CN107921129B - 组合及其用途 - Google Patents
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- CN107921129B CN107921129B CN201680048061.2A CN201680048061A CN107921129B CN 107921129 B CN107921129 B CN 107921129B CN 201680048061 A CN201680048061 A CN 201680048061A CN 107921129 B CN107921129 B CN 107921129B
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Abstract
本公开描述了用于治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的抗‑CD19抗体和磷酸肌醇3‑激酶抑制剂的药物组合。
Description
技术领域
本公开涉及用于治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的抗-CD19抗体和磷酸肌醇3-激酶抑制剂的药物组合。
背景技术
B细胞是在体液免疫应答中发挥重要作用的淋巴细胞。它们产生于大多数哺乳动物的骨髓中,占循环淋巴液(circulating lymphoid pool)的5-15%。B细胞的主要功能是制备针对各种抗原的抗体,并且是适应性免疫系统的必要组成部分。
由于它们在调节免疫系统中的关键作用,B细胞的失调与各种疾病如淋巴瘤和白血病有关。这些疾病包括非霍奇金淋巴瘤(“NHL”),慢性淋巴细胞性白血病(“CLL”)和急性成淋巴细胞性白血病(“ALL”)。
NHL是源自淋巴细胞的异质性恶性肿瘤。在美国(U.S.),发病率预计在65,000/年,死亡人数大约为20,000(美国癌症协会(American Cancer Society),2006;和SEER CancerStatistics Review)。该疾病可能在所有年龄发生,通常在40岁以上的成人中开始发作,发病率随着年龄增加。NHL的特征是淋巴结、血液、骨髓和脾中累积的淋巴细胞的克隆增殖,尽管其可以涉及到任何主要器官。目前病理学家和临床医生使用的分类系统是世界卫生组织(WHO)的肿瘤分类法,其将NHL组织成前体和成熟的B-细胞或T-细胞赘生物。PDQ目前将NHL分成对于进入临床试验是惰性(indolent)的或侵袭性的。惰性NHL组主要包括滤泡亚型、小淋巴细胞性淋巴瘤、MALT(粘膜相关淋巴样组织)和边缘区;惰性包括大约50%新诊断的B-细胞NHL患者。侵袭性NHL包括组织学诊断为原发性弥漫性大B细胞(DLBL、DLBCL或DLCL)(所有新诊断的患者中40%具有弥漫性大细胞)、Burkitt's和套细胞的患者。NHL的临床过程是高度变化的。临床过程的主要决定因素是组织学亚型。大多数惰性型NHL被视作是不能治愈的疾病。患者最初对化学疗法或抗体疗法有响应,大多数将会复发。迄今的研究尚未表明早期干预对存活率的改善。在无症状的患者中,“观察并等待”是可接受的,直至患者表现出症状或疾病进展看起来在加速。随着时间的推进,疾病可以转化为更加侵袭性的组织型(histology)。中位存活期为8-10年,惰性型的患者在其疾病的治疗期间常常接受3次或更多次治疗。对有症状的惰性型NHL患者的初始治疗在历史上已经结合化学疗法进行。最常用的药物包括:环磷酰胺、长春新碱和强的松(CVP);或环磷酰胺、阿霉素、长春新碱和强的松(CHOP)。大约70%到80%的患者将会对其初始的化疗有反应,缓解时间将会持续2-3年的量级。最终大多数患者会复发。抗-CD20抗体利妥昔单抗(rituximab)的发现和临床使用已经提供了响应和存活率的显著改善。目前大多数患者的护理标准是利妥昔单抗+CHOP(R-CHOP)或利妥昔单抗+CVP(R-CVP)。干扰素获准与烷基化药物结合用于NHL的最初治疗,但在美国的应用有限。利妥昔单抗疗法已经在若干种NHL显示出是有效的,目前获准作为惰性(滤泡性淋巴瘤)和侵袭性NHL(弥漫性大B细胞淋巴瘤)二者的一线治疗。但是,抗-CD20单克隆抗体(mAb)有明显的局限性,包括原发性耐药(复发惰性患者中50%响应)、获得性耐药(再治疗时50%响应率)、罕有完全响应(复发群体中2%完全响应率)和连续的复发模式。最后,许多B细胞并不表达CD20,因此许多B-细胞障碍使用抗-CD20抗体疗法是不能治疗的。
除NHL以外,还有几种类型的由B细胞调节异常引起的白血病。CLL是一种B淋巴细胞异常累积造成的成人白血病。在CLL中,恶性淋巴细胞可能看起来是正常和成熟的,但它们不能有效地应对感染。CLL是成人中最常见的白血病形式。男性发展CLL的可能性是女性的两倍。但是,关键风险因素是年龄。75%以上的新病例在年龄50岁以上的患者中诊断出。每年诊断出多于10,000例病例,死亡数为几乎5,000例每年(美国癌症协会,2006;和SEERCancer Statistics Review)。CLL是不能治愈的疾病,但大多数情况下进展缓慢。许多患有CLL的人正常、积极地生活许多年。由于其发病缓慢,早期CLL通常不予治疗,因为据信早期CLL干预不会提高生存时间或生活质量。取而代之地,随时间对病情进行监控。初始的CLL治疗取决于确切的诊断和疾病的发展而变化。有数十种药物用于CLL治疗。组合化疗方案例如FCR(氟达拉滨(fludarabine)、环磷酰胺和利妥昔单抗)和BR(Idelalisib和利妥昔单抗)在新诊断的和复发的CLL中均有效。异基因骨髓(干细胞)移植由于其风险性极少作为CLL一线治疗使用。
另一类型的白血病是ALL,也称作急性淋巴细胞性白血病。ALL的特征是骨髓中的恶性、不成熟的白细胞(也称作成淋巴细胞)过度产生和连续增殖。“急性”是指循环的淋巴细胞(“胚细胞”(blasts))的未分化、不成熟的状态,以及疾病迅速发展,如果不予治疗预期寿命为数周至数月。ALL最常见于儿童,发病高峰为年龄4-5岁。年龄12-16岁的儿童更易死于该病。目前,至少80%的儿童ALL被视为是可治愈的。每年诊断出少于4,000例病例,死亡数为几乎1,500例每年(美国癌症协会,2006;和SEER Cancer Statistics Review)。
人CD 19分子是在人B细胞表面上表达的结构确切的细胞表面受体,这些B细胞包括但不限于,前B细胞——早期发育的B细胞(即不成熟B细胞)、通过终末分化成为浆细胞的成熟B细胞以及恶性B细胞。CD 19由大多数前-B急性成淋巴细胞性白血病(ALL)、非霍奇金淋巴瘤、B细胞慢性淋巴细胞性白血病(CLL)、前淋巴细胞性白血病、毛细胞白血病、常见的急性淋巴细胞性白血病和一些Null型急性成淋巴细胞性白血病表达(Nadler等人,J.Immunol.,131:244-250(1983);Loken等人,Blood,70:1316-1324(1987);Uckun等人,Blood,71:13-29(1988);Anderson等人,1984.Blood,63:1424-1433(1984);Scheuermann,Leuk.Lymphoma,18:385-397(1995))。CD 19在浆细胞上的表达进一步表明其可以在分化的B细胞肿瘤例如多发性骨髓瘤、浆细胞瘤、Waldenstrom's肿瘤上表达(Grossbard等人,Br.J.Haematol,102:509-15(1998);Treon等人,Semin.Oncol,30:248-52(2003))。
因此,CD19抗原是非霍奇金淋巴瘤(包括本文所述的各种亚型)、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的治疗中的免疫疗法靶标。
已经显示了某些CD19疗法。对三名患有晚期CLL的患者施用表达包含CD3-ζ和4-BB共刺激结构域的抗-CD19嵌合抗原受体(CAR)的T细胞。Kalos等人,T cells with ChimericAntigen Receptors Have Potent Antitumor Effects and Can Establish Memory inPatients with Advanced Leukemia,Science Translational Medicine,vol.3,no.95(2011年8月10日),其通过引用整体并入。通过引用整体并入的Sadelain等人,The promiseand potential pitfalls of chimeric antigen receptors,Current Opinion inImmunology,Elsevier,vol.21,no.2,2April 2009,也描述了抗-CD19嵌合抗原受体(CAR)。
在WO2007076950(US2007154473)中讨论了CD19抗体在非特异性B细胞淋巴瘤中的用途,这两篇文献均通过引用整体并入。
在Scheuermann等人的“CD19Antigen in Leukemia and Lymphoma Diagnosisand Immunotherapy,Leukemia and Lymphoma,Vol.18,385-397(1995)”中描述了在CLL、NHL和ALL中使用CD19抗体,其通过引用整体并入。
在WO2005012493(US7109304)、WO2010053716(US12/266,999)(Immunomedics);WO2007002223(US8097703)(Medarex);WO2008022152(12/377,251)和WO2008150494(Xencor)、WO2008031056(US11/852,106)(Medimmune);WO 2007076950(US11/648,505)(Merck Patent GmbH);WO 2009/052431(US12/253,895)(Seattle Genetics);以及WO2010095031(12/710,442)(Glenmark Pharmaceuticals)、WO2012010562和WO2012010561(International Drug Development)、WO2011147834(Roche Glycart)和WO2012/156455(Sanofi)中描述了另外的CD19特异性的抗体,它们全部通过引用整体并入。
WO2010151341(US13/377,514)(The Feinstein Institute);US5686072(University of Texas)和WO2002022212(PCT/US01/29026)(IDEC Pharmaceuticals),WO2013/024097(14/126,928)(MorphoSys AG)和WO2013/024095(14/127,217)(MorphoSysAG)中描述了CD19特异性的抗体与其他试剂的结合,其全部通过引用整体并入。2014年4月5-9日在加利福尼亚州圣地亚哥举行的AACR 2014年会中标题为Drug synergies observedfor antibody and toxin components of SAR3419ADC contribute to overallconjugate efficacy and can be combination drug or tumor cell line dependent的摘要4765公开了含有在某些细胞系中的PI3K抑制剂的SAR3419抗-CD19抗体药物结合物(ADC)。
某些磷酸肌醇3-激酶抑制剂是可商购的。Idelalisib,也被称为GS-1101或CAL-101,由Gilead销售,在美国有一个商品名Zydelig。在美国专利第6,800,620;8,865,730;8,980,901;RE44599;和RE44638中描述了Idelalisib,它们全部通过引用整体并入。
显然,尽管在抗癌剂的发现和发展中近来有进展,但涉及表达CD19的肿瘤的许多形式的癌症仍然具有不良的预后。因此,需要改进的治疗这类癌症的方法。
发明内容
现有技术既没有单独也没有组合地表明示例性抗体和Idelalisib的组合在治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病中的协同作用。
一方面,本公开涉及CD19特异性抗体与磷酸肌醇3-激酶抑制剂的协同组合。这样的组合可用于治疗B细胞恶性肿瘤,如非霍奇金淋巴瘤(NHL)、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病(ALL)。
体外模型被认为指示了某些化合物或化合物的组合如何在人类中起作用。对多种细胞系进行了测试,例如,MEC-1细胞(DSMZ#ACC497)——一种慢性B细胞白血病细胞系。这种体外模型中的MEC-1细胞表明组合将如何在人类慢性淋巴细胞白血病(CLL)的治疗中起作用。
另外,当化合物在体外结合时,人们预期组合仅具有叠加作用。令人惊奇的是,发明人发现,与单独的抗体和Idelalisib相比,特异性针对CD19的特定抗体与Idelalisib的组合在体外介导协同水平的特异性细胞杀灭。
具体而言,本发明人发现,与单独的抗体和Idelalisib相比,MOR00208和Idelalisib的组合在MEC-1细胞中体外介导协同水平的特异性细胞杀灭。
此外,发明人还出人意料地发现,与单独的抗体和Idelalisib相比,CD19特异性的特定抗体和Idelalisib的组合具有某些优越的功能特性。
总之,示例性抗-CD19抗体和Idelalisib的组合在与CLL有关的模型中起协同作用。由于CLL是与B细胞相关的病症,而CD19在B细胞上高度表达,示例性的组合将具有相同的作用机制,并且还应该在其它B细胞相关病症(例如NHL和ALL)的治疗中起协同作用。
因此,示例性的CD19特异性抗体和Idelalisib的组合在人非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的治疗中应该是有效的。临床试验证实了示例的CD19特异性抗体和Idelalisib的预期功效。
由于Idelalisib和其他磷酸肌醇3-激酶抑制剂的作用机制相似,因为它们通过抑制作为PI3K/AKT/mTOR通路的一部分的一种或多种磷酸肌醇3-激酶而起作用,所述PI3K/AKT/mTOR通路对许多细胞功能诸如生长控制、代谢和翻译起始而言是重要的信号传导通路,相信当用示例的抗-CD19抗体与除Idelalisib之外的磷酸肌醇3-激酶抑制剂的组合治疗患有非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时也应该看到协同作用。
由于示例的抗-CD19抗体和其它抗-CD19抗体结合CD19,所以当用任何抗-CD19抗体与磷酸肌醇3-激酶抑制剂(例如Idelalisib)治疗患有非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应当看到协同作用。
本公开的一个方面包括CD19特异性抗体以及Idelalisib的协同组合,其中CD19特异性抗体包含:序列SYVMH(SEQ ID NO:1)的HCDR1区,序列NPYNDG(SEQ ID NO:2)的HCDR2区,序列GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区,序列RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区,序列RMSNLNS(SEQ ID NO:5)的LCDR2区和序列MQHLEYPIT(SEQ ID NO:6)的LCDR3区。在优选的方面,该组合用于治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病。
附图说明
图1显示了MOR00208的可变结构域的氨基酸序列。
图2显示了MOR00208的Fc区的氨基酸序列。
图3-6显示了来自四个独立实验的MOR00208与Idelalisib的组合在MEC-1细胞中的ADCC剂量响应曲线。
图7-10显示了来自四个独立实验的不同剂量的MOR00208与Idelalisib的组合的CI曲线。
具体实施方式
“协同性”、“协同作用”或“协同的”是指超过组合的预期叠加效果。在本文中,组合的“协同性”、“协同作用”或“协同的”效果通过Chou等人、Clarke等人和/或Webb等人的方法确定。参见:Ting-Chao Chou,药物组合研究中协同作用和拮抗作用的理论基础、实验设计和计算模拟(Theoretical Basis,Experimental Design,and Computerized Simulationof Synergism and Antagonism in Drug Combination Studies),Pharmacol Rev 58:621–681(2006),在此将其全文并入作为参考。另外参见:Clarke等人,乳腺癌和其他模型中实验细胞毒性剂体内研究中实验设计和终点分析中的问题(Issues in experimentaldesign and endpoint analysis in the study of experimental cytotoxic agents invivo in breast cancer and other models),Breast Cancer Research and Treatment46:255-278(1997),在此将其全文并入作为参考。另外参见:Webb,J.L.(1963)酶和代谢抑制剂(Enzyme and Metabolic Inhibitors),Academic Press,New York,在此将其全文并入作为参考。
术语“抗体”是指单克隆抗体,包括任意同种型,例如,IgG、IgM、IgA、IgD和IgE。IgG抗体由两个相同的重链和两个相同的轻链组成,其通过二硫键连接。每个重链和轻链均含有恒定区和可变区。每个可变区含有三个称作“互补决定区”(“CDR”)或“高变区”的区段,其主要负责与抗原表位结合。它们被称作CDR1、CDR2和CDR3,从N-端依次编号。可变区的在CDR外部的更加高度保守的部分称作“骨架区”。“抗体片段”是指Fv、scFv、dsFv、Fab、Fab'F(ab')2片段或其他片段,其含有至少一个各自含有CDR和骨架区的可变重链或可变轻链。
“磷酸肌醇3-激酶抑制剂”是一类药物,其通过抑制作为PI3K/AKT/mTOR通路的一部分的一种或多种磷酸肌醇3-激酶而起作用,所述PI3K/AKT/mTOR通路对许多细胞功能如生长控制、新陈代谢和翻译起始而言是重要的信号传导通路。
PI3K有许多不同的类别和同种型。I类PI3K具有称为p110的催化亚基,具有四种类型(同种型)-p110α、p110β、p110γ和p110δ。目前研究的抑制剂抑制I类PI3K的一种或多种同种型。
磷酸肌醇3-激酶抑制剂至少包括Idelalisib、Duvelisib和Copanlisib。
Idelalisib由Gilead Sciences,Inc.销售(商品名Zydelig,也被命名为GS-1101或CAL-101)。目前Idelalisib被标注为用于以下治疗:在因其他共病因此单用利妥昔单抗被认为是合适疗法的患者中,与利妥昔单抗结合治疗复发的慢性淋巴细胞性白血病(CLL);在至少接受过两次在先的全身性治疗的患者中治疗复发的滤泡性B细胞非霍奇金淋巴瘤(FL);在至少接受过两次在先的全身治疗的患者中治疗复发的小淋巴细胞淋巴瘤(SLL)。该物质作为磷酸肌醇3-激酶抑制剂起作用;更具体地说,它阻断磷酸肌醇3-激酶这种酶的δ亚型P110δ。Idelalisib的化学式是:
Duvelisib(IPI-145,INK1197)是一种新型的选择性PI3Kδ/γ(δ和γ)抑制剂。Duvelisib的化学式是:
由Bayer开发的Copanlisib(BAY 80-6946)是一种选择性I类磷酸肌醇3-激酶抑制剂。Copanlisib的化学式是:
“VH”是指抗体或抗体片段的免疫球蛋白重链的可变区。“VL”是指抗体或抗体片段的免疫球蛋白轻链的可变区。
术语“CD19”是指称作CD19的蛋白,其具有以下同义词:B4、B-淋巴细胞抗原CD19、B-淋巴细胞表面抗原B4、CVID3、分化抗原CD19、MGC12802和T细胞表面抗原Leu-12。
人CD19具有以下氨基酸序列:
MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSFGPSSPSGKLMSPKLYVWAKDRPFIWFGFPPCLPPRDSLNQSLSQDLTMAPGSILWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR.(SEQ ID NO:7)
“MOR00208”是一种抗-CD19抗体。图1中提供了可变结构域的氨基酸序列。图2中提供了MOR00208的重链和轻链Fc区的氨基酸序列。“MOR00208”、“XmAb 5574”和“MOR208”被用作同义词以描述图1和2中所示的抗体。在美国专利申请序列号12/377,251中描述了MOR00208抗体,其中完整轻链是SEQ ID NO:106,完整重链是SEQ ID NO:87,其通过引用整体并入。
已经在ALL、NHL、CLL和小淋巴细胞淋巴瘤(SLL)的人类临床试验中研究了MOR00208。
在美国专利第7,109,304号(Immunomedics)(其通过引用整体并入);美国申请序列号11/917,750(Medarex)(其通过引用整体并入);美国申请序列号11/852,106(Medimmune)(其通过引用整体并入);美国申请序列号11/648,505(Merck Patent GmbH)(其通过引用整体并入);美国专利第7,968,687号(Seattle Genetics)(其通过引用整体并入);和美国申请序列号12/710,442(Glenmark Pharmaceuticals)(其通过引用整体并入)中描述了对CD19特异性的其他抗体。
“Fc区”是指抗体的恒定区,其在人类中可以是IgG1、2、3、4亚类或其它。人类Fc区的序列可在IMGT,Human IGH C-REGIONs,http://www.imgt.org/IMGTrepertoire/Proteins/protein/human/IGH/IGHC/Hu_IGHCallgenes.html(2011年5月16日检索)获得。
“RefmAb33”是具有以下氨基酸序列的抗体:
重链包括Fc区:
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTAGMSVGWIRQPPGKALEWLADIWWDDKKHYNPSLKDRLTISKDTSKNQVVLKVTNMDPADTATYYCARDMIFNFYFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:8)
轻链包括Fc区:
DIQMTQSPSTLSASVGDRVTITCSASSRVGYMHWYQQKPGKAPKLLIYDTSKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCFQGSGYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:9)
RefmAb33对于RSV是特异性的,因其与MOR00208享有相同的Fc区,用作同种型对照。
“组合”是指多于一项,例如,化合物例如抗体与Idelalisib。
本公开还涉及包含所述组合的组合、药物和药物组合物。本发明协同组合的两个组分,例如CD19特异性抗体和Idelalisib,可以在物理上或时间上一起、同时、分别或随后给药。
Idelalisib目前每天两次口服150mg。MOR00208目前静脉内给药,目前每周给药一次或每两周给药一次。在一个实施方式中,在施用CD19特异性抗体(例如MOR00208)之前施用Idelalisib。在一个实施方式中,在施用CD19特异性抗体(例如MOR00208)之后施用Idelalisib。
优选地,两种药物的施用允许两种药物同时在患者中有活性。例如,如果MOR00208每周给药并且Idelalisib每天给药,那么即使两种药物不总是在同一天施用,理想情况下,两种药物的活性物质也同时存在于患者体内。
“同时”或“一起施用”是指这两种组分在两种组分(药物)同时在患者中有活性的时候施用。“协同作用”暗示两种药物同时在患者中有活性。“同时”或“一起施用”不必指在确切的同一时间或在总是在同一天施用药物。
这两种组分可以配制成不同的药物组合物。
药物组合物包含活性剂,例如一种用于人类治疗的抗体。药物组合物可以包含可接受的载体或赋形剂。
“施用”或“给药”包括但不限于,通过可注射形式递送,其包括例如静脉内、肌肉内、皮内、局部、经皮、腹膜内、眼眶内;通过植入或皮下途径或粘膜途径,例如鼻用喷雾或吸入用气溶胶、或作为可摄入的溶液、或作为胶囊剂或片剂口服。
化合物或组合的“治疗有效量”是指能够实现可测量的改善、缓解或部分抑制给定疾病或病症的临床表现的量。对于特定治疗用途来说有效的量将取决于疾病或损伤的严重性以及受试者的体重和一般状况。应当理解到,通过构建数值矩阵并对矩阵中不同的点进行试验,可以使用常规实验来实现合适剂量的确定,其均在受训医师或临床科学家普通技术能力范围内。
本文中的“CDR”由Chothia等人或Kabat等人定义。参见Chothia C,Lesk AM.(1987)免疫球蛋白高变区的正则结构(Canonical structures for the hypervariableregions of immunoglobulins).J Mol Biol.,196(4):901-17,在此将其全文并入作为参考。参见Kabat E.A,Wu T.T.,Perry H.M.,Gottesman K.S.和Foeller C.(1991).免疫学研究的蛋白质序列(Sequences of Proteins of Immunological Interest).5th edit.,NIHPublication no.91-3242,US Dept.of Health and Human Services,Washington,DC在此将其全文并入作为参考。
“交叉竞争”是指抗体或其他结合试剂在标准竞争结合测定中干扰其他抗体或结合试剂与CD19结合的能力。抗体或其他结合试剂能够干扰另一抗体或结合分子与CD19结合的能力或程度,以及相应地是否能根据本发明称为交叉竞争,可以使用标准竞争结合测定来确定。一种合适的测定涉及到使用Biacore技术(例如,通过使用BIAcore 3000仪器(Biacore,Uppsala,Sweden)),其可以使用表面等离子体共振技术测量相互作用的程度。另一种测量交叉竞争的测定使用基于ELISA的方法。国际专利申请第WO 2003/48731号中描述了基于其交叉竞争的“表位结合”抗体的高通量方法。
术语“表位”包括任何能够与抗体特异性结合或与分子以其他方式相互作用的蛋白决定子(determinant)。表位决定子通常由分子的化学活性表面基团例如氨基酸或碳水化合物类或糖侧链组成,其可以具有特定的三维结构特征,以及特定的电荷特征。表位可以是“线性的”或“构象的”。术语“线性表位”是指蛋白质与相互作用分子(例如抗体)之间的所有相互作用点沿蛋白质的一级氨基酸序列(连续的)线性出现的表位。术语“构象表位”是指其中不连续的氨基酸在三维构象中集合在一起的表位。在构象表位中,相互作用点跨过蛋白质上彼此隔开的氨基酸残基出现。
“结合相同表位”是指抗体或其他结合试剂与CD19结合的能力,且其与所例示的抗体具有相同表位。所例示的抗体和其他抗体对于CD19的表位可以使用标准表位图谱技术确定。表位图谱技术是本领域公知的,其包括以下文献中的表位图谱方案:Methods inMolecular Biology,Vol.66(Glenn E.Morris,Ed.,1996)Humana Press,Totowa,NewJersey。例如,线性表位可以通过以下方法确定:例如,在固体支撑物上同时合成大量的肽——与蛋白分子的一部分对应的肽,并在肽仍然连接在支撑物上的同时使肽与抗体反应。这些技术是本领域已知的,并描述于以下文献中:例如,U.S.专利第4,708,871号;Geysen等人,(1984)Proc.Natl.Acad.Sci.USA 8:3998-4002;Geysen等人,(1985)Proc.Natl.Acad.Sci.USA 82:78-182;Geysen等人,(1986)Mol.Immunol.23:709-715。类似地,构象表位很容易通过确定氨基酸的空间构象来鉴定,例如,通过如氢/氘交换、x-射线晶体学和二维核磁共振。参见,例如,表位图谱方案,同上。蛋白的抗原区也可以使用标准抗原性和亲水性图来鉴定,例如,使用如获自Oxford Molecular Group的Omiga 1.0版软件程序来计算的那些。该计算机程序采用Hopp/Woods方法(Hopp等人,(1981)Proc.Natl.Acad.SciUSA 78:3824-3828)用于抗原性图谱的确定,并采用Kyte-Doolittle技术(Kyte等人,(1982)J.MoI.Biol.157:105-132)用于亲水性图。
具体实施方式
本公开内容的一个方面是用于治疗非霍奇金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的CD19特异性抗体与磷酸肌醇3-激酶抑制剂的组合。在实施方式中,该组合是协同性的。
本文中,示例的抗-CD19抗体与Idelalisib的组合在与CLL相关的体外模型中起协同作用。由于CLL是一种B细胞相关疾病,并且CD19在B细胞上高度表达,所以示例的组合应当具有相同的作用机制,还应该在其它B细胞相关病症例如NHL和ALL的治疗中起协同作用。因此,示例的CD19特异性抗体和Idelalisib的组合应该在人的非霍奇金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的治疗中有效。临床试验将证实示例的CD19特异性抗体与Idelalisib的组合的预期功效。
对慢性B-细胞白血病细胞系MEC-1细胞(DSMZ#ACC497)进行测试。
评估另外的细胞系:Ramos细胞(ATCC号CRL-1596)——一种人Burkitt's淋巴瘤细胞。HG-3(DSMZ#ACC765)和Cll(DSMZ#ACC773)是慢性淋巴细胞性白血病细胞系。Su-DHL 6(DSMZ#ACC572)和U2932(DSMZ#ACC633)是弥漫性大B细胞淋巴瘤(DLBCL)细胞系。JVM-2(CRL-3002)是套细胞淋巴瘤细胞系。BALL-1(DSMZ#ACC742)是一种急性成淋巴细胞性白血病细胞系。
这种体外模型中的MEC-1细胞指示组合将如何在人的慢性淋巴细胞性白血病(CLL)的治疗中起作用。这种体外模型中的Ramos细胞指示该组合如何在人的非霍奇金淋巴瘤(NHL)的治疗中起作用。这种体外模型中的HG-3和Cll细胞指示该组合将如何在人的慢性淋巴细胞性白血病(CLL)的治疗中起作用。这种体外模型中的Su-DHL 6和U2932细胞指示该组合将如何在人的非霍奇金淋巴瘤的治疗中起作用。这种体外模型中的JVM-2细胞指示该组合将如何在人的非霍奇金淋巴瘤的治疗中起作用。这种体外模型中的BALL-1细胞指示该组合将如何在人的急性成淋巴细胞性白血病的治疗中起作用。
Chou指数和Clark等人的数值指示与单独的MOR00208和Idelalisib相比,MOR00208与Idelalisib的组合在MEC-1细胞的特异性杀灭中明显的协同作用。
总之,示例的抗-CD19抗体与Idelalisib的组合在与CLL相关的模型中起协同作用。因此,示例的CD19特异性抗体与Idelalisib的组合应该在人的非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的治疗中有效。
由于Idelalisib和其它磷酸肌醇3-激酶抑制剂的作用机制相似,因为它们都是通过抑制作为PI3K/AKT/mTOR通路(一种用于许多细胞功能如生长控制、代谢和翻译起始的重要信号传导通路)的一部分的一种或多种磷酸肌醇3-激酶而起作用,认为当用示例性抗-CD19抗体与除Idelalisib之外的磷酸肌醇3-激酶抑制剂的组合来治疗患有非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应该看到协同作用。
由于示例的抗-CD19抗体和其它抗-CD19抗体均结合CD19,所以认为在用任何抗-CD19抗体与磷酸肌醇3-激酶治疗患有非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应观察到协同性,其中抗-CD19抗体为,例如描述于US专利申请序列号12/377,251(Xencor)、WO2005012493、WO2010053716(Immunomedics);WO2007002223(Medarex);WO2008022152(Xencor);WO2008031056(Medimmune);WO 2007/076950(Merck Patent GmbH);WO 2009/052431(Seattle Genetics);和WO2010095031(Glenmark Pharmaceuticals)的那些,其均通过引用整体并入。
在实施方式中,CD19的特异性抗体包括与以下抗体交叉竞争的抗体,所述抗体包含序列SYVMH(SEQ ID NO:1)的HCDR1区、序列NPYNDG(SEQ ID NO:2)的HCDR2区、序列GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列RMSNLNS(SEQ ID NO:5)的LCDR2区和序列MQHLEYPIT(SEQ ID NO:6)的LCDR3区。
在实施方式中,CD19的特异性抗体包括与以下抗体结合相同表位的抗体,所述抗体包括序列SYVMH(SEQ ID NO:1)的HCDR1区、序列NPYNDG(SEQ ID NO:2)的HCDR2区、序列GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列RMSNLNS(SEQ ID NO:5)的LCDR2区和序列MQHLEYPIT(SEQ ID NO:6)的LCDR3区。
在实施方式中,CD19的特异性抗体包括序列SYVMH(SEQ ID NO:1)的HCDR1区、序列NPYNDG(SEQ ID NO:2)的HCDR2区、序列GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列RMSNLNS(SEQ ID NO:5)的LCDR2区和序列MQHLEYPIT(SEQ ID NO:6)的LCDR3区。
在实施方式中,CD19的特异性抗体包括序列EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(SEQ ID NO:10)的可变重链和序列DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK(SEQ ID NO:11)的可变轻链。
在某些实施方式中,所述抗体包含以下序列的重链恒定结构域:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:12)。
在实施方式中,CD19特异性抗体包含以下序列的轻链恒定结构域:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:13)。
在实施方式中,磷酸肌醇3-激酶抑制剂是Idelalisib。
在实施方式中,分别施用该组合的组分,CD19特异性抗体和Idelalisib。在一个实施方式中,在施用CD19特异性抗体之前施用Idelalisib。在一个实施方式中,在施用CD19特异性抗体之后施用Idelalisib。在一个实施方式中,同时或一起施用该组合的组分,CD19特异性抗体和Idelalisib。
在实施方式中,该组合是药物组合物。在实施方式中,该组合物包含可接受的载体。在实施方式中,该组合以有效量施用。
在另一方面,包含序列为SYVMH(SEQ ID NO:1)的HCDR1区、序列为NPYNDG(SEQ IDNO:2)的HCDR2区、序列为GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列为RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列为RMSNLNS(SEQ ID NO:5)的LCDR2区、和序列为MQHLEYPIT(SEQ ID NO:6)的LCDR3区的CD19特异性抗体与Idelalisib的协同组合在分离的人PBMC的存在下能够以相较于单独的Idelalisib好至少两倍、三倍、四倍或五倍的功效通过ADCC介导MEC-1细胞的杀灭。
本公开内容的一方面包括用于治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的CD19特异性抗体与Idelalisib的协同组合,所述CD19特异性抗体包含序列为SYVMH(SEQ ID NO:1)的HCDR1区、序列为NPYNDG(SEQ ID NO:2)的HCDR2区、序列为GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列为RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列为RMSNLNS(SEQ ID NO:5)的LCDR2区、和序列为MQHLEYPIT(SEQ ID NO:6)的LCDR3区。在实施方式中,非霍奇金淋巴瘤选自滤泡性淋巴瘤、小淋巴细胞性淋巴瘤、粘膜相关淋巴样组织、边缘区、弥漫性大B细胞、Burkitt's和套细胞。
另一方面包括一种在有此需要的个体中治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的方法,该方法包括施用CD19特异性抗体和磷酸肌醇3-激酶抑制剂。在该方法的实施方式中,CD19特异性抗体包含序列为SYVMH(SEQ ID NO:1)的HCDR1区、序列为NPYNDG(SEQ ID NO:2)的HCDR2区、序列为GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列为RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列为RMSNLNS(SEQ IDNO:5)的LCDR2区、和序列为MQHLEYPIT(SEQ ID NO:6)的LCDR3区。在该方法的实施方式中,抗体包括示例性的CD19特异性抗体。在该方法的实施方式中,磷酸肌醇3-激酶抑制剂是Idelalisib。
另一方面包括CD19特异性抗体与磷酸肌醇3-激酶抑制剂在制备用于治疗有此需要的个体中的非霍奇金淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的药物中的用途,该方法包括施用包含CD19特异性抗体和磷酸肌醇3-激酶抑制剂的药物。在该方法的实施方式中,所述CD19特异性抗体包含序列为SYVMH(SEQ ID NO:1)的HCDR1区、序列为NPYNDG(SEQ ID NO:2)的HCDR2区、序列为GTYYYGTRVFDY(SEQ ID NO:3)的HCDR3区、序列为RSSKSLQNVNGNTYLY(SEQ ID NO:4)的LCDR1区、序列为RMSNLNS(SEQ ID NO:5)的LCDR2区、和序列为MQHLEYPIT(SEQ ID NO:6)的LCDR3区。在该方法的实施方式中,抗体包括示例性的CD19特异性抗体。在该方法的实施方式中,磷酸肌醇3-激酶抑制剂是Idelalisib。
实施例
实施例1:使用单独的MOR00208和Idelalisib以及其组合对MEC-1细胞的细胞毒性
材料
细胞系:慢性B-细胞白血病细胞系MEC-1细胞(DSMZ#ACC497);套细胞淋巴瘤细胞系JVM-2(CRL-3002);Ramos细胞(ATCC号CRL-1596),一种人Burkitt’s淋巴瘤细胞;HG-3(DSMZ#ACC765)和Cll(DSMZ#ACC773)是慢性淋巴细胞性白血病细胞系;Su-DHL 6(DSMZ#ACC572)、和U2932(DSMZ#ACC633)是弥漫性大B细胞淋巴瘤(DLBCL)细胞系;BALL-1(DSMZ#ACC742)是急性成淋巴细胞性白血病细胞系。
所使用细胞系的培养条件遵从供应商的信息。
细胞培养基:Iscove's Modified Dulbecco's培养基(IMDM),Invitrogen,目录号:31980-048;RPMI1640,Invitrogen,目录号:31870-074;GlutaMAX,Invitrogen,目录号:35050-38,批次号1654740;FCS:Sigma目录号:F7524,批次号:111M3396。
NKs:RPMI1640,具有GlutaMAXTM,Invitrogen,目录号:31870-074,10%FCS;Biocoll:Biochrome AG,目录号:L6115,批次号:0034D;MACS NK细胞分离试剂盒:MiltenyiBiotec,目录号:130-092-657,批次号:5150327376;Idelalisib:Selleck Chem,批次号:S2226;FCS:Sigma,目录号:F7524,批次号:111M3396;以及与MOR00208具有相同Fc区的RefmAb33(抗-RSV)。
方法
在MEC-1细胞系中测试单独的MOR00208和Idelalisib以及其组合的细胞毒性。
Idelalisib是磷酸肌醇3-激酶抑制剂;更具体地说,它阻断磷酸肌醇3-激酶这种酶的δ亚型,P110δ。单独的Idelalisib对MEC-1细胞几乎没有细胞毒性作用。MOR00208靶向CD19并通过ADCC介导靶细胞杀灭。
以下用作对照:a)MEC-1细胞+RefmAb33+DMSO+NK细胞,b)MEC-1细胞+DMSO+NK细胞,c)MEC-1细胞+DMSO。
使用以下参数来测量靶细胞杀灭:浓度为0.3、1、3和10μM的Idelalisib;浓度为1.5、0.015和0.0015μg/ml的MOR00208,以及相同浓度下的MOR00208和Idelalisib的组合。
在单独的Idelalisib组、单独的MOR00208组和MOR00208+Idelalisib组合组中,在ADCC试验测定之前,用Idelalisib预处理靶细胞7天。对靶细胞计数并使用10μM CFSE终浓度进行染色。对于DMSO处理的靶细胞,选择2:1的效应物:靶(E:T)比率,对应于5x105/ml的细胞密度。通过调节抑制剂处理的细胞中的E:T比例,将因Idelalisib处理引起的靶细胞增殖效应包括在内。对NK细胞计数并将其调整至1x106/ml。靶细胞杀灭试验如下进行:使用96孔板,每孔加入100μl靶细胞悬浮液,然后向各孔中加入100μl的NK细胞的细胞悬浮液,得到2:1的E:T比率。将抗体在培养基中以10-0.00001nM范围内(对应于1.5-0.0000015μg/ml)进行稀释。将细胞离心并将靶:效应细胞颗粒重悬于100μl含有抗体的培养基或相应的对照溶液中。该试验在37℃的CO2-培养箱中温育4小时。冰上孵育10分钟后,向每个孔中加入50μlDAPI溶液(终浓度1μg/ml)并在冰上孵育10分钟。细胞杀灭测定使用FACS-Verse进行。死亡靶细胞是DAPI阳性的。
数据
总共进行六次实验,以便测定由MOR00208和Idelalisib的组合介导的对MEC-1细胞的ADCC。在六次实验中的两次中,将数据从分析中排除,因为与仅MEC-1细胞的对照相比,RefmAb对照和单独的DMSO对照显示25%更高的杀灭。NK细胞的自体反应性妨碍了这两个实验中的正确分析。
实验1-4的ADCC剂量响应曲线显示在图3-6中。
实验1-4的死细胞的百分比(%)(原始数据)在下表1-16中示出。
实验1
表1:10μM的Idelalisib
表2
3μM的Idelalisib
表3
1μM的Idelalisib
表4
0.3μM的Idelalisib
实验2
表5
10μM的Idelalisib
表6
3μM的Idelalisib
表7
1μM的Idelalisib
表8
0.3μM的Idelalisib
实验3
表9
10μM的Idelalisib
表10
3μM的Idelalisib
表11 1μM的Idelalisib
表12 0.3μM的Idelalisib
实验4
表13 10μM的Idelalisib
表14 3μM的Idelalisib
表15 1μM的Idelalisib
表16 0.3μM的Idelalisib
协同作用的计算:Clarke等人
当一种药物具有低活性时,如此处单独的Idelalisib对MEC-1细胞具有低细胞毒性活性,可以通过组合与单独的抑制药物显著不同的统计学证据确定协同作用。参见Clarke等人,Issues in experimental design and endpoint analysis in the studyof experimental cytotoxic agents in vivo in breast cancer and other models,Breast Cancer Research and Treatment 46:255-278(1997),其通过引用整体并入。
以下列方式分析表1-16的死细胞%(原始数据):
拮抗(AB)/C<(A/C)×(B/C)
叠加(AB)/C=(A/C)×(B/C)
协同(AB)/C>(A/C)×(B/C)
其中A是单独使用MOR00208的处理;B是单独使用Idelalisib的处理;C是对对照DMSO+RefMab33的响应;AB是A和B处理的组合。
实验1
表17:表1所示数据的Clarke分析
表18表2所示数据的Clarke分析
表19表3所示数据的Clarke分析
表20表4所示数据的Clarke分析
实验2
表21表5所示数据的Clarke分析
表22表6所示数据的Clarke分析
表23表7所示数据的Clarke分析
表24表8所示数据的Clarke分析
实验3
表25表9所示数据的Clarke分析
表26表10所示数据的Clarke分析
表27表11所示数据的Clarke分析
表28表12所示数据的Clarke分析
实验4
表29表13所示数据的Clarke分析
表30表14所示数据的Clarke分析
表31表15所示数据的Clarke分析
表32表16所示数据的Clarke分析
结果
使用Clarke等人的方法,在各浓度下的实验2-4显示了MOR00208+Idelalisib组合的明显协同作用。然而,实验1在一些浓度下没有显示出协同作用,因为Idelalisib组(见表1-3)显示了较弱的作用,这种作用略高于对照(比对照高约4%)。这个与对照相比较小的(~4%)差异在其他对照的范围内,因此可以归因于实验设置。
协同作用计算:组合指数(CI)
为了证实以上使用Clarke等人计算的协同作用的结果,将组合指数(CI)方法应用于表1-16的死细胞%(原始数据)。对于CI计算,我们使用0.3、1、3和10μM的Idelalisib和三个MOR208浓度(1.5、0.015和0.0015μg/ml)。
在通过引用整体并入的Ting-Chao Chou,Theoretical Basis,ExperimentalDesign,and Computerized Simulation of Synergism and Antagonism in DrugCombination Studies,Pharmacol Rev 58:621–681(2006)和通过引用整体并入的ChouTC,Talalay P,Quantitative analysis of dose-effect relationships:the combinedeffects of multiple drugs or enzyme inhibitors.Adv Enzyme Regul 22:27-55(1984)中描述了这样的计算。Chou-Talalay的方法使用CI-等效线方法(CI-isobolmethod)进行。
中值效应方程
中值效应方程将抑制剂(如药物)的作用建模为Fa/Fu=(D/D50)^m,其中D是剂量,Fa和Fu是受和不受剂量D影响的系统分数(Fa+Fu=1);D50是产生中值效应的剂量(例如IC50、ED50、LD50)。常数m确定剂量效应曲线的形状。
我们使用GraphPad Prism进行非线性回归计算来估计参数m和D50。
CI-等效线方法
CI-等效线方法提供药物之间协同效果的定量评估。组合指数(CI)是从单一和组合药物治疗的剂量-效应数据估算的。CI值小于1表示协同效应;CI=1表示叠加效应;CI>1表示拮抗效应。CI值离1越远,药物相互作用(协同或拮抗)越明显。
形式上,组合药物治疗的组合指数(CI)定义为
CI=D1/Dx1+D2/DX2
这里D1和D2分别是组合的药物1和药物2的剂量;Dx1和Dx2是仅用药物1和药物2进行治疗会产生与组合相同效果时的剂量。剂量Dx1和Dx2需要从单一药物治疗的剂量-效应数据估算。基本上,中值效应方程拟合到每个药物的数据。从药物的中值效应方程,我们可以估计产生效应(即Fa,Fu)所需的剂量(即D)。点离叠加线越远,1与CI的差别越大,(协同或拮抗)效应越强。
结果
图7-10显示了基于Chou的协同计算所产生的曲线。Chou指数值表明与单独的MOR00208和Idelalisib相比,MOR00208和Idelalisib的组合在所有实验1-4中在MEC-1细胞的特异性杀灭中显示了明显的协同作用。
MOR00208和Idelalisib的组合在MEC-1CLL细胞系中协同地起作用。因此,认为MOR00208和Idelalisib的组合在人CLL的治疗中是协同的。
此外,还认为MOR00208和Idelalisib的组合在人类非霍奇金淋巴瘤(NHL)、慢性淋巴细胞性白血病(CLL)和急性成淋巴细胞性白血病(ALL)的治疗中也协同地起作用。
应当理解到,尽管说明了示例性的实施方式,但说明书、具体实施例和数据均以例证的方式给出,并无意于对本发明进行限定。从本文包含的讨论、公开内容和数据,本发明中的各种变化和修改对于技术人员来说将会是显而易见的,因此视作本发明的一部分。
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<120> 组合及其用途
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<150> EP15181925.7
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<223> mab
<400> 11
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Lys Ser Leu Gln Asn Val
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Asn Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Ile Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 12
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> mab
<400> 12
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Asp Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Glu Glu Lys Thr Ile Ser Lys Thr Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 13
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> mab
<400> 13
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
15
Claims (17)
1.一种CD19特异性抗体与idelalisib组合用于制备用于治疗非霍奇金淋巴瘤、慢性淋巴细胞性白血病或急性成淋巴细胞性白血病的药物中的用途,其中所述抗体包含序列EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(SEQ ID NO:10)的可变重链,序列DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK(SEQ ID NO:11)的可变轻链,序列ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:12)的重链恒定结构域和序列RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:13)的轻链恒定结构域。
2.根据权利要求1所述的用途,其中所述CD19特异性抗体和idelalisib分别施用。
3.根据权利要求2所述的用途,其中所述CD19特异性抗体和idelalisib在物理上分别施用。
4.根据权利要求2所述的用途,其中所述CD19特异性抗体和idelalisib在时间上分别施用。
5.根据权利要求1所述的用途,其中所述CD19特异性抗体和idelalisib一起施用。
6.根据权利要求1所述的用途,其中在施用所述CD19特异性抗体之前施用idelalisib。
7.根据权利要求1所述的用途,其中在施用所述CD19特异性抗体之后施用idelalisib。
8.根据权利要求1-7中任一项所述的用途,其是用于制造用于治疗非霍奇金淋巴瘤的药物的用途。
9.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是滤泡性淋巴瘤。
10.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是小淋巴细胞性淋巴瘤。
11.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是粘膜相关淋巴样组织淋巴瘤。
12.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是弥漫性大B细胞淋巴瘤。
13.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是Burkitt's淋巴瘤。
14.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是套细胞淋巴瘤。
15.根据权利要求8所述的用途,其中所述非霍奇金淋巴瘤是边缘区淋巴瘤。
16.根据权利要求1-7中任一项所述的用途,其是用于制造用于治疗慢性淋巴细胞性白血病的药物的用途。
17.根据权利要求1-7中任一项所述的用途,其是用于制造用于治疗急性成淋巴细胞性白血病的药物的用途。
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CN110945028B (zh) | 2017-07-10 | 2023-09-08 | 国际药物发展生物技术公司 | 用非岩藻糖基化促凋亡抗cd19抗体与抗cd20抗体或化疗剂联合治疗b细胞恶性肿瘤 |
KR20200030337A (ko) * | 2018-09-12 | 2020-03-20 | 주식회사 녹십자랩셀 | 종양 치료를 위한 항-cd 19 항체 및 자연살해세포를 포함하는 약학적 조합물 |
TW202241436A (zh) * | 2020-11-30 | 2022-11-01 | 美商英塞特公司 | 抗cd19抗體及帕薩昔布(parsaclisib)之組合療法 |
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