CN101686971B - 用于治疗多发性骨髓瘤的药物产品及其用途 - Google Patents
用于治疗多发性骨髓瘤的药物产品及其用途 Download PDFInfo
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- CN101686971B CN101686971B CN200780033988XA CN200780033988A CN101686971B CN 101686971 B CN101686971 B CN 101686971B CN 200780033988X A CN200780033988X A CN 200780033988XA CN 200780033988 A CN200780033988 A CN 200780033988A CN 101686971 B CN101686971 B CN 101686971B
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Abstract
适合于治疗受试者中的多发性骨髓瘤的组合物,包含治疗有效量的HuLuc63,治疗有效量的来那度胺和/或硼替佐米,和药物可接受的载体,其中所述组合物能够以单剂量或多剂量方案给予。
Description
1.相关申请的交叉参考
本申请根据35U.S.C.§119(e)要求2006年8月7日提交的申请序列号60/836,185,和2007年6月15日提交的60/944,262的优先权,其内容通过参考并入本文。
2.背景技术
多发性骨髓瘤(“MM”)是指来源于单克隆的浆细胞的恶性增殖。术语多发性骨髓瘤和骨髓瘤可互换地用来指示相同的病症。骨髓瘤、其生成物和针对骨髓瘤的宿主应答导致多种器官的功能障碍和骨痛或骨折的症状,肾衰竭,易感染,贫血,低血钙症,和偶发性凝血异常,神经系统症状和粘滞性过高的血管表现。参见D.Longo,在Harrison′s Principles of Internal Medicine第14版,第713页(McGraw-Hill,New York,1998)。目前尚无针对MM的有效的长期治疗方法。骨髓瘤是浆细胞的恶性疾病,表现为高蛋白血症,贫血,肾功能障碍,骨损害和免疫缺陷。MM难以早期诊断因为在早期阶段可能无症状。如果不提供任何治疗该疾病具有6个月的中位生存期的进行性病程。全身性化学疗法是主要的治疗方法,且目前用化学疗法的中位生存期约为3年,然而少于5%的患者生存超过10年(参见Anderson,K.等人,Annual Meeting Report 1999.Recent Advances in the Biology and Treatment of Multiple Myeloma(1999))。
尽管多发性骨髓瘤被认为是药物敏感性疾病,但是几乎所有最初对化疗有反应的MM患者最终都复发(参见Ander son,K.等人,Annual Meeting Report 1999.Recent Advances in the Biology and Treatment of Multiple Myeloma(1999))。自从对MM引入美法仑和泼尼松疗法,试验了许多多药化学疗法包括长春花生物碱,蒽环类 和基于亚硝基脲的治疗(参见Case,DC等人(1977)Am.J.Med 63:897903),但是过去的三十年里在效果上几乎没有提高(参见Case,DC等人,(1977)Am.J.Med 63:897903;Otsuki,T.等人,(2000)Cancer Res.60:1)。需要新的治疗方法,诸如使用单克隆抗体和治疗剂的联合疗法。
3.概述
本发明描述了用于利用抗-CS1抗体的抗肿瘤特性的组合物和方法。可以用于所述方法和组合物中的抗-CS1抗体在U.S.专利公开号2005/0025763和2006/0024296中描述,其内容通过参考并入本文。抗-CS1抗体靶向CS1(CD2-亚型1),其也已知为SLAMF7、CRACC、19A、APEX-1和FOAP12(Genbank登录号NM_021181.3)。CS1为在来自诊断为MM的患者的骨髓样品中高表达的糖蛋白。在体内和体外研究中,抗-CS1抗体都显示了显著的抗骨髓瘤活性(参见例如US.专利公开号2005/0025763和2006/0024296,其内容通过参考并入本文)。通过实施例的方式,但是并不局限于此,抗-CS1抗体,HuLuc63经由抗体依赖性细胞毒性(ADCC)有效地介导骨髓瘤细胞的胞溶作用(参见,例如,U.S.专利公开号2005/0025763,其内容通过参考并入本文)。在骨髓瘤小鼠的肿瘤模型中,用HuLuc63治疗使瘤体显著缩小超过50%(参见,例如,U.S.专利公开号2005/0025763,其内容通过参考并入本文)。
本发明涉及用于治疗诊断为意义未定的单克隆丙种球蛋白病(Monoclonal Gammopathy of Undetermined Significance,MGUS)、郁积型骨髓瘤、无症状的MM和有症状的MM的患者的组合物和方法,范围从新诊断的至晚期复发/顽固性骨髓瘤。特别是,该方法涉及药物组合物的给予,所述药物组合物包含抗-CS1抗体诸如HuLuc63与一种或多种治疗剂的联合。抗-CS1抗体典型地在第一种药物组合物中作为静脉内输注以范围从0.5至20mg/kg的剂量给予,每周一次至每月一次。
包含一种或多种治疗剂诸如硼替佐米和来那度胺的第二种药物组合物,可以在给予抗-CS1抗体的同时、之前或之后给予。取决于所述药剂,所述组合物可以口服、静脉内或皮下给予。治疗剂可以以高剂量率、标准剂量率和低剂量率使用。
在某些实施方案中,本文所述药物组合物的给予提高了多发性骨髓瘤细胞对治疗剂的敏感性。通过实施例的方式,但是并不局限于此,抗-CS1抗体的包含可以提高治疗剂的活性,使得较低的剂量可以用在本文所述的组合物和方法中。
在某些实施方案中,本文所述药物组合物的给予引发至少一种根据欧洲血液和骨髓移植组织(EBMT)定义的有益反应。例如本文所述药物组合物的给予可以导致完全反应、部分反应、最小反应、无变化或平台期(plateau)。
4.附图说明
图1A-1C描绘了用HuLuc63治疗的MM细胞的自体ADCC-介导的胞溶作用;
图2A-2B描绘了HuLuc63诱导的ADCC,其针对Hsp90和硼替佐米耐药的患者的肿瘤细胞;
图3A-3B描绘了如果将效应细胞用来那度胺预处理,HuLuc63诱导的针对MM细胞的ADCC的提高;
图4A-4D描绘了硼替佐米预处理对HuLuc63介导的ADCC的体外作用。展示了对4个不同的捐献者的实施例;和
图5A-5B描绘了HuLuc63和硼替佐米在罹患OPM2肿瘤的小鼠中的作用。
5.发明详述
本文所述的组合物将抗-CS1抗体与一种或多种治疗剂以特定剂量联合来加强或补充相互的抗骨髓瘤活性。适合的抗-CS1抗体的实例包括,但是并不局限于此,结合一个或多个在CS1上识别的三个抗 原决定簇的经分离的抗体和由杂交瘤细胞系产生的单克隆抗体:Luc2、Luc3、Luc15、Luc22、Luc23、Luc29、Luc32、Luc34、Luc35、Luc37、Luc38、Luc39、Luc56、Luc60、Luc63、Luc69、LucX.1、LucX.2或Luc90。下文中这些单克隆抗体分别称为抗体:Luc2、Luc3、Luc15、Luc22、Luc23、Luc29、Luc32、Luc34、Luc35、Luc37、Luc38、Luc39、Luc56、Luc60、Luc63、Luc69、LucX和Luc90。人源化形式由前缀″hu″表示(参见,例如U.S.专利公开号2005/0025763和2006/0024296,其内容通过参考并入本文)。
在某些实施方案中,适合的抗-CS1抗体包括结合一个或多个在CS1上识别的三个抗原决定簇的经分离的抗体(SEQ ID NO:1,下表1;参见例如U.S.专利公开号2006/0024296,其内容通过参考并入本文)。如在U.S.专利公开号2006/0024296中所公开和以下在表1中所示,CS1抗体结合位点被分为3个抗原决定簇:
(1)由Luc90确定的抗原决定部位,其结合hu50/mu50(SEQ IDNO:2)。该抗原决定部位涵盖了人CS1的自约氨基酸残基23至约氨基酸残基151。该抗原决定部位位于胞外域的结构域1内(V结构域)。该抗原决定部位也由Luc34、LucX(包括LucX.1和LucX.2)和Luc69识别。
(2)由Luc38确定的抗原决定部位,其结合mu25/hu75(SEQ IDNO:3)和hu50/mu50(SEQ ID NO:81)。该抗原决定部位可能涵盖了人CS1的自约氨基酸残基68至约氨基酸残基151。该抗原决定部位也由Luc5识别。
(3)由Luc63确定的抗原决定部位,其结合mu75/hu25(SEQ IDNO:4)。该抗原决定部位涵盖了人CS1的自约氨基酸残基170至约氨基酸残基227。该抗原决定部位位于人CS1的结构域2(C2结构域)内。该抗原决定部位也由Luc4、Luc12、Luc23、Luc29、Luc32和Luc37识别。
所述方法和药物组合物以下将详细论及,但是典型地包含至少一种如上所述的抗-CS1抗体。在某些实施方案中,所述药物组合物包 含抗-CS1抗体HuLuc63。HuLuc63为指向CS1的人源化重组单克隆IgG1抗体。HuLuc63的重链可变区(SEQ ID NO:5)和轻链可变区(SEQID NO:6)的氨基酸序列在U.S.专利公开号2005/0025763中公开,其内容通过参考并入本文,并录入表1中。
表1
SEQ ID NO: | 氨基酸序列 |
SEQ ID NO:1 | Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln Glu Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu Thr Pro Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp Thr Ile Pro His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala Asn Thr Val Tyr Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn Pro His Ser Leu Leu Thr Met Pro Asp Thr Pro Arg Leu Phe Ala Tyr Glu Asn Val Ile |
SEQ ID NO:2 | Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr |
[0025]
SEQ ID NO: | 氨基酸序列 |
Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Ile Asp Arg Gln Ser Asn Lys Asn Gly Thr Cys Val Ile Asn Leu Thr Cys Ser Thr Asp Gln Asp Gly Glu Asn Val Thr Tyr Ser Trp Lys Ala Val Gly Gln Gly Asp Asn Gln Phe His Asp Gly Ala Thr Leu Ser Ile Ala Trp Arg Ser Gly Glu Lys Asp Gln Ala Leu Thr Cys Met Ala Arg Asn Pro Val Ser Asn Ser Phe Ser Thr Pro Val Phe Pro Gln Lys Leu Cys Glu Asp Ala Ala Thr Asp Leu Thr Ser Leu Arg Gly | |
SEQ ID NO:3 | Met Ala Arg Phe Ser Thr Tyr Ile Ile Phe Thr Ser Val Leu Cys Gln Leu Thr Val Thr Ala Ala Ser Gly Thr Leu Lys Lys Val Ala Gly Ala Leu Asp Gly Ser Val Thr Phe Thr Leu Asn Ile Thr Glu Ile Lys Val Asp Tyr Val Val Trp Thr Phe Asn Thr Phe Phe Leu Ala Met Val Lys Lys Asp Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val |
SEQ ID NO:4 | Met Ala Arg Phe Ser Thr Tyr Ile Ile Phe Thr Ser Val Leu Cys Gln Leu Thr Val Thr Ala Ala Ser Gly Thr Leu Lys Lys Val Ala Gly Ala Leu Asp Gly Ser Val Thr Phe Thr Leu Asn Ile Thr Glu Ile Lys Val Asp Tyr Val Val Trp Thr Phe Asn Thr Phe Phe Leu Ala Met Val Lys Lys Asp Gly Val Thr Ser Gln Ser Ser Asn Lys Glu Arg Ile Val Phe Pro Asp Gly Leu Tyr Ser Met Lys Leu Ser Gln Leu Lys Lys Asn Asp Ser Gly Ala Tyr Arg Ala Glu Ile Tyr Ser Thr Ser Ser Gln Ala Ser Leu Ile Gln Glu Tyr Val Leu His Val Tyr Lys His Leu Ser Arg Pro Lys Val Thr Ile Asp Arg Gln Ser Asn Lys Asn Gly Thr Cys Val Ile Asn Leu Thr Cys Ser Thr Asp Gln Asp Gly Glu Asn Val Thr Tyr Ser Trp Lys Ala Val Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys |
[0026]
SEQ ID NO: | 氨基酸序列 |
Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val | |
SEQ ID NO:5 | Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser |
SEQ ID NO:6 | Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys |
在某些剂量下观察到相加效应,在其它剂量下观察到协同效应。在某些实施方案中,所述协同效应允许一种或多种治疗剂与一种或多种抗-CS1抗体联合以减少的剂量给予,而仍保持效能。如果与使用这些药剂有关的副作用是剂量依赖性的,则本文所述的组合物和方法的使用,可以减少在用于治疗MM的传统和新治疗方案中观察到的有害副作用,当这些药剂以推荐剂量给予。
在其它实施方案中,协同效应允许一种或多种治疗剂与一种或多种抗-CS1抗体以批准剂量联合给予,但是具有高于预期的效能。
可以给予所述组合物用来治疗意义未定的单克隆丙种球蛋白病(MGUS)、郁积型骨髓瘤、无症状的MM和有症状的MM,范围从新诊断出的至晚期复发/顽固性的骨髓瘤。典型地,给予所述组合物导致血清或尿中M-蛋白的减少使得观察到由欧洲血液和骨髓移植组织(EBMT)定义的平台期、无变化、最小反应、部分反应或完全反应。
5.2药物组合物
在此提供在使诊断为多发性骨髓瘤的患者中瘤体缩小和/或肿瘤 生长退化方面有利的药物组合物。所述药物组合物的组分以下将详细论及,但是典型地包含抗-CS1抗体诸如HuLuc63和一种或多种治疗剂。在某些实施方案中,所述组合物的不同组分分开地提供。例如,抗-CS1抗体可以在第一种药物组合物中提供,治疗剂可以在第二种组合物中提供。如果所述组合物包含两种或更多种治疗剂,抗-CS1抗体可以在第一种药物组合物中提供,一种治疗剂可以在第二种组合物中提供且另一种治疗剂可以在第三种组合物中提供。在其它实施方案中,抗-CS1抗体可以在一种药物组合物中提供且治疗剂可以组合并在第二种药物组合物中提供。在另一些其它的实施方案中,可以提供包含抗-CS1抗体与一种或多种治疗剂联合的一种组合物。
在典型的实施方案中,抗-CS1抗体以浓度足以允许以0.5mg/kg至20mg/kg静脉内给药的药物组合物存在。在某些实施方案中适合用于所述组合物和方法中的HuLuc63浓度包括,但是并不局限于此,至少约0.5mg/kg,至少约0.75mg/kg,至少约1mg/kg,至少约2mg/kg,至少约2.5mg/kg,至少约3mg/kg,至少约4mg/kg,至少约5mg/kg,至少约6mg/kg,至少约7mg/kg,至少约8mg/kg,至少约9mg/kg,至少约10mg/kg,至少约11mg/kg,至少约12mg/kg,至少约13mg/kg,至少约14mg/kg,至少约15mg/kg,至少约16mg/kg,至少约17mg/kg,至少约18mg/kg,至少约19mg/kg,和至少约20mg/kg。
抗-CS1抗体可以单剂量或多剂量方案给予。通常,抗-CS1抗体在自约1小时至约24小时的时间段内给予,但是典型地在约1至2小时的时间段内给予。剂量可以重复约1周至约4周或更长时间,总共4剂或更多剂。典型地,剂量每周重复一次,每隔一周重复一次,或每月一次,最少4剂至最多52剂。
用抗-CS1抗体治疗的有效剂量、总剂数和治疗时间的长短的确定是在本领域技术人员的能力范围内的,并可以使用标准的剂量递增研究测定最大耐受剂量(MTD)来确定(参见,例如Richardson等人,2002,Blood,100(9):3063-3067,其内容通过参考并入本文)。
在某些实施方案中,一种或多种治疗剂与抗-CS1抗体联合给予。 所述药剂可以在给予抗-CS1抗体的同时、之前或之后给予。
在某些实施方案中,抗-CS1抗体在给予治疗剂之前给予。例如抗-CS1抗体可以在给予治疗剂之前约0至60天给予。在某些实施方案中,抗-CS1抗体诸如HuLuc63,在给予治疗剂之前约30分钟至约1小时,或在给予治疗剂之前约1小时至约2小时,或在给予治疗剂之前约2小时至约4小时,或在给予治疗剂之前约4小时至约6小时,或在给予治疗剂之前约6小时至约8小时,或在给予治疗剂之前约8小时至约16小时,或在给予治疗剂之前约16小时至1天,或在给予治疗剂之前约1至5天,或在给予治疗剂之前约5至10天,或在给予治疗剂之前约10至15天,或在给予治疗剂之前约15至20天,或在给予治疗剂之前约20至30天,或在给予治疗剂之前约30至40天和在给予治疗剂之前约40至50天给予,或在给予治疗剂之前约50至60天给予。
在某些实施方案中,在给予治疗剂的同时给予抗-CS1抗体。
在某些实施方案中,在给予治疗剂之后给予抗-CS1抗体。例如,抗-CS1抗体诸如HuLuc63,可以在给予治疗剂之后约0至60天给予。在某些实施方案中,HuLuc63在给予治疗剂之后约30分钟至约1小时,或在给予治疗剂之后约1小时至约2小时,或在给予治疗剂之后约2小时至约4小时,在给予治疗剂之后约4小时至约6小时,或在给予治疗剂之后约6小时至约8小时,或在给予治疗剂之后约8小时至约16小时,或在给予治疗剂之后约16小时至1天,或在给予治疗剂之后约1天至5天,或在给予治疗剂之后约5天至10天,或在给予治疗剂之后约10天至15天,或在给予治疗剂之后约15天至20天,或在给予治疗剂之后约20天至30天,或在给予治疗剂之后约30天至40天,或在给予治疗剂之后约40天至50天,或在给予治疗剂之后约50天至60天给予。
治疗剂可以以任何临床医生认为适合的方式给药并典型地以通常被接受的有效剂量范围提供,诸如在Physician Desk Reference,第56版(2002),Publisher Medical Economics,New Jersey中描述的那些。在其它实施方案中,可以实施标准剂量递增来确定最大耐受 剂量(MTD)(参见,例如,Richardson,等人,2002,Blood,100(9):3063-3067,其内容通过参考并入本文)。
在某些实施方案中,可以使用低于治疗剂的通常被接受的有效剂量的剂量。例如,在不同的实施方案中,所述组合物包含的剂量低于通常被接受的有效剂量范围的约10%至75%。在某些实施方案中,使用通常被接受的有效剂量范围的至少约10%或更低,至少约15%或更低,至少约25%,至少约30%或更低,至少约40%或更低,至少约50%或更低,至少约60%或更低,至少约75%或更低,和至少约90%。
治疗剂可以单独给予或相继给予,或以与其它治疗剂的混合剂给予,如下述。所述治疗剂可以口服给予、静脉内给予,全身性地通过注射经肌肉、皮下、鞘内或腹膜内给予。
可以用于本文所述的组合物中的治疗剂包括,但是并不局限于此,地塞米松、沙立度胺,美法仑、泼尼松、多柔比星、HCL脂质体注射剂、硼替佐米、来那度胺、和/或它们的组合。
相应地,在某些实施方案中,提供两种药物组合物:第一种包含治疗有效量的抗-CS1抗体诸如HuLuc63,和第二种包含治疗有效量的来那度胺。
在某些实施方案中,提供两种药物组合物:第一种包含治疗有效量的抗-CS1抗体诸如HuLuc63,和第二种包含治疗有效量的硼替佐米。
在某些实施方案中,提供至少两种药物组合物:第一种包含治疗有效量的抗-CS1抗体诸如HuLuc63,和第二种包含治疗有效量的来那度胺和治疗有效量的硼替佐米。在某些实施方案中,来那度胺和硼替佐米分开地提供,使得提供总共三种药物组合物:第一种包含抗-CS1抗体诸如HuLuc63,第二种包含来那度胺和第三种包含硼替佐米。
在某些实施方案中,提供至少两种药物组合物:第一种包含治疗有效量的抗-CS1抗体,诸如HuLuc63和第二种包含治疗有效量的来那度胺和地塞米松。在某些实施方案中,来那度胺和地塞米松分开地提供, 使得提供总共三种药物组合物:第一种包含抗-CS1抗体,诸如HuLuc63,第二种包含来那度胺,和第三种包含地塞米松。
在某些实施方案中提供至少两种药物组合物:第一种包含治疗有效量的抗-CS1抗体,诸如HuLuc63,和第二种包含治疗有效量的硼替佐米和地塞米松。在某些实施方案中,硼替佐米和地塞米松分开地提供,使得提供总共三种药物组合物:第一种包含抗-CS1抗体,诸如HuLuc63,第二种包含硼替佐米,和第三种包含地塞米松。
在某些实施方案中,提供至少两种药物组合物:第一种包含治疗有效量的抗-CS1抗体诸如HuLuc63,和第二种包含治疗有效量的来那度胺、硼替佐米、和地塞米松。在某些实施方案中,来那度胺、硼替佐米、和地塞米松分开地提供。如果所述药剂仍保持它们的效能,可以制备包含其它组分的组合物,部分取决于剂量、给药途径,和所述药剂是以固体、半固体还是液体形式提供。例如,可以制备总共三种组合物:第一种包含治疗有效量的抗-CS1抗体,诸如HuLuc63,第二种包含地塞米松,和第三种包含来那度胺和硼替佐米。
在某些实施方案中,提供至少两种药物组合物:第一种包含治疗有效量的抗-CS1抗体,诸如HuLuc63,和第二种包含治疗有效量的硼替佐米并任选地可以包含一种或多种以下药剂:沙立度胺、地塞米松、美法仑、多柔比星、多柔比星HCl脂质体注射剂、和/或泼尼松。如果所述药剂仍保持它们的效能,可以制备包含沙立度胺、地塞米松、美法仑、多柔比星、多柔比星HCl脂质体注射剂、和泼尼松的不同组合的组合物,部分取决于剂量、给药途径,和所述药剂是以固体、半固体还是液体形式提供。
所述药物组合物可以固体、半固体或液体药物剂型(例如,混悬剂或气雾剂)存在。典型地,所述组合物以适合于精确剂量的单次给药的单位剂型给予。例如抗-CS1抗体可以范围从约1至1000mg的剂量包装。在某些实施方案中,抗-CS1抗体可以剂量至少约1mg,至少约10mg,至少约20mg,至少约50mg,至少约100mg,至少约200mg,至少约300mg,至少约400mg,至少约500mg,至少约750 mg,至少约1000mg包装。
所述组合物还可以包括,取决于所希望的制剂,药物可接受的无毒载体或稀释剂,其定义为通常用于配制用于动物或人给药的药物组合物的赋形剂。以不影响组合物的生物活性为目的来选择稀释剂。这种稀释剂的实例为蒸馏水、生理盐水、Ringer′s溶液、葡萄糖溶液和Hank′s溶液。
此外,所述药物组合物或制剂还可以包括其它载体、辅料或无毒的、非治疗性的、非免疫原性的稳定剂等。这种稀释剂或载体的有效量为有效地获得在组分的溶解性或生物活性方面的药物可接受的制剂的那些量。
5.3方法
本文所述的药物组合物用于治疗MM。典型地所述组合物可以用于治疗意义未定的单克隆丙种球蛋白病(MGUS)、郁积型骨髓瘤、无症状的MM和有症状的MM的患者的组合物和方法,范围从新诊断的至晚期复发/顽固性骨髓瘤。
所述组合物可以与其它治疗措施结合,例如,自体干细胞移植和同种异源效应细胞移植,来开发基于治疗的骨髓瘤的分期的有效治疗措施(参见,例如Multiple Myeloma Research Foundation,MultipleMyeloma:Stem Cell Transplantation 1-30(2004);U.S.PatentNos.6,143,292,和5,928,639,Igarashi,等人,Blood 2004,104(1):170-177,Maloney,等人,2003,Blood,102(9):3447-3454,Badros,等人,2002,J Clin Oncol.,20:1295-1303,Tricot,等人,1996,Blood,87(3):1196-1198;其内容通过参考并入本文)。
自1975年以来最广泛采用的分期系统为Durie-Salmon系统,其中疾病的临床分期(I期,II期,或III期)基于四个衡量指标(参见,例如Durie and Salmon,1975,Cancer,36:842-854)。这四个衡量指标为:(1)血清和/或尿中的单克隆(M)蛋白的水平(也称为副蛋白);(2)溶骨性病变的数量;(3)血红蛋白值和(4)血清钙水平。 根据肾功能可以将这三个期进一步划分,分类为A(相对正常的肾功能血清肌酸酐值<2.0mg/dL)和B(异常的肾功能,肌酸酐值≥2.0mg/dL)。新的更简单的选择为International Staging System(ISS)(参见,例如Greipp等人,2003,″Development of an internationalprognostic index(IPI)for myeloma:report of the internationalmyeloma working group″,The Hematology)。ISS基于评估两项血液测试结果,β2-微球蛋白(β2-M)和白蛋白,其将患者分为与治疗类型无关的三个预后组。
以选择的剂量范围和途径给予药物组合物典型地引发由欧洲血液和骨髓移植组织(EBMT)定义的有益反应。表2列出了对于反应的EBMT标准。
1EBMT:欧洲血液和骨髓移植组织;IBMTR:国际骨髓移植登记处;ABMTR:自体血液和骨髓移植登记处。
2只针对罹患非分泌性骨髓瘤的患者,要求在骨髓中浆细胞减少原始数量的>50%(部分反应)或原始数量的25-49%(最小反应)。
3在非分泌性骨髓瘤中,骨髓浆细胞绝对值应该增加>25%和至少 10%;在选出的患者中MRI检查可能有帮助。
可用于衡量治疗效果的附加标准包括“接近完全反应”和“非常好的部分反应”。“接近完全反应”按照“完全反应”(CR)的标准定义,但是免疫固定试验呈阳性。“非常好的部分反应”定义为M蛋白减少超过90%(参见,例如Multiple Myeloma Research Foundation,Multiple Myeloma:Treatment Overview 9(2005))。
在临床上表现至少一种与MM相关的症状的个体中,给予所述组合物引发的反应达到的程度,部分地取决于疾病的严重性,例如I期、II期、或III期,并部分地取决于患者是新诊断的还是罹患晚期顽固性MM。因此,在某些实施方案中,所述药物组合物的给予引发完全反应。
在其它实施方案中,所述药物组合物的给予引发部分反应或非常好的部分反应。
在其它实施方案中,所述药物组合物的给予引发最小反应。
在其它实施方案中,所述药物组合物的给予阻止疾病发展,导致由EBMT分类为“无变化”或“平台期”的反应。
用于治疗诊断为MM的个体的包含抗-CS1抗体和一种或多种治疗剂的组合物的给药途径和剂量范围,可以使用本领域的标准技术,诸如标准剂量递增研究测定MTD来确定(参见,例如Richardson,等人,2002,Blood,100(9):3063-3067,其内容通过参考并入本文)。
典型地,抗-CS1抗体静脉内给药。本文中所述的其它治疗剂的给药可以通过本领域已知的任何方式。这些方式包括口服、直肠、鼻腔、局部(包括口腔和舌下)或肠胃外(包括皮下、肌肉内、静脉内和真皮内)给药并部分地取决于可获得的药物剂型。例如,可以丸剂或胶囊形式获得的治疗剂典型地口服给予。然而,口服给药通常需要给予相比静脉内给药的剂量较高的剂量。确定在具体情况下最好的实际给药途径是本领域技术人员在其能力范围内的,并部分地取决于需要的剂量与每月需要给予的次数的比较。
影响用在本文所述的组合物和方法中的抗-CS1抗体和治疗剂选 择剂量的因素包括,但是并不局限于此,药剂的类型、接受的患者的年龄、体重和临床症状,和给予治疗的临床医生或执业医师的经验和判断。通常,选择的剂量应该足以导致无变化,但是优选导致至少最小变化。有效量的药剂是提供客观上可辨认的反应,例如,最小反应,部分反应或完全反应,如由临床医生和其他有资格的观察者认定,且如由EBMT定义。
通常,抗-CS1抗体诸如HuLuc63,作为相对于包含治疗剂的组合物独立的组合物给予。如以上所讨论,治疗剂可以分别作为独立的组合物,或组合在混合剂中给予并作为单一的被组合的组合物给予。在某些实施方案中,包含抗-CS1抗体的组合物和一种或多种治疗剂同时给予。在其它实施方案中,抗-CS1抗体可以在给予包含治疗剂的组合物之前给予。在还有其它的实施方案中,抗-CS1抗体在给予包含治疗剂的组合物之后给予。
在给予治疗剂之前或之后给予抗-CS1抗体的那些实施方案中,确定给予抗-CS1抗体和给予所述药剂之间的间隔是在本领域技术人员的能力范围内的,并部分地取决于需要的剂量与每月需要的给药次数的比较。
用于本文所述的抗-CS1抗体的剂量典型地范围在0.5mg/kg至20mg/kg之间。治疗剂的最佳剂量为通常被接受的有效剂量,诸如在the Physician Desk Reference,第56版(2002)Publisher MedicalEconomics,New Jersey中所述的那些。未在Physician DeskReference中描述的药剂的最佳剂量可以使用标准剂量递增研究测定MTD来确定(参见,例如Richardson,等人,2002,Blood,100(9):3063-3067,其内容通过参考并入本文)。
在某些实施方案中,抗-CS1抗体在药物组合物中以浓度,或以重量/体积百分数或以重量,适合于以剂量率至少约0.5mg/kg,至少约0.75mg/kg,至少约1mg/kg,至少约2mg/kg,至少约2.5mg/kg,至少约3mg/kg,至少约4mg/kg,至少约5mg/kg,至少约6mg/kg,至少约7mg/kg,至少约8mg/kg,至少约9mg/kg,至少约10mg/kg, 至少约11mg/kg,至少约12mg/kg,至少约13mg/kg,至少约14mg/kg,至少约15mg/kg,至少约16mg/kg,至少约17mg/kg,至少约18mg/kg,至少约19mg/kg,和至少约20mg/kg静脉内给药来提供。
6.实施例
实施例1:HuLuc63与来那度胺联合
来那度胺是第一种新型的口服癌症药物称为IMiDs。这些免疫调节性衍生物化学上类似沙立度胺但是与沙立度胺相比更有效并具有不同的副作用谱。它们具有多种影响癌细胞和其微环境的作用机理。来那度胺显示引发免疫应答,提高免疫细胞的活性并抑制炎症。例如,来那度胺可以提高T细胞和NK细胞的活化,诱导白介素2的生产并抑制促炎症反应的细胞因子诸如肿瘤坏死因子-α和白介素1-β。目前来那度胺与地塞米松的联用批准为多发性骨髓瘤的第二线疗法。
体外ADCC试验:方法和结果
ADCC通过钙黄绿素-AM释放试验测量,具有类似于传统的Cr51试验的敏感性,如先前所述。在知情同意后,从正常捐献者的白细胞单采术产物中或来自MM患者的外周血中分离出外周血单核细胞(PBMCs)包括天然杀伤(NK)效应细胞。浓度递增(0-10μg/ml)的HuLuc63或人同型对照IgG1 MSL109mAbs以效应细胞:靶点(E∶T)的比为20∶1,添加至200μl每孔的最终体积。在某些实施方案中,在实施HuLuc63-介导的ADCC试验之前,将PBMC效应细胞用来那度胺于0.2μM下预处理3天。在4h的温育后,将100μl的培养上清液转移到BlackViewPlateTM-96平板上并在荧光计(Wallac VICTOR2)上读取任意荧光单位(arbitrary fluorescent units)(AFU)。该试验只有在如果(AFU平均最大释放-介质对照释放)/(AFU平均自发释放-介质对照释放)>7。使用以下的方程式计算由三次重复试验获得的特异性胞溶的%:
%的特异性胞溶=100×(AFU平均实验释放-AFU平均自发释放 1)/(AFU平均最大释放 2-AFU平均自发释放)
1不存在Ab或NK细胞的情形下靶细胞的钙黄绿素-AM释放
2经清洁剂胞溶作用后靶细胞的钙黄绿素-AM释放
通过来自同一患者的效应细胞使用ADCC试验测量患者MM细胞的HuLuc 63-介导的胞溶。HuLuc 63,但不是同型(iso)IgG1,在患者样本中诱导患者中显著的自体骨髓瘤细胞胞溶(图1A-1C)。HuLuc63-介导的自体肿瘤细胞胞溶也在罹患对新的抗-MM疗法包括硼替佐米和/或17-AAG(靶向热休克蛋白90)(图2A和2B)耐药或顽固性MM的患者中证实。这些数据表明HuLuc63可以靶向新诊断的患者或对标准的护理药物和/或新药剂耐药的患者的骨髓瘤细胞。
通过来自同一患者的PBMC效应细胞使用ADCC试验测量患者骨髓瘤细胞的HuLuc63-介导的胞溶。将来自罹患MM的患者CD138-纯化肿瘤细胞与自体效应细胞在HuLuc63(实心符号)或同型对照IgG1(空心符号)的系列稀释的存在下培养。将PBMC效应细胞在来那度胺(0.2mM)(正方形符号)或赋形剂对照(圆形符号)的存在或缺失下预温育3天,随后进行HuLuc63介导的ADCC。HuLuc63-介导的ADCC,但不是同型IgG1,在患者样本中诱导显著的自体骨髓瘤细胞胞溶。用来那度胺预温育PBMC效应细胞显著增加ADCC的活性(图3C)。类似地,用来那度胺预处理效应细胞增加了HuLuc63-诱导的骨髓瘤细胞系的胞溶(图3A和3B)。这些结果提供了在MM中将来那度胺与HuLuc63联合的治疗策略的框架。
实施例2:HuLuc63与硼替佐米联合
硼替佐米是有效的、特异性的和可逆的蛋白酶体抑制剂。蛋白酶体存在于所有细胞中并起帮助调节细胞生长的作用。蛋白酶体的抑制导致癌细胞凋亡。已经表明硼替佐米对杀死骨髓瘤细胞特别有效且目前批准用于多发性骨髓瘤的第二线和第三线疗法。新近的数据显示硼替佐米处理骨髓瘤细胞导致NK功能抑制剂MHC I类的细胞表面表达下调(Shi等人,Blood(ASH Annual Meeting Abstracts),Nov 2006;108:3498)。假设为硼替佐米处理骨髓瘤细胞将使它们对NK-介导的 杀伤更加敏感并因此提高HuLuc63-介导的ADCC。该研究的目的为检验是否HuLuc63与硼替佐米联合使用提供治疗优点。
HuLuc63和硼替佐米治疗对CS1在MM细胞系中的表达和小鼠异种移植肿瘤的作用分别通过流式细胞术和免疫组织化学来检查。
体外ADCC试验:方法和结果
在对数中期采集OPM2肿瘤细胞,以1.0×106个细胞/mL的密度悬浮于完全培养基(RPMI与10%FBS)中并具有或无Velcade(10nM)地处理过夜。将细胞收集、洗涤、以20×106个活细胞/mL的密度重悬,并用50mCiNa2[51Cr]O4每106个细胞标记1小时。将51Cr-标记的细胞洗涤然后以15,000个细胞每75μL补充了10%热灭活的FBS的RPMI的细胞密度添加到96-孔的V-底的聚苯乙烯板上。将HuLuc63和人IgG1同型对照抗体MSL-109添加到靶细胞中使最终抗体浓度范围从0.001至10μg/mL。使用RosetteSep人NK细胞富集混合剂(干细胞技术)从健康捐献者的全血中富集NK细胞。将富集的NK细胞以10∶1的比例添加到Velcade处理过或未处理过的OPM2细胞中。在于37℃温育4小时后,将细胞离心并用上清液测量释放的51Cr。用100mg/ml洋地黄皂甙胞溶靶细胞来测定最大释放。使用靶细胞、加培养基、加NK细胞测定抗体依赖性细胞毒性(AICC),而使用51Cr-标记的细胞加培养基无NK效应细胞测定自发溶解。
%细胞毒性计算为((样本-AICC)/(最大值-AICC)×100。
在OPM2多发性骨髓瘤细胞系上检查CS1蛋白的表达,在用HuLuc63、硼替佐米或用这二种药剂预处理或后处理观察的CS1表达方面无显著变化。然后使用ADCC试验测试HuLuc63与硼替佐米的联合的体外抗骨髓瘤活性。结果表明使用来自健康捐献者的NK效应细胞,用硼替佐米预处理显著提高HuLuc63-介导的针对OPM2细胞的ADCC。将OPM2细胞用赋形剂对照(正方形标记)或硼替佐米(10nM;圆形标记)预处理18小时并接着经受使用来自健康捐献者的人NK细胞的HuLuc63介导的ADCC。HuLuc63(实心符号)和同型对照抗体(空心符 号)以范围从0.001-10μg/ml的剂量使用。结果表明在体外硼替佐米预处理显著降低HuLuc63-介导的ADCC的EC50(图4A-4D,表3)。
体内异种移植小鼠模型:方法和结果
将获自Taconic Farms(Germantown,NY)的六周至八周龄的雌性IcrTac:ICR-Prkdcscid小鼠用1×107OPM2(American Type CultureCollection)细胞接种在右下胁。每周实施两次卡尺测量来使用下式计算肿瘤体积:LxWxH/2,其中L(长度)是在动物背部的平面中肿瘤的最长侧,W(宽度)是与长度垂直并在相同的平面中的最长尺寸和H(高度)在垂直于动物背部的最高点量取。如果肿瘤达到约100mm3的平均大小,将动物随机分为3组每组8-10只小鼠并用1mg/kg抗体处理,每周两次总共6剂腹膜内给予所述抗体。以0.75mg/kg的剂量每周两次总共6剂腹膜内给予硼替佐米。监控肿瘤生长1-2个月的时间。动物操作在NIH指南(″Guide for the Care and Use of LaboratoryAnimals″)的指导下使用由PDL BioPharma的IACUC批准的实验方案进行。
为了检验HuLuc63与硼替佐米的联合疗法的体内效果,将罹患OPM2肿瘤的小鼠用亚最适量的HuLuc63(1mg/kg)或同型对照每周两次治疗三周。硼替佐米以0.75mg/kg每周两次给予接受同型对照抗体或HuLuc63的小鼠。结果显示了单用HuLuc63和与硼替佐米联合的显著的抗肿瘤活性(图5A)。在联合治疗组中的小鼠展示了相比在HuLuc63单一疗法组中平均缩小40-50%的肿瘤,和相比硼替佐米组中缩小60-70%的肿瘤。
在第二个实施方案中,HuLuc63与硼替佐米体内联合,对于硼替佐米使用不同的剂量和给药方案,而保持原始的HuLuc63剂量和剂量 方案。将OPM2细胞接种到SCID小鼠的胁部。如果肿瘤达到约100mm3的平均大小,将动物随机分为4组每组各15只小鼠并用1mg/kg抗体处理,每周两次腹膜内给予总共10剂。将硼替佐米以剂量1mg/kg在第一周和第二周每周两次腹膜内给予,第三周不处理,和在第四周和第五周以1mg/kg每周两次总共给予8剂。该给药方案的目的为更近似地模拟硼替佐米的临床给药方案,其中各个治疗周期包括两周给药,一周不给药。监控肿瘤生长1-2个月的时间。
结果显示单用HuLuc63、单用硼替佐米和HuLuc63与硼替佐米联合的显著抗肿瘤活性(图5B)。联合治疗组中的小鼠相比单用任何药物的小鼠显示了显著较小的肿瘤。数据显示在抗肿瘤活性方面硼替佐米与HuLuc63协同作用。
实施例3:在属于一次或二次复发的多发性骨髓瘤患者中HuLuc63和硼替佐米的1b期、开标(open-label)、剂量递增研究
建议的1b期、多中心、开标、多剂量、剂量递增研究将评价在第一次或第二次复发后的罹患多发性肿瘤的患者中HuLuc63与硼替佐米的联合。HuLuc63通过静脉内注射(IV)以范围从2.5mg/kg至20mg/kg的直至5个剂量水平与以1.0mg/m2的固定剂量的硼替佐米IV联合给予。患者每10天接受HuLuc63且硼替佐米以21-天的周期给予(每周两次给予两周(第1、4、8、11天)接着10-天的休息期(第12-21天))。
在治疗9周后(6剂HuLuc63,3个周期的硼替佐米),评估EBMT标准。如果患者疾病发展,则根据现场研究人员的判断停用HuLuc63且可以撤消或继续使用硼替佐米。如果患者在第9周有反应或疾病稳定,继续给予HuLuc63和硼替佐米以便完成总共24周的治疗(16剂HuLuc63,8个周期的硼替佐米)或至出现疾病发展。继续给予HuLuc63和硼替佐米直至可获得第9周的数据。
患者每10天接受一次HuLuc63 IV,每剂输注超过1小时。将硼替佐米以IVP给予8个三周的周期,每个周期包括在第1、第4、第8 和第11天给予硼替佐米接着10天的休息期(第11至21天)。剂量组如下:2.5mg/kg HuLuc63/1.3mg/m2硼替佐米;5mg/kg HuLuc63/1.3mg/m2硼替佐米;10mg/kg HuLuc63/1.3mg/m2硼替佐米;15mg/kgHuLuc63/1.3mg/m2硼替佐米;和20mg/kg HuLuc63/1.3mg/m2硼替佐米。
HuLuc63以10mg/mL浓度的管形瓶中的静脉内注射制剂提供。硼替佐米在10mL管形瓶中以3.5mg的冻干块状物或粉末提供,并按照Velcade 包装说明书用3.5mL生理盐水(0.9%)、氯化钠注射液重配成3.5mL 1mg/mL的硼替佐米。
在该试验中在5个剂量组登记约15至30个患者。每个剂量组自3个患者开始。如果在治疗的最初6周内在任何患者中都没有发现剂量限制性毒性(DLT),开始登记下一个更高的剂量组,如果一个患者出现DLT,该剂量组将登记3个额外的患者。如果在该剂量组中无其他出现DLT的患者,可以继续增加到下一剂量组。如果在剂量组中第二个患者出现DLT,则达到最大耐受剂量(MTD)。
剂量限制性毒性(DLT)使用国家癌症中心研究所通用毒性标准3.0版(NCI CTCAE v3.0)定义为4级血液学毒性或高胆红素血症,或3级毒性在视为与HuLuc63或HuLuc63与硼替佐米的联合有关的任何系统中。对于剂量递增至下一剂量组,三个可评估的患者必需完成他们最初6周(4剂HuLuc63,2个周期的硼替佐米)的治疗。如果出现DLT,则增加额外的三个可评估的患者。通过评估由NCI CTCAE v3.0分类的不良事件对患者进行安全性监控并使用EBMT对患者监控临床有效性。最大耐受剂量(MTD)定义为研究的DLTs的发生率≤33%的最高剂量。如果未观察到剂量限制性毒性,最高耐受剂量为HuLuc63 20mg/kg+硼替佐米1.0mg/m2。
实施例4:HuLuc63和来那度胺的1b期、多中心、开标、剂量递增研究
建议的1b期、多中心、开标、多剂量、剂量递增研究将评价在第 一次或第二次复发的罹患多发性肿瘤的患者中HuLuc63与来那度胺的联合。HuLuc63通过静脉内注射(IV)以范围从2.5mg/kg至20mg/kg的直至5个剂量水平与以15mg的固定剂量的PO来那度胺联合给予。患者每7天将接受HuLuc63且来那度胺将以28-天的周期给予(每日1次给予21天接着7-天的休息期(第22-28天))。
治疗8周后(8剂HuLuc63,2个周期的来那度胺),评估EBMT标准。将地塞米松以每日40mg的口服剂量在4-周的周期的第1,8,15和22天添加到该方案中。如果在第12周(12剂HuLuc63,3个周期的来那度胺,1个周期的地塞米松)有证据表明疾病发展,则根据现场研究人员的判断将停用HuLuc63且来那度胺和地塞米松将继续直至16周。如果患者疾病稳定或改善,则HuLuc63继续至第16周(15个总剂量)或至疾病发展。在第16周评价EMBT标准。
患者每10天接受一次HuLuc63 IV,每剂输注超过1小时。每日口服给予来那度胺3周,接着为时一周的休息期。剂量组如下:2.5mg/kg HuLuc63/15mg来那度胺;5mg/kg HuLuc63/15mg来那度胺;10mg/kg HuLuc63/15mg来那度胺;15mg/kg HuLuc63/15mg来那度胺;和20mg/kg HuLuc63/15mg来那度胺。在第8周后,将地塞米松以每日40mg的口服剂量在4周的周期的第1,8,15和22日添加到上述方案中。
HuLuc63以10mg/mL浓度的在管形瓶中的静脉内注射制剂提供。来那度胺以口服给药的5mg和10mg的胶囊提供。
在该试验中在5个剂量组登记约15至30个患者。每个剂量组自3个患者开始。如果在治疗的最初4周内在任何患者中都没有发现剂量限制性毒性(DLT),开始登记下一个更高的剂量组,如果一个患者出现DLT,该剂量组将登记3个额外的患者。如果在该剂量组中无其他出现DLT的患者,可以继续增加到下一剂量组。如果在剂量组中第二个患者出现DLT,则达到最大耐受剂量(MTD)。
剂量限制性毒性(DLT)使用国家癌症中心研究所通用毒性标准3.0版(NCI CTCAE v3.0)定义为4级血液学毒性或高胆红素血症, 或3级毒性在视为与HuLuc63或HuLuc63与来那度胺的联合有关的任何系统中。对于剂量递增至下一剂量组,三个可评估的患者必需完成他们最初4周(4剂HuLuc63,1个周期的来那度胺)的治疗。如果出现DLT,则增加额外的三个可评估的患者。通过评估由NCI CTCAE v3.0分类的不良事件对患者进行安全性监控并使用EBMT对患者监控临床有效性。最大耐受剂量(MTD)定义为研究的DLTs的发生率≤33%的最高剂量。如果未观察到剂量限制性毒性,最高耐受剂量为HuLuc63 20mg/kg+来那度胺15mg。
本申请中引用的所有出版物、专利、专利申请和其它文件对于相同范围的所有目的的全部通过参考并入本申请,如同将各个出版物、专利、专利申请或其它文件对于所有目的单独说明的那样。
说明并描述了不同的具体实施方案,在不偏离本发明的精神和范围的情况下可以实施不同的变化。
Claims (11)
1.用于治疗多发性骨髓瘤的药物产品,其包含HuLuc63和来那度胺,其中HuLuc63为人源化IgG1抗体,其具有SEQ ID NO:5的重链可变区和SEQ I D NO:6的轻链可变区,其中在给予HuLuc63的同时、之前或之后给予来那度胺。
2.根据权利要求1的药物产品,在第一种药物组合物中提供HuLuc63和在第二种药物组合物中提供来那度胺。
3.根据权利要求1-2之一的药物产品,其进一步包含地塞米松,其中在给予HuLuc63的同时、之前或之后给予来那度胺和地塞米松。
4.根据权利要求1-2之一的药物产品,其中HuLuc63作为静脉内输注以0.5mg/kg至20mg/kg的剂量给予。
5.根据权利要求1-2之一的药物产品,其中来那度胺以1mg/日至50mg/日的剂量口服给予。
6.根据权利要求1-2之一的药物产品,其中所述第一种药物组合物和第二种药物组合物各自还含有药学可接受的载体。
7.包含HuLuc63的第一种药物组合物和包含来那度胺的第二种药物组合物用于制备治疗多发性骨髓瘤的药物的用途,其中HuLuc63为人源化IgG1抗体,其具有SEQ ID NO:5的重链可变区和SEQ ID NO:6的轻链可变区,其中在给予第二种药物组合物的同时、之前或之后给予第一种药物组合物。
8.包含HuLuc63的第一种药物组合物和包含来那度胺的第二种药物组合物与包含地塞米松的第三种药物组合物联合用于制备治疗多发性骨髓瘤的药物的用途,其中HuLuc63为人源化IgG1抗体,其具有SEQID NO:5的重链可变区和SEQ ID NO:6的轻链可变区,其中在给予第二种药物组合物的同时、之前或之后给予第一种药物组合物。
9.根据权利要求7或8的用途,其中HuLuc63作为静脉内输注以0.5mg/kg至20mg/kg的剂量给予。
10.根据权利要求7或8的用途,其中来那度胺以1mg/日至50mg/日的剂量口服给予。
11.根据权利要求7或8的用途,其中所述第一种药物组合物和所述第二种药物组合物各自还含有药学可接受的载体。
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