CN103396490A - 抗cd37抗体 - Google Patents
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- CN103396490A CN103396490A CN2013102616193A CN201310261619A CN103396490A CN 103396490 A CN103396490 A CN 103396490A CN 2013102616193 A CN2013102616193 A CN 2013102616193A CN 201310261619 A CN201310261619 A CN 201310261619A CN 103396490 A CN103396490 A CN 103396490A
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Abstract
本发明涉及抗CD37抗体。嵌合及人源化抗CD37抗体及含其的药用组合物可用于治疗B细胞恶性肿瘤及病理学涉及B细胞之自身免疫病及炎性疾病。
Description
本申请是申请日为2008年8月8日、中国申请号为200880102642.5、发明名称为“抗CD37抗体”的发明申请的分案申请。
介绍
本发明涉及基于B细胞去除(B cell depletion)的免疫疗法。尤其,本发明涉及用于所述疗法,例如,用于治疗B细胞恶性肿瘤及自身免疫病的抗CD37抗体分子。
使用单克隆抗体(mAb)的免疫疗法已呈现为一种用于治疗癌症及其它疾病之安全及选择性方法。详言之,自引入利妥昔单抗(rituximab)(针对B细胞表面上之CD20抗原的抗体)以来,单克隆抗体在基于B细胞去除之疗法(例如,B细胞恶性肿瘤之治疗)中的作用已得到扩展。大量研究已证实呈单一药剂及组合疗法形式之利妥昔单抗在轻度NHL(Hiddemann等人,2005a;Hiddemann等人,2005b;Hainsworth2004;McLaughlin等人,1998)、套细胞淋巴瘤(Forstpointner等人,2004;Kahl等人,2006;Foran等人,2000;Howard等人,2002;Romaguera等人,2005)、弥漫性大细胞淋巴瘤(DLCL)(Coiffier等人,1998;Feugier等人,2005)及伯基特(Burkitt)白血病/淋巴瘤(Thomas等人,2006)中的功效。然而,仅一部分患者对疗法起反应且其中大多数患者在利妥昔单抗治疗后最终复发。因此,已寻求对B细胞恶性肿瘤疗法而言比CD20潜在有效之新的B细胞治疗标靶(Zhao等人,2007)。CD37抗原为迄今为止尚未以与B细胞抗原CD20相同之程度被视为B细胞恶性肿瘤之标靶的细胞表面抗原。
CD37是四跨膜蛋白(tetraspanin)超家族之成员,是具有四个跨膜域及两个细胞外环之高度糖基化细胞表面分子。CD37几乎仅在成熟B细胞上表达,其中在外周血B细胞上表达程度最高,在浆细胞上表达程度降低,且在骨髓中之CD10+前驱B细胞上表达程度不可检测。亦已报导CD37在静止性及活化T细胞、粒细胞及单核细胞上的表达程度低。在B细胞的瘤形成中,主要在侵袭性非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma,NHL)及慢性淋巴白血病(CLL)中观测到CD37表达。亦在套细胞淋巴瘤(MCL)上发现高程度CD37表达。此表达模式使CD37成为抗体介导之癌症疗法的吸引人之标靶。
CD37在1986年被首次描述且其特征为鼠单克隆抗体MB-1(Link等人,1986)。
CD37之生理学作用尚未知晓。虽然缺乏CD37之小鼠未展示淋巴器官之发育及细胞组成的变化,但其具有降低之IgG1含量及衰减的T细胞介导之免疫反应(Knobeloch等人,2000)。对CD37-/-T细胞之研究表明CD37在T细胞增殖中之作用(van Spriel等人,2004)。
已报导CD37在各种疾病之恶性B细胞上表达。CD37在大多数成熟B细胞恶性肿瘤(例如,伯基特淋巴瘤(Burkitt’s lymphoma)、滤泡性淋巴瘤及淋巴细胞性淋巴瘤)中表达(Link等人,1986)。已在毛细胞白血病及患有慢性淋巴细胞白血病(CLL)及不同亚型非霍奇金氏淋巴瘤(NHL)(包括套细胞淋巴瘤(MCL))之患者样品中观测到高程度CD37表达(Schwartz-Albiez等人,1988;Barrena等人,2005)。一个利用抗体微数组进行免疫表型分类之报导声称CD37为恶性CLL细胞(高CD37表达)与正常外周血(PB)淋巴细胞(低CD37表达)之间的良好鉴别者(Belov等人,2001)。
CD37特异性mAb与癌细胞之结合可引发各种作用机制:首先,在抗体与CD37抗原之胞外域结合之后,其可活化补体级联且裂解标靶细胞。其次,抗CD37抗体可介导抗体依赖性细胞介导之细胞毒活性(ADCC)至标靶细胞,此发生在所结合抗体之Fc部分通过免疫系统之细胞毒活性细胞上的合适受体识别之后。
第三,该抗体可改变B细胞对抗原或其它刺激起反应的能力。最终,抗CD37抗体可引发程序性细胞死亡(细胞凋亡)。
抗CD37mAb MB-1用两个放射免疫疗法试验在B-NHL(B细胞非霍奇金氏淋巴瘤(B-cell non-Hodgkin's lymphoma);Press等人,1989;Kaminski等人,1992)患者中评估。在一试验中,向6名复发NHL之患者投与治疗剂量之131I-MB-1,且所有6名患者均实现临床完全缓解(CR),其中中位持续时间为7个月。值得注意地,6名患者中之2名在仅投与示踪剂量之MB-1以后显示临床消退,此表明抗体自身具有直接抗肿瘤作用。在第二试验中,应用放射性标记之MB-1以治疗难治NHL患者且引起9名可评估患者中之3名具有有限持续时间之目标反应(Kaminski等人,1992)。在两个试验中,均报导在注射示踪标记之MB-1抗体剂量后外周B细胞快速且瞬间去除。此等观测支持MB-1独立发挥细胞毒活性之结论。概言之,此等临床试验强调对于B细胞恶性肿瘤而言靶向CD37之可行性且表明抗CD37疗法之潜在临床相关性。
关于CD37特异性抗体样单链分子("小模块免疫药物"(Small ModularImmunoPharmaceutical),SMIP)之实验证据表明,用该分子治疗诱发活体外细胞凋亡且延迟活体内异种移植模型中之伯基特淋巴瘤生长。近来,描述来自Trubion之重组抗CD37SMIP Tru16.4之抗细胞凋亡活性(Zhao等人,2004)。Tru16.4在来自肿瘤患者之初级CLL细胞上诱发卡斯蛋白酶(caspase)非依赖性细胞凋亡。对此等细胞之细胞凋亡的诱发大于利妥昔单抗对此等细胞之细胞凋亡的诱发且可与阿来组单抗(Alemtuzumab)(CD52拮抗剂)对此等细胞之细胞凋亡的诱发相当。细胞凋亡诱发程度与CD37细胞表面表达成正比且可通过与抗人类IgG抗体交联而进一步得到增强。关于活体外细胞系,证明CD37表达与ADCC之相关性。在伯基特淋巴瘤小鼠模型(Raji)中,用抗CD37scFv治疗展示治疗功效(Zhao等人,2007)。此等数据首次证明靶向CD37为通过诱发细胞凋亡及ADCC进行之靶向抗肿瘤疗法的期望方法。
总之,已显示CD37抗原通常在若干人类B细胞恶性肿瘤中之肿瘤细胞及成熟的正常B淋巴细胞上表达且基于抗CD37之疗法可为用于治疗B细胞恶性肿瘤之期望方法。不认为对CD37呈阳性之正常B细胞的去除为关键性的,此系因为来自大量患者之临床数据显示甚至用抗CD20mAb长期去除B细胞达6个月亦不会显著降低IgG血清含量或增加感染危险(Van der Kolk等人,2002)。
虽然上述抗CD37抗体或抗体样分子(MB-1及SMIP Tru16.4)已显示在B细胞恶性肿瘤中之抗肿瘤功效及靶向CD37之潜能,但仍对改良基于B细胞去除之疗法的替代性抗CD37抑制剂存在需要。
发明概述
本发明涉及下述各项。
1.抗体分子,其与人CD37结合且源自以下抗体:
a)如下定义的鼠单克隆抗体:
i)含SEQ ID NO:2所示氨基酸序列的可变重链;及
ii)含SEQ ID NO:4所示氨基酸序列的可变轻链,或
b)非人抗体,其与a)中所定义的抗体识别相同的人CD37表位,或识别与该表位相似或重迭的表位;
其中该抗体分子为嵌合或人源化抗体。
2.项1的抗体分子,其为由以下定义的嵌合抗体:
i)由含SEQ ID NO:2所示氨基酸序列的可变重链定义的嵌合抗体;
ii)由含SEQ ID NO:4所示氨基酸序列的可变轻链定义的嵌合抗体;
iii)由人类起源的恒定重链及轻链定义的嵌合抗体。
3.项2的抗体,其中:
i)该恒定重链为IgG1链;且
ii)该恒定轻链为κ链。
4.项3的抗体,其中该恒定重链i)包含SEQ ID NO:24所示氨基酸序列,且该恒定轻链ii)包含SEQ ID NO:26所示氨基酸序列。
5.项1的抗体,其为由以下定义的人源化抗体:
a)由SEQ ID NO:2所示可变重链中的CDR定义的人源化抗体;
b)由SEQ ID NO:4所示可变轻链中的CDR定义的人源化抗体;
c)由来源于人类抗体、且支撑所述CDR的框架定义的人源化抗体;
d)由来自人类抗体的恒定重链及轻链定义的人源化抗体。
6.项5的抗体,其包含具有SEQ ID NO:6所示序列的可变重链。
7.项6的抗体,其包含具有SEQ ID NO:12、14、16、18、20或22所示序列的可变轻链。
8.项5的抗体,其包含具有SEQ ID NO:8所示序列的可变重链。
9.项8的抗体,其包含具有SEQ ID NO:12、14、16、18、20或22所示序列的可变轻链。
10.项5的抗体,其包含具有SEQ ID NO:10所示序列的可变重链。
11.项10的抗体,其包含具有SEQ ID NO:12、14、16、18、20或22所示序列的可变轻链。
12.项1至11中任一项的抗体,其中所述抗体在Fc区有一或多个改变一或多种效应功能的突变。
13.项12的抗体,其中所述改变效应功能为增加抗体依赖性细胞介导的细胞毒活性。
14.项12或13的抗体,其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置332的单一取代。
15.项12或13的抗体,其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置239及332的取代的组合。
16.项12或13的抗体,其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置236及332的取代的组合。
17.项12或13的抗体,其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置236、239及332的取代的组合。
18.项14-17中任一项的抗体,其中所述取代为I332E、S239D及G236A。
19.抗体,其与人CD37结合且具有含氨基酸序列SEQ ID NO:28的重链。
20.项19的抗体,其具有含氨基酸序列SEQ ID NO:30的轻链。
21.抗体,其与人CD37结合且具有含氨基酸序列SEQ ID NO:36的重链。
22.项21的抗体,其具有含氨基酸序列SEQ ID NO:38的轻链。
23.抗体,其与人CD37结合且具有含氨基酸序列SEQ ID NO:32的重链。
24.项23的抗体,其具有含氨基酸序列SEQ ID NO:34的轻链。
25.抗体,其与人CD37结合且具有含氨基酸序列SEQ ID NO:40的重链。
26.项25的抗体,其具有含氨基酸序列SEQ ID NO:42的轻链。
27.DNA分子,其包含编码项1至26中任一项的抗体的可变重链的区。
28.项27的DNA分子,其中该可变重链编码区与编码人类起源的恒定重链的区融合。
29.项28的DNA分子,其中该人类恒定重链为IgG1。
30.项29的DNA分子,其中该IgG1由SEQ ID NO:23所示序列编码。
31.项28至30中任一项的DNA分子,其中该人类恒定重链在Fc区中具有一或多个按照项14至18任一项所定义的取代。
32.DNA分子,包含编码项1至26任一项的抗体的可变轻链的区。
33.项32的DNA分子,其中该可变轻链编码区与编码人类起源的恒定轻链的区融合。
34.项33的DNA分子,其中该恒定轻链为 链。
35.项34的DNA分子,其中该κ轻链由SEQ ID NO:25所示序列编码。
36.表达载体,其含有项27至31中任一项的DNA分子及/或项32至35中任一项的DNA分子。
37.宿主细胞,其载运一或多个项36的载体。
38.项37的宿主细胞,其载运含项27至31中任一项的DNA分子的表达载体及含项32至35中任一项的DNA分子的第二表达载体。
39.项37的宿主细胞,其为哺乳动物细胞。
40.产生项1至26中任一项的抗体的方法,包括以一或多个按项36所述的载体转染哺乳动物宿主细胞,培养该宿主细胞,及回收且纯化抗体分子。
41.药用组合物,其包含一或多种按项1至26中任一项所述的抗CD37抗体分子作为活性成份,并包含可药用载剂。
42.项41的药用组合物,其进一步包含一或多种其它治疗剂。
43.项42的药用组合物,其中所述一或多种其它治疗剂选自靶向除CD37以外的B细胞抗原的药剂。
44.项43的药用组合物,其中所述B细胞抗原为CD20。
45.项42的药用组合物,其中所述一或多种其它治疗剂选自诱发细胞凋亡的药剂。
46.项45的药用组合物,其中该药剂为TRAIL受体的调节剂。
47.项41至46中任一项的药用组合物,其用于除去表面表达CD37的B细胞。
48.项47的药用组合物,其用于治疗B细胞恶性肿瘤。
49.项48的药用组合物,其中该B细胞恶性肿瘤选自B细胞非霍奇金氏淋巴瘤(non-Hodgkins lymphoma)、B细胞慢性淋巴细胞白血病及多发性骨髓瘤。
50.项47的药用组合物,其用于治疗病理学涉及B细胞的自身免疫病或炎性疾病。
51.从一群细胞中去除表达CD37的B细胞的方法,其包含向该细胞群体投与项1至26中任一项的抗体分子或含有该抗体分子的药用组合物。
52.项51的方法,其在体外进行。
53.治疗B细胞恶性肿瘤患者的方法,所述B细胞恶性肿瘤选自:B细胞非霍奇金氏淋巴瘤、B细胞慢性淋巴细胞白血病及多发性骨髓瘤,所述方法包括,对该患者施用有效量的按照项41至46中任一项所述的药用组合物。
本发明之一目标系提供用于治疗B细胞恶性肿瘤及对CD37阳性B细胞之去除起反应的其它病症之新颖CD37拮抗剂。
此外,本发明之一目标系提供具有改良效应功能之抗CD37抗体。详言之,本发明者试图提供具有抗体依赖性细胞介导之细胞毒活性(ADCC)之抗CD37mAB。
为解决本发明潜在之问题,使用鼠单克隆抗CD37抗体作为用于产生可用于人类疗法中之嵌合及人源化抗CD37抗体的起始抗体。
第一方面,本发明提供与人CD37结合且衍生自以下抗体的抗体分子:
a)鼠单克隆抗体,其由以下结构定义:
i)包含SEQ ID NO:2所示氨基酸序列的可变重链;及
ii)包含SEQ ID NO:4所示氨基酸序列的可变轻链,或
b)非人类抗体,其与a)中所定义的抗体识别相同的人CD37表位,或识别与该表位相近(close)或重叠(overlap)的表位;
其中该抗体分子为嵌合或人源化抗体。
正如从下文所述可以理解到的,“衍生自”另一抗体(即起始抗体)的抗体是指,对起始抗体如下述进行修饰而制得的抗体。
在一优选实施例中,所述抗体分子是从a)所述起始抗体衍生得到的嵌合或人源化抗体分子。具有相关序列的抗体称为G28.1且描述于WO2005/017148中。
b)类起始抗体可以选自,例如,象G28.1一样,在Third HLDA Workshop中表征为CD37抗原的CD37特异性抗体;此等抗体称为HD28、HH1、BI14、F97-3G6(Ling及MacLennan,1987)。其它已描述之CD37特异性抗体包括RFB-7、Y29/55、MB-1、M-B371、M-B372及IPO-24。根据Moldenhauer,2000及Schwartz-Albiez等人,1988,所有此等抗体(包括G28.1)识别相同或部分一致或相近之CD37表位。Schwartz-Albiez等人,1988指示该表位位于CD37之碳水化合物部分中。大量以上抗体可购得,例如HH1(SantaCruz)、RFB-7(Biodesign)、Y29/55(Biogenesis)、M-B371(BD Biosciences)、M-B372(SantaCruz)及IPO-24(AbCam)。
其它CD37特异性抗体有S-B3(Biosys)、NMN46(Chemicon)及ICO-66(Bioprobe)。可通过竞争性结合试验或通过如Moldenhauer等人,1987及Moldenhauer,2000所述之交叉抑制放射免疫试验来确定抗体是否识别与G28.1相同的表位。
举例来说,可在ELISA中,使用涂有CD37蛋白或CD37肽或CD37阳性细胞之板(细胞ELISA)且测量在竞争候选抗体存在下生物素标记抗体之结合来测定竞争性结合。在竞争抗体或抗体衍生片段存在下,在抗体识别共同表位之状况下,经生物素标记之G28.1(或已知识别相同表位之另一抗体)之结合减少。为鉴别G28.1表位肽,可合成或产生衍生自CD37序列之片段或短的多肽或重组蛋白且在ELISA试验中测量G28.1与所述肽/多肽之结合。如实施例中所述,亦可经FACS分析来测定竞争性结合。
b)中所定义的抗体可以以与G28.1类似之方式用作起始抗体,以产生嵌合或人源化抗体分子。
b)类起始抗体亦可从头(de novo)生成,是分别用含相关表位之肽或蛋白片段、或编码所述肽/片段的DNA分子进行免疫,以获得对G28.1的表位具反应性的抗体。
起始抗体b)亦可通过用载运相关表位的全细胞进行免疫;再筛检由此获得的杂交瘤细胞对分泌抗体的竞争性结合而获得。
术语“抗CD37抗体分子”包含抗CD37抗体、抗CD37抗体片段、以及与所述抗体分子之偶联物。在本发明之含义中,抗体包括嵌合单克隆抗体及人源化单克隆抗体。术语“抗体”与“抗体分子”可互换使用,应包含完整免疫球蛋白(其由淋巴细胞产生、且例如存在于血清中)、由杂交瘤细胞系分泌之单克隆抗体、宿主细胞重组表达之多肽(其具有免疫球蛋白或单克隆抗体之结合特异性)、及对所述抗体进行修饰或进一步加工但保留其结合特异性而衍生得到的分子。
在本发明之一实施例中,抗CD37抗体分子为由以下定义之嵌合抗体:
i)包含SEQ ID NO:2所示氨基酸序列的可变重链;
ii)包含SEQ ID NO:4所示氨基酸序列的可变轻链;
iii)具有人类起源之恒定重链及轻链。
嵌合小鼠/人类抗体之构建及产生为本领域已知(Boulianne等人,1984)。非人类抗体的可变区通常与人类免疫球蛋白之免疫球蛋白恒定区的至少一部分(Fc)连接。可根据熟知之方法自多种人类细胞、优选自永生化B细胞分离人类恒定区DNA序列(参见Kabat等人,1991;及WO87/02671)。所述抗体分子可含有所有或仅一部分恒定区,只要其展示与CD37抗原及Fc受体之特异性结合即可。恒定区之类型及长度的选择视是否需要效应功能(如补体结合或抗体依赖性细胞介导之毒性)及抗体分子之所欲药理学性质而定。
在某些实施例中,本发明的抗体分子为嵌合CD37特异性抗体,其具有与人类重链恒定区IgG1融合之a)或b)中所定义的非人类抗体的重链可变区及与人类轻链恒定区κ融合之a)或b)中所定义的非人类抗体的轻链可变区。
在另一实施例中,抗体分子为嵌合CD37特异性抗体,其具有与人类重链恒定区IgG1(其为具有SEQ ID NO:24所示序列(DNA编码序列:SEQ IDNO:23)之IgG1分子或自其衍生的突变IgG1分子)融合的SEQ ID NO:2所示重链可变区且其具有与SEQ ID NO:26所示人类轻链恒定区κ(DNA编码序列:SEQ ID NO:25)融合的SEQ ID NO:4所示轻链可变区。
用于嵌合a)或b)所定义之非人类起始抗体之其它人类恒定区是本领域技术人员可获得的,例如IgG2、IgG3、IgG4、IgA、IgE或IgM(替代IgG1)或λ(替代κ)。恒定区亦可为嵌合的,例如重链IgG1/IgG2或IgG1/IgG3嵌合体。
本发明某些实施例中,抗CD37抗体分子为由以下定义的人源化抗体:
i.SEQ ID NO:2所示可变重链内之CDR,及
ii.SEQ ID NO:4所示可变轻链内之CDR,
iii.支撑所述CDR之衍生自人类抗体之框架,
iv.来自人类抗体之恒定重链及轻链。
人源化形式之非人类抗体(例如,鼠、大鼠或兔抗体)为含有衍生自非人类免疫球蛋白之最小序列的免疫球蛋白、免疫球蛋白链或其片段(诸如,Fv、Fab、Fab'、F(ab')2或具有抗体子序列之其它抗原结合分子)。
人源化抗体包括其中来自受体抗体之互补决定区(CDR)的残基经来自非人类物种(供体抗体)(诸如,小鼠、大鼠或兔)之CDR之具有所欲特异性、亲和力及能力的残基置换之人类免疫球蛋白(来自受体抗体)。在一些情况下,人类免疫球蛋白之Fv框架残基经相应非人类残基置换。
在本发明的人源化抗体中,已将编码a)或b)中所定义之非人类起始抗体之CDR的序列移植至人类免疫球蛋白重链及轻链之各个基因中。
单克隆抗体之“互补决定区”(CDR)应理解为,按照Kabat等人,1991以及Chothia及Lesk(1987)所述,参与特异性抗原结合的那些氨基酸序列。在SEQ ID NO:2及SEQ ID NO:4所示可变区序列中,CDR序列常规上可通过在Kabat序列数据库中搜索序列特征来确定。
获得人源化抗体的技术通常是本领域技术人员可得知的,见例如US5,225,539、US6,548,640及US6,982,321。
可将CDR移植抗体之合适框架残基回复至鼠残基以改良结合亲和力。如上所述,根据本领域已知方法,专家知道如何自给定之非人类抗体获得CDR,选择及获得适当人类免疫球蛋白基因,将CDR移植至此等基因中,修饰所选框架残基,在适当宿主细胞(例如,中国仓鼠卵巢(CHO)细胞)中表达CDR移植抗体,及测试所得重组抗体之结合亲和力及特异性。
为获得人源化抗体,将由重链CDR及轻链CDR形成之抗原结合位点自分泌啮齿动物(鼠)单克隆抗体之细胞的DNA切出,移植至编码人类抗体框架之DNA中。
或者对于CDR移植而言,如US5,639,641中所述,可通过所谓的“表面重整(resurfacing)”技术来使非人类、尤其鼠抗CD37抗体人源化,藉此除表面暴露之残基外,啮齿动物框架保留无变化。
在另一方面中,本发明涉及含有具有SEQ ID NO:6所示序列的可变重链及具有选自SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20及SEQ ID NO:22所示序列之序列的可变轻链的人源化抗体。
在另一方面中,本发明涉及含有具有SEQ ID NO:8所示序列的可变重链及具有选自SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20及SEQ ID NO:22所示序列之序列的可变轻链的人源化抗体。
在另一方面中,本发明涉及含有具有SEQ ID NO:10所示序列的可变重链及具有选自SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20及SEQ ID NO:22所示序列之序列的可变轻链的人源化抗体。
以上所定义的人源化抗体显示于表1中。
在某些实施例中,人源化抗体具有人类重链恒定区IgG1及人类轻链恒定区κ。如上文关于嵌合抗体所述,恒定区可选自其它种类及亚类。
在某些实施例中,在本发明的人源化抗体中,人类恒定重链IgG1为具有SEQ ID NO:24所示序列之IgG1分子或自其衍生的突变IgG1分子,且人类轻链恒定区κ具有SEQ ID NO:26所示序列。
本发明之抗CD37抗体分子亦可为由序列表中所示氨基酸序列定义的抗体的变体。使用通常可用之技术,本领域技术人员将能够制备、测试及利用以上所定义的抗体的功能变体。实例为CDR及/或框架中至少一个位置改变之变异抗体、在框架区中具有单个氨基酸取代且偏离种系序列之变异抗体、具有保守氨基取代的抗体、由与序列表中编码抗体可变链的DNA分子在严格条件下杂交的DNA分子编码的抗体。
在指定各个氨基酸的性质的情况下,可进行合理取代以获得保守起始抗体的总体分子结构的抗体变体。可(例如)基于各个氨基酸之极性、电荷、溶解度、疏水性、亲水性及/或两性性质之相似性进行氨基酸取代,意即“保守取代”。本领域技术人员熟悉通常实施之氨基酸取代(举例而言,如WO2007/042309中所述)及获得由此修饰的抗体的方法。在给定遗传密码及重组及合成DNA技术之情况下,通常可设计编码具有一或多个保守氨基酸交换之变异抗体的DNA分子且易于获得各个抗体。
与由序列表中可变链所定义的抗体相比,本发明所包含的抗体变体在CDR区中具有至少60%、更优选至少70%或80%、更优选至少90%及最优选至少95%之序列同一性。优选抗体亦在CDR区中具有至少80%、更优选90%及最优选95%之序列相似性。优选抗体变体在可变区中具有至少60%、更优选至少70%或80%、更优选至少90%及最优选至少95%之序列同一性。优选抗体亦在可变区中具有至少80%、更优选90%及最优选95%之序列相似性。
两个多肽序列之间的“序列同一性”指示这些序列之间相同氨基酸的百分比。“序列相似性”指示相同或代表保守氨基酸取代的氨基酸的百分比。
亦可使用具有序列表中指定序列的抗体作为起点,使一或多个氨基酸残基、优选在一或多个CDR中的氨基酸残基优化及多样化,并筛检所得抗体变体集合中具有改良性质之变体,来获得变体。已证明可变轻链CDR3、可变重链CDR3、可变轻链CDR1及/或可变重链CDR2中一或多个氨基酸残基之多样化是有用的。多样化可通过本领域已知的方法(例如,WO2007/042309中提及之所谓TRIM技术)进行。
在另一实施例中,本发明之抗CD37抗体分子为“亲和力成熟”"抗体。
“亲和力成熟的”抗CD37抗体为衍生自具有序列表中序列的抗体的抗CD37抗体,其在一或多个CDR中具有一或多个改变,所述改变引起与各个原始未成熟抗体相比对抗原亲和力之改良。一种用于产生所述抗体突变体之方法包括噬菌体展示(Hawkins等人,1992;及Lowman等人,1991)。简言之,使若干高变区位点(例如,6-7个位点)突变以在各位点产生所有可能之氨基酸取代。由此产生的抗体突变体自丝状噬菌体颗粒以单价方式呈现为与封装于各颗粒中之M13之基因III产物的融合体。接着,筛检噬菌体展示的突变体的如本文所揭示之生物活性(例如,结合亲和力)。
亲和力成熟抗体亦可通过如以下所述的方法来产生:例如,Marks等人,1992(通过可变重链(VH)及可变轻链(VL)域改组实现亲和力成熟);或Barbas等人,1994;Shier等人,1995;Yelton等人,1995;Jackson等人,1995;及Hawkins等人,1992(CDR及/或框架残基之随机突变诱发)。优选之亲和力成熟抗体将对标靶抗原具有纳摩尔或甚至皮摩尔之亲和力。
在另一实施例中,本发明之抗CD37抗体分子为“去免疫的(de-immunized)”抗体。
“去免疫的”抗CD37抗体为衍生自具有序列表中所示序列之人源化或嵌合抗体的抗体,其在氨基酸序列中具有一或多个改变,所述改变引起与各个原始非去人源化抗体相比抗体的免疫原性减少。一种用于产生所述抗体突变体之方法包括鉴别及移除抗体分子之T-细胞表位(Baker及Jones,2007)。在第一步骤中,可通过如文献(Jones等人,2004;Jones等人,2005;Reche等人,2004;Hertz等人,2006)中所述之若干方法,例如通过活体外测定T-细胞表位或模拟预测(in silico prediction)所述表位来测定抗体分子之免疫原性。一旦已鉴别T-细胞表位功能之关键残基,则可进行突变以移除免疫原性且保留抗体活性(Jones等人,2005;Tangri等人,2005)。用于将突变引入蛋白中的方法为本领域已知,例如通过交迭PCR技术。
因为抗体的Fc区与多种Fc受体相互作用,引起多种重要的功能能力(称为“效应功能”),所以在某些实施例中,所述抗体为全长抗体或含有Fc区的抗体,后者只要展示与抗原的相关部分及与Fc受体均特异性结合即可。恒定区之类型及长度的选择视效应功能(如补体结合或抗体依赖性细胞介导之细胞毒活性)是否为所欲特征及抗体蛋白之所欲药理学性质而定。
在本发明之一实施例中,抗CD37抗体为具有Fc区或其相关部分之嵌合或人源化抗体,该Fc区或其相关部分已经工程化以调节效应功能,尤其增强抗体与一或多个Fc受体之结合,藉此增强效应功能ADDC。与未经Fc工程化之亲本抗体相比,Fc区之工程化在效应细胞存在下更有效地介导抗体之效应功能。在一实施例中,该抗体变体介导比亲本抗体介导的ADCC大的ADCC。(在下文中,若未另外说明,则在抗体分子之情形中或在IgG或Fc区之情形中术语“亲本”分别指未经工程化的抗体分子、Fc区或IgG,自其衍生突变(工程化)分子)。
多种Fc区之修饰已在本领域(科学文献及专利文献)中提出,例如在EP0307434、WO9304173、WO9734631、WO9744362、WO9805787、WO9943713、WO9951642、WO9958572、WO02060919、WO03074679、WO2004016750、WO2004029207、WO2004063351、WO2004074455、WO2004035752、WO2004099249、WO2005077981、WO2005092925、WO2006019447、WO2006031994、WO2006047350、WO2006053301、WO2006088494及WO2007041635中提出。
在优选实施例中,本发明的抗体为在位置332及/或239及/或236具有氨基酸取代之Fc变体。在优选实施例中,本发明的抗体在Fc区中具有选自以下之群的突变:
i)在位置332的单一取代,优选I332E;
ii)在位置239及332的取代组合,优选S239D/I332E;
iii)在位置236及332的取代组合,优选G236A/I332E;
iv)在位置236、239及332的取代组合,优选G236A/S239D/I332E。
以上所定义的取代可参见,例如Lazar等人,2006,WO2004029207及WO2007041635。
本发明抗体之Fc变体根据其包含之氨基酸修饰来定义。因此,举例而言,I332E为相对于亲本Fc多肽具有I332E取代之Fc变体。同样,S239D/I332E定义相对于亲本Fc多肽具有取代S239D及I332E之Fc变体,且S239D/I332E/G236A定义相对于亲本Fc多肽具有取代S239D、I332E及G236A之Fc变体。
编号系根据EU编号方案(Kabat等人,1991),EU编号方案系指EU抗体之编号(Edelman等人,1969)。本领域技术人员将了解此等惯例由免疫球蛋白序列之特异性区中的非序列编号组成,使得能够归一化提及免疫球蛋白家族之保守位置。
在以上所定义的抗体中,经取代之位置236、239及332分别对应于SEQID NO:24中描绘的IgG1重链之位置119、122及215。(在SEQ ID NO:28、32、36及40所示抗体A2、A4、B2及B4的重链的全长序列中,经取代之氨基酸在位置235、238及331处)。
在某些实施例中,本发明之Fc变体系基于人类IgG序列,且因此将人类IgG序列用作与其它序列相比较之“基础”序列。对于本发明的抗体而言,工程化Fc区优选为IgG、尤其IgG1,但其亦可为IgG2或来自其它免疫球蛋白种类(诸如,IgA、IgE、IgGD、IgM)或两种或两种以上免疫球蛋白种类之嵌合形式(例如,IgG2/IgG1)之变异序列及其类似物。虽然在一个亲本IgG之情形中将本发明之Fc变体工程化,但所述变体亦可在另一第二亲本IgG情形下经工程化或“转移”至另一第二亲本IgG情形。此系通过通常基于第一IgG序列与第二IgG序列之间的序列或结构同源性确定第一IgG与第二IgG之间的“等效”或“相应”残基及取代来进行。为确定同源性,将本文所概述之第一IgG之氨基酸序列直接与第二IgG之序列相比。在比对所述序列之后,使用本领域已知的一或多个同源性比对程序,允许必需之插入及缺失以维持比对(亦即,避免经由任意缺失及插入而消除保守残基),从而确定与第一Fc变体之初始序列中之特定氨基酸等效的残基。无论如何确定等效或相应残基,且无论制造IgG之亲本IgG的一致性如何,均意欲说明本发明中所用之Fc变体可工程化为与Fc变体具有显著序列或结构同源性之任何第二亲本IgG。因此,举例而言,若通过使用上述方法或用于确定等效残基之其它方法来产生亲本抗体为人类IgG1之变异抗体,则可在(例如)人类lgG2亲本抗体、人类IgA亲本抗体中将变异抗体工程化(参见WO2007041635)。
本发明的抗体靶向抗原CD37,在CD37表达程度高于CD20表达程度之疾病中靶向抗原CD37可比靶向CD20有利,举例而言,如在慢性淋巴细胞白血病(其中样品已显示与CD20mRNA之低程度表达相比,CD37mRNA表达程度高)中。
已显示在拉莫斯(Ramos)细胞上的ADCC活性、全血中之正常B细胞去除及拉莫斯伯基特淋巴瘤细胞去除方面,本发明抗体优于利妥昔单抗(登记之抗CD20抗体)。如可在本发明之实验所示,本发明的抗体(未经Fc工程化及经Fc工程化抗体)具有优于利妥昔单抗的B细胞去除活性的B细胞去除活性。具有突变Fc区的抗体显示如与利妥昔单抗相比增加约10倍的B细胞去除活性(图11B)。
本发明之CD37抗体之代表在未交联之情况下显示有效的促细胞凋亡活性;在此方面,具有此性质的抗体优于在未交联情况下不显示细胞凋亡之抗CD37SMIP Tru16.4(Zhao等人,2007)。在未交联情况下诱发细胞凋亡(其可由经Fc工程化或未经Fc工程化之本发明抗体显示)在活体内缺乏交联剂(例如,具有Fcγ受体之效应细胞)之情况下或在低密度标靶抗原CD37(例如,具有CD37低表达程度之肿瘤细胞)下为有利的。在未交联情况下诱发细胞凋亡的抗体可能仍引起细胞死亡,而依赖于交联的抗体不会引起细胞死亡。
在另一方面中,本发明之抗CD37抗体分子为衍生自根据本发明之人源化或嵌合CD37特异性抗体的抗体片段。为获得抗体片段,例如Fab片段,可藉助于常规技术(例如,使用木瓜蛋白酶)来实现消化。木瓜蛋白酶消化之实例描述于WO94/29348及US4,342,566中。抗体之木瓜蛋白酶消化通常产生两个一致之抗原结合片段(所谓的Fab片段),各片段具有单一抗原结合位点及残余Fc片段。胃蛋白酶处理产生具有两个抗原结合位点且仍能够与抗原交联之F(ab')2片段。
通过抗体消化获得之Fab片段亦含有轻链恒定域及重链之第一恒定域(CH1)。Fab'片段与Fab片段不同,其不同之处在于其在重链CH1域之羧基末端含有其它残基,包括一或多个来自抗体铰链区的半胱氨酸。Fab'-SH在本文中表示恒定域之半胱氨酸残基带有游离硫醇基之Fab'。F(ab')2抗体片段最初以其间具有铰链半胱氨酸之Fab'片段对的形式产生。抗体片段亦可通过产生各个编码性DNA片段之分子生物学方法而产生。
抗体分子通常为由两个轻链/重链对组成之四聚体,但亦可为二聚体,亦即,由轻链/重链对组成(例如,Fab或Fv片段),或其可为单体单链抗体(scFv;Johnson及Bird,1991)、微型抗体或双功能抗体。
抗CD37抗体分子亦可呈偶联物形式,亦即,与细胞毒活性剂、尤其诱发肿瘤细胞之细胞毒活性(例如,细胞凋亡或有丝分裂停滞)之细胞毒活性剂化学偶合的抗体分子。由于正常药理学清除机制,药物偶联物("免疫偶联物")中所用的抗体仅以有限量与标靶细胞接触且结合。因此,偶联物中所用之细胞毒活性剂必须具有高度细胞毒活性,使得出现足够细胞杀死以引起治疗效应。如US2004/0241174中所述,所述细胞毒活性剂之实例包括紫杉烷(taxane)(参见例如WO01/38318及WO03/097625)、DNA烷基化剂(例如,CC-1065类似物)、蒽环霉素(anthracycline)、土布力辛(tubulysin)类似物、多卡米辛(duocarmycin)类似物、羟道诺红霉素(doxorubicin)、阿瑞他汀E(auristatin E)、篦麻毒素A毒素及包含反应性聚乙二醇部分之细胞毒活性剂(参见例如Sasse等人,2000;Suzawa等人,2000;Ichimura等人,1991;Francisco等人,2003;US5,475,092、US6,340,701、US6,372,738及US6,436,931、US2001/0036923、US2004/0001838、US2003/0199519及WO01/49698)。
在一优选实施例中,细胞毒活性剂为美登素类化合物(maytansinoid)(亦即,美登素(maytansine)之衍生物(CAS35846538)),美登素类化合物为本领域已知,包括美登素、美登醇(maytansinol)、美登醇之C-3酯及其它美登醇类似物及衍生物(参见例如US5,208,020及US6,441,163)。
可如WO2007077173中关于抗FAP免疫偶联物所述来设计及合成抗CD37抗体免疫偶联物。
在另一实施例中,本发明之抗CD37分子可经放射性标记以形成放射免疫偶联物,此为一种关于抗CD37抗体MB-1所提出的方法(Buchsbaum等人,1992,参见上文)。具有有利放射性质之放射性核素为本领域已知,实例为磷-32、锶-89、钇-90、碘-131、钐-153、铒-169、镱-175、铼-188,其已成功且稳定地与MAb偶合。可使用如US6,241,961中所述之本领域已知之直接标记或间接标记方法,以各种放射性核素标记本发明之抗CD37抗体分子。关于用于产生及应用适用于本发明之新颖放射性标记的抗体偶联物之技术的评论由Goldenberg及Sharkey,2007给出。
本发明的抗体分子(无论Fc经工程化或未经工程化)亦可具有双特异性,亦即,抗体分子与两个不同标靶结合,标靶之一为CD37,另一者选自(例如)T细胞表达之表面抗原,例如CD3、CD16及CD56。
本发明亦涉及编码本发明之嵌合或人源化抗CD37抗体分子的DNA分子。编码本发明的抗体分子的可变重链的序列显示于SEQ ID NO:1、SEQ IDNO:5、SEQ ID NO:7及SEQ ID NO:9中。编码本发明的抗体分子的可变轻链的序列显示于SEQ ID NO:3、SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:17、SEQ ID NO:19、SEQ ID NO:21中。
可通过标准方法以化学方式及酶方式(PCR扩增)合成编码轻链及重链之核酸分子。首先,可通过本领域已知的方法(例如Gait,1984)合成合适之寡核苷酸,所述寡核苷酸可用于产生合成基因。自寡核苷酸产生合成基因的方法为本领域已知(例如,Stemmer等人,1995;Ye等人,1992;Hayden et Mandecki,1988;Frank等人,1987)。
本发明的DNA分子包括(但不限于)序列表所示DNA分子。因此,本发明亦涉及如WO2007/042309中所定义在高严格结合及洗涤条件下与序列表中所述的DNA分子杂交的核酸分子,其中所述核酸分子编码具有等效于或优于序列表所示序列所编码的抗体之性质的抗体或其功能片段。优选分子(自mRNA角度)为与本文所述之一种DNA分子具有至少75%或80%(优选至少85%,更优选至少90%且最优选至少95%)同源性或序列同一性的彼等分子。
在本发明之范畴内的另一类DNA变体可根据其编码之多肽来定义。此等DNA分子的序列偏离序列表中所述DNA分子,但由于遗传密码简并性而编码具有一致氨基酸序列的抗体。举例来说,鉴于在真核细胞中表达抗体,序列表所示DNA序列经过设计能符合真核细胞中的密码子使用习惯。若希望在大肠杆菌(E.coli)中表达抗体,则可使此等序列变化以匹配大肠杆菌密码子使用。举例而言,如WO2007/042309中所述,可以若干不同方式构建本发明的DNA分子之变体。
为产生本发明之重组抗CD37抗体分子,将编码全长轻链及重链或其片段的DNA分子插入表达载体中,使得所述序列可操作地连接于转录及翻译控制序列。
为制造本发明的抗体,本领域技术人员可自本领域熟知之多种表达系统进行选择,例如Kipriyanow及Le Gall,2004评述的那些表达系统。
表达载体包括质粒、反转录病毒、粘粒、EBV衍生之游离体及其类似物。表达载体及表达控制序列系经选择以与宿主细胞兼容。抗体轻链基因及抗体重链基因可插入单独载体中。在某些实施例中,将两个DNA序列插入同一表达载体中。适宜的载体为编码功能完整之人类CH或CL免疫球蛋白序列者,其具有经工程化之适当限制位点以使任何VH或VL序列可易于如上所述般插入及表达。对于抗体轻链而言,恒定链通常为κ或λ,对于抗体重链而言,恒定链可为(不限于)任何IgG同型(IgG1、IgG2、IgG3、IgG4)或其它免疫球蛋白,包括对偶基因变体。
重组表达载体亦可编码促进自宿主细胞分泌抗体链之信号肽。可将编码抗体链之DNA克隆至载体中,使得信号肽同框连接于成熟抗体链DNA之氨基末端。信号肽可为免疫球蛋白信号肽或来自非免疫球蛋白之异源肽。或者,编码抗体链之DNA序列可已含有信号肽序列。
除编码抗体链之DNA序列以外,重组表达载体亦携带调节序列,包括启动子、强化子、终止及聚腺苷酸化及控制抗体链在宿主细胞中的表达之其它表达控制组件。启动子序列之实例(关于哺乳动物细胞中的表达所例示)为衍生自(CMV)(诸如,CMV猴病毒40(SV40)(诸如,SV40启动子/强化子))、腺病毒(例如,腺病毒主要晚期启动子(AdMLP))、多形瘤之启动子及/或强化子及强哺乳动物启动子,诸如天然免疫球蛋白及肌动蛋白启动子。聚腺苷酸化之实例为BGH polyA、SV40晚期或早期polyA;或者,可使用免疫球蛋白基因之3'UTR等。
重组表达载体亦可携带调节宿主细胞中的载体复制之序列(例如,复制起点)及可选标记基因。可根据本领域熟知之转染方法,包括脂质体介导之转染、聚阳离子介导之转染、原生质体融合、显微注射、磷酸钙沉淀、电穿孔或通过病毒载体转移,将编码抗CD37抗体的重链或其抗原结合部分及/或轻链或其抗原结合部分之核酸分子及包含此等DNA分子的载体引入宿主细胞(例如细菌细胞或高级真核细胞,例如哺乳动物细胞)中。
编码重链及轻链的DNA分子优选存在于共转染至宿主细胞、优选哺乳动物细胞中之两个载体上。
可用作用于表达之宿主的哺乳动物细胞系为本领域已知且包括中国仓鼠卵巢(CHO,CHO-DG44)细胞、NSO、SP2/0细胞、海拉细胞(HeLa cell)、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人类癌细胞(例如,Hep G2)、A549细胞、3T3细胞或任何该细胞系之衍生物/子代。可使用其它哺乳动物细胞,包括(但不限于)人类、小鼠、大鼠、猴及啮齿动物细胞系;或其它真核细胞,包括(但不限于)酵母、昆虫及植物细胞;或原核细胞,诸如细菌。通过培养宿主细胞历时足以允许抗体分子在宿主细胞中表达之一段时间来产生本发明之抗CD37抗体分子。
抗体分子优选以分泌多肽形式自培养基回收,或若(例如)在无分泌信号之情况下表达,则其可自宿主细胞裂解产物回收。有必要使用用于重组蛋白及宿主细胞蛋白之标准蛋白纯化方法,以获得大体上同源抗体制剂之方式来纯化抗体分子。举例来说,适用于获得本发明之抗CD37抗体分子的目前技术水平之纯化方法包括自培养基或裂解产物移除细胞及/或微粒细胞碎片作为第一步骤。接着,(例如)通过在免疫亲和或离子交换管柱上进行分级分离、乙醇沉淀、反相HPLC、Sephadex层析、二氧化硅或阳离子交换树脂上之层析而自污染之可溶性蛋白、多肽及核酸纯化抗体。作为获得抗CD37抗体分子制剂之过程中的最后步骤,可如下文关于治疗应用所述来干燥经纯化的抗体分子,例如冷冻干燥。
在另一方面中,本发明涉及药用组合物,含有本发明之抗CD37抗体分子作为活性成份。
为用于疗法中,将抗CD37抗体包括在适于促进向动物或人类投与的药用组合物中。可通过将抗CD37抗体分子与生理学上可接受之载剂、赋形剂或稳定剂混合而以冷冻干燥或以其它方式干燥之配制物或水溶液或水性或非水性悬浮液形式制备抗CD37抗体分子之典型配制物。载剂、赋形剂、改质剂或稳定剂在所用剂量及浓度下为无毒的。其包括:缓冲系统,诸如磷酸盐、柠檬酸盐、乙酸盐及其它无机酸或有机酸及其盐;抗氧化剂,包括抗坏血酸及甲硫氨酸;防腐剂(诸如,氯化十八烷基二甲基苄基铵;氯化六羟季铵(hexamethonium chloride);氯苄烷铵(benzalkonium chloride);苯酚;丁醇或苄醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;及间甲酚);蛋白,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯啶酮或聚乙二醇(PEG);氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、双糖、寡糖或多糖及其它碳水化合物,包括葡萄糖、甘露糖、蔗糖、海藻糖、糊精或葡聚糖(dextran);螯合剂,诸如EDTA;糖醇,诸如甘露糖醇或山梨糖醇;成盐平衡离子,诸如钠;金属错合物(例如,Zn-蛋白错合物);及/或离子型或非离子型界面活性剂,诸如TWEENTM(聚山梨醇酯)、PLURONICSTM或脂肪酸酯、脂肪酸醚或糖酯。抗体配制物中亦可含有有机溶剂,诸如乙醇或异丙醇。赋形剂亦可具有释放改良或吸收改良功能。
抗CD37抗体分子亦可经干燥(冷冻干燥、喷雾干燥、喷雾冷冻干燥、通过近或超临界气体干燥、真空干燥、空气干燥),沉淀或结晶或包埋于(例如)通过凝聚技术或通过界面聚合(例如)分别使用羟甲基纤维素或明胶及聚(甲基丙烯酸甲酯)而制备之微胶囊中,包埋于胶状药物传递系统(例如,脂质体、白蛋白微球体、微乳液、纳米颗粒及纳米胶囊)中,包埋于大乳液中,或(例如)通过pcmc技术(蛋白涂覆微晶)而沉淀或固定于载剂或表面上。所述技术揭示于Remington:The Science and Practice of Pharmacy,第21版,Hendrickson R.编中。
自然地,待用于活体内投与之配制物必须无菌;可通过习知技术(例如,通过经由无菌过滤膜过滤)来实现杀菌。
可适用的是增加抗CD37抗体浓度以达到所谓的高浓度液体配制物(HCLF);已描述产生所述HCLF之各种方式。
抗CD37抗体分子亦可含于持续释放制剂中。所述制剂包括疏水性或亲水性聚合物之固体、半固体或液体基质,且可呈成形物品形式,例如薄膜、条状物或微胶囊,且可经由应用装置来应用。持续释放基质之实例包括聚酯、水凝胶(例如,聚(2-羟基乙基-甲基丙烯酸酯)或蔗糖乙酸丁酸酯或聚(乙烯醇))、聚交酯(US3,773,919)、L-谷氨酸与γ-L-谷氨酸乙酯之共聚物、不可降解之乙烯-乙酸乙烯酯、可降解之乳酸-乙醇酸共聚物(诸如,LUPRONDEPOTTM(由乳酸-乙醇酸共聚物及乙酸亮丙瑞林(leuprolide acetate)组成之可注射微球体))及聚-D-(-)-3-羟基丁酸。虽然诸如乙烯-乙酸乙烯酯及乳酸-乙醇酸之聚合物使分子能够释放超过100天,但某些水凝胶释放蛋白历时较短时段。当经囊封的抗体长时间保留于体内时,其因暴露于37℃下之水分而可能变性或聚集,从而导致生物活性损失且使免疫原性可能变化。视所涉及之机制而定,可设计合理策略以达成稳定。举例而言,若发现凝集机制系经由硫基-二硫化物互换而形成分子间S-S键,则可通过使巯基残基改质、自酸性溶液冻干(例如,如WO89/011297中所述)、控制水分含量、使用适当添加剂及形成特定聚合物基质组合物来达成稳定。
亦可用于本发明之抗CD37抗体分子之配制物描述于US7,060,268及US6,991,790中。
CD37抗体分子亦可并入其它应用形式中,诸如并入分散液、悬浮液或脂质体、片剂、胶囊、粉剂、喷雾剂、具有或不具有渗透增强装置之经皮或皮内贴片或乳膏、糯米纸囊剂(wafer)、经鼻、经颊或经肺配制物中,或可通过植入之细胞或在基因疗法后通过个体的自身细胞来产生。
抗CD37抗体分子亦可由化学基团(诸如,聚乙二醇(PEG)、甲基或乙基或碳水化合物基团)衍生。此等基团可用于改良抗体之生物学特征,例如增加血清半衰期或增加组织结合。
优选应用模式为通过输注或注射(静脉内、肌肉内、皮下、腹膜内、皮内)进行非经肠应用,但诸如通过吸入、经皮、鼻内、经颊、经口之其它应用模式亦可为适用的。
为预防或治疗疾病,抗体之适当剂量将视待治疗之疾病类型、疾病之严重程度及过程、投与抗体为达成预防或治疗目的、先前疗法、患者病史及对抗体之反应以及主治医师之判断而定。合适地,一次性或经一系列治疗向患者投与抗体。
视疾病之类型及严重程度而定,无论(例如)通过一或多次分开投与或通过连续输注,约0.01μg/kg至40mg/kg(例如,0.1mg/kg-20mg/kg)的抗体为向患者投与之最初候选剂量。对于经数天或更长时间之重复投药而言,视病状而定,持续治疗直至出现疾病症状之所需抑制作用。然而,其它给药方案亦可为有用的。此疗法之进程易于通过习知技术及试验来监测,例如通过测定B细胞去除之程度(例如,使用流式细胞仪)来监测。
待投与的抗体之“治疗有效量”为预防、改善或治疗疾病或病症所需之最低量。
本发明之抗CD37抗体分子及含其的药用组合物可用于去除在表面上表达CD37且引起癌症或自身免疫/炎性疾病的B细胞。
在第一方面中,本发明的药用组合物可用于治疗癌症,尤其任何CD37阳性恶性肿瘤。
B细胞恶性肿瘤包括(但不限于)B细胞淋巴瘤(例如,各种形式之霍奇金氏病(Hodgkin's disease)、B细胞非霍奇金氏淋巴瘤(NHL)及相关淋巴瘤(例如,瓦尔登斯特伦巨球蛋白血症(macroglobulinaemia)(亦称为淋巴浆细胞淋巴瘤或免疫细胞瘤))或中枢神经系统淋巴瘤)、白血病(例如,急性淋巴母细胞白血病(ALL)、慢性淋巴细胞白血病(CLL;亦称为B细胞慢性淋巴细胞白血病BCLL)、毛细胞白血病及慢性肌胚细胞白血病)及骨髓瘤(例如,多发性骨髓瘤)。其它B细胞恶性肿瘤包括小淋巴细胞淋巴瘤、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、脾边缘区淋巴瘤、浆细胞骨髓瘤、骨孤立性浆细胞瘤、骨外浆细胞瘤、黏膜相关(MALT)淋巴组织之结外边缘区B细胞淋巴瘤、结边缘区B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特氏淋巴瘤/白血病、灰区淋巴瘤、未定恶性肿瘤潜能的B细胞增殖、淋巴瘤样肉芽肿病及移植后淋巴组织增生病症。
在另一方面中,含有抗CD37抗体的药用组合物可用于治疗那些在病理学方面涉及B细胞的自身免疫病及炎性疾病。
所述疾病包括(但不限于):关节炎、类风湿性关节炎、幼年型类风湿性关节炎、骨关节炎、多软骨炎、牛皮癣性关节炎、牛皮癣、皮炎、多发性肌炎/皮肌炎、包涵体肌炎、发炎性肌炎、中毒性表皮坏死松解症、全身性硬皮病及硬化症、CREST征候群、与发炎性肠病相关之反应、克罗恩氏病(Crohn's disease)、溃疡性结肠炎、呼吸窘迫症候群、成人呼吸窘迫症候群(ARDS)、脑膜炎、脑炎、葡萄膜炎、结肠炎、丝球体肾炎、过敏病状、湿疹、哮喘、包含T细胞浸润及慢性发炎反应之病状、动脉粥样硬化、自身免疫心肌炎、白血球黏着缺乏、全身性红斑狼疮(SLE)、亚急性皮肤性红斑狼疮、盘状狼疮(discoid lupus)、狼疮性脊髓炎、狼疮性大脑炎、幼年发作型糖尿病、多发性硬化症、过敏性脑脊髓炎、视神经脊髓炎、风湿热、西登哈姆氏舞蹈病(Sydenham's chorea)、与通过细胞因子及T-淋巴细胞介导之急性及延迟性过敏相关的免疫反应、结核病、肉状瘤病、肉牙肿病(包括韦格纳氏肉牙肿病(Wegener's granulomatosis)及丘-施二氏疾病(Churg-Strauss disease))、颗粒性球缺乏症、血管炎(包括过敏性血管炎(vasculitis/angiitis)、ANCA及类风湿性血管炎)、再生障碍性贫血、戴-布二氏贫血(Diamond Blackfan anemia)、免疫性溶血性贫血(包括自身免疫性溶血性贫血(AIHA))、恶性贫血、纯红血球发育不全(PRCA)、因子VIII缺乏、A型血友病、自身免疫嗜中性球减少症、全部血球减少症、白血球减少症、涉及白血球渗出之疾病、中枢神经系统(CNS)发炎病症、多发性器官损伤征候群、重症肌无力、抗原抗体复合物介导之疾病、抗肾小球基底膜疾病、抗磷脂抗体征候群、过敏性神经炎、贝切特氏病(Behcet disease)、卡斯特尔曼氏征候群(Castleman's syndrome)、古德帕斯彻氏征候群(Goodpasture's syndrome)、兰姆博特-伊顿二氏重症肌无力症候群(Lambert-Eaton Myasthenic Syndrome)、雷诺氏征候群(Reynaud'ssyndrome)、休格连氏征候群(Sjorgen's syndrome)、史蒂芬-琼森症候群(Stevens-Johnson syndrome)、实体器官移植排斥反应、移植物抗宿主疾病(GVHD)、大疱性类天疱疮、天疱疮、自身免疫多内分泌病变、血清阴性脊椎关节病、莱特尔氏病(Reiter's disease)、全身肌强直征候群、巨细胞性动脉炎、免疫复合物肾炎、IgA肾病、IgM多发性神经病或IgM介导之神经病、特发性血小板减少性紫癜(ITP)、血栓性血小板减少性紫癜(TTP)、亨-舍二氏紫癜(Henoch-Schonlein purpura)、自身免疫血小板减少症、睾丸及卵巢之自身免疫疾病(包括自身免疫睾丸炎及卵巢炎)、原发性甲状腺功能低下、自身免疫内分泌疾病(包括自身免疫甲状腺炎)、慢性甲状腺炎(桥本甲状腺炎(Hashimoto's Thyroiditis))、亚急性甲状腺炎、特发性甲状腺功能低下、阿狄森氏病(Addison's disease)、格雷氏病(Grave's disease)、自身免疫多腺体征候群(或多腺体内分泌病征候群)、I型糖尿病(亦称为胰岛素依赖性糖尿病(IDDM))及席汉氏症候群(Sheehan's syndrome)、自身免疫肝炎、淋巴组织间质性肺炎(HIV)、闭塞性细支气管炎(非移植)对NSIP、格-巴二氏征候群(Guillain-Barre'Syndrome)、大血管血管炎(包括风湿性多肌痛及巨细胞(高安氏(Takayasu's))动脉炎)、中血管血管炎(包括川崎氏病(Kawasaki's disease)及结节性多动脉炎)、结节性多动脉炎(PAN)、强直性脊椎炎、伯杰氏病(Berger'sdisease)(IgA肾病)、快速进行性丝球体肾炎、原发性胆汁性肝硬化、口炎性腹泻(麸质肠病)、冷凝球蛋白血症、与肝炎相关之冷凝球蛋白血症、肌萎缩性侧索硬化(ALS)、冠状动脉疾病、家族性地中海热(familial Mediterraneanfever)、显微性多血管炎、耳蜗前庭症候群(Cogan's syndrome)、维-奥二氏症候群(Whiskott-Aldrich syndrome)及闭塞性血栓血管炎(参见WO2007014278)。
视待治疗之病症而定,本发明之抗CD37抗体分子可单独使用或与一或多种其它治疗剂组合使用,该或所述其它治疗剂尤其选自DNA破坏或微管蛋白结合剂或抑制癌细胞中的血管生成、信号转导路径或有丝分裂检查点之治疗活性化合物。
其它治疗剂可视情况作为同一医药制剂之组份与抗CD37抗体分子同时投与,或在抗CD37抗体分子投与之前或之后投与。
在某些实施例中,其它治疗剂可为(但不限于)一或多种选自以下之群之抑制剂:EGFR家族、VEGFR家族、IGF-1R、胰岛素受体、AuroraA、AuroraB、PLK及PI3激酶、FGFR、PDGFR、Raf、KSP或PDK1之抑制剂。
其它治疗剂之其它实例为CDK、Akt、Src、Bcr-Abl、cKit、cMet/HGF、c-Myc、Flt3、HSP90之抑制剂、hedgehog拮抗剂、JAK/STAT、Mek、mTor、NFκB、蛋白酶体、Rho之抑制剂、Wnt信号转导或Notch信号转导之抑制剂或泛素化路径抑制剂。
Aurora抑制剂之实例为(但不限于)PHA-739358、AZD-1152、AT-9283、CYC-116、R-763、VX-667、MLN-8045、PF-3814735、SNS-314、VX-689、GSK-1070916、TTP-607、PHA-680626、MLN-8237及ENMD-2076。
PLK抑制剂之实例为GSK-461364。
raf抑制剂之实例为BAY-73-4506(亦为VEGFR抑制剂)、PLX-4032、RAF-265(亦为VEGFR抑制剂)、索拉非尼(sorafenib)(亦为VEGFR抑制剂)、XL-281及Nevavar(亦为VEGFR之抑制剂)。
KSP抑制剂之实例为伊平丝博(ispinesib)、ARRY-520、AZD-4877、CK-1122697、GSK-246053A、GSK-923295、MK-0731、SB-743921、LY-2523355及EMD-534085。
src及/或bcr-abl抑制剂之实例为达沙替尼(dasatinib)、AZD-0530、伯舒替尼(bosutinib)、XL-228(亦为IGF-1R抑制剂)、尼罗替尼(nilotinib)(亦为PDGFR及cKit抑制剂)、伊马替尼(亦为cKit抑制剂)、NS-187、KX2-391、AP-24534(亦为EGFR、FGFR、Tie2、Flt3之抑制剂)、KM-80及LS-104(亦为Flt3、Jak2之抑制剂)。
PDK1抑制剂之一实例为AR-12。
Rho抑制剂之一实例为BA-210。
PI3激酶抑制剂之实例为PX-866、PX-867、BEZ-235(亦为mTor抑制剂)、XL-147及XL-765(亦为mTor抑制剂)、BGT-226、CDC-0941。
cMet或HGF抑制剂之实例为XL-184(亦为VEGFR、cKit、Flt3之抑制剂)、PF-2341066、MK-2461、XL-880(亦为VEGFR之抑制剂)、MGCD-265(亦为VEGFR、Ron、Tie2之抑制剂)、SU-11274、PHA-665752、AMG-102、AV-299、ARQ-197、MetMAb、CGEN-241、BMS-777607、JNJ-38877605、PF-4217903、SGX-126、CEP-17940、AMG-458、INCB-028060及E-7050。
c-Myc抑制剂之一实例为CX-3543。
Flt3抑制剂之实例为AC-220(亦为cKit及PDGFR之抑制剂)、KW-2449、LS-104(亦为bcr-abl及Jak2之抑制剂)、MC-2002、SB-1317、来妥替尼(lestaurtinib)(亦为VEGFR、PDGFR、PKC之抑制剂)、TG-101348(亦为JAK2之抑制剂)、XL-999(亦为cKit、FGFR、PDGFR及VEGFR之抑制剂)、舒尼替尼(sunitinib)(亦为PDGFR、VEGFR及cKit之抑制剂)及坦度替尼(tandutinib)(亦为PDGFR及cKit之抑制剂)。
HSP90抑制剂之实例为坦螺旋霉素(tanespimycin)、阿螺旋霉素(alvespimycin)、IPI-504、STA-9090、MEDI-561、AUY-922、CNF-2024及SNX-5422。
JAK/STAT抑制剂之实例为CYT-997(亦与微管蛋白相互作用)、TG-101348(亦为Flt3抑制剂)及XL-019。
Mek抑制剂之实例为ARRY-142886、AS-703026、PD-325901、AZD-8330、ARRY-704、RDEA-119及XL-518。
mTor抑制剂之实例为泰西罗莫司(temsirolimus)、德福罗莫司(deforolimus)(其亦用作VEGF抑制剂)、依维莫司(everolimus)(此外,VEGF抑制剂)、XL-765(亦为PI3激酶抑制剂)及BEZ-235(亦为PI3激酶抑制剂)。
Akt抑制剂之实例为哌立福新(perifosine)、GSK-690693、RX-0201及曲西立滨(triciribine)。
cKit抑制剂之实例为马赛替尼(masitinib)、OSI-930(亦用作VEGFR抑制剂)、AC-220(亦为Flt3及PDGFR之抑制剂)、坦度替尼(亦为Flt3及PDGFR之抑制剂)、阿西替尼(axitinib)(亦为VEGFR及PDGFR之抑制剂)、舒尼替尼(亦为Flt3、PDGFR、VEGFR之抑制剂)及XL-820(亦用作VEGFR及PDGFR之抑制剂)、伊马替尼(imatinib)(亦为bcr-abl抑制剂)、尼罗替尼(亦为bcr-abl及PDGFR之抑制剂)。
hedgehog拮抗剂之实例为IPI-609、CUR-61414、GDC-0449、IPI-926及XL-139。
CDK抑制剂之实例为塞力丝伯(seliciclib)、AT-7519、P-276、ZK-CDK(亦抑制VEGFR2及PDGFR)、PD-332991、R-547、SNS-032、PHA-690509、PHA-848125及SCH-727965。
蛋白酶体抑制剂之实例为硼替佐米(bortezomib)、卡菲佐米(carfilzomib)及NPI-0052(亦为NFκB之抑制剂)。
蛋白酶体抑制剂/NFκB路径抑制剂之实例为硼替佐米、卡菲佐米、NPI-0052、CEP-18770、MLN-2238、PR-047、PR-957、AVE-8680及SPC-839。
泛素化路径抑制剂之实例为HBX-41108。
抗血管生成剂之实例为FGFR、PDGFR及VEGF(R)之抑制剂及沙力度胺(thalidomide),所述药剂选自(但不限于)贝伐单抗(bevacizumab)、莫替尼伯(motesanib)、CDP-791、SU-14813、替拉替尼(telatinib)、KRN-951、ZK-CDK(亦为CDK抑制剂)、ABT-869、BMS-690514、RAF-265、IMC-KDR、IMC-18F1、IMiD、沙力度胺、CC-4047、来那度胺(lenalidomide)、ENMD-0995、IMC-D11、Ki-23057、布瑞伐尼(brivanib)、西地尼布(cediranib)、1B3、CP-868596、IMC-3G3、R-1530(亦为Flt3抑制剂)、舒尼替尼(亦为cKit及Flt3之抑制剂)、阿西替尼(axitinib)(亦为cKit抑制剂)、来妥替尼(lestaurtinib)(亦为Flt3及PKC之抑制剂)、凡塔蓝尼(vatalanib)、坦度替尼(亦为Flt3及cKit之抑制剂)、帕佐尼布(pazopanib)、PF-337210、阿柏西普(aflibercept)、E-7080、CHIR-258、索拉非尼甲苯磺酸盐(亦为Raf之抑制剂)、范得他尼(vandetanib)、CP-547632、OSI-930、AEE-788(亦为EGFR及Her2之抑制剂)、BAY-57-9352(亦为Raf抑制剂)、BAY-73-4506(亦为Raf抑制剂)、XL-880(亦为cMet抑制剂)、XL-647(亦为EGFR及EphB4之抑制剂)、XL-820(亦为cKit之抑制剂)、尼罗替尼(亦为cKit及brc-abl之抑制剂)、CYT-116、PTC-299、BMS-584622、CEP-11981、多福替尼(dovitinib)、CY-2401401及ENMD-2976。
其它治疗剂亦可选自EGFR抑制剂,所述EGFR抑制剂可为小分子EGFR抑制剂或抗EGFR抗体。抗EGFR抗体之实例为(但不限于)西妥昔单抗(cetuximab)、盘尼图单抗(panitumumab)、尼妥珠单抗(nimotuzumab)、札鲁目单抗(zalutumumab);小分子EGFR抑制剂之实例为吉非替尼(gefitinib)、埃罗替尼(erlotinib)及范得他尼(亦为VEGFR抑制剂)。EGFR调节剂之另一实例为EGF融合毒素。
可用于与本发明之抗CD37抗体分子组合的其它EGFR及/或Her2抑制剂为拉帕替尼(lapatinib)、曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、XL-647、奈拉替尼(neratinib)、BMS-599626、ARRY-334543、AV-412、mAB-806、BMS-690514、JNJ-26483327、AEE-788(亦为VEGFR抑制剂)、AZD-8931、ARRY-380ARRY-333786、IMC-11F8、Zemab、TAK-285、AZD-4769。
其它药物亦可选自靶向IGF-1R及胰岛素受体路径的药剂。所述药剂包括与IGF-1R结合的抗体(例如,CP-751871、AMG-479、IMC-A12、MK-0646、AVE-1642、R-1507、BIIB-022、SCH-717454、rhu Mab IGFR)及靶向IGF1-R之激酶域的新颖化学实体(例如,OSI-906或BMS-554417、XL-228、BMS-754807)。
可在疗法中与本发明之抗CD37抗体分子有利组合的其它药剂为靶向CD20之分子,包括CD20特异性抗体(例如利妥昔单抗、LY-2469298、欧克利单抗(ocrelizumab)、MEDI-552、IMMU-106、GA-101(=R7159)、XmAb-0367、欧伐吐单抗(ofatumumab))、放射性标记之CD20抗体(例如托丝吐单抗(tositumumab)及替坦异贝莫单抗(ibritumomab tiuxetan))或其它针对CD20之蛋白,例如SMIP Tru015、PRO-131921、FBT-A05、伐吐珠单抗(veltuzumab)、R-7159。
CD37抗体可与白血球上表达之其它表面抗原之抑制剂、尤其抗体或抗体样分子组合,例如抗CD2(希普利珠单抗(siplizumab))、抗CD4(扎木单抗(zanolimumab))、抗CD19(MT-103、MDX-1342、SAR-3419、XmAb-5574)、抗CD22(依帕珠单抗(epratuzumab))、抗CD23(鲁昔单抗(lumiliximab))、抗CD30(伊莫单抗(iratumumab))、抗CD32B(MGA-321)、抗CD38(HuMax-CD38)、抗CD40(SGN40)、抗CD52(阿来组单抗)、抗CD80(加利昔单抗(galiximab))。本发明的抗体亦可与另一CD37拮抗剂(例如,TRU-016)组合。
待与CD37抗体组合之其它药剂为免疫毒素(例如BL-22(抗CD22免疫毒素))、伊妥珠单抗奥唑米星(inotuzumab ozogamicin)(抗CD23抗体-刺孢霉素(calicheamicin)偶联物)、RFT5.dgA(抗CD25篦麻毒素A链)、SGN-35(抗CD30阿瑞他汀E偶联物)及吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)(抗CD33刺孢霉素偶联物)、MDX-1411(抗CD70偶联物)或放射性标记的抗体(例如90Y-依帕珠单抗(抗CD22放射免疫偶联物))。
此外,抗CD37抗体亦可与免疫调节剂组合,所述免疫调节剂例如诱发细胞凋亡或修饰信号传递路径的抗体,例如TRAIL受体调节剂马帕妥单抗(mapatumumab)(TRAIL-1受体促效剂)、来沙木单抗(lexatumumab)(TRAIL-2受体促效剂)、替加妥珠单抗(tigatuzumab)、阿泊单抗(Apomab)、AMG-951及AMG-655;抗HLA-DR抗体(例如1D09C3)、抗CD74、破骨细胞分化因子配位体抑制剂(例如狄诺塞单抗(denosumab))、BAFF拮抗剂(例如AMG-623a)或Toll样受体促效剂(例如,TLR-4或TLR-9)。
可与本发明之抗CD37抗体分子组合使用的其它药物选自(但不限于)激素、激素类似物及抗激素(例如,他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷诺昔酚(raloxifene)、氟维司群(fulvestrant)、乙酸甲地孕酮(megestrolacetate)、氟他胺(flutamide)、尼鲁胺(nilutamide)、比卡鲁胺(bicalutamide)、乙酸环丙孕酮(cyproterone acetate)、非那雄安(finasteride)、乙酸布舍瑞林(buserelin acetate)、氟氢可的松(fludrocortinsone)、氟甲睾酮(fluoxymesterone)、甲羟孕酮(medroxyprogesterone)、己酸羟孕酮(hydroxyprogesterone caproate)、己烯雌酚(diethylstilbestrol)、丙酸睾酮(testosterone propionate)、氟甲睾酮(fluoxymesterone)/等效物、奥曲肽(octreotide)、阿佐普芬(arzoxifene)、帕瑞肽(pasireotide)、伐普肽(vapreotide)、肾上腺类固醇(adrenocorticosteroid)/拮抗剂、泼尼松(prednisone)、地塞米松(dexamethasone)、胺鲁米特(ainoglutethimide));芳香酶抑制剂(例如,安美达锭(anastrozole)、来曲唑(letrozole)、利阿唑(liarozole)、依西美坦(exemestane)、阿他美坦(atamestane)、福美司坦(formestane));LHRH促效剂及拮抗剂(例如,乙酸戈舍瑞林(goserelin acetate)、亮丙立德(leuprolide)、阿巴瑞克(abarelix)、西曲瑞克(cetrorelix)、地洛瑞林(deslorelin)、组胺瑞林(histrelin)、曲普瑞林(triptorelin));抗代谢物(例如,抗叶酸物,例如氨甲蝶呤(methotrexate)、三甲曲沙(trimetrexate)、培美曲唑(pemetrexed);嘧啶类似物,例如5-氟尿嘧啶(5-fluorouracil)、氟脱氧尿苷(fluorodeoxyuridine)、卡西他滨(capecitabine)、地西他滨(decitabine)、奈拉滨(nelarabine)、5-氮胞苷(5-azacytidine)及吉西他滨(gemcitabine);嘌呤及腺苷类似物(诸如,巯嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、咪唑硫嘌呤(azathioprine)、克拉屈滨(cladribine)及喷司他丁(pentostatin)、阿糖胞苷(cytarabine)、氟达拉滨(fludarabine)、氯法拉滨(clofarabine));抗肿瘤抗生素(例如,蒽环霉素,例如羟道诺红霉素、道诺霉素(daunorubicin)、表柔比星(epirubicin)及伊达比星(idarubicin)、丝裂霉素-C(mitomycin-C)、博莱霉素(bleomycin)、放线菌素D(dactinomycin)、普卡霉素(plicamycin)、丝普卡霉素(splicamycin)、阿替莫霉素D(actimomycin D)、米托蒽醌(mitoxantrone)、米托蒽醌伊达比星(mitoxantroneidarubicin)、皮克蒽醌(pixantrone)、链脲佐菌素(streptozocin)、阿非迪霉素(aphidicolin));铂衍生物(例如,顺铂(cisplatin)、奥赛力铂(oxaliplatin)、卡波铂(carboplatin)、洛铂(lobaplatin)、撒塔铂(satraplatin));烷基化剂(例如,雌莫司汀(estramustine)、司莫司汀(semustine)、氮芥(mechlorethamine)、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、马利兰(busulphan)、达卡巴嗪(dacarbazine)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、羟基脲(hydroxyurea)、替莫唑胺(temozolomide)、亚硝基脲(nitrosourea)(诸如,卡莫司汀(carmustine)及洛莫司汀(lomustine))、塞替派(thiotepa));抗有丝分裂剂(例如,长春花碱(vincaalkaloid),例如长春碱(vinblastine)、长春花碱酰胺(vindesine)、长春瑞宾(vinorelbine)、长春氟宁(vinflunine)及长春新碱(vincristine);及紫杉烷,例如紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)及其配制物拉若他西(larotaxel);丝莫他西(simotaxel)及埃坡霉素(epothilone),例如伊沙匹隆(ixabepilone)、帕妥匹隆(patupilone)、ZK-EPO);拓扑异构酶抑制剂(例如,表鬼臼素(epipodophyllotoxin),例如依托泊苷(etoposide)及磷酸依托泊苷(etopophos)、替尼泊甙(teniposide)、安吖啶(amsacrine)、拓朴替康(topotecan)、伊立替康(irinotecan)、巴诺蒽醌(banoxantrone)、喜树碱(camptothecin));及混杂化学治疗剂,诸如视黄酸衍生物、胺磷汀(amifostine)、阿那格雷(anagrelide)、干扰素α、干扰素β、干扰素γ、介白素-2(interleukin-2)、丙卡巴肼(procarbazine)、N-甲肼(N-methylhydrazine)、米托坦(mitotane)及卟吩姆(porfimer)、贝瑟罗汀(bexarotene)、赛利克西(celecoxib)、乙烯亚胺(ethylenemine)/甲基三聚氰胺、三乙烯三聚氰胺(triethyienemelamine)、三乙烯硫代磷酰胺(triethylenethiophosphoramide)、六甲基三聚氰胺(hexamethylmelamine)及酶L-天冬酰胺酶、L-精氨酸酶及甲硝哒唑(metronidazole)、米索硝唑(misonidazole)、去甲基醚醇硝唑(desmethylmisonidazole)、哌莫硝唑(pimonidazole)、依他硝唑(etanidazole)、尼莫唑(nimorazole)、RSU1069、EO9、RB6145、SR4233、烟碱酰胺(nicotinamide)、5-溴脱氧尿苷(5-bromodeozyuridine)、5-碘脱氧尿苷(5-iododeoxyuridine)、溴脱氧胞苷(bromodeoxycytidine)、赤式羟基壬基腺嘌呤(erythrohydroxynonyl-adenine)、蒽二酮(anthracenedione)、GRN-163L(竞争性端粒酶模板拮抗剂)、SDX-101(PPAR促效剂)、他拉伯特(talabostat)(DPP抑制剂)、福罗地辛(forodesine)(PNP抑制剂)、阿他塞泊(atacicept)(靶向TNF家族成员BLyS及APRIL之可溶性受体)、TNF-α中和剂(恩博(Enbrel)、胡米拉(Humira)、雷米卡德(Remicade))、XL-844(CHK1/2抑制剂)、VNP-40101M(DNA烷基化剂)、SPC-2996(反义bcl2抑制剂)、欧巴妥拉(obatoclax)(bcl2抑制剂)、恩丝他瑞(enzastaurin)(PKCβ调节剂)、沃瑞塞特(vorinistat)(HDAC抑制剂)、罗米地辛(romidepsin)(HDAC抑制剂)、AT-101(Bcl-2/Bcl-xL抑制剂)、普利地辛(plitidepsin)(多作用缩肽)、SL-11047(多元胺代谢调节剂)。
在某些实施例中,将抗CD37抗体分子与"CHOP"(环磷酰胺、羟道诺红霉素、长春新碱及泼尼松之组合)一起应用。
本发明之抗CD37抗体分子亦可与其它疗法组合使用,所述疗法包括外科手术、放射疗法、内分泌疗法、生物反应改质剂、高温及冷冻疗法及减弱任何不利影响的药剂(例如,止吐药)、G-CSF、GM-CSF、光敏剂(诸如,血卟啉衍生物、苯并卟啉衍生物、Npe6、锡本卟啉、苯博瑞德a(pheoboride-a)、细菌叶绿素a(bacteriochlorophyll-a)、萘酞菁(naphthalocyanine)、酞菁(phthalocyanine)、锌酞菁)。
单克隆抗体显示灵敏的抗原特异性且通常仅与人类标靶抗原反应,而不与来自动物物种之同源蛋白反应。为支持治疗抗体之研制,可需要用于评估活体内毒性及药效行为之适当动物模型。活体内模型之一种可能性为内源标靶抗原经人类同源物置换之转基因小鼠("基因剔除/基因敲入"小鼠)。详言之,为研制治疗性抗CD37抗体,可由人CD37基因置换鼠CD37基因。此可通过构建含有侧接未翻译序列之人CD37基因之编码性基因组序列的靶向载体来实现。此靶向载体可用于使用小鼠ES细胞进行同源重组。用于人CD37表达之纯合之转基因动物可用以(例如)通过监测抗体应用后外周B细胞的数目来评估抗体关于人CD37之药效作用。或者,彼等小鼠可用于研究在静脉内(i.v.)应用后人CD37特异性抗体之潜在毒性作用。
在缺乏单克隆抗体之动物交叉反应性之状况下,另一可能性为产生所谓的替代抗体。替代抗体为与可用于研究药效及毒性作用之相关动物物种(例如,小鼠或食蟹猴)之同源蛋白反应的抗体。在CD37之状况下,分别研制对猕猴CD37或小鼠CD37具特异性之单克隆抗体。理想地,此类替代抗体应具有与研制抗体类似之结合及功能性质。此可通过使用试验系统来研究,所述试验系统利用猕猴或小鼠的表达CD37之细胞作为标靶细胞,例如对于结合而言,可使用FACS Scatchard分析、ADCC及细胞凋亡试验。最终,可根据活体外猕猴或小鼠血液中的B细胞去除活性来选择替代抗体。
附图说明
图1:经FACS竞争试验测定,嵌合抗体A0特异性识别CD37抗原。
图2:经FACS测定的A0的人源化形式对细胞性CD37抗原的结合。
图3:经FACS测定的A0的人源化形式对细胞性CD37抗原的结合。
图4:经FACS scatchard分析测定的A0的人源化形式对细胞性CD37抗原的亲和力。
图5:A0的人源化形式对拉莫斯细胞的ADCC活性。
图6:A0的人源化形式对拉莫斯细胞的促细胞凋亡活性。
图7:mAb A0的Fc工程化形式对拉莫斯细胞的ADCC活性。
图8:mAb B0的Fc工程化形式对拉莫斯细胞的ADCC活性。
图9:mAb A0及B0的促细胞凋亡活性。
图10:mAb A0的Fc工程化形式的促细胞凋亡活性。
图11A:Fc工程化抗体A2及B2对正常人类B细胞的去除,全血试验,与利妥昔单抗相比。
图11B:与利妥昔单抗相比,抗体经Fc工程化后的B细胞去除活性更好。
图11C:抗体A2和B2在全血试验中未除去T细胞和单核细胞。
图12:与利妥昔单抗相比,Fc工程化后ADCC活性更好。
图13:Fc工程化抗体A2及B2对拉莫斯伯基特淋巴瘤细胞的去除,全血试验,与利妥昔单抗相比。
图14:Fc工程化抗体A2及B2对裸小鼠中拉莫斯异种移植肿瘤的体内肿瘤生长抑制作用。
图15:CD37在多发性骨髓瘤细胞上的表达。
图16:抗体A2及B2在多发性骨髓瘤细胞上的ADCC活性。
图17:抗体A2及B2在来自患者的CLL细胞上的促细胞凋亡活性。
实施例1
制备嵌合及人源化的抗CD37抗体
a)制备嵌合抗体A0
基于SEQ ID NO:2及SEQ ID NO:4所示可变重链及轻链氨基酸序列,应用哺乳动物细胞的最佳密码子使用规律(GeneArt,Regensburg,Germany)合成相应DNA序列,在5'末端添加HindIII克隆位点及在3'末端添加BamH1克隆位点,藉此。合成的DNA分子经HindIII及BamHI消化,且基于分别编码人类IgG1恒定区及人类κ轻链恒定区(SEQ ID NO:24及SEQ ID NO:26)的表达载体,将所得DNA片段(SEQ ID NO:1及SEQ ID NO:3加上限制位点)克隆至pcDNA3.1中。制备EndoFree质粒制剂(Qiagen),且根据供货商之方案,将重链及轻链质粒以各质粒1mg/L之浓度共转染至HEK293自由式(freestyle)细胞(Invitrogen)中。72小时后,采集上清液且通过ELISA测定IgG浓度。将所得嵌合抗CD37抗体(称为A0)在改良之蛋白A管柱(GE Healthcare)上纯化,洗脱至柠檬酸盐缓冲液中,接着在PBS中透析。
b)制备嵌合抗体A0的人源化形式
使用如(例如)US5,225,539、US6,548,640、US6,982,321中所述之CDR移植方法,对a)中所得嵌合mAb A0进行人源化。
为建立mAb A0VL域之结构模型,自布鲁克哈芬国家实验室(Brookhaven National Laboratory)之蛋白数据库(PDB)中选择结构模板。自鼠单克隆抗体路径"1KB5"选择具有88%序列同一性/81%相似性及2.5分辨率之VL域。对于mAb A0VH域,选择具有90%序列同一性及91%相似性之同一小鼠单克隆抗体结构"1KB5"作为主要模型化模板。发现人类Vκ1(hVK1)及人类VH1(hVH1)类型与人类共有框架达到最优选配合。作为替代性设计,选择最稳定人类共有域hVK3及hVH3之移植物。为进行移植,将mAb A0_VL及mAb A0_VH模型与人类共有域模型hVK1、hVK3、hVH1A及hVH3组合,且将其组合以产生Fv模型。通过将鼠mAb A0CDR区包埋至人类抗体框架中来执行环移植,且合成人源化链构建体的DNA分子。
合成各自的人源化可变区,将其克隆至免疫球蛋白表达载体中,与表1所示的重链及轻链序列一起,如a)所述在HEK293自由式表达系统(Invitrogen)中瞬间表达,且在蛋白A柱上进行纯化。
表1实施例中用的嵌合及人源化抗CD37抗体的可变重链及轻链序列
c)制备Fc工程化之嵌合及人源化抗CD37抗体
如Lazar等人,2006所述,制备Fc突变体。将所得Fc工程化的重链序列引入表达载体pAD-CMV1(EP393438中所述)中且与含有轻链编码序列之质粒一起共转染至CHO-DG44细胞中。在转染后5至7天自细胞培养基收集抗体,且经由蛋白A层析进行纯化,将其洗脱至柠檬酸盐缓冲液中,接着在PBS中透析。经由蛋白A HPLC来测定样品之蛋白含量,经由Kinetic-QCL动力学显色试验(Kinetic Chromogenic Assay,Lonza)来测定内毒素含量。通过HP-SEC来测定样品之单体含量,用于功能测试之所有样品均显示单体含量>95%。
表2
嵌合及人源化抗CD37抗体的重链可变区和轻链可变区的序列(第III和第IV栏)以及Fc突变(第II栏)(抗体A0、B0、C0等与表1中的抗体A及B、C等一致)。
重链和轻链的全长序列在第V和VI栏列出。(第V栏中标记了*的序列是指SEQ ID NO24和23(野生型序列)的IgG1序列经修饰后具有对应于第II栏的取代的序列,以及编码性DNA中的相应突变)。
实施例2
嵌合mAb A0特异性识别CD37抗原
在FACS竞争试验中,在拉莫斯伯基特淋巴瘤细胞(ATCC#CRL-1596)上测试MAb A0对细胞性CD37之特异性。使细胞在组织培养瓶(175cm2)中生长,瓶中有RPMI-1640+GlutaMAX作为培养基,并补充有10%热灭活胎牛血清、12.5mM HEPES、1mM丙酮酸钠、1%MEM非必需氨基酸。在湿润气氛中,细胞以3×105个细胞/毫升之初始密度在37℃、5%CO2中培养3天。通过每周用新鲜培养基以1:6之比率转种2-3次,将培养物维持在3×105-1.8×106/ml的细胞浓度。用浓度为1μg/ml、由藻红蛋白(PE)直接标记的CD37特异性mAb HH1(Santa Cruz)进行FACS竞争分析。所述抗体与未标记的竞争抗体A0以指定摩尔比在4℃预培育10min。此后,将1×105个拉莫斯细胞用抗体混合物在冰上培育30min。此后,将细胞在磷酸盐缓冲液(PBS)中洗涤两次,再悬浮于FACS缓冲液中且在BD FACS Canto上进行测量。此类试验结果显示于图1中。以20倍摩尔过量添加对照人类IgG1抗体(Sigma IgG1κ)并未显著降低拉莫斯细胞之平均荧光强度(MFI)。以20倍摩尔过量添加未标记之HH1抗体或A0抗体几乎完全消除直接标记之HH1抗体的结合。此表明,A0及HH1抗体识别拉莫斯细胞上的相同或相似表位,且竞争与细胞性CD37抗原之结合。
实施例3
mAb A0的人源化形式与细胞性CD37抗原的结合
经FACS分析来测试A0的人源化形式与细胞性CD37抗原之结合。以所指示之浓度将抗体添加至拉莫斯细胞中且使其在4℃下结合30min。此后,用PE标记之山羊抗人类IgG抗体(Sigma)检测结合抗体,将细胞用PBS洗涤2次,此后使细胞再悬浮于FACS缓冲液中,在BD FACS Canto上通过FACS进行分析。实例显示于图2及3中(分别为抗体A、B、C、D、I或A、H、I、J、K、L及M;参见表1)。数个A0人源化形式显示与拉莫斯细胞之结合与亲本抗体A0相似,表明人源化不会降低与细胞性CD37抗原之结合。
实施例4
嵌合mAb A0的人源化形式的FACS scatchard分析
通过如其它文献(Brockhoff等人,1994)所述之FACS scatchard分析来测定抗体A0的人源化形式(称为B、C、D、H、I及K;参见表1)对细胞性CD37抗原之亲和力。简言之,在96孔板中制备抗体稀释液,在第一孔中以100-400nM开始(80μl),接着11个稀释步骤(1:2,40+40μl)。将50μl mAb稀释液添加至FACS管中,将150μl细胞(0.8×106/ml=1.2×105个细胞/管)添加至各FACS管中。将细胞轻轻混合且在冰上培育1h。此后,添加50μl偶联了FITC的第二抗体(浓度为15μg/ml;小鼠mAb抗hu IgG所有亚类,Zymed05-4211),混合,冰上培育30min。此后添加4ml含有0.02%酸之PBS(ph7.2),将细胞沉降后,重悬于300μl PBS(pH7.2)中,用BD FACS Canto进行FACS分析。所有实验步骤均在湿冰上执行,所有抗体稀释均在PBS/0.5%BSA+0.02%酸中进行。使用Quantum FITC MESF(Premix)高含量珠粒(Bangs Laboratories)来执行FACS校准。所有样品均使用相同FACS参数来测量。根据不同抗体浓度之MFI值来计算结合IgG对游离IgG之比率,将其展示为scatchard墨点。图4显示数个A0人源化变体之MFI/抗体浓度关系。结果显示,一些人源化形式对拉莫斯细胞之结合与起始抗体相似,其解离常数(Kd)为2.15-4.90纳摩尔/升。
实施例5
嵌合mAb A0的人源化形式的ADCC活性
使用拉莫斯细胞作为标靶细胞及使用IL2刺激之人类PBMC作为效应细胞,来评估A0的人源化形式(称为B、C、D、H、J、K;参见表1)介导抗体依赖性细胞介导之细胞毒活性(ADCC)的能力。拉莫斯细胞(伯基特淋巴瘤;ATCC#CRL-1596)自ATCC购得。使细胞在组织培养瓶(175cm2)中生长,瓶中有RPMI-1640+GlutaMAX作为培养基,并补充有10%热灭活胎牛血清、12.5mM HEPES、1mM丙酮酸钠、1%MEM非必需氨基酸。在湿润气氛中,细胞以3×105个细胞/毫升之初始密度在37℃、5%CO2中培养3天。通过每周用新鲜培养基以1:6之比率转种2-3次,将培养物维持在3×105-1.8×106/ml的细胞浓度。将细胞密度为1.5×106/ml-1.8×106/ml的对数生长期细胞培养物的等分试样离心(200×g,亦即1000rpm)10min。将细胞用洗涤培养基(RPMI1640,不含L-谷氨酰胺)洗涤一次,沉降(200×g,亦即1000rpm;10min)。使细胞团再悬浮于试验培养基[RPMI,含1%BSA,不含L-谷氨酰胺],进行细胞计数。将细胞浓度调整至2×105/ml。
自健康供体抽出约50-80ml全血,用于分离PBMC。在50ml管中,将10ml全血用26ml HBSS(Hanks'平衡盐溶液,不含钙及镁)以1:3.6稀释。在50ml管中,将18ml经稀释之全血加在12ml Lymphoprep(Nycomed Pharma)顶部,以370×g(1400rpm)离心35min。自界面吸出单核细胞,先用HBSS洗涤(750×g,亦即1900rpm;10min),接着用HBSS进行第二次洗涤(300×g,亦即1200rpm;10min),最终用HBSS洗涤(160×g,亦即900rpm;10min)。用移液管使沉降细胞轻轻再悬浮于培养基/试验培养基(RPMI1640,含10%热灭活人类AB血清,不含L-谷氨酰胺)中,在细胞计数器中测定细胞数。将PBMC浓度调整至1×107/ml。在37℃、CO2恒温箱中的组织培养烧瓶(75cm2)中,将新鲜分离之PBMC(5×105/ml)在培养基(RPMI1640,含10%人类AB血清,不含L-谷氨酰胺)中维持隔夜。第二天,用终浓度为1U/ml的hIL-2刺激细胞,历时另外3天。在Lymphoprep梯度上,自细胞碎片分离经IL-2刺激之PBMC。使纯化并经IL-2刺激的PBMC以1×107/ml悬浮于培养基/试验培养基中。
效应细胞与标靶细胞在特异性或非特异性抗体存在的条件下的共培养,一式双份或一式三份地在96孔圆底微量滴定板中进行,每孔的试验培养基终体积为200μl,由10%人类AB血清及1%BSA的RPMI液以1:1的比率组成。首先,涂上效应细胞(于每孔100μl于RPMI中之10%人类AB血清中的刚分离之PBMC细胞),接着涂上标靶细胞及在50μl含1%BSA的RPMI中稀释的抗体溶液。作为对照,在单独试验培养基中培养效应细胞(效应细胞对照),且在单独试验培养基(自发裂解)或在补充有1%Triton X-100之试验培养基(最大裂解)中培养标靶细胞。将共培养物在潮湿CO2恒温箱中于37℃下培育3小时。在培育结束时,在室温下通过离心(200×g,亦即1000rpm;10min)自培养基移除细胞。将不含细胞之上清液(每孔100μl)转移至96孔平底板之相应孔中。为测定此等上清液中之LDH活性,将100μl反应混合物(将250μl催化剂与11.25ml染料溶液新鲜混合)添加至各孔中,室温避光培育30min。接着,如下所述来测量吸光度。
用细胞毒活性检测试剂盒(LDH;Roche)来测量ADCC活性。细胞毒活性的检测是基于对浆膜受损细胞释放的LDH酶活性的测量。释放至培养物上清液中之LDH将来自试剂盒之四唑盐还原成甲臜(formazan)。相对于参考波长650nm,在ELISA板式读数器中测量490nm下甲臜染料之吸收最大值。为计算细胞介导之细胞毒活性百分比,在每组实验中执行五个对照。
背景对照I(1):试验培养基中的LDH活性,将其自值(3)及(5)减去。
背景对照II(2):含1%Triton-X100的试验培养基中的LDH活性,将其自最大LDH释放值(4)减去。
自发LDH释放值(3):仅有标靶细胞时释放的LDH活性。
最大LDH释放值(4):标靶细胞中最大可释放的LDH活性。
效应细胞对照(5):仅有效应细胞时释放的LDH活性。
为测定细胞介导之细胞毒活性百分比,根据制造商之说明计算一式三份或一式双份实验之平均吸光度,且减去背景。在图5中,显示使用25:1之E:T比率及拉莫斯标靶细胞的ADCC试验的结果。添加30ng/ml浓度的抗体。起始mAb及其人源化形式对拉莫斯细胞展示相似的ADCC活性。可见,抗CD37mAb A之人源化不会显著改变其诱发ADCC之能力。
实施例6
嵌合mAb A0的人源化形式的促细胞凋亡活性
mAb A0(=A)及其人源化形式(B、C、D及I;参见表1)的促细胞凋亡活性,通过将拉莫斯细胞与mAb一起培育,再测量膜联蛋白(Annexin)V/PI阳性细胞来评估。拉莫斯细胞(伯基特淋巴瘤;ATCC#CRL-1596)来源于ATCC。
使细胞在组织培养瓶(175cm2)中生长,瓶中有RPMI-1640+GlutaMAX作为培养基,并补充有10%热灭活胎牛血清、12.5mM HEPES、1mM丙酮酸钠、1%MEM非必需氨基酸。在湿润气氛中,细胞以3×105个细胞/毫升之初始密度在37℃、5%CO2中培养3天。通过每周用新鲜培养基以1:6之比率转种2-3次,将培养物维持在3×105-1.8×106/ml的细胞浓度。将细胞密度为1.5×106/ml-1.8×106/ml的对数生长期细胞培养物的等分试样离心(200×g,亦即1000rpm)10min。将细胞用洗涤培养基(RPMI1640,不含L-谷氨酰胺)洗涤一次,沉降(200×g,亦即1000rpm;10min)。使细胞团再悬浮于培养基中,进行细胞计数。将细胞浓度调整至1×106/ml。将每孔100μl细胞悬浮液涂于96孔圆底板中。在含有10%FBS之细胞培养基中稀释抗体,每孔添加100μl抗体溶液。细胞在CO2恒温箱中37℃培育20至24小时,此后以Vybrant凋亡实验盒#2进行染色。将Alexa Fluor488标记之膜联蛋白V及碘化丙啶溶液添加至细胞中,避光培育15min。此后,使细胞再悬浮于400μl膜联蛋白V结合缓冲液中,用BD FACS Canto进行FACS分析。使用FL1/FL2通道,以二维点印迹法测定膜联蛋白V阳性/PI阴性细胞及膜联蛋白V/PI阳性细胞的百分比。用同种型相匹配的未结合抗体(Sigma人类IgG1)作阴性对照。
图6显示mAb A之各种人源化形式对拉莫斯细胞的促细胞凋亡作用。用10μg/ml的抗体将细胞培育24小时,展示膜联蛋白V阳性细胞(PI阳性及PI阴性)之总百分比。亲本mAb A显示较强促细胞凋亡活性。意外地,人源化形式显示与亲本mAb A相比显著减少之膜联蛋白V阳性细胞数目,表明人源化抗体的促细胞凋亡活性改变。可见,在此组实验中,MAb A的人源化使其促细胞凋亡活性降低。
实施例7
嵌合mAb A0的Fc工程化形式的ADCC活性
使用拉莫斯细胞作为标靶细胞来评估mAb A0的Fc工程化形式(称为A1、A2、A3、A4,参见表2)的ADCC活性。如上所述来执行ADCC试验(实施例5)。实验结果显示于图7中。A0的Fc工程化形式与亲本mAb A0相比在潜力(potency)及功效(efficacy)方面都明显进步。一些Fc变体与亲本mAb相比,最大裂解增幅多达100%,EC50增幅多达10倍。可见,引入特异性Fc突变大大增加嵌合mAb A0的ADCC活性。
实施例8
mAb B0的Fc工程化形式的ADCC活性
使用拉莫斯细胞作为标靶细胞来评估mAb B0的Fc工程化形式(称为B1、B2、B3、B4;参见表2)的ADCC活性。如上所述来执行ADCC试验(实施例5)。B0的Fc工程化形式与亲本mAb B0相比在潜力及功效方面都明显进步。一些Fc变体与亲本mAb相比,最大裂解增幅多达80%,EC50增幅多达20倍。可见,引入特异性Fc突变大大增加嵌合mAb B0的ADCC活性。实验结果见图8。
实施例9
mAb A0及B0的促细胞凋亡活性
图9中展示mAb A0及B0在与抗IgG mAb交联之前及之后对拉莫斯细胞的促细胞凋亡活性。如实施例6中所述来执行细胞凋亡试验,为进行抗体交联,以1:1之比率向所述抗体添加抗人类IgG抗体(γ-链特异性;Sigma),37℃培育15min,接着添加标靶细胞。在图9中,以1μg/ml之浓度添加交联及未交联之CD37特异性mAb。嵌合mAb A0即使未交联亦为细胞凋亡之强效诱发剂,此作用在mAb交联之后显著增强。意外地,未交联之人源化mAb B0完全缺乏促细胞凋亡活性,然而在与抗IgG Ab交联之后显示强效促细胞凋亡活性。总之,此实验显示,人源化mAb A0的促细胞凋亡活性可在抗体交联后恢复。
实施例10
mAb A0的Fc工程化形式的促细胞凋亡活性
嵌合mAb A0的Fc工程化形式对拉莫斯细胞的促细胞凋亡活性通过实施例6所述膜联蛋白V/PI染色来评估。在0.1至10.000ng/ml之浓度范围内,对亲本抗体A0及Fc工程化变体A2及A4进行滴定。如图10中可见,所有3种抗体均显示相似的促细胞凋亡活性。总之,此实验显示mAb A0之Fc工程化不会改变其促细胞凋亡活性。
实施例11
a)全血试验中Fc工程化抗体A2及B2的B细胞去除活性
从人类血液去除正常B细胞之潜力及功效用全血试验来评估。在此试验形式中,将受试抗体添加至健康人体血样经EDTA处理的样品中,37℃培育3至4小时后,通过4色FACS试验定量测量B细胞数目。通过与缓冲液或IgG对照相比,可计算受试药剂去除B细胞之程度。由于存在与人体内情况相似的人类IgG含量及效应细胞,所以认为此试验类型对于预测该受试抗体的体内效应有高度相关性。
用定量FACS试验来测定健康个体血样中的B细胞数及/或添加的(spiked)拉莫斯细胞的数目。定量分析用含已知数量荧光珠的BD Trucount管来进行,所述珠作为对目标细胞群进行定量的内标。用4种不同的CD标记(CD3/CD14/CD19/CD45)进行4色分析,并联合FSC/SSC分析来鉴别B细胞。
将每孔270μl新鲜血液与30μl抗体稀释液(在PBS中)或PBS(缓冲液对照)一起在48孔板中一式双份进行培育。将样品在37℃培育4h,此后立即将其置于冰上。将33μl CD标记主混合物添加至Trucount管中,添加50μl血液-抗体混合物。使样品涡旋,室温培育15分钟。此后,添加450μl裂解缓冲液,使其涡旋,室温再培育15分钟。将样品置于冰上,立即用BD FACS CantoTM流式细胞仪进行FACS分析。用BD FACSDiva软件(5.0.2版)进行数据评估。
Fc工程化的嵌合及人源化mAb A2及B2在正常B细胞的去除能力方面显示优秀的潜力,其EC50值为0.15-0.35nM。正常B细胞的去除水平为57%-65%。利妥昔单抗(获准治疗B-NHL的抗体)在此试验形式中平行测试,其B细胞去除活性显著较低(图11A)。
b)Fc工程化使A0及B0的B细胞去除活性比利妥昔单抗更好
mAb对健康人体血液中B细胞去除的效应按a)所述来评估。未经Fc工程化之mAb A0及B0显示B细胞去除活性为13%-26%,与利妥昔单抗类似。Fc工程化使两种mAb的B细胞去除活性均显著增加,平均去除百分比为75%。此显然证明A2及B2与利妥昔单抗相比的优越性(图11B)。
c)抗体A2和B2在全血试验中不去除T细胞和单核细胞
在评估对B淋巴细胞的影响的同时,也评估A2和B2对T淋巴细胞(CD3+)和单核细胞(CD14+)的影响。未观察到T细胞数或单核细胞数的显著变化,但观察到B细胞数显著减少(图11C)。这表明,A2和B2从人血中特异性除去B细胞。
实施例12
Fc工程化导致比利妥昔单抗更好的ADCC活性
mAb A0的Fc工程化形式A2的ADCC活性用拉莫斯细胞作标靶细胞进行评估。如上所述来执行ADCC试验(实施例5)。未经Fc工程化的抗体A0对拉莫斯标靶细胞的最大裂解次于利妥昔单抗(对CD20具特异性的抗体,其经批准用于治疗罹患B细胞淋巴瘤之患者)。意外发现,A0的Fc工程化使A2在潜力和功效方面比利妥昔单抗明显进步。此表明,当拉莫斯细胞上CD20及CD37的抗原密度相似时,经Fc工程化的抗CD37mAb A2的ADCC活性比利妥昔单抗明显更好(图12)。
实施例13
全血试验中Fc工程化抗体A2及B2之淋巴瘤细胞去除活性
拉莫斯细胞(来自人类血液的伯基特淋巴瘤细胞系)去除活性之潜力及功效用实施例11所述全血试验来评估。在该试验之改良版中,向全血基质中添加(spike in)拉莫斯肿瘤细胞,其与内源性B细胞相比约十倍过量,其去除用FACS分析来监测。Fc工程化之嵌合及人源化mAb A2及B2在拉莫斯细胞去除活性方面显示良好潜力,其EC50值为0.35-0.54nM。拉莫斯细胞去除水平为36%-55%。利妥昔单抗(获准治疗B-NHL的抗体)在此试验形式中平行测试,其拉莫斯细胞去除活性显著较低(图13)。
实施例14
疾病相关模型中Fc工程化抗体A2及B2之活体内功效
mAb A2及B2之活体内抗肿瘤功效用拉莫斯伯基特淋巴瘤裸小鼠模型来评估。将CD37阳性拉莫斯细胞经皮下注射至动物腰窝中,当肿瘤形成时,开始静脉内治疗所述动物。选择每周两次之治疗方案(q3/4d),平行测试两种不同剂量(8mg/kg及25mg/kg)。两种mAb均显示显著抗肿瘤功效,其T/C值为0.2%-26%。未观测到两种剂量水平之间及两种抗体之间的显著差异。然而,经大剂量A2治疗之动物中存在功效更佳之倾向,T/C为0.2%,且5/10的肿瘤完全消退。所有治疗均良好耐受,无明显重量减轻。总之,mAb A2及B2显示在拉莫斯伯基特淋巴瘤模型中具有显著抗肿瘤功效,在8mg/kg剂量水平获得最大活性。该活性可与平行测试之利妥昔单抗之活性相当。必须注意的是,在Fc工程化抗体A2及B2中观测到之体内活性可能被低估,因为此等mAb针对与人类效应细胞而非鼠效应细胞之相互作用进行了优化。此种经优化的相互作用在使用人类效应细胞时引起体外ADCC活性大大改善(实施例8),但在所用小鼠模型中并未有所反映。然而,此实验中获得之数据(图14所示)提供活体内证据证明靶向CD37之概念、且因此可用于评估人类之治疗剂量。
实施例15
小鼠中A2及B2的药物动力学(PK)与药效作用(PD)的相关性,用以评估对人的治疗剂量
使用拉莫斯肿瘤异种移植模型,在小鼠中建立A2及B2之血清浓度与其药效作用之间的相关性。此等研究证明,在小鼠中采用标准的q3或4d抗体给药方案时,8mg/kg A2及B2的剂量(配制在柠檬酸盐缓冲液中:25mM柠檬酸钠、115mM NaCl、0.04%Tween80,pH6.0)在此侵袭性皮下(s.c.)肿瘤模型中引起肿瘤生长显著延缓,从而表明在整个给药间隔期具有持续之活性。此外,亦确立同一剂量之药物动力学数据。
利用这种小鼠中的PK/PD关联性,人体的估计用量可以用人体中人源化抗体清除率(CL)的已公开数据(Lobo等人,2004)来计算。
A2的完整计算:
·单一剂量8mg/kg后的平均AUC(0-∞)=6099μg·h/mL
·小鼠中的指定AUC(0-∞)=小鼠中AUC(ss,τ),且AUC(ss,τ)/τ=C(ave,ss)
·小鼠中C(ave,ss)(τ=84小时)=73μg/mL,假定其等同于人体中的C(ave,ss)(τ=168h)。
·因为人体AUC(ss,τ)=D/CL,且利用Lobo等人2004所报导的人体中人源化抗体清除率(CL)范围:CL=7mL/h/70kg至15mL/h/70kg。
·对于7mL/h/70kg:168hr×7=1176mL×73μg=86mg。
·对于15mL/h/70kg:168hr×15=2520mL×73μg=184mg。
因此,对于70kg的人而言,A2的每周估计剂量为86-184mg。使用与上述相同之假定,对于70kg的人而言,经计算,B2的每周估计人用剂量为189至404mg。
实施例16
抗体A2及B2对多发性骨髓瘤细胞显示ADCC活性
CD37在一组多发性骨髓瘤细胞系上的表达用CD37特异性抗体经FACS分析来评估。细胞与直接荧光标记之抗CD37抗体或与未标记之CD37特异性抗体一起保温,接着与荧光标记的抗第一抗体的第二抗体一起保温。带标记的细胞的荧光活性用FACS Canto流式细胞仪(BD Biosciences)测量,荧光强度用FACS Diva软件记录为MFI。11例所测试的多发性骨髓瘤中,有6例表明细胞表面表达CD37(图15)。接着,将细胞系(RPMI8226)用CD37特异性抗体A2及B2按实施例5所述的ADCC试验进行测试。两种抗体均证明在RPMI8226细胞上具有强效ADCC活性,EC50值为25ng/ml,最大细胞裂解为约20%(图16)。此实施例证明,在使用CD37特异性mAb A2及B2的情况下,CD37阳性多发性骨髓瘤细胞易感于ADCC介导的细胞裂解作用。
图15显示6例多发性骨髓瘤细胞系的CD37表达的FACS分析。空心曲线表示与CD37特异性抗体的反应性,实心曲线表示阴性对照抗体。
实施例17
抗体A2和B2对来自患者的CLL细胞的促细胞凋亡活性
A2和B2的促凋亡活性在衍生自患者的慢性淋巴细胞白血病(CLL)细胞上进行评估。从诊断为CLL的患者制得外周血单核细胞(PBMC),所述患者事先都已按赫尔辛基声明(the declaration of Helsinki)取得知情同意。用plus方法(StemCell Technologies,Meylan,France)从新鲜采集的血液纯化出原代CLL细胞,在含10%热灭活人AB血清(Sigma,France)的RPMI1640培养基中4°C储存备用。原代CLL细胞的培养基是RPMI1640,补加2mML-谷氨酰胺和10%热灭活的人AB血清。为了进行实验,原代CLL细胞用血细胞计数仪计数,并用0.25%台盼蓝排除法评估其活力。CLL样品的活力在90%以上。按实施例6所述,将细胞与30μg/ml抗体在37°C保温24小时后,测定膜联蛋白V阳性细胞百分比。如图17所示,Fc工程化抗体A2和B2对原代CLL细胞显示强劲的促细胞凋亡活性,其膜联蛋白V阳性细胞分别为约90%(A2)和40%(B2)。这两种mAb都明显优于rituximab,后者是已获准治疗B-NHL的B细胞特异性抗体。Mab A2的活性还明显优于阿来组单抗,后者是获准治疗B-CLL的抗体。
实施例18
生成转基因小鼠模型,其中的内源CD37基因被其人类同源物置换。
构建靶向载体,其含有人CD37(BAC(细菌人工染色体)ID:RP11-433N13、RP11-50I11)的编码序列,且该编码序列侧翼是非翻译序列。该靶向载体还含有侧翼于外显子3-4的loxP位点、以及被frt位点侧接的neo选择标记。接着,用此靶向载体和小鼠ES细胞按照标准技术进行同源重组,以便将小鼠基因组序列的外显子1-8替换为相应的人类序列。为此,使C57BL/6N ES细胞系在失去有丝分裂活性的喂养层上生长,所述喂养层在补加20%FBS(PAN)及1200u/mL白血病抑制因子(Millipore ESG1107)的DMEM高葡萄糖培养基中含有小鼠胚胎成纤维细胞(MEF)。在240V及500F下,将1×107个细胞及30g线性化DNA载体电穿孔(Biorad Gene Pulser)。G418选择(200g/mL)在第2天开始。用更昔洛韦(Gancyclovir)(2M)进行之反选择在电穿孔后第5天(d5)开始。在第8天(d8)分离ES克隆,对克隆进行扩增及在液氮中冷冻后,根据标准方法,(例如)通过使用对标靶基因具特异性之放射性标记之DNA探针,通过Southern印迹法进行分析。接着,通过本领域已知之标准方法,例如通过囊胚注射(blastocyst injection)及随后产生嵌合动物,而产生转基因动物。分别对嵌合及杂合动物进行常规育种,获得对人CD37的杂合型及纯合型动物。使用标准方法,例如外周血淋巴细胞之FACS分析或组织切片之免疫组织化学分析,在蛋白水平监测鼠CD37基因之成功基因剔除及人CD37基因之基因敲入。
实施例19
制备替代抗体(surrogate antibody)
用猕猴(macaque)CD37抗原之完整编码序列(登录号ENSMMUT00000020744)对小鼠及兔进行基因免疫,产生猕猴CD37特异性单克隆抗体。特异性抗体用表达猕猴CD37抗原之重组HEK293或CHO细胞来选择,使用例如标准ELISA或FACS技术。这些抗体的可变重链及轻链编码序列通过PCR克隆重新获得,并用于(按实施例1所述)产生嵌合抗体,使所述嵌合抗体具有来源于鼠或兔起始抗体的VH及VL区、以及与本发明抗体(例如,A2或B2)的Fc部分一致的Fc部分。结合及功能性质可利用试验来研究,所述试验例如,利用猕猴CD37表达细胞作为例如结合作用的标靶细胞的试验系统、FACS、Scatchard分析、ADCC及细胞凋亡试验。最后,替代抗体根据食蟹猴(Cynomolgus monkey)血液的体外B细胞去除活性来选择。
实施例20
制备产生所述抗体之克隆
为制备用于产生本发明抗体(例如,抗体A2、A4、B2或B4)之克隆,将编码完整重链(例如分别具有SEQ ID NO:27、31、35或39所示序列)的DNA分子插入真核表达载体pBI-26中,该载体亦编码来自仓鼠之二氢叶酸还原酶选择标记。
将编码SEQ ID NO:29、33、37及41分别所示的完整轻链的DNA分子插入真核表达载体pBI-49中,该载体亦编码新霉素磷酸转移酶选择标记。对完整重链及轻链的DNA序列进行充分测序。
对于在化学合成培养基(chemically defined media)中悬浮生长的仓鼠细胞系CHO-DG44,用上述编码抗体重链及轻链的真核表达载体共转染。被转染的细胞在不含次黄嘌呤及胸苷、但有G418抗生素的培养基中选择。接着,将细胞用浓度递增的氨甲蝶呤(MTX)进行分步选择及扩增。在800nM MTX扩增步骤中,基于旋转器运行中之生长效能及抗体生成而选出一个细胞系,将其冻存于Safety Cell Bank(SCB)中。
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Claims (9)
1.抗体分子,其与人CD37结合且源自以下抗体:
a)如下定义的鼠单克隆抗体:
i)含SEQ ID NO:2所示氨基酸序列的可变重链;及
ii)含SEQ ID NO:4所示氨基酸序列的可变轻链,
其中所述抗体为如下定义的人源化抗体:
a)SEQ ID NO:2所示可变重链中含的CDR,
b)SEQ ID NO:4所示可变轻链中含的CDR,
c)来源于人类抗体、且支撑所述CDR的框架,
d)来自人类抗体的恒定重链及轻链。
2.权利要求1的抗体,其包含具有SEQ ID NO:6所示序列的可变重链和优选地具有SEQ ID NO:12所示序列的可变轻链。
3.权利要求1或2的抗体,其中所述抗体在Fc区有一或多个改变一或多种效应功能的突变,优选地,所述改变效应功能为增加抗体依赖性细胞介导的细胞毒活性。
4.权利要求3的抗体,其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置239及332的取代的组合,或其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置236及332的取代的组合,或其中所述Fc区的一或多个突变是按Kabat EU编号索引编号之位置236、239及332的取代的组合,且其中所述取代优选为I332E、S239D及G236A。
5.抗体,其与人CD37结合且具有含氨基酸序列SEQ ID NO:36的重链和优选地含氨基酸序列SEQ ID NO:38的轻链。
6.抗体,其与人CD37结合且具有含氨基酸序列SEQ ID NO:40的重链和优选地含氨基酸序列SEQ ID NO:42的轻链。
7.DNA分子,其包含编码权利要求1至6中任一项的抗体的可变重链的区。
8.权利要求7的DNA分子,其中该可变重链编码区与编码人类起源的恒定重链的区融合,优选地,该人类恒定重链为IgG1,且优选地,该人类恒定重链在Fc区中具有一或多个按照权利要求4所定义的取代。
9.权利要求8的DNA分子,其中该IgG1由SEQ ID NO:23、或SEQ IDNO:39、或SEQ ID NO:35所示序列编码。
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