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CN1330554A - 接受bmt或pbsc移植患者的抗cd20嵌合抗体治疗 - Google Patents

接受bmt或pbsc移植患者的抗cd20嵌合抗体治疗 Download PDF

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CN1330554A
CN1330554A CN99814330A CN99814330A CN1330554A CN 1330554 A CN1330554 A CN 1330554A CN 99814330 A CN99814330 A CN 99814330A CN 99814330 A CN99814330 A CN 99814330A CN 1330554 A CN1330554 A CN 1330554A
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A·J·格瑞罗-鲁佩兹
J·E·莱昂纳德
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Abstract

本发明公开了抗CD20嵌合抗体RITUXANR,作为在B细胞相关的恶性肿瘤,如B细胞淋巴瘤或白血病的治疗过程中接受了骨髓或外周血干细胞移植的患者的体内或体外清除剂的应用。这种清除可在该患者中增强植入和/或预防疾病复发。

Description

接受BMT或PBSC移植患者的抗CD20嵌合抗体治疗
发明领域
本发明公开了抗CD20嵌合抗体或其片段，作为接受了骨髓移植或外周血干细胞移植的患者的体内或体外清除剂的应用。
发明背景
先前已报道了抗CD20抗原的抗体作为B细胞淋巴瘤的诊断和/或治疗剂的应用。CD20是B细胞淋巴瘤的有用标志或靶标，因为该抗原在恶性B细胞，即其中居高不下的增殖能导致B细胞淋巴瘤的B细胞，的表面以极高的密度表达。
CD20或Bp35是在早期前B细胞发育过程中表达并保持到浆细胞分化的B淋巴细胞限制性分化抗原。一些人认为CD20分子可调节细胞周期起始和分化所必需的B细胞激活过程中的一个步骤。而且，正如指出的那样，CD20通常在赘生性(“肿瘤”)B细胞中以极高水平表达。
先前报道的涉及抗CD20抗体的治疗包括单独施用治疗性抗CD20抗体，或治疗性抗CD20抗体结合第二个放射性标记的抗CD20抗体或化学治疗剂一起施用。
事实上，食品和药物管理局(Food and Drug Administration)已同意了一个这种治疗性抗CD20抗体RITUXAN在复发的以前治疗过的低级非何杰金淋巴瘤(NHL)中的治疗应用。
另外，RITUXAN联合放射性标记的鼠抗CD20抗体也被建议用于治疗B细胞淋巴瘤。
但是，尽管已报道抗CD20抗体特别是RITUXAN，可有效治疗B细胞淋巴瘤如非Hodgkin淋巴瘤，但被治疗的患者常常会有疾病复发。因此，如果可开发更有效的抗体治疗，将会是有益的。更具体地，如果能开发抗CD20抗体的其它治疗应用，将会是有利的。同样，如果能改善B细胞淋巴瘤的现有治疗方法，防止或进一步降低疾病复发，将会是有帮助的。
本发明简述
因此，本发明的目标是改进B细胞相关疾病如B细胞淋巴瘤和白血病的现有治疗方法的问题，特别是疾病治疗后的疾病复发问题。
更具体地，本发明的目标是，通过在移植前、同时和/或之后应用抗CD20抗体作为体外和/或体内清除剂，降低接受骨髓或外周血干细胞移植的B细胞相关疾病患者的疾病复发率。
本发明更具体的目标是，在骨髓或外周血干细胞移植前、同时和/或之后使用RITUXAN作为体外和/或体内清除剂。
本发明详述
治疗涉及表达CD20抗原的B细胞和其它细胞的疾病，包括B细胞淋巴瘤和白血病，有关的一个重要问题是治疗后的疾病复发问题。
疾病复发的确切原因还不清楚。但是，已知这种复发甚至可在接受主动治疗干涉如高剂量的化学治疗剂、细胞因子、放射线、和/或抗体的患者中发生。尽管疾病复发的确切原因还不清楚，但一些研究者推测疾病复发之所以发生，可能是因为患者可能在主动治疗之后仍然含有少量的患病细胞。还推测骨髓移植或外周血干细胞移植的组织可能本身被表达CD20抗原的患病细胞如B细胞淋巴瘤细胞污染。因此，这些组织的移植可能无意地导入了患病细胞，从而事实上增加了疾病复发的危险性。
正如所讨论的，本发明寻求通过用有效清除移植组织的致病性CD20抗原表达细胞的量的抗CD20抗体或其片段，处理移植的骨髓或外周血干细胞，在接受移植骨髓或外周血干细胞的患者中预防或降低疾病的发生。这种清除可在体内和/或体外进行。
例如，移植前骨髓或外周血干细胞在组织培养中可用抗CD20抗体接触。在优选实施方案中，该抗体将包含嵌合、灵长类、灵长类源化(primatized)、人源化或人抗CD20抗体，优选RITUXAN。
替代或结合这种体外清除，可在骨髓或外周血干细胞移植的同时或之后用有效(体内)清除或至少降低可能在该移植物中存在的表达CD20抗原的致病细胞数量的抗CD20抗体量来治疗患者。
同样，用于体内清除的抗体优选包含嵌合、人源化、灵长类、灵长类源化(primatized)、或人抗CD20抗体，优选RITUXAN。该体内清除可在骨髓或外周血干细胞移植的同时或基本同时实施。优选地，该清除可在移植后一周或更长时间内，优选在移植后1到12小时内实施。但是，该清除可在移植后长达约1到100天内实施。在优选实施方案中，体内清除在移植后约1个月内实施，更优选在移植后约1周内实施，最优选在移植后约1到12小时内实施。
正如上面提到的，所述CD20抗原表达细胞的体内或体外清除，期望在先前接受治疗以试图消灭致病性B细胞或疾病中涉及的其它CD20抗原表达细胞的患者中实施。该先前治疗方法包括例如细胞因子治疗、抗体治疗(如RITUXAN或其它靶向B细胞的抗体)、化疗和/或放疗，如全身辐射、放射免疫治疗。
在一个特别优选的实施方案中，所述体内或体外清除将在先前用RITUXAN和/或放射免疫治疗法进行治疗并在RIT和/或RITUXAN治疗后接受了自体骨髓或外周血干细胞移植的患者中实施。
例如，在治疗处理前收集患有B细胞相关疾病如B细胞淋巴瘤或白血病的患者的骨髓或外周血干细胞。这可通过已知方法实施。
然后该患者接受主动治疗方案，如施用RITUXAN或肿瘤细胞表达的抗原特异的放射性标记抗体、全身辐射、和/或化学治疗或细胞因子。该治疗方案将在理论上设计成消灭可能存在的任何B细胞或其它CD20抗原表达肿瘤细胞的条件下实施。
在该治疗完成后，然后将骨髓或外周血干细胞，其可任选性地在体外用抗CD20抗体如RITUXAN处理以消耗CD20表达细胞，移植至患者体内以重建其免疫系统。
同时或其后短时间内，给该患者施用有效清除骨髓或外周血干细胞移植物中存在的任何致病细胞的量的抗CD20抗体如RITUXAN。有效剂量典型地是约0.01-约3.0mg/kg体重。优选剂量是在移植约1周内施用约0.1-约20mg/kg体重，更优选约0.1-约5.0mg/kg体重。
在接受可能污染了致病性细胞的移植细胞的患者完成治疗之后，所述体外和/或体内清除可减少B细胞相关疾病例如B细胞淋巴瘤和白血病如非Hodgkin淋巴瘤、慢性淋巴细胞白血病等的复发危险。
而且，根据抗CD20抗体如RITUXAN的相对无毒性，本发明方法将被很好地耐受，因此应不会对移植的自体细胞的移入有不利影响。事实上，还可促进该移植物的移入。
正如在优选实施方案中所描述的，所述清除剂将包含RITUXAN。但是也可使用其它抗CD20抗体，如其它嵌合、灵长类、灵长类源化、人源化或人抗体。而且，也可使用抗体片段，如Fv’s、FAB、F(ab)’、F(ab2)1和其聚集体。此外，也可使用针对其它B细胞表面标志如CD19的抗体或抗体片段。
制备嵌合、灵长类、灵长类源化、人源化或人抗体的方法是本领域熟知的。见例如，颁发给Queen等的美国专利5,530,101，颁发给Winter等的美国专利5,225,539，分别颁发给Boss等和Cabilly等的美国专利4,816,397和美国专利4,816,567，所有这些均完整地以参考文献方式并入。
人恒定区的选择对于本发明抗CD20抗体的治疗效力可能是重要的。在优选的实施方案中，本发明抗CD20抗体含人γ1或γ3恒定区，更优选人γ1恒定区。γ1抗CD20抗体作为治疗剂的使用公开于颁发给Robinson等的美国专利5,500,362。
制备人抗体的方法也是已知的，包括例如在SCID小鼠中生产和体外免疫。
正如指出的，尤其优选的抗CD20嵌合抗体是RITUXAN，它是嵌合γ1抗人CD20抗体。该抗体的完整氨基酸和相应核酸序列可在美国专利5,736,137中找到，该专利完整地以参考文献方式并入本文。在IDEC制药公司商品化的专利CHO细胞表达系统中产生的该抗体是用CHO细胞转染瘤制备的，该CHO细胞转染瘤根据布达佩斯条约的规定于1992年11月4日保藏在位于12301 Parklawn Drive，Rockville，MD20852的美国典型培养物保藏中心(American TypeCulture Collection)。该细胞系经测定是存活的，而且如果在保藏期间它变得不能存活了，也将更新。该细胞系随着5,736,137专利的公布便不可更改地可为公众所获得，而且可不受限制地从ATCC获得。该细胞系也可在根据本申请可能发布的任何专利的有效期内不受限制地获得。
本发明抗CD20抗体在用作清除剂时可通过各种给药途径给药，典型的途径是肠胃外途径。这应包括静脉内、肌肉内、皮下、直肠、阴道等途径，优选静脉内。
抗CD20抗体可通过标准方法配制用于治疗用途，例如通过添加药学上可接受的缓冲液如无菌盐水、无菌缓冲水、丙二醇、以及它们的组合。
实施例
在166位患有复发或难以治疗的低级或滤泡(low-grade orfollicular)NHL(International Working Formulation[IWF]A-D型和REAL分类，小淋巴细胞淋巴瘤，滤泡中心(Follicularcenter)，滤泡等级I、II、III)的患者中进行每周四次以375mg/m2灌注Rituximab的单臂优势研究(McLaughlin P，Grillo-López A，Link B，Levy R，Czuczman M，Williams M，Heyman M，Bence-Bruckler I，White C，Cabanillas F，Jain V，Ho A，Lister J，Wey K，Shen D，Dallaire B.用于复发的惰性淋巴瘤的Rituximab嵌合抗CD-20单克隆抗体疗法：半数患者对4个剂量的治疗程序有反应，临床肿瘤学杂志(Journal of Clinical Oncology)1998；16：2825-2833)。该研究中排除了肿瘤块＞10cm或外周血中＞5000淋巴细胞/μl的患者。平均年龄是58岁(男性105名，女性61名)，先前治疗的平均次数是3。在149名被评价的患者中有56％存在骨髓疾病。45％患者具有≥2个淋巴结外部位，41％患者患有大体积疾患(≥5cm)。
完全应答要求在颈、胸、腹和骨盆的CT扫描间隔至少28天两次测定显示所有淋巴结退化到＜1×1cm2，淋巴瘤的所有症状和信号的消退，以及骨髓、肝和脾的正常化。部分应答要求持续至少28天在没有疾病发展迹象的情况下损伤垂直测量的乘积之和降低≥50％。没有达到完全应答或部分应答的患者被认为是不应答者，即使观察到可测量疾患的净减少(＞50％)。从第一次灌注至发展测量发展时间。
总应答率(ORR)是48％，其中6％完全应答和42％部分应答(McLaughlin P，Grillo-López A，Link B，Levy R，Czuczman M，Williams M，Heyman M，Bence-Bruckler I，White C，CabanillasF，Jain V，Ho A，Lister J，Wey K，Shen D，Dallaire B.用于复发的惰性淋巴瘤的Rituximab嵌合抗CD-20单克隆抗体疗法：半数患者对4个剂量的治疗程序有反应，临床肿瘤学杂志，1998；16：2825-2833)。对于应答者平均发展时间(TTP)是13.2个月，应答平均持续时间(DR)是11.6个月。在第20.9+至32.9+个月80个应答者中的22个(28％)仍保持疾病消减(McLaughlin P，Grillo-López A，Link B，Levy R，Czuczman M，Cabanillas F，DallaireB，White C，在长期随访的rituximab治疗的患者中对复发或难以治疗的低级或滤泡NHL的有效控制，血液(Blood)1998；92：414a-415a)。
Rituximab的施用导致B细胞的快速持续耗竭。在83％的患者中治疗后循环B细胞在头三个剂量中减少，并持续减少长达6-9个月。平均B细胞水平在治疗后12个月返回正常。尽管平均NK细胞计数保持不变，但在NK细胞基线上的较高绝对计数和对Rituximab的应答之间观察到正相关(Janakiraman N，McLaughlin P，White C，Maloney D，Shen D，Grillo-López A，Rituximab：NHL中效应细胞和临床活性之间的关系，血液1998；92(10 Suppl 1)：337a)。
分析几个基线预后因素以确定它们与应答的相关性。显著地，在23名ABMT或PBSC之后复发的患者中，ORR为78％，相对地在没有经过预先高剂量治疗的患者中ORR为43％(p＜0.01)。这提示，在移植后施用时，抗CD20治疗可有效地用于清除体内CD20抗原表达细胞。而且，因为接受预先高剂量治疗和骨髓或外周干细胞移植的患者表现出比没有接受预先治疗和移植的患者从随后的Rituximab治疗中受益更多，这说明，与任何一种单独治疗相比，包括骨髓或干细胞移植的联合治疗方案提供协同作用。
尽管为清楚和理解的目的，本发明通过说明和实施例相当详细地进行了描述，但应明白在所附权利要求的范围之内进行某些变化和修改是可行的。

Claims (6)

1.在接受骨髓或外周血干细胞移植的患者中降低B细胞相关疾病的复发危险的方法，包括用可有效减少(清除)移植物中致病性CD20抗原表达细胞数的抗CD20抗体量体外和/或体内处理所述移植物。
2.权利要求1的方法，其中所述疾病是B细胞淋巴瘤或白血病。
3.权利要求1的方法，其中所述清除是通过在移植后不迟于约1个月施用RITUXAN来体内实现的。
4.权利要求1的方法，其中RITUXAN在移植后约1周以约0.1-20mg/kg的剂量施用。
5.权利要求4的方法，其中接受移植的患者预先在设计成消灭致病性B细胞的条件下接受处理。
6.权利要求4的方法，其中所述患者预先接受选自全身辐射、RITUXAN免疫治疗、化学治疗、细胞因子治疗和放射免疫治疗或其组合的治疗方案。
CN99814330A 1998-11-09 1999-11-09 接受bmt或pbsc移植患者的抗cd20嵌合抗体治疗 Pending CN1330554A (zh)

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