CN1679934B - 使用抗cd20嵌合抗体治疗循环肿瘤细胞相关的血液恶性肿瘤 - Google Patents

使用抗cd20嵌合抗体治疗循环肿瘤细胞相关的血液恶性肿瘤 Download PDF

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CN1679934B
CN1679934B CN2005100043686A CN200510004368A CN1679934B CN 1679934 B CN1679934 B CN 1679934B CN 2005100043686 A CN2005100043686 A CN 2005100043686A CN 200510004368 A CN200510004368 A CN 200510004368A CN 1679934 B CN1679934 B CN 1679934B
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A·J·格瑞罗-鲁佩兹
C·A·怀特
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Abstract

通过施用治疗性抗CD20嵌合抗体治疗与高循环肿瘤细胞数相关的血液恶性肿瘤的方法。这些恶性肿瘤尤其包括B-幼淋巴细胞白血病(B-PLL)、慢性淋巴细胞白血病(CLL)、和转化的非何杰金淋巴瘤。

Description

使用抗CD20嵌合抗体治疗循环肿瘤细胞相关的血液恶性肿瘤
本发明为分案申请，母案申请日为1999年11月9日，申请号为99814329.4，发明名称为“使用抗CD20嵌合抗体治疗循环肿瘤细胞相关的血液恶性肿瘤”。
                   本发明领域
本发明涉及通过施用治疗上有效量的结合B细胞表面抗原Bp35(CD20)的嵌合或人源化抗体，治疗大量的循环肿瘤细胞相关的血液恶性肿瘤。
                   本发明背景
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细胞淋巴瘤如非何杰金淋巴瘤，但如果可开发对其它恶性肿瘤的有效抗体治疗将会是有益的。更具体地，如果抗CD20抗体可用于治疗其它类型的恶性肿瘤，将是有益的。
                       本发明简述
为此，本发明人针对以血液中含有大量肿瘤细胞为特征的血液恶性肿瘤，开发了一种新的治疗方法，该方法涉及施用治疗上有效量的抗CD20抗体。在优选实施方案中，该抗CD20抗体含嵌合、人源化或人抗人CD20抗体。该血液恶性肿瘤的例子包括B幼淋巴细胞白血病(B-PLL)、慢性淋巴细胞白血病(CLL)和转化的非何杰金淋巴瘤。
因此，本发明的一个目标是提供一种新的血液恶性肿瘤治疗方法，该方法包括施用抗CD20抗体。
本发明的一个更具有的目标是提供一种新的治疗B幼淋巴细胞白血病(B-PLL)、慢性淋巴细胞白血病(CLL)和转化的非何杰金淋巴瘤的方法，该方法包括施用抗CD20抗体。
本发明的一个更为具体的目标是治疗B幼淋巴细胞白血病(B-PLL)或慢性淋巴细胞白血病(CLL)，包括施用治疗上有效量的RITUXAN
Figure 10003_2
。
                       本发明详述
本发明涉及如下发现，即通过施用治疗性抗CD20抗体可有效地治疗血液恶性肿瘤，尤其是那些以血液中含有大量肿瘤细胞为特征的血液恶性肿瘤。这些恶性肿瘤包括，尤其是，CLL、B-PLL和转化的非何杰金淋巴瘤。
该发现是令人惊奇的，尽管已有RITUXAN可极为成功地治疗复发的以前治疗过的低级非何杰金淋巴瘤的报道。尤其是，考虑到这些患者中所观察到的非常大量的肿瘤细胞，以及考虑到这些恶性肿瘤细胞例如CLL细胞典型地并不表达高密度的CD20抗原这一事实，该发现是令人惊奇的，其中CD20抗原的高密度表达是一些B细胞淋巴瘤例如先前已治疗过的复发低级非何杰金淋巴瘤的特征。因此，不能合理预测，CD20抗原可构成这些恶性肿瘤的治疗性抗体治疗的合适靶标。
根据本发明，血液恶性肿瘤如CLL、B-PLL和转化的非何杰金淋巴肿瘤的治疗包括施用治疗上有效量的抗CD20抗体，该施用可单独或与其它治疗例如化疗、放疗(如全身辐射、或用放射性标记抗体进行的治疗)联合进行。此外，和细胞因子一起进行的联合治疗可能对于上调淋巴瘤细胞表面的CD20是有用的。
在优选的实施方案中，抗CD20抗体以高亲和性，即从10-5至10-9M，与CD20结合。优选地，抗CD20抗体包括嵌合、灵长类、灵长类源化(primatize
Figure 10003_4
)、人、人源化抗体。此外，本发明包括抗体片段的使用，例如Fab、Fv、Fab、F(ab)2和它们的聚集体。
嵌合抗体是指含有非人可变区和人恒定区的抗体，最典型的是啮齿类动物的可变区和人的恒定区。
灵长类源化(primatize
Figure 10003_5
)抗体是指具有灵长类可变区如CDR和人恒定区的抗体。优选地，该灵长类可变区来源于(Old World monkey)旧大陆猴。
人源化抗体是指主要具有人的框架和恒定区，以及非人互补决定区(CDR)的抗体。“主要”是指人源化抗体典型地保留有至少几个(CDR所来源的非人亲本抗体的)供体框架残基这一事实。
制备嵌合、灵长类、灵长类源化、人源化和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。
人恒定区的选择可能对于目的抗CD20抗体的治疗效果是重要的。在优选实施方案中，目的抗CD20抗体含有人γ1或γ3恒定区，更优选地含有人γ1恒定区。颁发给Robinson等的美国专利中公开了γ1抗CD20抗体作为治疗剂的应用。
制备人抗体的方法也是已知的，包括例如SCID小鼠中生产和体外免疫。
正如指出的，特别优选的抗CD20嵌合抗体是RITUXAN，其是嵌合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。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可通过CHO细胞转染瘤进行制备，该CHO细胞转染瘤依据布达佩斯条约的规定于1992年11月4日保藏在美国典型培养物保藏中心，该保藏中心位于12301 ParklawnDrive，Rockville，MD 20852，现在位于10801 University Boulevard，Manassas，Virginia 20110-2209(ATCC 69119)。该细胞系被确定是存活的，并且在保藏期间如果其不能存活则将被更换。根据5,736,137专利的发布该细胞系不可改变地可为公众获得，而且可无限制地从ATCC获得。该细胞系还可在根据本申请授予的任何专利的有效期中无限制地获得。
所述抗CD20抗体可通过各种给药途径，典型的是非肠胃途径进行施用。非肠胃途径包括静脉内、肌肉内、皮下、直肠、阴道、并且优选静脉内灌注。
该抗CD20抗体可通过标准方法配制用于治疗用途，这些方法例如有加入药物上可接受缓冲液如无菌盐水、无菌缓冲水、丙二醇、和它们的组合。
有效剂量取决于具体的抗体、患者情况、年龄、重量、或任何其它治疗和其它因素。典型地，有效剂量从0.001-大约30mg/kg体重，更优选从0.01-25mg/kg体重，最优选从0.1-大约20mg/kg体重。
取决于施用的剂量和患者的反应，所述给药可通过各种方案实现，例如每周、每两周、或每月一次。而且，所述给药与其它治疗的联合可能是可取的，这些治疗例如有靶向和非靶向的放疗、化疗、以及淋巴因子或细胞因子如白介素、干扰素、TNF、集落刺激因子等的施用。
典型地，治疗可每周进行，持续大约2-10周，更典型地持续大约4周。一种尤其优选的给药方案包括每周施用大约0.375mg/kg，总共进行4次灌注。此外，可能甚至更优选累加给药的方案(stepped-up dosingschedule)。
如果联合使用放射和治疗性抗CD20抗体，则优选使用钇标记的抗CD20抗体，正如以参考文献形式完整地并入本文的美国专利5,736,137所公开的。已报道抗体2B8-MX-DTPA在治疗B细胞淋巴瘤中的有效性。产生2B8抗体的细胞系根据布达佩斯条约的规定于1993年6月2日保藏在美国典型培养物保藏中心，根据美国专利5,736,137的发布可无任何限制和不可更改地为公众获得。该细胞系是存活的，而且如果发现其不存活，则在根据本申请授予的任何专利的有效期内会进行相似更换。
可以联合所述抗体的免疫治疗一起使用的一个尤其优选的化疗方案包括CHOP免疫治疗，该治疗包括联合施用环磷酰胺、阿霉素、长春新碱和强的松。其它已知的化疗剂包括氨甲蝶呤、顺铂、托瑞米芬和他莫昔芬。
以下的实施例并不旨在，也不应理解为限制本发明。这些实施例旨在提供临床证据支持本发明的有效性。
实施例1
我们对两名患者进行了研究，这两名患者出现与严重肺灌注相关毒性和血小板减少有关的血液肿瘤细胞的快速减少。而且，从医师提交的RITUXAN治疗相关的不利事件的报告中收集了其它两名患者。这些患者治疗前的状况包括平均年龄60岁(范围是26-73)，诊断患有B幼淋巴细胞白血病(B-PLL)、慢性淋巴细胞白血病(CLL)或转化的非何杰金淋巴瘤。所有这些患者由于血液肿瘤疾病、肿大性腺病和内脏增大而出现白细胞计数增加。所有这4个患者均出现严重灌注相关反应的独特症状，特征是发烧、寒战、支气管痉挛和伴随的缺氧，需要暂时停止RITUXAN
Figure 10003_8
治疗。伴随这些症状出现的是循环肿瘤细胞负载的快速减少(治疗前平均98×109/L；范围73-132，相对于治疗后平均11×109/L；范围3.7-24.6)和快速肿瘤溶解的轻微电解迹象。在所有4个患者中均注意到血小板减少，一种不常与RITUXAN
Figure 10003_9
治疗相关的现象(治疗前平均145×109/L；范围57-277，相对于治疗后平均56×109/L；范围2-120)，在一个病例中需要输血。该综合症的症状需要住院治疗但经支持性医护后消退。所有患者对随后的RITUXAN治疗均有很好的耐受。对两个后来的具有高血液肿瘤计数的CLL患者使用累加给药(第1天100mg/m2，之后在第2天进行其余治疗)，产生明显效果，血小板减少但灌注相关的毒性很小。在患有血液肿瘤细胞疾病的血液恶性肿瘤患者中施用RITUXAN
Figure 10003_11
可能与较高频率的要求谨慎临床监护的严重初始灌注相关反应和血小板减少有关。考虑到这些患者中的RITUXAN
Figure 10003_12
初步活性，应使用累加给药计划在CLL和PLL中进行进一步的研究。
                      实施例2
对于NHL治疗，未标记的免疫球蛋白(Mab)是有吸引力的，因为它们可：介导补体(CDC)或效应细胞(ADCC)的细胞毒性；实现细胞程序化死亡；比连接毒素或药物的Mab具有更小的毒性、更小的免疫原性以及可能更有效；不需要放射性标记的Mab治疗(RIT)所需的复杂程序，而且不产生高剂量RIT典型的骨髓抑制。直到最近，Mab在血液恶性肿瘤治疗中的使用仍是有限的。然而，嵌合抗CD20 Mab，RITUXAN，具有低毒性和显著的临床效果，而且目前已被食品和药物管理局同意用于治疗复发或顽固性、低级或滤泡性(R＝LG/F)NHL。在单因素临床试验(PIII)中，用RITUXAN以每周375mg/m2治疗166个R-LG/F NHL患者，进行4次灌注(102-05号研究)，总应答率(ORR)为48％(6％完全应答(CR)和42％部分应答(PR))。对于应答者，发展的平均时间是13.1个月，应答持续时间是11.2个月。在第一次给药后，平均循环B淋巴细胞计数降至零。CD3、CD4、CD8和NK细胞计数保持不变。外周血中的B细胞恢复开始于第6-9个月，第9-12个月后完全恢复。没有观察到血清补体水平的明显改变。用CDC、ADCC、细胞程序化死亡和/或其它考虑的因素仍不能解释该反应机制。尽管缺乏临床/实验室的相关性，但CDC的作用不可忽视。我们观察到基线上的较高NK绝对细胞数和对Mab应答间的相关性。
细胞类型   #患者CR+PR   绝对计数   #患者NR   绝对计数     P值
NK     98     180     15     98     0.02
MK+ANC     98     185     15     102     0.02
ANC     101     3.7     15     3.4     0.40
CD3+     98     761     15     576     0.37
血小板     101     187     15     206     0.32
注：N＝来自102-05号研究的166名患者，和来自102-06号研究的37名患者。绝对计数：NK，CD3＝细胞数/mm3；ANC，Pts.＝细胞数×10e3/mm3。P值表示绝对计数间的差异。
ADCC可能对于在RITUXAN治疗的患者中所观察到的临床活性是一个重要机制。增强效应细胞数目和活性的试剂可与Mab协同作用。此外正在进行RITUXAN
Figure 10003_16
联合细胞因子如IL-2、G-CSF、GM-CSF、INF的研究。
                       实施例3
CLL中RITUXAN 的I/II期研究
RITUXAN
Figure 10003_18
是靶向CD20的单克隆抗体，在治疗低级淋巴瘤(LGL)中有显著效果。当以375mg/m2剂量的方式每周4次给药，复发患者(PTS)的应答率为43％(McClaughlin等，J Clin.Oncol，16(8)：2825-33)。小淋巴细胞淋巴瘤患者比其它亚型LGL有较低的应答率(13％)和较低的RITUXAN
Figure 10003_19
血清水平。SLL中所见的降低的应答可能与较低的CD20抗原密度和/或较高的循环B细胞计数相关。这两个因素被认为可能(负面)影响CLL中所见的应答。为了最大化CLL中的活性，我们进行了I/II期研究。所有患者接受375mg/m2的首剂量以最小化灌注-复发的副作用。之后每周给药(3次)保持不变，但给予增加的剂量水平。16名患者以500-1500mg/m3的剂量治疗。平均年龄为66岁(范围，25-78)。81％的患者患有III/IV末期疾病。平均白细胞数为40×109/L(范围，4-200)，Hgb为11.6g/dl(范围，7.7-14.7)，血小板为75×109/L(范围，16-160)，平均β2免疫球蛋白为4.5mg/L(范围，3.1-9.2)。预先治疗的平均数为2.5(范围，1-9)。60％患者对治疗不反应。两名患者在服用第一个剂量(375mg/m3)后出现严重的高血压；另一名患者接受进一步治疗。尽管没有对患者在1500mg/m3剂量水平进行全部评价，随后增加剂量的毒性是轻微的。8名患者完成治疗(500mg/m2 4次、650mg/m2 3次、825mg/m21次)。以560mg/m2治疗的一名患者获得完全的症状缓解。一名患者在治疗时出现进行性淋巴细胞增生，所有其它患者的外周血淋巴细胞增生减少，但较少影响淋巴结。剂量增加研究正在进行中。
                       实施例4
细胞因子用于上调CD20的表达
改善CLL患者中应答的另一个方法是使用细胞因子上调CD20抗原。在体外研究中，将来自CLL患者的单核细胞与各种细胞因子一起孵育24小时。流式细胞计结果显示IL-4、GM-CSF和TNF-α引起显著上调。Venugopal P，Sivararnan S，Huang X，Chopra H，O’Brein T，Jajeh A，Preisler H，通过体外暴露于细胞因子慢性淋巴细胞白血病(CLL)细胞中的CD20表达上调，血液(Blood)1998；10：247a。实际上，最近的数据提示CLL细胞上所观察到的CD20上调可能限于肿瘤细胞(Venogopal等，海报-泛太平洋淋巴瘤会议，1999年6月，慢性淋巴细胞白血病(CLL)细胞中细胞因子诱导的CD20抗原表达上调可能限于肿瘤细胞。初步数据还提示α干扰素当以500-1000U/ml的浓度应用时仅在24小时后也可上调CLL细胞上的CD20。
因此，在施用Rituximab之前或同时通过给CLL患者施用某些细胞因子，可上调恶性B细胞表面的CD20表达，由此使得CD20以及其它细胞表面标志如CD19，成为免疫治疗的更具有吸引力的靶标。
已启动一个测试用于体内CD20上调的最佳细胞因子剂量的协作研究。研究步骤包括10名患者最初以250mcg/m2SQ QD X3的GM-CSF进行治疗、10名患者以mcg/kg SQ QD X3的IL-4进行治疗、10名患者以5mcg/kgSQ QD X3的G-CSF进行治疗。通过Ficon Hypaque离心分离单核细胞用于细胞凋亡研究，以确定CD20的上调是否导致Rituximab
Figure 10003_21
对肿瘤细胞的杀伤增强。
                       实施例5
联合抗体和化疗的方法
CLL的抗体治疗可联合其它常规已知对CLL治疗有用的化疗法。对于CLL最为经常使用的单个试剂是苯丁酸氮芥(瘤可宁)，给药方法为每天0.1mg/kg或每4周0.4-1.0mg/kg。苯丁酸氮芥通常联合口服强的松(30-100mg/m2/d)，这在处理自身免疫性血细胞减少方面是有用的。环磷酰胺是苯丁酸氮芥的一种替代物，通常使用剂量为每3-4周1-2g/m2，并联合长春新碱和类固醇一起使用(如COP疗法)。
已有各种药物组合用于CLL，包括COP(环磷酰胺、长春新碱和强的松)，和CHOP(这三种药加上阿霉素)。氟达拉滨在CLL治疗中显示出有作用，而且在以每3-4周25-30mg/m2/d方式治疗的患者群中产生50％的ORR。http：//www.cancernetwork.com。尽管一些患者表现出对氟达拉滨不起反应。这些患者可能也抗2-CdA，因为通常对氟达拉滨不起反应的患者也对2-CdA不起反应(O’Brien等，N.Engl.J.Med.330：319-322(1994))。
因此，抗CD20抗体治疗将对那些顽固性或化疗药物治疗后复发的患者尤其有用。在这些患者中Rituximab
Figure 10003_22
治疗还可与放疗联合。相对75-150cGy总剂量有15cGy低剂量的TBI在大约三分之一的患者中显示有效。
目前正在通过CALGB在CLL患者中进行II期实验。Rituximab
Figure 10003_23
和氟达拉滨同时施用，之后进行Rituximab巩固，或是在氟达拉滨诱导后给予Rituximab
Figure 10003_25
。
研究的目的是(1)确定氟达拉滨治疗的CLL患者的完全应答(CR)率，和同时和巩固性Rituximab治疗(Arm I)的毒性以及巩固性Rituximab
Figure 10003_27
治疗(Arm II)的毒性；(2)在接受Rituximab和氟达拉滨(Arm I的诱导期)同时治疗的患者中评价CR率；(3)在接受Rituximab巩固性治疗的CLL患者中评价部分应答(PR)转化成CR或稳定性疾病转化成PR或CR的频率；(4)跟踪Rituximab
Figure 10003_30
和氟达拉滨治疗对免疫学标志CD4、CD8、IgG、IgA和IgM的影响；和(5)检查Arm I和II中的无疾病恶化性存活和完全存活。
尽管对于清楚和理解的目的，本发明通过说明和实施例进行了相当详细地描述，但明显地在所附权利要求的范围内进行的某些改变和修饰可能是可行的。

Claims (12)

1.Rituximab在制备用于在人类患者中治疗慢性淋巴细胞白血病的药物中的应用，其中配制所述药物，以便以500-1500mg/m2的剂量的Rituximab
Figure FFW00000042646400012
施用给人类患者。
2.权利要求1的应用，其中配制所述药物，以便以500mg/m2的剂量的Rituximab施用给人类患者。
3.权利要求1的应用，其中配制所述药物，以便以650mg/m2的剂量的Rituximab
Figure FFW00000042646400014
施用给人类患者。
4.权利要求1的应用，其中配制所述药物，以便以825mg/m2的剂量的Rituximab
Figure FFW00000042646400015
施用给人类患者。
5.权利要求1的应用，其中配制所述药物，以便以1500mg/m2的剂量的Rituximab
Figure FFW00000042646400016
施用给人类患者。
6.权利要求1-5中任一项的应用，其中所述药物用于与化疗一起使用。
7.权利要求6的应用，其中所述化疗包含苯丁酸氮芥。
8.权利要求6的应用，其中所述化疗包含环磷酰胺。
9.权利要求6的应用，其中所述化疗包含长春新碱。
10.权利要求6的应用，其中所述化疗包含泼尼松。
11.权利要求6的应用，其中所述化疗包含多柔比星。
12.权利要求6的应用，其中所述化疗包含氟达拉滨。
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