CN102264385B - 含特异性识别cd38的抗体和苯丙氨酸氮芥的抗肿瘤组合 - Google Patents
含特异性识别cd38的抗体和苯丙氨酸氮芥的抗肿瘤组合 Download PDFInfo
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Abstract
包含特异性识别CD38的抗体和苯丙氨酸氮芥的药物组合物。
Description
本发明涉及针对CD38的单克隆抗体和苯丙氨酸氮芥的组合,其在肿瘤疾病的治疗中是治疗上有用的。
CD38是带有长C-端胞外域和短N-端胞质域的45kD II型跨膜糖蛋白。CD38蛋白是双功能胞外酶,其可催化NAD+转化成环ADP-核糖(cADPR)并且还将cADPR水解为ADP-核糖。CD38在许多造血恶性肿瘤中被上调,并已涉及其中。
特异性识别CD38的单克隆抗体38SB13、38SB18、38SB19、38SB30、38SB31和38SB39参见PCT申请WO2008/047242。所述抗CD38抗体能够通过三种不同细胞毒性机制即细胞凋亡的诱导、抗体依赖性细胞介导的细胞毒性作用(ADCC)和补体依赖的细胞毒作用(CDC)杀死CD38+细胞。此外,即便不存在基质细胞或基质衍生细胞因子,这些抗体也能够直接诱导CD38+细胞的凋亡。苯丙氨酸氮芥是化学治疗中所用的烷化剂。然而,仍然需要新型有效的用于治疗癌症的药物。
对于本发明,现在已发现:当将人源化抗CD38抗体与在抗癌治疗中是治疗上有用的并具有与人源化抗CD38抗体之一相同或不同的机制且在本发明中限定为苯丙氨酸氮芥的至少一种物质联合给药时,其功效可被显著提高。
术语“抗体”在本文中以最广含义使用,并特别涵盖任意同种型如IgG、IgM、IgA、IgD和IgE的单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体、嵌合抗体和抗体片段。典型的IgG抗体由通过二硫键连接的两条相同重链和两条相同轻链构成。每条重链和轻链包含恒定区和可变区。每个可变区包含三个称为“互补决定区”(“CDR”)或“高变区”的区段,它们主要负责结合抗原表位。它们通常被称为CDR1、CDR2和CDR3,从N-端按顺序编号。可变区除CDR之外的更高度保守部分称作“构架区”。
本文所用″VH″或″VH″指抗体免疫球蛋白重链(包括Fv、scFv、dsFv、Fab、Fab′或F(ab′)2片段的重链)的可变区。提及″VL″或″VL″是指抗体免疫球蛋白轻链(包括Fv、scFv、dsFv、Fab、Fab′或F(ab′)2片段的轻链)的可变区。
38SB13抗体包括至少一个具有由SEQ ID NO:50组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:38组成的氨基酸序列的轻链,所述重链包括具有由SEQ ID NO:1、2和3组成的氨基酸序列的三个顺序CDR,且所述轻链包括具有由SEQ ID NO:4、5和6组成的氨基酸序列的三个顺序CDR。
38SB18抗体包括至少一个具有由SEQ ID NO:52组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:40组成的氨基酸序列的轻链,所述重链包括具有由SEQ ID NO:7、8和9组成的氨基酸序列的三个顺序CDR,且所述轻链包括具有由SEQ ID NO:10、11和12组成的氨基酸序列的三个顺序CDR。
38SB19抗体包括至少一个具有由SEQ ID NO:54组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:42组成的氨基酸序列的轻链,所述重链包括具有由SEQ ID NO:13、14和15组成的氨基酸序列的三个顺序CDR,且所述轻链包括具有由SEQ ID NO:16、17和18组成的氨基酸序列的三个顺序CDR。
38SB30抗体包括至少一个具有由SEQ ID NO:56组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:44组成的氨基酸序列的轻链,所述重链包括具有由SEQ ID NO:19、20和21组成的氨基酸序列的三个顺序CDR,且所述轻链包括具有由SEQ ID NO:22、23和24组成的氨基酸序列的三个顺序CDR。
38SB31抗体包括至少一个具有由SEQ ID NO:58组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:46组成的氨基酸序列的轻链,所述重链包括具有由SEQ ID NO:25、26和27组成的氨基酸序列的三个顺序CDR,且所述轻链包括具有由SEQ ID NO:28、29和30组成的氨基酸序列的三个顺序CDR。
38SB39抗体包括至少一个具有由SEQ ID NO:60组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:48组成的氨基酸序列的轻链,所述重链包括具有由SEQ ID NO:31、32和33组成的氨基酸序列的三个顺序CDR,且所述轻链包括具有由SEQ ID NO:34、35和36组成的氨基酸序列的三个顺序CDR。
产生38SB13、38SB18、38SB19、38SB30、38SB31和38SB39鼠抗CD38抗体的杂交瘤细胞系已于2006年6月21日保藏于美国典型培养物保藏中心(10801 University Bld,Manassas,VA,20110-2209,USA),保藏编号分别为PTA-7667、PTA-7669、PTA-7670、PTA-7666、PTA-7668和PTA-7671(如WO2008/047242中所述)。
本文所用术语“人源化抗体”指含有源自非人免疫球蛋白最小序列的嵌合抗体。人源化目的是减少异种抗体如鼠抗体的免疫原性以引入人体内,同时保留抗体的全部抗原结合亲和性和特异性。人源化抗体或改造为不被其他哺乳动物排斥的抗体可利用数种技术如表面重塑(resurfacing)和CDR移植(CDR grafting)产生。本文所用表面重塑技术利用制作分子模型、统计分析和诱变的组合改变抗体可变区的非CDR表面,以模拟已知靶宿主抗体的表面。CDR移植技术涉及将例如小鼠抗体的互补决定区替换到人构架结构域中,例如参见WO 92/22653。人源化嵌合抗体优选具有基本上或唯独地源自相应人抗体区域的恒定区和可变区(互补决定区(CDR)除外),以及基本上或唯独地源自非人哺乳动物的CDR。
抗体表面重塑的策略和方法以及用于减少抗体在不同宿主中的免疫原性的其他方法公开于美国专利5,639,641,其整体通过引用结合到本文中。抗体可利用多种其他技术人源化,包括CDR移植(EP 0239 400;WO 91/09967;美国专利号5,530,101和5,585,089)、镶饰或表面重塑(EP 0 592 106;EP 0 519 596;Padlan E.A.,1991,MolecularImmunology 28(4/5):489-498;Studnicka G.M.等,1994,ProteinEngineering,7(6):805-814;Roguska M.A.等,1994,PNAS,91:969-973)、链改组(美国专利号5,565,332)和柔性残基鉴定(PCT/US2008/074381)。人抗体可通过包括噬菌体展示法在内的多种本领域已知方法产生。亦参见美国专利号4,444,887、4,716,111、5,545,806和5,814,318;以及国际专利申请公开号WO 98/46645、WO 98/50433、WO 98/24893、WO 98/16654、WO 96/34096、WO96/33735和WO 91/10741(所述文献通过引用以其整体结合)。
本发明的药学组合中的抗CD38抗体是人源化抗体,其识别CD38并通过细胞凋亡、ADCC和CDC杀死CD38+细胞。在另一实施方案中,即便不存在基质细胞或基质衍生细胞因子,本发明的人源化抗体也能够通过细胞凋亡杀死所述CD38+细胞。
这样的人源化抗体的优选实施方案是人源化38SB13、38SB18、38SB19、38SB30、38SB31或38SB39抗体,或者其表位结合片段。
通过建模鉴定38SB13、38SB18、38SB19、38SB30、38SB31和38SB39抗体的CDR,并已预测它们的分子结构。因此,在一个实施方案中,本发明提供包括一个或多个具有选自SEQ ID NO:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35和36的氨基酸序列的CDR的人源化抗体或其表位结合片段。在优选实施方案中,提供一种人源化形式的38SB13,其包括至少一个重链和至少一个轻链,其中所述重链包括具有由SEQ IDNO:1、2和3表示的氨基酸序列的三个顺序互补决定区,且所述轻链包括具有由SEQ ID NO:4、5和6表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中,提供一种人源化形式的38SB18,其包括至少一个重链和至少一个轻链,其中所述重链包括具有由SEQ ID NO:7、8和9表示的氨基酸序列的三个顺序互补决定区,且所述轻链包括具有由SEQ ID NO:10、11和12表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中,提供一种人源化形式的38SB19,其包括至少一个重链和至少一个轻链,其中所述重链包括具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区,且所述轻链包括具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中,提供一种人源化形式的38SB30,其包括至少一个重链和至少一个轻链,其中所述重链包括具有由SEQ ID NO:19、20和21表示的氨基酸序列的三个顺序互补决定区,且所述轻链包括具有由SEQ IDNO:22、23和24表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中,提供一种人源化形式的38SB31,其包括至少一个重链和至少一个轻链,其中所述重链包括具有由SEQ ID NO:25、26和27表示的氨基酸序列的三个顺序互补决定区,且所述轻链包括具有由SEQ ID NO:28、29和30表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中,提供一种人源化形式的38SB39,其包括至少一个重链和至少一个轻链,其中所述重链包括具有由SEQID NO:31、32和33表示的氨基酸序列的三个顺序互补决定区,且所述轻链包括具有由SEQ ID NO:34、35和36表示的氨基酸序列的三个顺序互补决定区。
在一个实施方案中,本发明提供包括具有选自SEQ ID NO:66和72的氨基酸序列的VH的人源化抗体或其片段。在优选实施方案中,提供包括具有由SEQ ID NO:66表示的氨基酸序列的VH的人源化38SB19抗体。在另一优选实施方案中,提供包括具有由SEQ ID NO:72表示的氨基酸序列的VH的人源化38SB31抗体。
在另一实施方案中,本发明提供包括具有选自SEQ ID NO:62、64、68和70的氨基酸序列的VL的人源化抗体或其片段。在优选实施方案中,提供包括具有选自SEQ ID NO:62和64的氨基酸序列的VL的人源化38SB19抗体。在另一优选实施方案中,提供包括具有选自SEQ ID NO:68和70的氨基酸序列的VL的人源化38SB31抗体。
已表明,每种人源化形式的38SB13、38SB18、38SB19、38SB30、38SB31和38SB39抗体作为抗癌剂是特别有利的。它们的制备、物理性质和有益药学性质参见WO 2008/047242,通过引用以其整体结合到本文中。一般而言,用于治疗人的剂量为1-150mg/kg(口服给药)或1-150mg/kg(静脉内给药),视因待治疗受试者而不同的因素而定。
苯丙氨酸氮芥(商标AlkeranTM)是属于氮芥烷化剂类的化学治疗药物。别名为L-苯丙氨酸氮芥或L-PAM,苯丙氨酸氮芥是双氯乙基甲胺的苯丙氨酸衍生物和双功能烷化剂。从两个双-2-氯乙基中的每个形成碳中间体使得能够通过与DNA上鸟嘌呤的7-氮共价结合而烷化、交联两条DNA链和由此防止细胞复制。苯丙氨酸氮芥主要用于治疗多发性骨髓瘤和卵巢癌,偶尔用于治疗恶性黑色素瘤。其通常口服给药或静脉内给药。
本发明一个方面是包含与至少苯丙氨酸氮芥联合的抗CD38抗体的药物组合物。由于制品活性取决于所用剂量,所以可能的是使用较小剂量和提高活性,同时减少毒性现象。本发明组合的提高的功效可通过确定治疗协同作用来证明。如果在治疗上优于以其最大耐受剂量或其在动物物种中不能达到毒性时测试的最高剂量单独使用受试最佳药剂,则组合表现出治疗协同作用。
该功效可量化,例如通过log10细胞杀伤,其根据下式确定:
log10细胞杀伤=T-C(天数)/3.32×Td
其中,T-C表示肿瘤生长延迟,是治疗组(T)肿瘤和对照组(C)肿瘤达到预定值(例如1g)以天数计的中位数时间,Td表示对照动物中肿瘤体积加倍所需以天数计的时间[T.H.Corbett等,Cancer,40:2660-2680(1977);F.M.Schabel等,Cancer Drug Development,B部分,Methods in Cancer Research,17:3-51,New York,Academic Press Inc.(1979)]。如果log10细胞杀伤大于等于0.7,那么制品被视为有活性。如果log10细胞杀伤大于2.8,那么制品被视为非常有活性。
当log10细胞杀伤大于最佳成分单独给药且以其最大耐受剂量或其最高受试剂量使用时的log10细胞杀伤值时,组合将表现治疗协同作用。
组合对实体瘤的功效可通过下述方式进行实验测定:
在第0天用30-60mg肿瘤碎片双侧皮下移植接受实验的动物(通常为小鼠)。在经历各种治疗和对照前,基于它们的肿瘤大小将荷瘤动物随机化。当移植后肿瘤已达到预定大小(取决于肿瘤类型)时,开始化学治疗,并每天观察动物。在治疗过程中,每天对不同动物组称重,直到达到最大体重减轻且已发生随后的完全体重恢复。之后每周称重组别一次或两次,直到试验结束。
根据肿瘤加倍时间,每周测量肿瘤1-5次,直到肿瘤达到约2g,或直到动物死亡(如果这发生在肿瘤达到2g之前)。在安乐死或死亡后,立即对动物进行尸体剖检。
依据记录的不同参数确定抗肿瘤活性。
利用hu38SB19和苯丙氨酸氮芥以它们的最佳剂量使用的组合所得结果在下文作为实施例表示。
因此,本发明还涉及包含本发明组合的药物组合物。
构成组合的成分可同时、半同时、单独或间隔一段时间给药,以便获得组合的最大功效;可能的是,每次给药在快速给药和连续灌注之间改变其持续时间。
因此,为本发明之目的,组合不唯独限于通过成分的物理关联获得的那些组合,而且还为允许可同时或间隔一段时间的单独给药的那些组合。
本发明组合物优选为可胃肠外(parentally)给药的组合物。但是,在局限区域疗法(localized regional therapy)的情况下,这些组合物可口服、皮下或腹膜内给药。
用于胃肠外给药的组合物通常是药学上可接受的无菌溶液剂或混悬剂,其可任选地在使用时按需制备。为制备非水溶液剂或混悬剂,可使用天然植物油(例如橄榄油、芝麻油)或液化石蜡(liquidpetroleum)或可注射有机酯(例如油酸乙酯)。无菌水溶液剂可由制品在水中的溶液构成。如果适当调节pH,且例如用足够量的氯化钠或葡萄糖使溶液等渗,则水溶液剂适合静脉内给药。灭菌可通过加热或通过不有害地影响组合物的任意其他方法进行。组合亦可采用脂质体形式或与载体如环糊精或聚乙二醇联合的形式。
用于口服、皮下或腹膜内给药的组合物优选为水混悬剂或溶液剂。
在本发明组合(其成分可同时、单独或间隔一段时间施用)中,尤其有利的是人源化抗CD38抗体的量表示为10-90%的组合重量,该含量可依据联合物质的性质、所需功效和待治疗癌症的性质而变化。
本发明组合尤其可用于包括(但不限于)下述的数种癌症类型的治疗:癌和腺癌,包括膀胱、乳腺、结肠、头颈、前列腺、肾、肝、肺、卵巢、胰腺、胃、子宫颈、甲状腺和皮肤的癌,以及包括鳞状细胞癌;淋巴系造血肿瘤,包括多发性骨髓瘤、白血病、急性和慢性淋巴细胞性(淋巴系)白血病、急性和慢性成淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、非Hodgkin淋巴瘤(例如Burkitt淋巴瘤);骨髓系造血肿瘤,包括急性和慢性髓细胞性(骨髓或髓细胞的)白血病和前髓细胞性白血病;间质起源的肿瘤,包括纤维肉瘤、骨肉瘤和横纹肌肉瘤;中枢和外周神经系统肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;和其他肿瘤,包括黑色素瘤、畸胎癌、着色性干皮病、角化棘皮瘤和精原细胞瘤,以及表达CD38的尚未被确定的其他癌症。它们主要可用于治疗白血病、淋巴瘤和对常用抗癌剂产生抗性的癌症,因为本发明的抗CD38抗体具有独特的作用机制。
因此,本发明还包括上述组合在制备用于治疗癌症的药物中的用途。
实施例:
在该实施例中,体内证明了本发明的抗CD38抗体/苯丙氨酸氮芥组合对肿瘤生长抑制的有效性。
首先选择的肿瘤模型是植入SCID小鼠的可移植的人多发性骨髓瘤细胞系RPMI-8226。
在不含Ca2+和Mg2+、pH 7.4的磷酸盐缓冲液中配制hu38SB19。在肿瘤植入后的第16、19、22、25天静脉内给予hu38SB19。
在5%乙醇、5%聚山梨酯80、90%含0.9%氯化钠的水中配制苯丙氨酸氮芥。在肿瘤植入后的第16、19、22、25天与hu38SB19同时静脉内给予苯丙氨酸氮芥(除了在达到毒性时在第19天停止治疗的组合的最高剂量)。
实验结果汇总于表1。
肿瘤加倍时间=3.2天。
已利用下述终点:
●在诱导≥20%体重减轻或10%药物死亡的剂量下表明毒性,
●通过计算log10细胞杀伤=(T-C)/[3.32x(以天数计的肿瘤加倍时间)]测定抗肿瘤功效
(T指受治疗小鼠达到1000mg的中位数时间,C指对照小鼠达到相同大小的中位数时间(25.3天);从这些计算中排除无肿瘤存活小鼠,并单独列表显示)。log细胞杀伤<0.7表明无抗肿瘤活性,log细胞杀伤≥2.8表明治疗非常有效
●无肿瘤存活小鼠(TFS):对应于在整个研究持续期间(最后一次治疗后>100天)内低于触诊限(63mg)的完全消退。
●治疗协同作用:如果其比最佳单一受试药剂更具活性(大至少1log细胞杀伤),则组合具有治疗协同作用。
在16.1mg/kg/注射的剂量下观察到苯丙氨酸氮芥单独使用的毒性为5只小鼠中3只药物相关死亡,即超出10%阈值。苯丙氨酸氮芥的最高无毒剂量(HNTD)是10mg/kg/注射(总注射剂量=40mg/kg)。发现10mg/kg/注射的剂量的活性为1.9的log细胞杀伤。
至于hu38SB19,该制品在40mg/kg/注射的剂量下良好耐受。未观察到毒性,这可通过缺乏抗体与鼠CD38的交叉反应性解释。log细胞杀伤为0.5,表明hu38DB19在这些条件下无活性。
16.1mg/kg/注射的苯丙氨酸氮芥与40mg/kg/注射的hu38SB19组合的毒性为5只中5只药物相关死亡,即与苯丙氨酸氮芥以相同剂量单独使用时的观察结果非常相似。10mg/kg/注射的苯丙氨酸氮芥与40mg/kg/注射的hu38SB19的剂量被认为是HNTD。在该剂量下,log细胞杀伤是2.2,表明组合与最佳药剂即苯丙氨酸氮芥活性相同。
另一实验利用LP1进行,LP1是相比RPMI-8226对苯丙氨酸氮芥高度敏感的人多发性骨髓瘤模型。将模型植入SCID小鼠。
在含5%葡萄糖的水中配制hu38SB19。在肿瘤植入后的第12、15、18、21天静脉内给予hu38SB19。
在5%乙醇、5%聚山梨酯80、90%含0.9%氯化钠的水中配制苯丙氨酸氮芥。在肿瘤植入后的第12、15、18、21天与hu38SB19同时静脉内给予苯丙氨酸氮芥。
实验结果汇总于表2。
肿瘤加倍时间=1.5天。
已利用下述终点:
●在诱导≥20%体重减轻或10%药物死亡的剂量下表明毒性,
●通过计算log10细胞杀伤=(T-C)/[3.32x(以天数计的肿瘤加倍时间)]测定抗肿瘤功效
(T指受治疗小鼠达到1000mg的中位数时间,C指对照小鼠达到相同大小的中位数时间(16.8天);从这些计算中排除无肿瘤存活小鼠,并单独列表显示)。log细胞杀伤<0.7表明无抗肿瘤活性,log细胞杀伤≥2.8表明治疗非常有效
●治疗协同作用:如果其比最佳单一受试药剂更具活性(大至少1log细胞杀伤),则组合具有治疗协同作用。
在16.1mg/kg/注射的剂量下观察到苯丙氨酸氮芥单独使用的毒性为第22天最低点的33.6%体重减轻,即超出20%阈值和4/5的药物相关死亡。苯丙氨酸氮芥的HNTD是10mg/kg/注射(总注射剂量=40mg/kg)。发现10mg/kg/注射的剂量具有9.3log细胞杀伤的高度活性。
至于hu38SB19,该制品在40mg/kg/注射的剂量下良好耐受。未观察到毒性,这可通过缺乏抗体与鼠CD38的交叉反应性解释。log细胞杀伤为0.2,表明hu38DB19在这些条件下无活性。
16.1mg/kg/注射的苯丙氨酸氮芥与40mg/kg/注射的hu38SB19组合的毒性为第22天最低点的33.6%体重减轻和5/5药物相关死亡,即与苯丙氨酸氮芥以相同剂量单独使用时的观察结果非常相似。10mg/kg/注射的苯丙氨酸氮芥与40mg/kg/注射的hu38SB19的剂量被认为是最高无毒剂量。显著的是,该剂量表现出18.9log细胞杀伤(和第148天1/5TFS)的高抗肿瘤功效,证明了相比苯丙氨酸氮芥单独使用的HNTD(9.3log细胞杀伤)的治疗协同作用。相比苯丙氨酸氮芥单独使用的等同毒性剂量,在组合的较低剂量水平下保持了治疗协同作用。
Claims (5)
1.一种用于制备治疗癌症的药物的药物组合产品,其中所述癌症表达CD38+,其中所述药物组合产品包含特异性识别CD38的抗体和至少苯丙氨酸氮芥,其中所述抗体能够通过凋亡、抗体依赖性细胞介导的细胞毒性、和补体依赖性细胞毒性来杀死CD38+细胞,
其中所述抗体是鼠38SB19抗体的人源化形式,其中所述鼠38SB19抗体的重链包含三个序贯的CDR,并且其中所述鼠38SB19抗体重链中的所述三个贯序的CDR的氨基酸序列是SEQ ID NOS:13、14和15,并且其中所述鼠38SB19抗体的轻链包含三个序贯的CDR,并且其中所述鼠38SB19抗体轻链中的所述三个贯序的CDR的氨基酸序列是SEQ ID NOS:16、17和18;
并且其中所述组合允许所述抗体和苯丙氨酸氮芥的单独给药。
2.权利要求1的组合产品,其中所述抗体包含至少一条重链和至少一条轻链,其中所述重链的可变区由SEQ ID NO:66所示氨基酸序列组成,且其中所述轻链的可变区由选自SEQ ID NO:62和64的氨基酸序列组成。
3.权利要求2的药物组合产品,其包含特异性识别CD38的抗体和至少苯丙氨酸氮芥,其中所述抗体由下列组成:
-轻链,其中所述轻链的可变区由SEQ ID NOS:62的氨基酸序列组成;和
-重链,其中所述重链的可变区由SEQ ID NOS:66的氨基酸序列组成。
4.权利要求1-3任一项的组合产品,其中所述组合的成分单独给药。
5.权利要求1-3任一项的组合产品,其中所述组合的成分同时给药。
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