2003234736B2 (en) | 2008-09-25 |
EP1503794A4 (en) | 2005-06-15 |
AU2003234736A1 (en) | 2003-10-27 |
CA2481207A1 (en) | 2003-10-23 |
IL164287A0 (en) | 2005-12-18 |
ZA200408732B (en) | 2005-09-28 |
BR0309254A (pt) | 2005-03-01 |
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