CN109890418B - 抗cd19抗体与bcl-2抑制剂的组合及其用途 - Google Patents
抗cd19抗体与bcl-2抑制剂的组合及其用途 Download PDFInfo
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Abstract
本公开内容说明了一种用于治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的抗CD19抗体和BCL‑2抑制剂的药物组合。
Description
发明领域
本公开内容涉及用于治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的抗CD19抗体和BCL-2抑制剂的药物组合。
背景技术
B细胞是在体液免疫反应中发挥重大作用的淋巴细胞。它们在大多数哺乳动物的骨髓中产生,代表着循环淋巴池(lymphoid pool)的5-15%。B细胞的主要功能是产生针对各种抗原的抗体,是适应性免疫系统的必要组分。
由于其在调节免疫系统中的关键作用,B细胞的调节异常(disregulation)与多种病症相关,例如淋巴瘤和白血病。这些病症包括非何杰金氏淋巴瘤(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-细胞肿瘤。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期的改善。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。在历史上对有症状的惰性型NHL患者的初始治疗已经是组合化学疗法。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学疗法有反应,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期的显著改善。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-细胞病症使用抗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。慢性淋巴细胞性白血病(也称作“慢性淋巴样白血病”或“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。男性患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SEER Cancer 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(依鲁替尼(Ibrutinib)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急性成淋巴细胞性白血病(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的未分化、不成熟的状态(“胚细胞”(blasts)),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 CancerStatistics 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)、非何杰金氏淋巴瘤、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,CD 19抗原是非何杰金氏淋巴瘤(包括本文所述的每种亚型)、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。将表达包括CD3-ζ和4-BB共刺激结构域的抗CD19嵌合抗原受体(CAR)的T细胞施用于患有晚期CLL的患者。Kalos等人,具有嵌合抗原受体的T细胞具有有效的抗肿瘤效果并可以在患有晚期白血病的患者中建立记忆(T cells withChimeric Antigen Receptors Have Potent Antitumor Effects and CanEstablishMemory in Patients with Advanced Leukemia),Science TranslationalMedicine,vol.3,no.95(2011年8月10日),在此将其全文并入作为参考。Sadelain等人,嵌合抗原受体的希望和潜在障碍(The promise and potential pitfalls of chimericantigen receptors),Current Opinion in Immunology,Elsevier,vol.21,no.2,2009年4月2日,在此将其全文并入作为参考,该文献也描述了抗CD19嵌合抗原受体(CAR)。但是,Kalos等人和Sadelain等人均没有描述本文所例示的CD19特异性抗体与BCL-2抑制剂的组合。
WO2007076950(US2007154473)中讨论了CD19抗体在非特异性B细胞淋巴瘤中的应用,在此将其全文并入作为参考,该文献一并在一长列可能的组合配偶体名单中粗略地提到lbrutinib,但没有教导本文所例示的抗体,也没有暗示如本文所例示的组合在治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病中的协同效果。
CD19抗体在CLL、NHL和ALL中的应用描述于以下文献:Scheuermann等人,白血病和淋巴瘤诊断和免疫疗法中的CD19抗原(CD19Antigen in Leukemia and LymphomaDiagnosis and Immunotherapy),Leukemia and Lymphoma,Vol.18,385-397(1995),在此将其全文并入作为参考,但该文献没有暗示本文所例示的组合。
其他的CD19特异性抗体描述于以下文献中: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);和WO2010095031(12/710,442)(GlenmarkPharmaceuticals)、WO2012010562和WO2012010561(International Drug Development)、WO2011147834(Roche Glycart)和WO2012/156455(Sanofi),在此将其均全文并入作为参考。
CD19特异性抗体与其他药物的组合描述于以下文献中:WO2010151341(US13/377,514)(The Feinstein Institute);US5686072(University of Texas)和WO2002022212(PCT/US01/29026)(IDEC Pharmaceuticals)、WO2013/024097(14/126,928)(MorphoSysAG)、和WO2013/024095(14/127,217)(MorphoSys AG),在此将其均全文并入作为参考。
某些BCL-2抑制剂是市售的。VENCLEXTATM(维奈托克(venetoclax))也称作是GDC-0199、ABT-199和RG7601,它是适用于治疗通过PDA批准的测试检测出具有17p缺失的、已接收过至少一种在先治疗的慢性淋巴细胞性白血病(CLL)患者的BCL-2。美国专利第8,546,399号和第9,174,982号中对维奈托克加以说明,在此将其全文并入作为参考。
尽管近来在抗癌药物的发现和开发方面取得进展,许多形式的涉及表达CD19的肿瘤的癌症仍然预后很差。因此,需要有治疗这些形式癌症的改善的方法。
发明内容
现有技术中没有单独地或组合地暗示所例示的抗体和维奈托克的组合在非何杰金氏淋巴瘤、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的协同效果。
在一方面,本公开内容涉及CD19特异性抗体与BCL-2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,例如,非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病。
体外模型被视为指示着某些化合物或化合物的组合将如何在人体内发挥作用。
MEC-1细胞(DSMZ#ACC497)是慢性B-细胞白血病细胞系。MEC-1细胞在目前体外模型中指示着该组合将如何在人的慢性淋巴样白血病(CLL)的治疗中发挥作用。
此外,当化合物在体外组合时,预计组合只具有累加的效果。出人意料地,发明人发现,与单独的抗体和维奈托克相比较,特定的CD19特异性抗体和维奈托克的组合在体外介导协同水平的特异性细胞杀灭。具体地,发明人发现,与单独的抗体和维奈托克相比较,MOR00208和维奈托克的组合在体外在MEC-1细胞中介导协同水平的特异性细胞杀灭。
简言之,示例性抗CD19抗体和维奈托克的组合在CLL相关模型中协同发挥作用。由于CLL是与B细胞有关的疾病,且CD19在B细胞上高度表达,因此所例示的组合在其他B细胞相关疾病例如ALL和NHL的治疗中将具有相同的作用机制并也应当协同地发挥作用。
因此,所例示的CD19特异性抗体和维奈托克的组合在人非何杰金氏淋巴瘤、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将会是有效的。所例示的CD19特异性抗体和维奈托克的组合的预期效力将会在临床试验中加以确认。
由于维奈托克和其他BCL-2抑制剂的作用机制是类似的,因为它们通过抑制抗凋亡B细胞淋巴瘤-2(Bcl-2)蛋白质、导致细胞的程序性细胞死亡而发挥作用,因此据信,当使用所例示的抗CD19抗体和维奈托克以外的BCL-2抑制剂的组合来治疗患有非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应当观察到协同效应。
由于所例示的抗CD19抗体和其他的抗CD19抗体与CD19结合,因此据信当使用任何抗CD19抗体和BCL-2抑制剂例如维奈托克的组合来治疗患有非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应当观察到协同效应。
本公开内容的一方面包括一种组合,其中CD19特异性抗体包括序列SYVMH(SEQ IDNO: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,以及维奈托克。在实施方式中,该组合是协同的。在优选的方面,该组合用于治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病。
附图说明
图1-3显示了MOR00208和维奈托克组合起来在MEC-1细胞系中的细胞毒性。MEC-1细胞用维奈托克预处理24小时。
图4显示了MOR00208的可变结构域的氨基酸序列。
图5显示了MOR00208的Fc区的氨基酸序列。
图6-8显示了MEC-1细胞系中MOR00208和维奈托克的Chou-Talay组合指数曲线。
图9在s.c.Toledo SCID小鼠模型中,与任一单一疗法相比较,MOR00208与ABT-199的组合表现出优异的肿瘤生长减少。示出组平均值±均值标准误差(SEM)。星号表示组合治疗vs MOR0028单一治疗或分别的ABT-199单一治疗的肿瘤倍增时间的统计学显著性:*p-值<0.05,**p-值<0.01,****p-值<0.0001。肿瘤注射之后23天,中值肿瘤体积266mm3(123-406mm3)处随机化时,开始治疗。通过每周两次腹腔注射(i.p.),施用MOR00208(11mg/kg)。通过每日os(p.o.),施用ABT-199(20或40mg/kg)。
图10在s.c.Toledo SCID小鼠模型中,与任一单一疗法相比较,MOR00208与ABT的组合表现出优异的中值存活率。Kaplan-Meier曲线示出自随机化直至人道终点(肿瘤体积2000mm3)的存活率。肿瘤注射之后23天,中值肿瘤体积266mm3(123-406mm3)处随机化时,开始治疗。通过每周两次腹腔注射(i.p.),施用MOR00208(11mg/kg)。通过每日os(p.o.),施用ABT-199(20或40mg/kg)。
具体实施方式
“协同效应”、“协同作用”或“协同的”是指组合超过预期的叠加效果。关于体外研究,组合的“协同效应”、“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 ComputerizedSimulation of Synergism and Antagonism in Drug Combination Studies),PharmacolRev 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体内实验细胞毒性试剂研究中实验设计和终点分析中的问题(Issues inexperimental design and endpoint analysis in the study of experimentalcytotoxic agents in vivo in breast cancer and other models),Breast CancerResearch and Treatment 46:255-278(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),AcademicPress,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抗体包括两个相同的重链和两个相同的轻链,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,其含有至少一个均含有CDR和骨架区的可变重链或可变轻链。
Bcl-2(B-细胞淋巴瘤2)在人体内由BCL2基因编码,其是通过诱导(促凋亡)或抑制(抗凋亡)凋亡而调节细胞死亡(凋亡)的调节蛋白质Bcl-2家族的创始成员。Bcl-2的NCBI基因编号596。Bcl-2具体被视作是重要的抗凋亡蛋白质,因此分类为致癌基因。Bcl-2的名字源自B-细胞淋巴瘤2,因为它是在滤泡性淋巴瘤中在涉及染色体14和18的染色体易位中最初描述的一系列蛋白质中的第二个成员。在完整基因组数据可得的许多种哺乳动物中已经识别出直系同源物(例如,小鼠中的Bcl2)。
“BCL-2抑制剂”是一类通过抑制抗凋亡B细胞淋巴瘤-2(Bcl-2)蛋白质、导致细胞的程序化细胞死亡来发挥作用的药物。BCL-2抑制剂包括维奈托克(venetoclax)。维奈托克由Abbvie和Genentech销售(商品名称为VENCLEXTATM,也称作是GDC-0199、ABT-199和RG7601)。维奈托克目前的说明书注明是用于治疗通过FDA批准的测试检测出具有17p缺失的、已接收过至少一种在先治疗的慢性淋巴细胞性白血病(CLL)的患者。维奈托克的分子式是:4-(4-{[2-(4-氯苯基)-4,4-二甲基-1-环己烯-1-基]甲基}-1-哌嗪基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺,结构如下:
在本文中“维奈托克”、“ABT”和“ABT-199”作为同义词使用。
其他BCL-2抑制剂包括:
Genasense:Genta Incorporated开发出靶向Bcl-2的反义寡核苷酸药物Genasense(G3139)。反义DNA或RNA链是非编码的,其与编码链(其为分别用于产生RNA或蛋白质的模版)互补。反义药物是与mRNA杂交并使其失活的RNA短序列,其防止蛋白质的形成。人淋巴瘤细胞增殖(具有t(14;18)易位)可以通过靶向Bcl-2mRNA的起始密码子区域的反义RNA受到抑制。体外研究导致识别出与Bcl-2mRNA的前6个密码子互补的Genasense。这些在淋巴瘤I/II期试验中显示出成功的结果。2004年启动了大规模的III期试验。到2016年,该药物尚未获批,其开发者已破产。
ABT-737和ABT-263:在2000年代中期,Abbott Laboratories开发出一种新的称作ABT-737的Bcl-2、Bcl-xL和Bcl-w的抑制剂。该化合物是靶向这些Bcl-2家族蛋白质、但不靶向A1或Mcl-1的BH3模拟物小分子抑制剂(SMI)类别的一部分。由于其对于Bcl-2、Bcl-xL和Bcl-w的亲和力更高,ABT-737要优于之前的BCL-2抑制剂。体外研究示出,来自B细胞恶性肿瘤患者的原代细胞对于ABT-737敏感。在动物模型中,其提高了存活率,导致肿瘤消退,并治愈了高百分比的小鼠。在使用患者异种移植物的临床前研究中,ABT-737显示出治疗淋巴瘤和其他血液癌的效力。由于其药理学性质不利,ABT-737不适合于临床试验,而其衍生物ABT-263对于小细胞肺癌(SCLC)细胞系具有相似活性,已经进入临床试验。
“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的蛋白质,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:
“MOR00208”是一种抗CD19抗体。可变结构域的氨基酸序列提供于图4中。MOR00208的重链和轻链Fc区的氨基酸序列提供于图5中。“MOR00208”和“XmAb 5574”用作描述图4和图5所示抗体的同义词。MOR00208抗体描述于US专利申请第12/377,251号,在此将其全文并入作为参考。
美国专利申请第12/377,251号描述了称作4G7 H1.52 Hybrid S239D/I332E/4G7L1.155(之后称作MOR00208)的如下抗体:
其他的CD19特异性抗体描述于以下专利文献中:US专利第7,109,304号(Immunomedics),在此将其全文并入作为参考;US申请第11/917,750号(Medarex),在此将其全文并入作为参考;US申请第11/852,106号(Medimmune),在此将其全文并入作为参考;US申请第11/648,505号(Merck Patent GmbH),在此将其全文并入作为参考;US专利第7,968,687号(Seattle Genetics),在此将其全文并入作为参考;和US申请第12/710,442号(Glenmark Pharmaceuticals),在此将其全文并入作为参考。
“Fc区”是指抗体的恒定区,在人中可以是IgG1、2、3、4亚类或其他。人Fc区的序列可得自IMGT,Human IGH C-REGIONs,www.imgt.org/IMGTrepertoire/Proteins/protein/human/IGH/IGHC/Hu_IGHCallgenes.html(2011年5月16日检索)。
“RefmAb33”是氨基酸序列如下所示的抗体:
包括Fc区的重链:
包括Fc区的轻链:
RefmAb33对RSV有特异性,因其与MOR00208享有相同的Fc区而用作同种型对照。
“组合”是指多于一项,例如,化合物例如抗体和维奈托克。
本公开内容还涉及含有所述组合的组合、药物和药物组合物。本发明的组合的两种组分,例如,CD19特异性抗体和维奈托克,可以在物理上或者在时间上一起、同时、分开或相继给药。
维奈托克目前口服服用,目前每天给药一次。MOR00208目前是静脉内给药,目前每周一次或每两周一次给药。
优选地,将两种药物给药允许两种药物同时在患者中具有活性。例如,如果MOR208每周给药,维奈托克每天给药,则两种药物的活性物质同时存在于患者中。在一实施方式中,在施用CD19特异性抗体例如MOR00208之前和/或与其分开地,施用维奈托克。
同时是指两种组分在两种组分(药物)同时在患者中有活性的时刻给药。“协同作用”意味着两种药物同时在患者中有活性。
一起给药可以意味着同时给药。
组合的组分可以配制在不同的药物组合物中。药物组合物包括活性药剂,例如用于人的治疗用途的抗体。药物组合物可以包括可接受的载体或赋形剂。
“给药”或“施用”包括但不限于,通过可注射的形式输送,例如,如静脉内、肌肉内、真皮内或皮下途径,或者粘膜途径,例如作为鼻用喷雾或吸入用气溶胶,或作为可摄取的溶液、胶囊或片剂。
化合物或组合的“治疗有效量”是指足以治愈、缓解或部分控制指定疾病或病症及其并发症的量。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重量和一般状况。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。
“交叉竞争”是指抗体或其他结合试剂在标准竞争结合检定中干扰其他抗体或结合试剂与CD19结合的能力。因此,无论其是否根据本发明称为交叉竞争,抗体或其他结合试剂能够干扰其他抗体或结合分子与CD19结合的能力或程度可以使用标准竞争结合检定来确定。一种合适的检定涉及到使用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检定使用基于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“表位框并(epitope binning)”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(该肽与蛋白分子的一部分对应),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,参见同上。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.Sci USA 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。
实施方式
本公开内容的一个方面是用于治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的包括CD19特异性抗体与BCL-2的组合。在实施方式中,该组合是协同的。
在此,所例示的抗CD19抗体与维奈托克的组合在CLL相关的体外模型中协同发挥作用。由于CLL是B细胞相关的疾病,且CD19在B细胞上高度表达,因此所例示的组合在其他B细胞相关疾病例如ALL和NHL的治疗中应当具有相同的作用机制并也应当协同地发挥作用。因此,所例示的CD19特异性抗体与维奈托克的组合在人的非何杰金氏淋巴瘤、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将会是有效的。所例示的CD19特异性抗体和维奈托克的组合的预期效力将会在临床试验中加以确认。
对慢性B-细胞淋巴瘤细胞系MEC-1细胞(DSMZ#ACC497)进行测试。MEC-1细胞在目前体外模型中指示着该组合将如何在人的慢性淋巴样白血病(CLL)的治疗中发挥作用。Chou指数值表明,与单独的MOR00208和维奈托克相比较,MOR00208和维奈托克的组合在MEC-1细胞的特异性杀灭中具有明显的协同作用。
简言之,所例示的抗CD19抗体和维奈托克的组合在CLL相关模型中协同发挥作用。
因此,所例示的CD19特异性抗体与维奈托克的组合在人的非何杰金氏淋巴瘤、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将会是有效的。
由于维奈托克和其他BCL-2抑制剂的作用机制是类似的,因此据信当使用所例示的抗CD19抗体和维奈托克以外的BCL-2抑制剂的组合来治疗患有非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应当观察到协同效应。
由于所例示的抗CD19抗体和其他的抗CD19抗体均与CD19结合,因此据信当使用任何抗CD19抗体和B细胞淋巴瘤-2(Bcl-2)蛋白抑制剂的组合来治疗患有非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的人时,也应当观察到协同效应,其中抗CD19抗体描述于,例如,US专利申请第12/377,251号(Xencor)、WO2005012493、WO2010053716(Immunomedics);WO2007002223(Medarex);WO2008022152(Xencor);WO2008031056(Medimmune);WO 2007/076950(Merck Patent GmbH);WO 2009/052431(SeattleGenetics);和WO2010095031(Glenmark Pharmaceuticals),在此将其均全文并入作为参考。
在实施方式中,CD19特异性抗体包括与包括序列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区的抗体交叉竞争的抗体。
在实施方式中,CD19特异性抗体包括结合与包括序列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区的抗体相同的表位的抗体。
在实施方式中,CD19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特异性抗体具有细胞毒性活性。在实施方式中,CD19特异性抗体包括具有ADCC诱导活性的恒定区。在实施方式中,CD19特异性抗体诱导ADCC。
在实施方式中,CD19特异性抗体诱导ADCC,并包括序列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区以及具有ADCC诱导活性的恒定区。
在实施方式中,CD19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,所述抗体包括以下序列的重链恒定区:
在实施方式中,CD19特异性抗体包括以下序列的轻链恒定区:
在实施方式中,BCL-2抑制剂是维奈托克。
在实施方式中,将组合的组分即CD19特异性抗体和维奈托克分开给药。在实施方式中,在施用CD19特异性抗体之前施用维奈托克。
在实施方式中,将组合的组分在两种组分(药物)同时在患者中有活性的时刻给药。“协同作用”意味着两种药物同时在患者中有活性。在实施方式中,将组合的组分在物理上或者在时间上一起、同时、分开或相继给药。在实施方式中,组合的组分同时给药。
在实施方式中,组合是药物组合物。在实施方式中,组合物包括可接受的载体。在实施方式中,将组合以有效的量给药。
本公开内容的一方面包括用于治疗非何杰金氏淋巴瘤、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,其包括序列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,其中所述抗体以与维奈托克的协同组合使用。
本公开内容的一方面包括用于治疗非何杰金氏淋巴瘤、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,其包括序列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,其中所述抗体以与维奈托克的协同组合使用。在一实施方式中,所述抗体与维奈托克联合给药。在另一实施方式中,所述抗体和维奈托克分开给药。在其它实施方式中,在施用维奈托克之前,施用所述抗体。在其它实施方式中,在施用所述抗体之前,施用维奈托克。
本公开内容的一方面包括用于治疗非何杰金氏淋巴瘤、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特异性抗体与维奈托克的协同组合,该CD19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,非何杰金氏淋巴瘤选自滤泡性淋巴瘤、小淋巴细胞性淋巴瘤、黏膜相关淋巴样组织、边缘区、弥漫性大B细胞、Burkitt's和套细胞淋巴瘤。
在实施方式中,非何杰金氏淋巴瘤是滤泡性淋巴瘤。在实施方式中,非何杰金氏淋巴瘤是小淋巴细胞性淋巴瘤。在实施方式中,非何杰金氏淋巴瘤是黏膜相关淋巴样组织。在实施方式中,非何杰金氏淋巴瘤是边缘区淋巴瘤。在实施方式中,非何杰金氏淋巴瘤是弥漫性大B细胞淋巴瘤。在实施方式中,非何杰金氏淋巴瘤是Burkitt's淋巴瘤。在实施方式中,非何杰金氏淋巴瘤是套细胞淋巴瘤。
在实施方式中,组合用于治疗慢性淋巴细胞性白血病。在实施方式中,组合用于治疗急性成淋巴细胞性白血病。
另一方面包括一种治疗对其有需要的个体的非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的方法,该方法包括施用CD19特异性抗体和BCL-2抑制剂。在该方法的实施方式中,CD19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区和序列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。在该方法的实施方式中,抗体包括所例示的CD19特异性抗体。在该方法的实施方式中,BCL-2抑制剂是维奈托克。
另一方面包括CD19特异性抗体在制造用于与维奈托克协同组合治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的药物中的用途,其中所述抗体包括序列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区和序列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。
实施例
实施例1:单独以及组合使用MOR00208和维奈托克的MEC-1细胞的细胞毒性
材料
测试的细胞系:MEC-1细胞(DSMZ#ACC497)。根据供应商的信息使用细胞系的培养条件。细胞培养基:Iscove改良的Dulbecco培养基(IMDM),Invitrogen,Cat No.:31980;RPMI1640,Invitrogen,Cat No.:31870;GlutaMAX,Invitrogen,CAT No.:35050;FCS:SigmaCAT No.:F7524LOT No.:111M3396。NKs:RPMI1640,具有GlutaMAX,Invitrogen,Cat No.:31870,10%FCS;Biocoll:Biochrome AG CAT No.:L6115LOT No.:0034D;MACS NK细胞分离试剂盒:Miltenyi Biotec CAT No.:130-092-657LOT No.:5150402327;维奈托克:SelleckChem.CAT No.:S8048LOT No.:S804803;FCS:Sigma CAT No.:F7524 LOT No.:111M3396;和RefmAb33(抗-RSV),Fc区与MOR00208相同。
方法
在MEC-1细胞系(CLL)中测试MOR00208和维奈托克单独以及组合的细胞毒性潜力。使用以下参数测量目标细胞杀灭:浓度3μΜ、6.5μΜ和10μΜ的维奈托克单一治疗;浓度0.01pM、0.1pM、1pM、10pM、100pM和10nM的MOR00208单一治疗;以及所列的维奈托克和MOR00208浓度的联合治疗。使用以下作为对照:RefmAb33,单独的NK细胞,单独的MEC-1细胞,或者DMSO。在维奈托克单一组以及MOR00208+维奈托克联合组中,将目标细胞用维奈托克或者用DMSO对照预处理24小时,之后,在ADCC检定之前除去死细胞。使用死细胞去除试剂盒,除去通过维奈托克的细胞毒性作用杀死的细胞。实施死细胞去除试剂盒,以模拟体内也会发生的死细胞的去除,并防止死细胞对后续ADCC检定的假阴性干扰。对于ADCC检定,对目标细胞进行计数,并使用最终浓度为1μg/mL的CFSE进行染色。对于对照组,即经DMSO处理的目标细胞,效应:目标(E:T)细胞比调节至2:1,即,1x10E6/mL效应细胞(NK细胞)和5x10E5/mL目标细胞(MEC-1细胞)。对于维奈托克单一组以及对于MOR00208+维奈托克联合组,目标细胞的数量在24小时处理的过程中根据观察到的维奈托克的细胞毒性作用而减少,同时效应细胞的数量保持恒定在1x106/mL。ADCC检定进行如下:使用96孔板,每孔加入100μL MEC-1目标细胞悬液,然后向每孔加入100μL NK效应细胞悬液。将混合的细胞悬液离心,并重悬在含有100μL抗体的培养基或相应的对照溶液中。抗体在培养基中在10nM-0.01pM(对应于1.5μg/mL-1.5pg/mL)的范围内稀释。ADCC检定物在CO2-孵育器中在37℃下孵育2小时。在冰上孵育10分钟之后,向每孔中加入50μL DAPI溶液(最终浓度1μg/mL),并在冰上再孵育10分钟。ADCC测量在BD FACSVerse仪器上进行。死亡的目标细胞识别为DAPI阳性细胞。
数据
总体上,进行三组独立的实验,以确定MOR00208和维奈托克的组合的细胞毒性潜力。所有三组实验各自的原始数据表格显示于表1-6中。所有三组实验各自的ADCC剂量反应曲线显示于图1-3中。所有三组实验对于各个维奈托克浓度的平均值(+/-SEM)组合指数曲线显示于图6-8中。
实验1:
表1:MOR00208和维奈托克的单一活性
实际MOR00208剂量[μg/mL] | 实际MOR00208效果[%死细胞] |
1.50E-06 | 15.3 |
1.50E-05 | 17.4 |
1.50E-04 | 22.8 |
1.50E-03 | 43.4 |
1.50E-02 | 66.8 |
1.50E+00 | 69.4 |
实际维奈托克剂量[μM] | 实际维奈托克效果[%死细胞] |
3.0 | 8.9 |
6.5 | 17.7 |
10.0 | 38.8 |
表2:MOR00208和维奈托克的组合活性
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
实验2:
表3:MOR00208和维奈托克的单一活性
表4:MOR00208和维奈托克的组合活性
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
实验3:
表5:MOR00208和维奈托克的单一活性
实际MOR00208剂量[μg/mL] | 实际MOR00208效果[%死细胞] |
1.50E-06 | 11.8 |
1.50E-05 | 18.9 |
1.50E-04 | 26.6 |
1.50E-03 | 45.3 |
1.50E-02 | 69.1 |
1.50E+00 | 74.8 |
实际维奈托克剂量[μM] | 实际维奈托克效果[%死细胞] |
3.0 | 7.7 |
6.5 | 16.3 |
10.0 | 48.1 |
表6:MOR00208和维奈托克的组合活性
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
*实际MOR00208效果在MOR00208+维奈托克效果之下饱和时的无限理论MOR00208剂量
协同作用计算
进行组合指数(CI)的计算,以确定所例示的抗CD19抗体和维奈托克的组合与单独的MOR00208和维奈托克相比较时的协同作用。该计算描述于以下文献中: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(TheoreticalBasis,Experimental Design,and Computerized Simulation of Synergism andAntagonism in Drug Combination Studies),Pharmacol Rev 58:621–681(2006),在此将其全文并入作为参考;以及Chou TC,Talalay P,剂量-效果关系的量化分析:多种药物或酶抑制剂的组合效果(Quantitative analysis of dose-effect relationships:thecombined effects of multiple drugs or enzyme inhibitors).Adv Enzyme Regul 22:27-55(1984),在此将其全文并入作为参考。使用CI-isobol方法进行Chou-Talalay的方法。
中效方程式
中效方程式模拟抑制剂(例如药物)的效果:Fa/Fu=(D/D50)^m,其中D是剂量,Fa和Fu是体系受剂量D影响和不受该剂量影响的部分(Fa+Fu=1);D50是产生中效的剂量(例如IC50、ED50、LD50)。常数m决定剂量-效果曲线的形状。我们使用GraphPad Prism来进行非线性回归计算,以估计参数m和D50。
CI-isobol方法
CI-isobol方法提供了对药物间协同作用的量化评估。组合指数(CI)由单独的和组合的药物治疗的剂量-效果数据估算。CI值小于1表示协同作用;CI=1表示叠加效果;CI>1表示拮抗作用。CI值与1越远,药物相互作用(协同作用或拮抗作用)就越显著。通常,组合药物治疗的组合指数(CI)定义为:CI=D1/Dx1+D2/DX2。在此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治疗给出与组合同样效果时的剂量。剂量Dx1和Dx2需要由单独药物治疗的剂量-效果数据估算。基本上,中效方程式适合于每种药物的数据。由药物的中效方程式,我们可以估算出产生效果(即Fa、Fu)所需的剂量(即D)。点距离叠加线越远,1及其CI之间的差别就越大,因此(协同或拮抗)效果就越强。
结果
每个维奈托克浓度下所有三组实验的平均值(+/-SEM)组合指数显示于图6-8中。该组合指数值表明,与单独的MOR00208和维奈托克相比,MOR00208和维奈托克的组合在MEC-1细胞的特异性杀灭方面有明显的协同作用。非常低剂量的MOR00208在例示的ADCC细胞杀灭检定中效果极低或没有效果。因此,非常低剂量MOR00208的CI值显示出1或略高于1的数值,该数值仅代表维奈托克的活性。在单独的MOR00208显示出正常的细胞杀灭活性的MOR00208浓度下,通过小于1的CI值显示出明显的协同作用,这代表MOR00208和维奈托克的活性。在此例示的MOR00208的最高浓度在进行中的临床试验中取得,其中MOR00208以每周一次12mg/kg的剂量给药。因此,据信例示的体外模型预测了在人体内的活性。因此,MOR00208和维奈托克的组合在人非何杰金氏淋巴瘤(NHL)、慢性淋巴样白血病(CLL)和急性成淋巴细胞性白血病(ALL)的治疗中也应当会协同地发挥作用。
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示例说明的方式给出,并无意于对本发明进行限定。根据本文包含的讨论、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变得明显,因此视作本发明的一部分。
实施例2:MOR00208联合ABT-199在SCID小鼠中在皮下人淋巴瘤细胞异种移植物模
型中的效力
在具有皮下TOLEDO人淋巴瘤细胞肿瘤的SCID小鼠模型中对MOR00208联合维奈托克(ABT-199)的效力益处进行了进一步的研究。对肿瘤生长和死亡率加以评价。
材料&方法
购入Toledo细胞系和培养基,其由Oncodesign提供。肿瘤细胞在加湿的气氛(5%CO2,95%空气)中在37℃下生长成单层。培养基为补充有10%胎牛血清(ref:P30-1506,Lonza)、HBSS(ref:BE10-543F)、葡萄糖(ref:G8769,Sigma,France)、Hepes(ref:BE17-737E,Lonza)和丙酮酸钠(ref:BE13-115E,Lonza)的含有2mM L-谷氨酰胺(ref:BE12-702F,Lonza,Verviers,Belgium)的RPMI 1640。细胞贴附于塑料瓶。出于实验用途,通过在没有钙或镁的Hanks培养基(ref:BE10-543F,Lonza)中用胰蛋白酶-维尔烯(ref:BE02-007E,Lonza)处理5分钟,使肿瘤细胞从培养瓶上分离,然后加入完全培养基中和。在血细胞计数器中对细胞进行计数,通过0.25%台盼蓝拒染检定对其存活力进行评价。
通过将200μl含有基质胶(50:50,v:v,ref:356237,BD Biosciences,France)的RPMI 1640中的10x106Toledo细胞皮下注射到SCID小鼠的右肋,诱导肿瘤。在第23天,在肿瘤达到256±68mm3的平均体积时,使用Vivo软件(Biosystemes,Couternon,France)将60只小鼠根据其各自的肿瘤体积随机化成每组10只动物的6个组。进行统计学测试(方差分析,ANOVA),以测试组间的一致性。将MOR208腹腔内注射(IP)到小鼠的腹腔内。通过经由强饲管强饲口服(per os,PO),施用组合的物质。
在D23开始的治疗日程如下:
第1组的动物每日1次接受PEP的PO给药,每周2次接受一次PBS的IP注射。
第2组的动物每日接受20mg/kg/adm的ABT-199的PO给药。
第3组的动物每日接受40mg/kg/adm的ABT-199的PO给药。
第4组的动物在D23、D27、D30、D34、D37和D41接受一次11mg/kg/inj的MOR208的IP注射,然后在D48接受单次的11mg/kg/inj的MOR208的IP注射(一周2次)。
第5组的动物每日接受20mg/kg/adm的ABT-199的PO给药,并联合在D23、D27、D30、D34、D37和D41以及在D48、D51、D55和D58接受11mg/kg/inj的MOR208的IP注射。
第6组的动物每日接受40mg/kg/adm的ABT-199的PO给药,并联合在D23、D27、D30、D34、D37和D41以及在D48、D51、D55和D58接受两轮11mg/kg/inj的MOR208的一次IP注射。
所有研究数据,包括动物体重测量、临床和死亡率记录以及处理,均在Vivo数据库(Biosystemes,Dijon,France)上安排并记录。存活力和行为均每天记录。体重和肿瘤体积一周测量2次。肿瘤的长度和宽度用卡尺一周测量2次,肿瘤体积通过下式估算:
结果
与载体对照和两种单一疗法方案相比,以20和40mg/kg的剂量用MOR00208和ABT-199联合治疗导致优异的、统计学上显著的对Toledo淋巴瘤细胞生长的抑制。当对小鼠从随机化直至人道终点(肿瘤体积2000mm3)的存活率进行分析时,MOR00208联合ABT-199显示出更加显著的抗肿瘤效果。与各个单一疗法相比,联合组的中值存活率和各个寿命增加都要优异。由于组合的效果要大于各个单一疗法的总和,因此对组合效果的进一步表征将作为增强作用的MOR00208的组合的结果加以分类(图9,表7,图10,表8)。
表7:单独的和组合的MOR00208和ABT-199对s.c.Toledo SCID小鼠模型中中值存
活期的影响
§vs.PEP/PBS对照,a显著不同于PBS对照,b显著不同于载体对照和各个单一疗法组,c协同效应vs.各个单一疗法组,因为IDT组合ABT-199 20mg/kg&MOR00208 11mg/kg(70%)>各个单一疗法组效果的总和IDT ABT-199 20mg/kg(44%)+IDT MOR00208 11mg/kg(18%)=62%。d协同效应vs.各个单一疗法组,因为IDT组合ABT-199 40mg/kg&MOR0020811mg/kg(100%)>各个单一疗法组效果的总和IDT ABT-199 40mg/kg(64%)+IDT MOR0020811mg/kg(18%)=82%。
表8:单独的和组合的MOR00208和ABT-199对s.c.Toledo SCID小鼠模型中中值存
活期的影响
§vs.PEP/PBS对照,a显著不同于PBS对照,b显著不同于载体对照和各个单一疗法组,c协同效应vs.各个单一疗法组,因为ILS组合ABT-199 20mg/kg&MOR00208 11mg/kg(72%)>各个单一疗法组效果的总和ILS ABT-199 20mg/kg(43%)+ILS MOR00208 11mg/kg(20%)=63%。d协同vs.各个单一疗法组,因为ILS组合ABT-199 40mg/kg&MOR00208 11mg/kg(134%)>各个单一疗法组效果的总和ILS ABT-199 40mg/kg(72%)+ILS MOR0020811mg/kg(20%)=92%。
序列表
<110> 莫佛塞斯公司
<120> 组合及其用途
<130> MS255
<150>
<151>
<160> 15
<170> BiSSAP 1.0
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 1
Ser Tyr Val Met His
1 5
<210> 2
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 2
Asn Pro Tyr Asn Asp Gly
1 5
<210> 3
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 3
Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp Tyr
1 5 10
<210> 4
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 4
Arg Ser Ser Lys Ser Leu Gln Asn Val Asn Gly Asn Thr Tyr Leu Tyr
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 5
Arg Met Ser Asn Leu Asn Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 6
Met Gln His Leu Glu Tyr Pro Ile Thr
1 5
<210> 7
<211> 556
<212> PRT
<213> 智人(Homo sapiens)
<220>
<223> CD19
<400> 7
Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met
1 5 10 15
Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp
20 25 30
Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln
35 40 45
Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu
50 55 60
Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile
65 70 75 80
Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu
85 90 95
Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr
100 105 110
Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp
115 120 125
Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro
130 135 140
Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala
145 150 155 160
Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro
165 170 175
Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro
180 185 190
Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser
195 200 205
Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser
210 215 220
Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp
225 230 235 240
Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala
245 250 255
Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu
260 265 270
Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly
275 280 285
Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu
290 295 300
Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg
305 310 315 320
Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val
325 330 335
Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu
340 345 350
Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala
355 360 365
Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp
370 375 380
Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly
385 390 395 400
Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu
405 410 415
Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu
420 425 430
Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly
435 440 445
Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu
450 455 460
Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser
465 470 475 480
Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Gly
485 490 495
Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro Gln
500 505 510
Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp Ala
515 520 525
Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala Trp
530 535 540
Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg
545 550 555
<210> 8
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 重链RefMab33
<400> 8
Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ala
20 25 30
Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys His Tyr Asn Pro Ser
50 55 60
Leu Lys Asp Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Asp Met Ile Phe Asn Phe Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
290 295 300
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Glu Glu
325 330 335
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 9
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 轻链RefMab33
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Arg Val Gly Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 10
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Ser Ser Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<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> 合成构建体
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> 合成构建体
<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
<210> 14
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Ser Ser Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
290 295 300
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Glu
325 330 335
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 15
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 15
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
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (15)
1.CD19特异性抗体联合维奈托克在制备用于治疗非何杰金氏淋巴瘤、慢性淋巴细胞性白血病和/或急性成淋巴细胞性白血病的药物中的应用,其中所述抗体包括:序列为EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGK GLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDT AMYYCARGTYYYGTRVFDYWGQGTLVTVSS(SEQ ID NO:10)的可变重链和序列为DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNG NTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTIS SLEPEDFAVYYCMQHLEYPITFGAGTKLEIK(SEQ ID NO:11)的可变轻链;
其中所述抗体包括:序列为ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV
SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ IDNO:12)的重链恒定区;
且其中所述抗体包括:序列为RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:13)的轻链恒定区。
2.根据权利要求1所述的应用,其中所述CD19特异性抗体和维奈托克分开给药。
3.根据权利要求1所述的应用,其中在施用所述CD19特异性抗体之前,施用维奈托克。
4.根据权利要求1所述的应用,其中将所述CD19特异性抗体和维奈托克同时给药。
5.根据权利要求1所述的应用,其中将所述CD19特异性抗体和维奈托克在两种药物同时在患者中有活性的时刻给药。
6.根据权利要求1-5中任一项所述的应用,其是用于治疗慢性淋巴细胞性白血病。
7.根据权利要求1-5中任一项所述的应用,其是用于治疗急性成淋巴细胞性白血病。
8.根据权利要求1-5中任一项所述的应用,其是用于治疗非何杰金氏淋巴瘤。
9.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是滤泡性淋巴瘤。
10.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是小淋巴细胞性淋巴瘤。
11.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是黏膜相关淋巴样组织淋巴瘤。
12.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是边缘区淋巴瘤。
13.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是弥漫性大B细胞淋巴瘤。
14.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是Burkitt's淋巴瘤。
15.根据权利要求8所述的应用,其中所述非何杰金氏淋巴瘤是套细胞淋巴瘤。
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SG11201909715VA (en) * | 2017-05-31 | 2019-11-28 | Morphosys Ag | Treatment paradigm for an anti-cd19 antibody and venetoclax combination treatment |
GB201809746D0 (en) * | 2018-06-14 | 2018-08-01 | Berlin Chemie Ag | Pharmaceutical combinations |
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