CN107847600A - 抗CD20抗体与Bcl‑2抑制剂和MDM2抑制剂的组合疗法 - Google Patents
抗CD20抗体与Bcl‑2抑制剂和MDM2抑制剂的组合疗法 Download PDFInfo
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Abstract
本发明涉及用于治疗癌症的抗CD20抗体与Bcl‑2抑制剂和MDM2抑制剂的组合疗法,特别是涉及具有I型抗CD20抗体或无岩藻糖化人源化B‑Ly1抗体及Bcl‑2抑制剂和MDM2抑制剂的表达CD20的癌症的组合疗法。
Description
本发明涉及抗CD20抗体与Bcl-2抑制剂和MDM2抑制剂用于治疗癌症的组合疗法。
发明背景
无岩藻糖基化的抗体
单克隆抗体的细胞介导的效应器功能可通过工程化改造其寡糖组分来增强,如P.等,Nature Biotechnol.17(1999)176-180和US 6,602,684 中所述。IgG1型抗体(即在癌症免疫疗法中最常用的抗体)是在每个CH2域中的Asn297处具有保守的N连接的糖基化位点的糖蛋白。附着于Asn297 的两个复合双触角寡糖掩埋于各CH2域间,与多肽主链形成广泛的接触,并且其存在对于抗体介导效应器功能诸如抗体依赖性细胞的细胞毒性(ADCC)是至关重要的(Lifely,M.R.等,Glycobiology 5(1995)813-822;Jefferis, R.等,Immunol.Rev.163(1998)59-76;Wright,A和Morrison,S.L.,Trends Biotechnol.15(1997)26-32)。P.等.Nature Biotechnol.17(1999) 176-180和WO 99/154342显示了β(1,4)-N-乙酰葡糖胺转移酶III(“GnTIII”) (一种催化两分型寡糖形成的糖基转移酶)在中华仓鼠卵巢(CHO)细胞中的过表达显著提高抗体的体外ADCC活性。N297碳水化合物的组成变化或其消除也影响Fc结合FcγR和C1qP.等,Nature Biotechnol.17(1999) 176-180;Davies,J.等,Biotechnol.Bioeng.74(2001)288-294;Mimura,Y.等,J.Biol.Chem.276(2001)45539-45547;Radaev,S.等,J.Biol.Chem.276(2001) 16478-16483;Shields,R.L.等,J.Biol.Chem.276(2001)6591-6604;Shields, R.L.等,J.Biol.Chem.277(2002)26733-26740;Simmons,L.C.等,J.Immunol. Methods 263(2002)133-147)。
已经报道了讨论无岩藻糖基化的和岩藻糖基化的抗体(包括抗CD20抗体)的活性的研究(例如,Iida,S.等,Clin.Cancer Res.12(2006)2879-2887; Natsume,A.等,J.Immunol.Methods 306(2005)93-103;Satoh,M.等,Expert Opin.Biol.Ther.6(2006)1161-1173;Kanda,Y.等,Biotechnol.Bioeng.94(2006) 680-688;Davies,J.等,Biotechnol.Bioeng.74(2001)288-294。
CD20和抗CD20抗体
CD20分子(也称作人B淋巴细胞限制性分化抗原或Bp35)是一种已经广泛描述的位于前B和成熟B淋巴细胞上的疏水性跨膜蛋白(Valentine,M.A. 等,J.Biol.Chem.264(1989)11282-11287;及Einfeld,D.A.等,EMBO J.7 (1988)711-717;Tedder,T.F.等,Proc.Natl.Acad.Sci.U.S.A.85(1988)208-212; Stamenkovic,I.等,J.Exp.Med.167(1988)1975-1980;Tedder,T.F.等,J. Immunol.142(1989)2560-2568)。CD20在大于90%的B细胞非霍奇金淋巴瘤(NHL)上表达(Anderson,K.C.等,Blood 63(1984)1424-1433),但是在造血干细胞、原B细胞、正常的浆细胞、或其它正常的组织上没有找到(Tedder,T.F. 等,J.Immunol.135(1985)973-979)。
存在着在其CD20结合模式和生物学活性方面显著不同的两种不同类型的抗CD20抗体(Cragg,M.S.等,Blood 103(2004)2738-2743;及Cragg,M.S. 等,Blood 101(2003)1045-1052)。I型抗体,如例如利妥昔单抗(rituximab)(一种具有85%或更高的岩藻糖量的非无岩藻糖基化抗体)、奥法木单抗 (ofatumumab)、维妥珠单抗(veltuzumab)、奥瑞珠单抗(ocrelizumab)在补体介导的细胞毒性中是有力的。
II型抗体,如例如托西莫单抗(Tositumomab)(B1)、11B8、AT80或人源化B-Ly1抗体经由不依赖于胱天蛋白酶的细胞死亡诱导及伴随的磷脂酰丝氨酸暴露而有效启动靶细胞死亡。
MDM2
p53是一种在针对癌症形成提供保护中发挥中心作用的肿瘤阻抑物蛋白。它保护细胞完整性,并且通过诱导生长停滞或凋亡来防止永久受损的细胞克隆的增殖。在分子水平,p53是一种可激活一组牵涉细胞周期调节和凋亡的基因的转录因子。p53是一种在细胞水平通过MDM2紧密调节的有力的细胞周期抑制剂。MDM2和p53形成一种反馈控制环。MDM2可结合p53,并且抑制其反式激活p53调节的基因的能力。另外,MDM2介导泛素依赖性p53降解。p53可激活MDM2基因的表达,如此提高MDM2蛋白的细胞水平。此反馈控制环确保MDM2和p53两者在正常增殖细胞中保持于低水平。MDM2也是E2F(其在细胞周期调节中发挥中心作用)的辅因子。
MDM2与p53(E2F)的比率在许多癌症中是失调的。例如,已经显示了p16INK4/p19ARF基因座中经常存在的分子缺陷影响MDM2蛋白降解。用野生型p53抑制肿瘤细胞中MDM2-p53相互作用应当导致p53的积累、细胞周期阻滞和/或凋亡。因此,MDM2拮抗剂可以作为单一药剂或与广谱的其它抗肿瘤疗法组合提供癌症治疗的新办法。已经通过使用用于抑制 MDM2-p53相互作用的不同大分子工具(例如抗体、反义寡核苷酸、肽)显示了此策略的可行性。与p53一样,MDM2也经由保守结合区结合E2F,并且激活E2F依赖性细胞周期蛋白A转录,提示MDM2拮抗剂在p53突变体细胞中可具有效果。
Bcl-2和Bcl-2抑制剂
Bcl-2蛋白在许多疾病中发挥作用,特别是在癌症、白血病、免疫性疾病和自身免疫性疾病中。据称Bcl-2蛋白涉及膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、结直肠癌、食管癌、肝细胞癌、成淋巴细胞性白血病、滤泡淋巴瘤、T细胞或B细胞源性淋巴样恶性肿瘤、黑素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌、脾癌。Bcl-2蛋白的过表达与各种癌症和免疫系统病症的化疗耐受性、临床结果、疾病进展、总体预后或其组合相关。
发明内容
我们现在已经发现了I型抗CD20抗体或无岩藻糖基化II型抗CD20抗体与Bcl-2抑制剂和MDM2抑制剂的组合显示显著增强的抗增殖作用。令人惊讶的是,这种组合不只是加合的,即是高度协同的。
本发明的一个方面是具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体,其用于与Bcl-2抑制剂和MDM2抑制剂联合治疗癌症。
本发明的另一个方面是具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体用于制备与Bcl-2抑制剂和MDM2 抑制剂联合治疗癌症的药物的用途。
本发明的另一个方面是治疗罹患癌症的患者的方法,其通过与Bcl-2抑制剂和MDM2抑制剂组合对需要此类治疗的患者施用具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体来进行。
在一个实施方案中,所述岩藻糖量占Asn297处的寡糖(糖)总量的40%-60%。在另一个实施方案中,所述岩藻糖量占Asn297处的寡糖(糖)总量的0%。
在一个实施方案中,所述I性抗CD20抗体是利妥昔单抗。在一个实施方案中,所述无岩藻糖基化抗CD20抗体是IgG1抗体。在另一个实施方案中,所述癌症是表达CD20的癌症,优选淋巴瘤或淋巴细胞性白血病。在一个实施方案中,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。在另一个实施方案中,所述无岩藻糖基化抗体是II型抗CD20抗体。在一个优选的实施方案中,所述无岩藻糖基化抗体是奥滨尤妥珠单抗(obinutuzumab)。
在一个实施方案中,所述Bcl-2抑制剂是选自WO2010/138588中描述的化合物的化合物。WO2010/138588中还公开了所述Bcl-2抑制剂的生产方法。
最优选地,所述Bcl-2抑制剂是具有下式的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-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)苯甲酰胺或其盐、酯或多晶型物。WO2010/138588的实施例5描述了所述化合物的制备方法。
所述Bcl-2抑制剂还描述于下式中:
所述化合物也称为ABT-199(GDC-0199或Venetoclax)。
在一个实施方案中,所述MDM2抑制剂是选自WO2011/098398中描述的化合物的化合物。所述MDM2抑制剂的制备方法也披露于 WO2011/098398。
最优选地,所述MDM2抑制剂是如下式所述的4-{[(2R,3S,4R,5S)-4-(4- 氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐、酯或多晶型物。WO2011/098398的实施例448描述了所述化合物的制备方法。
在一个实施方案中,所述I型抗CD20抗体是利妥昔单抗,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体,优选奥滨尤妥珠单抗及Bcl-2抑制剂和MDM2抑制剂,其中所述Bcl-2抑制剂选自WO 2010/138588中描述的化合物并且所述MDM2抑制剂选自WO2011/098398中描述的化合物。所述MDM2抑制剂优选是如上述本说明书中公开的依据式I或依据式I-1的化合物。优选地,所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3- 甲氧基-苯甲酸或其盐,并且所述癌症是表达CD20的癌症,在一个实施方案中是淋巴瘤或淋巴细胞性白血病。
在一个实施方案中,所述无岩藻糖基化抗CD20抗体以10-8M至10-13M 的KD结合CD20。
本发明的一个实施方案是药物组合物,其包含I型抗CD20抗体(在一个实施方案中是利妥昔单抗)或者具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体(在一个实施方案中,无岩藻糖基化人源化B-Ly1抗体),及Bcl-2抑制剂和MDM2抑制剂的组合,其中所述 Bcl-2抑制剂选自选自WO 2010/138588中描述的化合物并且所述MDM2抑制剂选自WO2011/098398中描述的化合物。所述MDM2抑制剂优选是如上述本说明书中公开的依据式I或依据式I-1的化合物。优选地,所述MDM2 抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐是用于治疗癌症的4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐。
附图说明
图1:直至第29天的肿瘤体积发展和IQR值(实施例1)
图2:直至第32天的肿瘤体积发展和TGI值(实施例2)
图3:直至第125天的生存曲线分析(Time-to-event analysis)(实施例2)
具体实施方式
本发明包括I型抗CD20抗体,或IgG1或IgG3同工型的具有占Asn297 处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体,其用于与Bcl-2抑制剂和MDM2抑制剂组合治疗癌症。
本发明包括I型抗CD20抗体,IgG1或IgG3同工型的具有占Asn297 处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体用于制备与Bcl-2抑制剂和MDM2抑制剂联合治疗癌症的药物的用途。
在一个实施方案中,岩藻糖量占Asn297处的寡糖(糖)总量的40%至 60%。
术语“抗体”涵盖各种抗体形式,包括但不限于完整的抗体、人抗体、人源化抗体和遗传工程抗体,像单克隆抗体、嵌合抗体或重组抗体及此类抗体的片段,只要依照本发明的特征性特性得到保留。本文使用的术语“单克隆抗体”或“单克隆抗体组合物”指单一氨基酸组成的抗体分子的制备物。因而,术语“人单克隆抗体”指具有自人种系免疫球蛋白序列衍生的可变和恒定区的展现出单一结合特异性的抗体。在一个实施方案中,人单克隆抗体是由杂交瘤产生的,所述杂交瘤包括与永生化细胞融合的自具有包含人重链转基因和人轻链转基因的基因组的转基因非人动物,例如转基因小鼠获得的 B细胞。
术语“嵌合抗体”指通常通过重组DNA技术制备的包含来自一种来源或物种的可变区,即结合区和自不同来源或物种衍生的恒定区的至少一部分的单克隆抗体。包含鼠可变区和人恒定区的嵌合抗体是特别优选的。此类鼠 /人嵌合抗体是包含编码鼠免疫球蛋白可变区的DNA区段和编码人免疫球蛋白恒定区的DNA区段的所表达免疫球蛋白基因的产物。本发明所涵盖的“嵌合抗体”的其它形式是那些其中类别或亚类已经自初始抗体的类别或亚类修饰或改变的。此类“嵌合”抗体又称为“类别转换抗体”。用于生成嵌合抗体的方法牵涉本领域现在公知的常规重组DNA和基因转染技术。参见例如 Morrison,S.L.等,Proc.Natl.Acad Sci.USA 81(1984)6851-6855;US 5,202,238 和US 5,204,244。
术语“人源化抗体”指其中的框架或“互补决定区”(CDR)已经进行过修饰以包含与亲本免疫球蛋白的特异性相比不同特异性的免疫球蛋白的 CDR的抗体。在一个优选的实施方案中,将鼠CDR嫁接入人抗体的框架区中以制备“人源化抗体”。参见例如Riechmann,L.等,Nature 332(1988) 323-327;及Neuberger,M.S.等,Nature 314(1985)268-270。特别优选的CDR 对应于那些代表上文对嵌合和双或多特异性抗体记录的识别抗原的序列的。
本文使用的术语“人抗体”意图包括具有自人种系免疫球蛋白序列衍生的可变和恒定区的抗体。人抗体是现有技术中公知的(van Dijk,M.A.和van de Winkel,J.G.,Curr.Opin.in Chem.Biol.5(2001)368-374)。基于此类技术,可产生针对极其多种靶物的人抗体。人抗体的例子述于例如Kellermann,S.A. 等,Curr.Opin.Biotechnol.13(2002)593-597。
本文使用的术语“重组人抗体”意图包括通过重组手段制备、表达、创建或分离的所有人抗体,诸如自宿主细胞诸如NS0或CHO细胞或者自对于使用转染入宿主细胞中的重组表达载体表达的人免疫球蛋白基因或抗体而言转基因的动物(例如小鼠)分离的抗体。此类重组人抗体具有重排形式的自人种系免疫球蛋白序列衍生的可变和恒定区。依照本发明的重组人抗体已经进行过体内体细胞超突变。如此,重组抗体的VH和VL区的氨基酸序列是虽然自人种系VH和VL序列衍生及与其相关,但可以不天然存在于体内的人抗体种系全集内的序列。
本文使用的术语“双特异性或多特异性抗体”涉及对至少两个不同位点具有结合特异性的单克隆抗体。在某些实施方案中,结合特异性之一针对 CD20,并且另一个针对任何其它抗原。在某些实施方案中,双特异性抗体可结合两种不同的CD20表位。双特异性抗体也可用于将细胞毒性剂定位于表达CD20的细胞。双特异性抗体可制备成全长抗体或抗体片段。
本文使用的术语“结合”或“特异性结合”指用纯化的野生型抗原在体外测定中,优选在等离子共振测定(BIAcore,GE-Healthcare Uppsala,Sweden) 中抗体对肿瘤抗原的表位的结合。结合的亲和力通过术语ka(抗体自抗体/ 抗原复合物结合的速率常数)、kD(解离常数)和KD(kD/ka)限定。结合或特异性结合意指10-8M或更小,优选10-8M至10-13M(在一个实施方案中,10-9M 至10-13M)的结合亲和力(KD)。如此,依照本发明的无岩藻糖基化抗体以10-8mol/l或更小,优选10-8M至10-13M(在一个实施方案中,10-9M至10-13M) 的结合亲和力(KD)特异性结合肿瘤抗原。
本文使用的术语“核酸分子”意图包括DNA分子和RNA分子。核酸分子可以是单链或双链,但是优选的是双链DNA。
“恒定域”不直接牵涉抗体对抗原的结合,但是牵涉效应器功能(ADCC、补体结合和CDC)。
本文使用的“可变区”(轻链的可变区(VL)、重链的可变区(VH))意为直接牵涉抗体结合抗原的轻链和重链对中的每种。人轻链和重链可变域具有相同的一般结构,并且每个域包含通过三个“高变区”(或互补决定区,CDR) 连接的其序列广泛保守的四个框架(FR)区。框架区采用β-片层构象,而CDR 可形成连接β-片层结构的环。每条链中的CDR通过框架区保持其三维结构,并且与来自另一条链的CDR一起形成抗原结合位点。
术语“高变区”在本文中使用时指抗体中负责抗原结合的氨基酸残基。高变区包含来自“互补决定区”或“CDR”的氨基酸残基。“框架”或“FR”区是与如本文中所限定的高变区残基不同的那些可变域区。因此,抗体的轻链和重链包含自N至C端的域FR1、CDR1、FR2、CDR2、FR3、CDR3、和FR4。特别地,重链的CDR3是对抗原结合贡献最大的区。CDR和FR区依照Kabat等,Sequences of Proteins of Immunological Interest,第5版,Public HealthService,National Institutes of Health,Bethesda,MD(1991)的标准定义和/或那些来自“高变环”的残基来确定。
术语“无岩藻糖基化抗体”指在Fc区中在Asn297处具有改变的糖基化样式且具有降低的岩藻糖残基水平的IgG1或IgG3同工型(优选IgG1同工型)的抗体。在Asn297处发生人IgG1或IgG3的糖基化,作为以多至2个 Gal残基为末端的核心岩藻糖化双触角复合寡糖糖基化。根据末端Gal残基的量,这些结构称为G0、G1(α1,6或α1,3)或G2聚糖残基(Raju,T.S.,BioProcess Int.1(2003)44-53)。抗体Fc部分的CHO型糖基化例如由Routier, F.H.,Glycoconjugate J.14(1997)201-207描述。在非糖修饰的CHO宿主细胞中重组表达的抗体在Asn297处通常以至少85%的量进行岩藻糖基化。应当理解,本文使用的术语无岩藻糖基化抗体包括在其糖基化样式中没有岩藻糖的抗体。通常已知的是,抗体中典型的糖基化残基位置是依照EU编号系统的第297位的天冬酰胺(“Asn297”)。
“EU编号系统”或“EU索引”一般在提及免疫球蛋白重链恒定区中的残基时使用(例如Kabat等,Sequences of Proteins of Immunological Interest,第 5版,PublicHealth Service,National Institutes of Health,Bethesda,MD(1991) 中报道的EU索引,通过提及而将其明确并入本文)。
如此,依照本发明的无岩藻糖基化抗体意指其中岩藻糖的量占Asn297 处的寡糖(糖)总量的60%或更少(这意味着在Fc区中Asn297处的寡糖的至少 40%或更多是无岩藻糖基化的)的IgG1或IgG3同工型(优选IgG1同工型)的抗体。在一个实施方案中,岩藻糖的量占Fc区中Asn297处的寡糖的40%至60%。在另一个实施方案中,岩藻糖的量是50%或更小,并且在又一个实施方案中,岩藻糖的量占Fc区中Asn297处的寡糖的30%或更小。依照本发明,“岩藻糖的量”意指通过MALDI-TOF质谱测量的,并以平均值计算的,相对于附着于Asn297的所有寡糖(糖)(例如复合的、杂合的和高甘露糖结构) 的总和,Asn297处寡糖(糖)链内所述寡糖(岩藻糖)的量(关于测定岩藻糖的量的详细规程,见例如WO 2008/077546)。此外,在一个实施方案中,Fc区的寡糖是两分的。可在工程化改造成表达至少一种核酸的糖修饰的宿主细胞中表达依照本发明的无岩藻糖基化抗体,所述核酸编码具有GnTIII活性的多肽,其量足以部分岩藻糖基化Fc区中的寡糖。在一个实施方案中,具有GnTIII 活性的多肽是融合多肽。或者,可依照US 6,946,292降低或消除宿主细胞的α1,6-岩藻糖基转移酶活性以生成糖修饰的宿主细胞。可例如通过发酵条件 (例如发酵时间)或者通过组合至少两种具有不同岩藻糖基化量的抗体来预先确定抗体岩藻糖基化的量。此类无岩藻糖基化抗体及相应的糖工程方法记载于WO 2005/044859,WO 2004/065540,WO 2007/031875,Umana,P.等,Nature Biotechnol.17(1999)176-180,WO 99/154342,WO 2005/018572,WO 2006/116260,WO 2006/114700,WO 2005/011735,WO 2005/027966,WO 97/028267,US 2006/0134709,US 2005/0054048,US 2005/0152894,WO 2003/035835,WO 2000/061739。这些糖工程抗体具有升高的ADCC。产生依照本发明的无岩藻糖基化抗体的其它糖工程方法记载于例如Niwa,R.等,J. Immunol.Methods 306(2005)151-160;Shinkawa,T.等,J.Biol.Chem.278 (2003)3466-3473;WO 03/055993或US 2005/0249722。
如此,本发明的一个方面是I型抗CD20抗体,或者IgG1或IgG3同工型(优选IgG1同工型)的、具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖的量的特异性结合CD20的无岩藻糖基化抗CD20抗体,其用于与Bcl-2抑制剂和MDM2抑制剂组合治疗癌症。在本发明的另一个方面是IgG1 或IgG3同工型(优选IgG1同工型)的、具有占Asn297处的寡糖(糖)总量的 60%或更少的岩藻糖的量的特异性结合CD20的无岩藻糖基化抗CD20抗体用于制造用于与Bcl-2抑制剂和MDM2抑制剂组合治疗癌症的药物的用途。在一个实施方案中,岩藻糖的量占Asn297处的寡糖(糖)总量的60%和20%之间。在一个实施方案中,岩藻糖的量占Asn297处的寡糖(糖)总量的60%和40%之间。在一个实施方案中,岩藻糖的量占Asn297处的寡糖(糖)总量的0%。
CD20(也称为B淋巴细胞抗原CD20、B淋巴细胞表面抗原B1、Leu-16、 Bp35、BM5和LF5;序列以SwissProt数据库条目P11836为特征)是一种位于前B和成熟B淋巴细胞上的具有约35kD分子量的疏水性跨膜蛋白 (Valentine,M.A.等,J.Biol.Chem.264(1989)11282-11287;Tedder,T.F.等,Proc. Natl.Acad.Sci.U.S.A.85(1988)208-212;Stamenkovic,I.等,J.Exp.Med.167 (1988)1975-1980;Einfeld,D.A.等,EMBO J.7(1988)711-717;Tedder,T.F.等,J. Immunol.142(1989)2560-2568)。相应的人基因是跨膜4域,A亚家族,成员1,又称为MS4A1。此基因编码跨膜4A基因家族的一个成员。此初生蛋白家族的成员以共同的结构特征和相似的内含子/外显子剪接边界为特征,并且在造血细胞和非淋巴样组织中展现出独特的表达样式。此基因编码B淋巴细胞表面分子,其在B细胞发育及分化成浆细胞中发挥作用。在一簇家族成员中,此家族成员定位于11q12。此基因的可变剪接产生编码相同蛋白的两种转录物变体。
术语“CD20”和“CD20抗原”在本文中可互换使用,包括由细胞天然表达的或者在用CD20基因转染的细胞上表达的人CD20的任何变体、同等型和物种同系物。本发明的抗体对CD20抗原的结合通过灭活CD20而介导对表达CD20的细胞(例如,肿瘤细胞)的杀伤。可通过下列一项或多项机制而发生对表达CD20的细胞的杀伤:细胞死亡/凋亡诱导、ADCC和CDC。
如本领域中认可的,CD20的同义词包括B淋巴细胞抗原CD20、B淋巴细胞表面抗原B1、Leu-16、Bp35、BM5和LF5。
依照本发明的术语“抗CD20抗体”是特异性结合CD20抗原的抗体。根据抗CD20抗体对CD20抗原的结合特性和生物学活性,两种类型的抗 CD20抗体(I型和II型抗CD20抗体)可依照Cragg,M.S.等,Blood 103(2004) 2738-2743;及Cragg,M.S.等,Blood 101(2003)1045-1052区别,参见表1。
表1:I型和II型抗CD20抗体的特性
II型抗CD20抗体的例子包括例如人源化B-Ly1抗体IgG1(一种嵌合的人源化IgG1抗体,如披露于WO 2005/044859中的)、11B8IgG1(如披露于 WO 2004/035607中的)和AT80IgG1。通常,IgG1同工型的II型抗CD20抗体显示特征性的CDC特性。与IgG1同工型的I型抗体相比,II型抗CD20 抗体具有降低的CDC(若为IgG1同工型的话)。
I型抗CD20抗体的例子包括例如利妥昔单抗、HI47IgG3(ECACC,杂交瘤)、2C6IgG1(如披露于WO 2005/103081中的)、2F2IgG1(如披露于WO 2004/035607和WO 2005/103081的)和2H7IgG1(如披露于WO 2004/056312 中的)。
依照本发明的无岩藻糖基化抗CD20抗体在一个实施方案中是II型抗 CD20抗体,在另一个实施方案中是无岩藻糖基化人源化B-Ly1抗体。
与没有降低岩藻糖的抗CD20抗体不一样,依照本发明的无岩藻糖基化抗CD20抗体具有升高的抗体依赖性细胞的细胞毒性(ADCC)。
“具有升高的抗体依赖性细胞的细胞毒性(ADCC)的无岩藻糖基化抗CD20抗体”意指具有如通过本领域普通技术人员已知的任何合适的方法测定的升高的ADCC的无岩藻糖基化抗CD20抗体,如该术语在本文中所定义的。一种公认的体外ADCC测定法如下:
1)该测定法使用已知表达受抗体的抗原结合区识别的靶抗原的靶细胞;
2)该测定法使用自随机选定的健康供体的血液分离的人外周血单个核细胞(PBMC)作为效应细胞;
3)依照下列方案来实施测定法:
i)使用标准的密度离心规程来分离PBMC,并将其以5x 106个细胞 /ml在RPMI细胞培养基中悬浮;
ii)将靶细胞通过标准的组织培养方法来培养,自具有高于90%的存活力的指数生长期收获,在RPMI细胞培养基中清洗,用100微居里51Cr 标记,用细胞培养基清洗两次,并以105个细胞/ml的密度在细胞培养基中重悬浮;
iii)将100微升上述最终靶细胞悬浮液转移至96孔微量滴定板的每孔;
iv)将抗体在细胞培养基中连续稀释,自4000ng/ml至0.04ng/ml,并将50微升所得的抗体溶液添加至96孔微量滴定板中的靶细胞,一式三份测试覆盖上述整个浓度范围的多种抗体浓度;
v)对于最大释放(MR)对照,含有经标记的靶细胞的平板中的3个另外的孔接受50微升非离子型去污剂(Nonidet,Sigma,St.Louis)的2%(VN)水溶液,代替抗体溶液(上述第iv点);
vi)对于自发释放(SR)对照,含有经标记的靶细胞的平板中的3个另外的孔接受50微升RPMI细胞培养基,代替抗体溶液(上述第iv点);
vii)然后,将96孔微量滴定板以50x g离心1分钟,并于4℃温育 1小时;
viii)将50微升PBMC悬浮液(上述第i点)添加至每孔以产生效应: 靶细胞比率25:1,并将平板在培养箱中在5%CO2气氛下于37℃放置4小时;
ix)收获来自每孔的无细胞上清液,并使用γ计数器来量化实验释放的放射性(ER);
x)依照公式(ER-MR)/(MR-SR)x 100对每个抗体浓度计算比裂解的百分比,其中ER是对所述抗体浓度量化(参见上述第ix点)的平均放射性,MR是对MR对照(参见上述第v点)量化(参见上述第ix点)的平均放射性,而SR是对SR对照(参见上述第vi点)量化(参见上述第ix点)的平均放射性;
4)“升高的ADCC”定义为上文测试的抗体浓度范围内观察到的比溶解的最大百分比的增加和/或达到上文测试的抗体浓度范围内观察到的比溶解的最大百分比的一半所需要的抗体浓度降低。ADCC的升高相对于用上述测定法测量的,使用本领域技术人员已知的相同的标准生成、纯化、配制和贮存方法,由相同类型的宿主细胞产生的,但是并非由工程化改造成过表达 GnTIII的宿主细胞产生的相同抗体介导的ADCC。
4)“升高的ADCC”定义为上文测试的抗体浓度范围内观察到的比裂解的最大百分比的增加和/或达到上文测试的抗体浓度范围内观察到的比裂解的最大百分比的一半所需要的抗体浓度降低。ADCC的升高相对于用上述测定法测量的,使用本领域技术人员已知的相同的标准生成、纯化、配制和贮存方法,由相同类型的宿主细胞产生的,但是并非由工程化改造成过表达 GnTIII的宿主细胞产生的相同抗体介导的ADCC。
可通过所述抗体的糖工程化来获得所述“升高的ADCC”,其意味着通过工程化改造其寡糖组分来增强单克隆抗体的所述天然的、细胞介导的效应器功能,如记载于Umana,P.等,Nature Biotechnol.17(1999)176-180和US 6,602,684的。
术语“补体依赖性细胞毒性(CDC)”指在存在补体的情况中依照本发明的抗体对人肿瘤靶细胞的裂解。优选地,通过在存在补体的情况中用依照本发明的抗CD20抗体处理表达CD20的细胞的制备物来测量CDC。若抗体在浓度100nM时在4小时后诱导20%或更多的肿瘤细胞裂解(细胞死亡),则发现CDC。优选地,用经51Cr或Eu标记的肿瘤细胞和释放的51Cr或Eu测量来实施测定法。对照包括将肿瘤靶细胞与补体但不与抗体一起温育。
“利妥昔单抗”抗体(I型抗CD20抗体的例子)是一种针对人CD20抗原的含有人γ1鼠恒定域的遗传工程化嵌合单克隆抗体。
“利妥昔单抗”抗体(I型抗CD20抗体的例子)是一种针对人CD20抗原的含有人γ1鼠恒定域的遗传工程化嵌合单克隆抗体。此嵌合抗体含有人γ1 恒定域,并且在1998年4月17日公告的归于IDEC Pharmaceuticals Corporation的US 5,736,137(Anderson等)中以名称“C2B8”鉴定。利妥昔单抗批准用于治疗复发性或顽固性低级或滤泡性、CD20阳性、B细胞非霍奇金淋巴瘤患者。体外作用机制研究已经显示了利妥昔单抗展现出人补体依赖性细胞毒性(CDC)(Reff,M.E.等,Blood 83(1994)435-445)。另外,它在测量抗体依赖性细胞的细胞毒性(ADCC)的测定法中展现出显著的活性。利妥昔单抗不是无岩藻糖基化的。
表2
术语“人源化B-Ly1抗体”指如WO 2005/044859和WO 2007/031875 中所披露的人源化B-Ly1抗体,其通过用来自IgG1的人恒定域嵌合化及接着的人源化自鼠单克隆抗CD20抗体B-Ly1(鼠重链可变区(VH):SEQ ID NO: 1;鼠轻链可变区(VL):SEQ ID NO:2(参见Poppema,S.和Visser,L.,Biotest Bulletin 3(1987)131-139)获得(参见WO 2005/044859和WO 2007/031875)。这些“人源化B-Ly1抗体”详细披露于WO 2005/044859和WO 2007/031875 中。
在一个实施方案中,“人源化B-Ly1抗体”具有选自下组的重链可变区 (VH):SEQID NO:3至SEQ ID NO:19(WO 2005/044859和WO 2007/031875 的B-HH2至B-HH9和B-HL8至B-HL17)。在一个具体的实施方案中,此类可变域选自下组:SEQ ID NO:3、SEQ ID NO:4、SEQID NO:7、SEQ ID NO:9、 SEQ ID NO:11、SEQ ID NO:13和SEQ ID NO:15(WO 2005/044859和WO 2007/031875的B-HH2、B-HH3、B-HH6、B-HH8、B-HL8、B-HL11和B-HL13)。在一个具体的实施方案中,“人源化B-Ly1抗体”具有轻链的可变区(VL) SEQ ID NO:20(WO 2005/044859和WO 2007/031875的B-KV1)。在一个具体的实施方案中,“人源化B-Ly1抗体”具有重链的可变区(VH)SEQ ID NO:7(WO 2005/044859和WO 2007/031875的B-HH6)和轻链的可变区(VL)SEQ ID NO:20(WO 2005/044859和WO 2007/031875的B-KV1)。此外,在一个实施方案中,人源化B-Ly1抗体是IgG1抗体。依照本发明,依照记载于WO 2005/044859、WO 2004/065540、WO2007/031875、Umana,P.等,Nature Biotechnol.17(1999)176-180及WO 99/154342中的规程在Fc区中糖工程化改造(GE)此类无岩藻糖基化人源化B-Ly1抗体。在一个实施方案中,无岩藻糖基化糖工程人源化B-Ly1是B-HH6-B-KV1GE。在一个实施方案中,所述抗CD20抗体是奥滨尤妥珠单抗(推荐的INN,WHO药物信息,Vol.26,No.4, 2012,p.453)。本文使用的奥滨尤妥珠单抗与GA101同义。商品名是GAZYVA 或GAZYVARO。WHO药物信息文件取代了以前的所有版本(例如Vol.25,No. 1,2011,p.75-76),并且以前称为阿夫土珠单抗(afutuzumab)(推荐的INN, WHO药物信息,Vol.23,No.2,2009,p.176;Vol.22,No.2,2008,p.124)。
依照本发明的术语“MDM2抑制剂”指以0.001μM至约2μM,在一个实施方案中,以0.002μM至约2μM的IC50抑制MDM2的活性的药剂。
在另一个实施方案中,所述MDM2抑制剂是具有小于1500道尔顿(Da) 的分子量(MW)的小分子量化合物。
在一个实施方案中,所述MDM2抑制剂是选自WO2011/098398中描述的化合物的化合物。WO2011/098398中还公开了制备所述MDM2抑制剂的方法。所述MDM2抑制剂优选是如本文公开的依据式I或依据式Ia的化合物(WO2011/098398的式II或式IIa)。
其中
X选自H、F、Cl、Br、I、氰基、硝基、乙炔基、环丙基、甲基、乙基、异丙基、乙烯基和甲氧基,
Y是一至四个独立选自以下的基团:H、F、Cl、Br、I、CN、OH、硝基、低级烷基、环烷基、低级烷氧基、低级烯基、环烯基、低级炔基、芳基、杂芳基、杂环、COOR’、OCOR’、CONR’R”、NR’COR”、NR”SO2R’、SO2NR’R”和NR’R”,其中
R’和R”独立选自H、低级烷基、经取代的低级烷基、低级环烷基、经取代的低级环烷基、低级烯基、经取代的低级烯基、低级环烯基、经取代的低级环烯基、芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环、或经取代的杂环,
且其中R’和R”还可独立连接形成选自以下环状结构:经取代的或未经取代的环烷基、经取代的或未经取代的环烯基、经取代的或未经取代的杂芳基或经取代的或未经取代的杂环,
R1选自低级烷基、经取代的低级烷基、低级烯基、经取代的低级烯基、芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环、经取代的杂环、环烷基、经取代的环烷基、环烯基和经取代的环烯基,
R2是氢或低级烷基,
R3是H或低级烷基,
R5选自低级烷基、经取代的低级烷基、低级烯基、经取代的低级烯基、芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环、经取代的杂环、环烷基、经取代的环烷基、环烯基和经取代的环烯基,
R4是氢,
R6和R7选自(CH2)n-R’、(CH2)n-NR’R”、(CH2)n-NR’COR”、 (CH2)n-NR’SO2R”、(CH2)n-COOH、(CH2)n-COOR’、(CH2)n-CONR’R”、 (CH2)n-OR’、(CH2)n-SR’、(CH2)n-SOR’、(CH2)n-SO2R’、(CH2)n-COR’、 (CH2)n-SO3H、(CH2)n-SONR’R”、(CH2)n-SO2NR’R”、(CH2CH2O)m-(CH2)n-R’、(CH2CH2O)m-(CH2)n-OH、(CH2CH2O)m-(CH2)n-OR’、 (CH2CH2O)m-(CH2)n-NR’R”、(CH2CH2O)m-(CH2)n-NR’COR”、 (CH2CH2O)m-(CH2)n-NR’SO2R”、(CH2CH2O)m-(CH2)n-COOH、 (CH2CH2O)m-(CH2)n-COOR’、(CH2CH2O)m-(CH2)n-CONR’R”、 (CH2CH2O)m-(CH2)n-SO2R’、(CH2CH2O)m-(CH2)n-COR’、 (CH2CH2O)m-(CH2)n-SONR’R”、(CH2CH2O)m-(CH2)n-SO2NR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-R’、(CH2)p-(CH2CH2O)m-(CH2)n-OH、 (CH2)p-(CH2CH2O)m-(CH2)n-OR’、(CH2)p-(CH2CH2O)m-(CH2)n-NR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-NR’COR”、 (CH2)p-(CH2CH2O)m-(CH2)n-NR’SO2R”、(CH2)p-(CH2CH2O)m-(CH2)n-COOH、 (CH2)p-(CH2CH2O)m-(CH2)n-COOR’、(CH2)p-(CH2CH2O)m-(CH2)n-CONR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-SO2R’、(CH2)p-(CH2CH2O)m-(CH2)n-COR’、 (CH2)p-(CH2CH2O)m-(CH2)n-SONR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-SO2NR’R”、-COR’、-SOR’和SO2R’
其中R’和R”如上所述,
m、n和p独立地是0至6
及其药学上可接受的盐和酯。
特别优选式I化合物,其中
X是F、Cl或Br,
Y是一至四个独立选自以下的基团:H、F、Cl、Br、I、CN、OH、硝基、低级烷基、环烷基、低级烷氧基、低级烯基、低级环烯基和低级炔基,
R1选自低级烷基、经取代的低级烷基、低级烯基、经取代的低级烯基、芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环、经取代的杂环、环烷基、经取代的环烷基、环烯基和经取代的环烯基,
R2是氢,
R3是H,
R5选自芳基、经取代的芳基、杂芳基和经取代的杂芳基,
R4是氢,
R6和R7选自(CH2)n-R’、(CH2)n-NR’R”、(CH2)n-NR’COR”、 (CH2)n-NR’SO2R”、(CH2)n-COOH、(CH2)n-COOR’、(CH2)n-CONR’R”、 (CH2)n-OR’、(CH2)n-SR’、(CH2)n-SOR’、(CH2)n-SO2R’、(CH2)n-COR’、 (CH2)n-SO3H、(CH2)n-SONR’R”、(CH2)n-SO2NR’R”、(CH2CH2O)m-(CH2)n-R’、(CH2CH2O)m-(CH2)n-OH、(CH2CH2O)m-(CH2)n-OR’、 (CH2CH2O)m-(CH2)n-NR’R”、(CH2CH2O)m-(CH2)n-NR’COR”、 (CH2CH2O)m-(CH2)n-NR’SO2R”、(CH2CH2O)m-(CH2)n-COOH、 (CH2CH2O)m-(CH2)n-COOR’、(CH2CH2O)m-(CH2)n-CONR’R”、 (CH2CH2O)m-(CH2)n-SO2R’、(CH2CH2O)m-(CH2)n-COR’、 (CH2CH2O)m-(CH2)n-SONR’R”、(CH2CH2O)m-(CH2)n-SO2NR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-R’、(CH2)p-(CH2CH2O)m-(CH2)n-OH、 (CH2)p-(CH2CH2O)m-(CH2)n-OR’、(CH2)p-(CH2CH2O)m-(CH2)n-NR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-NR’COR”、 (CH2)p-(CH2CH2O)m-(CH2)n-NR’SO2R”、(CH2)p-(CH2CH2O)m-(CH2)n-COOH、 (CH2)p-(CH2CH2O)m-(CH2)n-COOR’、(CH2)p-(CH2CH2O)m-(CH2)n-CONR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-SO2R’、(CH2)p-(CH2CH2O)m-(CH2)n-COR’、 (CH2)p-(CH2CH2O)m-(CH2)n-SONR’R”、 (CH2)p-(CH2CH2O)m-(CH2)n-SO2NR’R”、-COR’、-SOR’和SO2R’,其中
R’和R”独立选自H、低级烷基、经取代的低级烷基、低级环烷基、经取代的低级环烷基、低级烯基、经取代的低级烯基、低级环烯基、经取代的低级环烯基、芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环、或经取代的杂环,
且其中R’和R”还可独立连接形成选自以下环状结构:经取代的或未经取代的环烷基、经取代的或未经取代的环烯基、经取代的或未经取代的杂芳基或经取代的或未经取代的杂环,
m、n和p独立地是0至6
及其药学上可接受的盐和酯。
进一步优选式I化合物,其中:
X是F、Cl或Br,
Y是选自H或F的单取代基团:,且
R1选自低级烷基、经取代的低级烷基、低级烯基、经取代的低级烯基、杂环、经取代的杂环、环烷基、经取代的环烷基、环烯基和经取代的环烯基。
进一步优选,R1是选自以下的经取代的低级烷基:
其中R8、R9都是甲基,或连接形成环丙基、环丁基、环戊基或环己基,
R10是(CH2)m-R11,
m是0、1或2,
R11选自氢、羟基、低级烷基、低级烷氧基、芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环或经取代的杂环,
R2是H,
R3是H,
R5是选自以下的经取代的苯基:
W是F、Cl或Br,
V式H或F,
R4是氢,
R6和R7中的一个是氢且另一个是(CH2)n-R’,
n是0或1,且
R’选自芳基、经取代的芳基、杂芳基、经取代的杂芳基、杂环或经取代的杂环。
在再一个实施方案中,本发明涉及式Ia化合物
其中R6及R6定义中提到的所有变量和取代基具有上述式I给出的含义。
在再一个实施方案中,本发明提供式Ia化合物,其中R6是-(CH2)n-R’,且R’是环己基,或5至10元单环或二环芳族烃,其中1或2个碳原子可被 N、S或O替代,并且其中任何上述环己基或芳族烃可被独立选自以下的基团取代一次或两次:低级烷基、低级-烯基、低级-炔基、二氧代-低级-亚烷基(形成例如苯并二噁烷基)、卤素、氰基、CN、CF3、NH2、N(H、低级-烷基)、N(低级-烷基)2、氨基羰基、羧基、NO2、低级-烷氧基、硫基-低级-烷氧基、低级-烷基磺酰基、氨基磺酰基、低级-烷基羰基、低级-烷基羧基、低级 -烷氧基羰基、低级-烷基-羰基-NH、氟-低级-烷基、氟-低级-烷氧基、低级- 烷氧基-羰基-低级-烷氧基、羧基-低级-烷氧基、氨甲酰基-低级-烷氧基、羟基-低级-烷氧基、NH2-低级-烷氧基、N(H、低级-烷基)-低级-烷氧基、N(低级-烷基)2-低级-烷氧基、低级-烷基-1-氧杂环丙烷基-低级-烷氧基-低级-烷基、2-氧代-吡咯烷-1-基、(1,1-二氧代)-2-异噻唑烷、3-低级-烷基亚磺酰基、经取代的或未经取代的杂环、经取代的或未经取代的芳基环、经取代的或未经取代的杂芳基环、三氟-低级-烷基磺酰基氨基-芳基、低级-烷基磺酰基氨基羰基、低级-烷基磺酰基氨基羰基-芳基、羟基氨甲酰基-苯基、苄基氧基-低级- 烷氧基、单-或二-低级烷基取代的氨基-磺酰基和低级-烷基,其可任选取代有卤素、羟基、NH2、N(H、低级-烷基)或N(低级-烷基)2;且
n是0或1。
在再一个优选的实施方案中,本发明提供式Ia化合物,其中
R6是-(CH2)n-R’,且
R’是苯基、吡啶基、吡嗪基或嘧啶基,其各自可未经取代或被独立选自以下的取代基取代一次或两次:卤素、C1-6烷氧基、C1-6烷基、羟基羰基、羧基、羧基C1-6烷氧基、氧代和CN;和
n是0。
特别优选的是式Ia化合物,其选自
rac-4-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-环己烷甲酸甲酯,
rac-4-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-环己烷甲酸,
rac-4-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-2-甲氧基-苯甲酸甲酯,
rac-4-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-2-甲氧基-苯甲酸,
rac-4-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-2-氟-苯甲酸甲酯,
rac-4-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-2-氟-苯甲酸,
手性5-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-吡啶-2-甲酸甲酯,
手性5-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-吡啶-2-甲酸,
手性6-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-吡啶-3-甲酸乙酯,
手性6-({[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-吡啶-3-甲酸,
rac 4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-乙氧基-苯甲酸,
手性(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸(4-肼基羰基-苯基)-酰胺,
手性[2-(4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-乙基]-氨基甲酸叔丁酯,
手性(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸[4-(2-氨基-乙基)-苯基]-酰胺,
手性5-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡嗪-2-甲酸,
手性4-(((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)甲基)-2-甲氧基苯甲酸,
手性-4-({[(2S,3R,4S,5R)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-甲基)-2-甲氧基-苯甲酸,
手性3-(4-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯基)丙酸甲酯,
手性3-(4-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯基)丙酸,
手性-4-(((2S,3R,4S,5R)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)甲基)-2-氟苯甲酸,
手性4-(((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)甲基)-2-氟苯甲酸,
手性(2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-N-(2-吗啉代嘧啶-5-基)-5-新戊基吡咯烷-2-甲酰胺,
手性(2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基-N-(嘧啶-5-基)吡咯烷-2-甲酰胺,
手性(2S,3R,4S,5R)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸(4-二甲基氨基甲基-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-二甲基氨基甲基-苯基)-酰胺,
手性5-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)-1H-苯并[d]咪唑-2-甲酸甲酯,
手性-5-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)-1H-苯并[d]咪唑-2-甲酸,
手性-5-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯并呋喃-2-甲酸甲酯,
手性-5-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯并呋喃-2-甲酸,
手性-4-(4-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5- 新戊基吡咯烷-2-甲酰胺基)苯基)丁酸甲酯,
手性-4-(4-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5- 新戊基吡咯烷-2-甲酰胺基)苯基)丁酸,
手性5-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯并[d]噁唑-2-甲酸甲酯,
手性-5-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯并[d]噁唑-2-甲酸,
手性-(2R,3S,4R,5S)-N-(苯并[d]噁唑-5-基)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺,
rac-(4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苄基)-氨基甲酸叔丁酯,
rac-(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸(4-氨基甲基-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸[4-(甲磺酰基氨基-甲基)-苯基]-酰胺,
1-(4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-哌啶-4-甲酸乙酯,
1-(4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-哌啶-4-甲酸,
rac-(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸(4-二甲基氨基甲基-苯基)-酰胺,
rac-5-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-吡咯烷-1-基-苯甲酸,
rac-4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-4-甲基-哌啶-1-甲酸叔丁酯,
rac-(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸(4-甲基-哌啶-4-基)-酰胺,
rac-(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸(1-甲磺酰基-4-甲基-哌啶-4-基)-酰胺,
1-(4-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯基)吡咯烷-2-甲酸甲酯,
1-(4-((2R,3S,4R,5S)-3-(3-氯-2-氟苯基)-4-(4-氯-2-氟苯基)-4-氰基-5-新戊基吡咯烷-2-甲酰胺基)苯基)吡咯烷-2-甲酸,
手性5-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-1H-吡咯-2-甲酸,
手性5-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-1H-吡咯-2-甲酸乙酯,
手性(R)-2-(4-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-丁酸,
手性(S)-2-(4-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-丁酸,
手性(S)-2-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-噻唑-4-基-丙酸甲酯,
手性(S)-2-{[(2S,3R,4S,5R)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-噻唑-4-基-丙酸甲酯,
手性(S)-2-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-噻唑-4-基-丙酸,
手性(S)-2-{[(2S,3R,4S,5R)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-噻唑-4-基-丙酸,
手性4-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-1H-吲哚-2-甲酸,
rac(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(5-碘-吡啶-2-基)-酰胺,
2-氯-4-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯甲酸,
6-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡啶-3-甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸吡啶-2-基酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸吡啶-4-基酰胺,
5-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡啶-2-甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸吡啶-3-基酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-碘-3,5-二甲基-苯基)-酰胺,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-氟-苯甲酸叔丁酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-氟-苯甲酸,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-氟-苯甲酸,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-三氟甲基-苯甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-碘-2-三氟甲氧基-苯基)-酰胺,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-三氟甲氧基-苯甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-三氟甲氧基-苯甲酸,
6-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡啶-3-甲酸,
6-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡啶-3-甲酸甲酯,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(6-碘-吡啶-3-基)-酰胺,
5-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡啶-2-甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(6-氨甲酰基-萘-2-基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-3-氯-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-3-三氟甲基-苯基)-酰胺,
5-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-吡啶-2-甲酸,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-氟-苯甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-氯-苯甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-氯-苯甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-2-氟-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-2-甲氧基-苯基)-酰胺,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2,5-二氟-苯甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2,5-二氟-苯甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(3,5-二氟-4-碘-苯基)-酰胺,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2,6-二氟-苯甲酸,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-羟基-苯甲酸,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-3-甲氧基-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-3-三氟甲氧基-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-3-氟-苯基)-酰胺,
(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-甲酸(4-氨甲酰基-2-氯-苯基)-酰胺,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-氟-5-甲氧基-苯甲酸甲酯,
4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-2-氟-5-甲氧基-苯甲酸,
2-(4-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-4-甲基-戊酸,
手性2-(4-{[(2S,3R,4S,5R)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-2-甲基-丙酸甲酯,
手性2-(4-{[(2R,3S,4R,5S)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-苯基)-2-甲基-丙酸,
手性(2S,3R,4S,5R)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸[4-(1-甲基-1-甲基氨甲酰基-乙基)-苯基]-酰胺,
手性(2S,3R,4S,5R)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸{4-[1-(3-羟基-丙基氨甲酰基)-1-甲基-乙基]-苯基}酰胺,和
手性(2S,3R,4S,5R)-3-(3-氯-2-氟-苯基)-4-(4-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-甲酸[4-(1-氨甲酰基-1-甲基-乙基)-苯基]-酰胺。
在说明书中,当指出时,各种基团可被1-5个或优选1-3个独立选自以下的取代基取代:低级烷基、低级-烯基、低级-炔基、二氧代-低级-亚烷基(形成例如苯并二噁烷基)、卤素、氰基、CN、CF3、NH2、N(H、低级-烷基)、 N(低级-烷基)2、氨基羰基、羧基、NO2、低级-烷氧基、硫基-低级-烷氧基、低级-烷基磺酰基、氨基磺酰基、低级-烷基羰基、低级-烷基羧基、低级-烷氧基羰基、低级-烷基-羰基-NH、氟-低级-烷基、氟-低级-烷氧基、低级-烷氧基-羰基-低级-烷氧基、羧基-低级-烷氧基、氨甲酰基-低级-烷氧基、羟基-低级-烷氧基、NH2-低级-烷氧基、N(H、低级-烷基)-低级-烷氧基、N(低级-烷基)2-低级-烷氧基、低级-烷基-1-氧杂环丙烷基-低级-烷氧基-低级-烷基、2- 氧代-吡咯烷-1-基、(1,1-二氧代)-2-异噻唑烷、3-低级-烷基亚磺酰基、经取代的或未经取代的杂环、经取代的或未经取代的芳基环、经取代的或未经取代的杂芳基环、三氟-低级-烷基磺酰基氨基-芳基、低级-烷基磺酰基氨基羰基、低级-烷基磺酰基氨基羰基-芳基、羟基氨甲酰基-苯基、苄基氧基-低级-烷氧基、单-或二-低级烷基取代的氨基-磺酰基和低级-烷基,其可任选取代有卤素、羟基、NH2、N(H、低级-烷基)或N(低级-烷基)2。对于环烷基环、环烯基环、芳基环、杂芳基环和杂环而言优选的取代基是卤素、低级烷氧基、低级烷基、羟基羰基、羧基、羧基低级烷氧基、氧代和CN。对于烷基而言优选的取代基是烷氧基和N(低级烷基)2。
术语“烷基”是指具有1至约20个碳原子的直链或支链饱和烃基,包括具有1至约7个碳原子的基团。在某些实施方案中,烷基取代基可以是低级烷基取代基。术语“低级烷基”是指具有1至6个碳原子的烷基,且在某些实施方案中是指具有1至4个碳原子的烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和仲戊基。
本文使用的“环烷基”意图指仅由碳原子组成的任何稳定的单环或多环体系,其中任何环都是饱和的,而术语“环烯基”意图指仅由碳原子组成的任何稳定的单环或多环体系,其中至少一个环是部分不饱和的。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、二环烷基,包括二环辛烷诸如[2.2.2]二环辛烷或[3.3.0]二环辛烷,二环壬烷诸如[4.3.0]二环壬烷和二环癸烷诸如[4.4.0]二环癸烷(十氢化萘)或螺环化合物。环烯基的实例包括但不限于环戊烯基或环己烯基。
本文使用的术语“烯基”意指含有一个双键且具有2至6个,优选2 至4个碳原子的不饱和直链或支链脂族烃基。此种“烯基”的实例是乙烯基 (vinyl)、乙烯基(ethenyl)、烯丙基、异丙烯基、1-丙烯基、2-甲基-1-丙烯基、 1-丁烯基、2-丁烯基、3-丁烯基、2-乙基-1-丁烯基、3-甲基-2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、4-甲基-3-戊烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基和5-己烯基。
本文使用的术语“炔基”意指含有一个三键并具有2至6个,优选2 至4个碳原子的不饱和直链或支链脂族烃基。此种“炔基”的实例是乙炔基、 1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、 3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基和5-己炔基。
定义中使用的术语“卤素”意指氟、氯、溴或碘,优选氟和氯。
“芳基”意指单价单环或二环芳族碳环烃基,优选6-10元芳族环体系。优选的芳基包括但不限于苯基、萘基、甲苯基和二甲苯基。当芳基是二环时,优选的基团是1,3-二氧代-2,3-二氢-1H-异吲哚-5-基。
“杂芳基”意指最多含有两个环的芳族杂环体系。优选的杂芳基基团包括但不限于噻吩基、呋喃基、吲哚基、吡咯基、吡啶基、吡嗪基、噁唑基、噻唑基、喹啉基、嘧啶基、咪唑基、经取代的或未经取代的三唑基和经取代的或未经取代的四唑基。
在作为二环的芳基或杂芳基的情况下,应当理解的是一个环可以是芳基而另一个是杂芳基并且两个都是经取代的或未经取代的。
“杂环”或“杂环的环”是指经取代或未经取代的5至8元单环或二环非芳族烃,其中1至3个碳原子被选自氮、氧或硫原子的杂原子替代。实例包括吡咯烷-2-基;吡咯烷-3-基;哌啶基;吗啉-4-基等,其转而可被取代。“杂原子”意指选自N、O和S的原子。
“烷氧基或低级烷氧基”是指与氧原子连接的任何上述低级烷基。典型的低级烷氧基包括甲氧基、乙氧基、异丙氧基或丙氧基、丁氧基等。还包括在烷氧基的含义内的是多个烷氧基侧链,例如乙氧基乙氧基、甲氧基乙氧基、甲氧基乙氧基乙氧基等,和经取代的烷氧基侧链,例如二甲基氨基乙氧基、二乙基氨基乙氧基,二甲氧基-磷酰基甲氧基等。
“药学上可接受的”,诸如药学上可接受的载体、赋形剂等意指药理学上可接受的且对施用特定化合物的受试者基本上无毒。
“药学上可接受的盐”是指保留本发明化合物的生物有效性和特性并由合适的无毒有机或无机酸或者有机或无机碱形成的常规酸加成盐或碱加成盐。样品酸加成盐包括衍生自无机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸的那些,及衍生自有机酸诸如对甲苯磺酸、水杨酸、甲磺酸、草酸、琥珀酸、柠檬酸、苹果酸、乳酸、富马酸、三氟乙酸等的那些。样品碱加成盐包括衍生自铵、钾、钠和季铵氢氧化物(诸如例如四甲基氢氧化铵)的那些。药物化合物(即药物)化学修饰成盐是药物化学家公知的技术,以获得化合物的改进的物理和化学稳定性、吸湿性、流动性和溶解性。参见例如Ansel等,PharmaceuticalDosage Forms and Drug Delivery Systems(第6 版,1995),第196和1456-1457页。
具有至少一个不对称碳原子的式I或Ia化合物及其盐可作为外消旋混合物或不同的立体异构体存在。各种异构体可通过已知的分离方法例如色谱法分离。
本文公开的并且由上述式I或Ia覆盖的化合物可展现出互变异构现象或结构异构现象。意图是本发明包括这些化合物的任何互变异构或结构异构形式,或这些形式的混合物,并且不限于上述式中描述的任何一种互变异构或结构异构形式。
最优选地,所述MDM2抑制剂是如下式所述的4-{[(2R,3S,4R,5S)-4-(4- 氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐、酯或多晶型物。WO2011/098398的实施例448描述了所述化合物的制备方法。所述化合物也称为MDM2(4)或 RG7388或RO5503781,在本文中作为同义术语使用。
依据本发明的MDM2抑制剂的制备如WO2011/098398所公开的那样进行。
“盐”是指作为药学上可接受的盐的化合物的盐。此种盐的实例可以是与碱金属(钾、钠等)的盐,与碱土金属的盐(钙、镁等)的盐、铵盐、与药学上可接受的有机胺(四甲基铵、三乙胺、甲胺、二甲胺、环戊胺、苄胺、苯乙胺、哌啶、单乙醇胺、二乙醇胺、三(羟基甲基)氨基甲烷、赖氨酸、精氨酸、N-甲基-D-葡糖胺等)的盐,和酸加成盐(无机酸盐(盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、硝酸盐等)和有机酸盐(乙酸盐、三氟乙酸盐、乳酸盐、酒石酸盐、草酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、羟乙基磺酸盐、葡糖醛酸盐,葡糖酸盐等)。
“IC50”指抑制50%的特定测量活性需要的具体化合物的浓度。
寡糖组分可显著影响与治疗性糖蛋白的功效有关的特性,包括物理稳定性、对蛋白酶攻击的抗性、与免疫系统的相互作用、药物动力学和特异性生物学活性。此类特性可能不仅取决于寡糖的存在或缺乏,而且还取决于寡糖的特定结构。可做出寡糖结构与糖蛋白功能间的一些概括。例如,某些寡糖结构经由与特定碳水化合物结合蛋白的相互作用而介导糖蛋白自血流的快速清除,而其它寡糖结构可被抗体结合,并触发不期望的免疫反应(Jenkins,N. 等,Nature Biotechnol.14(1996)975-981)。
由于哺乳动物细胞以对于人应用最相容的形式糖基化蛋白的性能,它们是用于生成治疗性糖蛋白的卓越的宿主(Cumming,D.A.等,Glycobiology 1 (1991)115-130;Jenkins,N.等,Nature Biotechnol.14(1996)975-981)。细菌糖基化蛋白质非常罕见,并且与其它类型的常见宿主,诸如酵母、丝状真菌、昆虫和植物细胞一样,其产生与自血流快速清除、不期望的免疫相互作用、和(在一些特定的情况中)降低的生物学活性有关的糖基化样式。在哺乳动物细胞中,在过去二十年期间最常使用中华仓鼠卵巢(CHO)细胞。除了给予合适的糖基化样式外,这些细胞容许遗传稳定的、高生产性克隆细胞系的一致生成。它们可使用无血清培养基在简单的生物反应器中培养至高密度,并容许开发安全且可再现的生物工艺。其它通常使用的动物细胞包括幼仓鼠肾 (BHK)细胞、NSO和SP2/0小鼠骨髓瘤细胞。最近,还已经测试了自转基因动物的生成(Jenkins,N.等,Nature Biotechnol.14(1996)975-981)。
所有抗体在重链恒定区中的保守位置处都含有碳水化合物结构,其中每种同工型拥有独特阵列的N连接的碳水化合物结构,其易变地影响蛋白质装配、分泌或功能性活性(Wright,A.和Morrison,S.L.,Trends Biotech.15(1997) 26-32)。根据加工程度,附着的N连接的碳水化合物结构变化得相当大,并且可包括高甘露糖的、多分支的及双触角的复合寡糖(Wright,A.和Morrison, S.L.,Trends Biotech.15(1997)26-32)。通常,存在着特定糖基化位点处附着的核心寡糖结构的异质加工,使得甚至单克隆抗体以多种糖型存在。同样地,已经显示细胞系间存在抗体糖基化的主要差异,而且甚至对不同培养条件下培养的给定细胞系看到次要差异(Lifely,M.R.等,Glycobiology 5(1995) 813-822)。
一种在维持简单的生成过程并潜在地避免显著的、不期望的副作用的情况中获得效力大幅升高的方式是通过工程化改造单克隆抗体的寡糖组分来增强其天然的、细胞介导的效应器功能,如记载于Umana,P.等,Nature Biotechnol.17(1999)176-180及US 6,602,684的。IgG1型抗体(即在癌症免疫疗法中最常用的抗体)是在每个CH2域中的Asn297处具有保守的N连接的糖基化位点的糖蛋白。附着于Asn297的两个复合双触角寡糖掩埋于各 CH2域间,与多肽主链形成广泛的接触,并且其存在对于抗体介导效应器功能诸如抗体依赖性细胞的细胞毒性(ADCC)是至关重要的(Lifely,M.R.等, Glycobiology 5(1995)813-822;Jefferis,R.等,Immunol.Rev.163(1998)59-76; Wright,A和Morrison,S.L.,TrendsBiotechnol.15(1997)26-32)。
先前显示了β(1,4)-N-乙酰葡糖胺转移酶III("GnTIII7y")(一种催化两分型寡糖形成的糖基转移酶)在中华仓鼠卵巢(CHO)细胞中的过表达显著提高由工程化改造的CHO细胞生成的抗成神经细胞瘤嵌合单克隆抗体(chCE7) 的体外ADCC活性(参见Umana,P.等,Nature Biotechnol.17(1999)176-180;及WO 99/154342,在此通过提及而并入其全部内容)。抗体chCE7属于具有高肿瘤亲和力和特异性,但是在缺乏GnTIII酶的标准工业细胞系中生产时具有太小的效力以致在临床上无用的一大类未缀合的单克隆抗体(Umana,P. 等,Nature Biotechnol.17(1999)176-180)。所述研究第一次显示了可通过工程化改造抗体生成细胞以表达GnTIII来获得ADCC活性的大幅升高,其还导致恒定区(Fc)结合的两分型寡糖(包括两分型非岩藻糖基化寡糖)比例的增加,高于天然存在的抗体中发现的水平。
本文使用的术语“癌症”包括淋巴瘤、淋巴细胞性白血病、肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌(stomach cancer)、胃癌(gastric cancer)、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金(Hodgkin)病、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆癌(biliary cancer)、中枢神经系统(CNS)赘生物、脊柱轴肿瘤、脑干胶质瘤、多形性成胶质细胞瘤(glioblastomamultiforme)、星形细胞瘤、神经鞘瘤(schwanoma)、室鼓膜瘤(ependymona)、成神经管细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤,包括任何上述癌症的难治性形式、或一种或多种上述癌症的组合。在一个实施方案中,术语癌症指表达CD20的癌症。
术语“表达CD20”抗原意图指示细胞中的CD20抗原的显著水平的表达,优选在T或B细胞,更优选分别来自肿瘤或癌症,优选非实体瘤的B 细胞的细胞表面上的。可通过本领域已知的标准测定法来确定具有“表达 CD20的癌症”的患者。例如,可使用免疫组织化学(IHC)检测、FACS或者经由相应mRNA的基于PCR的检测来测量CD20抗原表达。
本文使用的术语“表达CD20的癌症”指癌细胞显示CD20抗原表达的所有癌症。优选地,本文使用的表达CD20的癌症指淋巴瘤(优选B细胞非霍奇金淋巴瘤(NHL))和淋巴细胞性白血病。此类淋巴瘤和淋巴细胞性白血病包括例如a)滤泡性淋巴瘤、b)小无核裂细胞淋巴瘤(Small Non-Cleaved Cell Lymphoma)/伯基特(Burkitt)淋巴瘤(包括地方性伯基特淋巴瘤、散发性伯基特淋巴瘤和非伯基特淋巴瘤)、c)边缘区淋巴瘤(包括结外边缘区B细胞淋巴瘤 (粘膜相关淋巴组织淋巴瘤,MALT)、结边缘区B细胞淋巴瘤和脾边缘区淋巴瘤)、d)套细胞淋巴瘤(MCL)、e)大细胞淋巴瘤(包括B细胞弥漫性大细胞淋巴瘤(DLCL)、弥漫性混合细胞淋巴瘤、成免疫细胞性淋巴瘤、原发性纵隔B细胞淋巴瘤、血管中心性淋巴瘤-肺B细胞淋巴瘤)、f)毛细胞白血病、 g)淋巴细胞性淋巴瘤、瓦尔登斯特伦(waldenstrom)巨球蛋白血症、h)急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)/小淋巴细胞性淋巴瘤(SLL)、B细胞幼淋巴细胞性白血病、i)浆细胞赘生物、浆细胞骨髓瘤、多发性骨髓瘤、浆细胞瘤、j)霍奇金病。
在一个实施方案中,表达CD20的癌症是B细胞非霍奇金淋巴瘤(NHL)。在另一个实施方案中,表达CD20的癌症是套细胞淋巴瘤(MCL)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、B细胞弥漫性大细胞淋巴瘤(DLCL)、伯基特淋巴瘤、毛细胞白血病、滤泡性淋巴瘤、多发性骨髓瘤、边缘区淋巴瘤、移植后淋巴增殖性病症(PTLD)、HIV相关淋巴瘤、瓦尔登斯特伦巨球蛋白血症或原发性CNS淋巴瘤。
术语“治疗方法”、“治疗的方法”或其等同用语在应用于例如癌症时指设计为降低或消除患者中的癌细胞数目,或者减轻癌症症状的规程或作用过程。癌症或另一种增殖性病症的“治疗方法”不必意味着实际上会消除癌细胞或其它病症,实际上会降低细胞数目或病症,或实际上会减轻癌症或其它病症的症状。经常,甚至会实施具有较低的成功概率,但是然而鉴于医学史和估计的患者存活预期认为诱导总体有益的作用过程的治疗癌症的方法。
术语“组合”、“共施用”或“共同施用”指作为两种分开的配制剂(或者作为一种单一配制剂)施用所述I型抗CD20抗体或所述无岩藻糖基化抗 CD20及所述Bcl-2抑制剂和所述MDM2抑制剂。共施用可以是同时的或者以任意次序序贯的,其中优选地,存在着所有活性剂同时施加其生物学活性的时段。同时或序贯(例如静脉内(i.v.)经由连续输注;对于抗CD20抗体一次,及最终对于所述Bcl-2抑制剂和所述MDM2抑制剂一次;或者,例如经由连续输注静脉内(i.v.)施用抗CD20抗体,且口服施用所述Bcl-2抑制剂和所述 MDM2抑制剂)共施用所述I型抗CD20抗体或所述无岩藻糖基化抗CD20 抗体及所述Bcl-2抑制剂和和所述MDM2抑制剂。在序贯共施用这两种治疗剂时,在同一天在两次分开的施用中施用剂量,或者在第1天施用药剂之一,而在第2天至第7天,优选在第2天至第4天共施用第二种。如此,在一个实施方案中,术语“序贯地”意指在第一组分(抗CD20抗体或所述Bcl-2抑制剂和所述MDM2抑制剂)的剂量后7天内,优选在第一组分的剂量后4天内;而术语“同时地”意指在同一时间。术语“共施用”就所述I型抗CD20 抗体或所述无岩藻糖基化抗CD20抗体及所述Bcl-2抑制剂和所述MDM2抑制剂的维持剂量而言意指若治疗周期对于这两种药物都是合适的,例如每周,则可同时共施用维持剂量。或者,例如,每第一至第三天施用所述Bcl-2 抑制剂和所述MDM2抑制剂,而每周施用所述无岩藻糖基化抗体。或者,在一天内或在几天内序贯共施用维持剂量。
不证自明的是,以“治疗有效量”(或仅为“有效量”)对患者施用抗体,所述治疗有效量是相应化合物或组合会引发研究人员、兽医、医学医生或其它临床医生寻找的组织、系统、动物或人的生物学或医学应答的量。
所述I型抗CD20抗体或所述无岩藻糖基化抗CD20抗体及所述Bcl-2 抑制剂和所述MDM2抑制剂的共施用量和共施用时机会取决于所治疗患者的类型(物种、性别、年龄、重量等)和状况和所治疗疾病或状况的严重性。可以一次或在一系列治疗里,例如在同一天或在次日对患者适当地共施用所述I型抗CD20抗体或所述无岩藻糖基化抗CD20抗体及所述Bcl-2抑制剂和所述MDM2抑制剂。
若施用是静脉内的,则所述I型抗CD20抗体、所述无岩藻糖基化抗 CD20抗体或所述Bcl-2抑制剂和所述MDM2抑制剂的初始输注时间可比随后的输注时间长,例如初始输注为约90分钟,而随后的输注为约30分钟(若初始输注耐受良好的话)。
根据疾病的类型和严重性,约0.1mg/kg至50mg/kg(例如0.1-20mg/kg) 所述I型抗CD20抗体或所述无岩藻糖基化抗CD20抗体和1μg/kg至 50mg/kg(例如0.1-20mg/kg)所述Bcl-2抑制剂和所述MDM2抑制剂是对患者共施用这两种药物的初始候选剂量。在一个实施方案中,所述无岩藻糖基化抗CD20抗体(优选无岩藻糖基化人源化B-Ly1抗体,更优选奥滨尤妥珠单抗)的优选剂量会在约0.05mg/kg至约30mg/kg的范围中。如此,可对患者共施用一剂或多剂的约0.5mg/kg、2.0mg/kg、4.0mg/kg、10mg/kg或30mg/kg(或其任何组合)。
在一个实施方案中,所述Bcl-2抑制剂(优选4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基) 苯甲酰胺或其盐或多晶型物)的优选剂量会在约0.05mg/kg至约30mg/kg的范围中。如此,可对患者共施用一剂或多剂的约0.5mg/kg、2.0mg/kg、4.0mg/kg、 10mg/kg或30mg/kg(或其任何组合)。
在一个实施方案中,所述MDM2抑制剂(优选4-{[(2R,3S,4R,5S)-4-(4- 氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物)的优选剂量会在约0.05mg/kg 至约30mg/kg的范围中。如此,可对患者共施用一剂或多剂的约0.5mg/kg、 2.0mg/kg、4.0mg/kg、10mg/kg或30mg/kg(或其任何组合)。
根据患者的类型(物种、性别、年龄、重量等)和状况及I型抗CD20抗体,优选利妥昔单抗或无岩藻糖基化抗CD20抗体的类型,优选无岩藻糖基化人源化B-Ly1抗体,更优选奥滨尤妥珠单抗,所述I型抗CD20抗体或所述无岩藻糖基化抗CD20抗体的剂量和施用日程表可与所述Bcl-2抑制剂和所述MDM2抑制剂不同。例如,可例如每1至3周施用所述I型抗CD20 抗体或所述无岩藻糖基化抗CD20抗体,并且可每天或每2至10天施用所述Bcl-2抑制剂和所述MDM2抑制剂。也可施用较高的初始加载剂量,接着是较低的一剂或多剂。
在一个实施方案中,在8周剂量周期的1、8、15、22、29、36、43、 50、57天,第I型抗CD20抗体(优选利妥昔单抗)的优选剂量会在约100mg/m2至约1000mg/m2的范围中。
在一个实施方案中,所述无岩藻糖基化抗CD20抗体(优选无岩藻糖基化人源化B-Ly1抗体,更优选奥滨尤妥珠单抗)的优选剂量会是一个3至6 周剂量周期的第1天、第8天、第15天的800至1600mg(在一个实施方案中,800至1200mg),然后剂量是多至9个3至4周剂量周期的第1天的400 至1200mg(在一个实施方案中,800至1200mg)。
在一个实施方案中,所述Bcl-2抑制剂(其中Bcl-2抑制剂选自如上文所述的Bcl-2抑制剂且优选是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4- 基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺)的剂量如下。依据本发明的所述剂量是10mg/kg至70mg/kg,优选20mg/kg至55mg/kg,每天一次或每隔一天一次,口服施用。
在一个实施方案中,所述MDM2抑制剂(其中MDM2抑制剂选自如上文所述的MDM2抑制剂且优选是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3- 氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基- 苯甲酸)的剂量如下。依据本发明的所述剂量是10mg/kg至70mg/kg,优选 20mg/kg至55mg/kg,每天一次或每隔一天一次,口服施用。
推荐剂量可随是否存在有化疗剂的其它共施用及基于化疗剂的类型而变化。
在一个实施方案中,本发明可用于预防或降低罹患癌症,优选表达CD20 的癌症的此类患者中的转移或进一步散布。本发明可用于延长此类患者的存活持续时间,延长此类患者的无进展存活,延长响应的持续时间,导致经治疗的患者的统计学显著的且临床上有意义的改善,如通过存活的持续时间、无进展存活、响应率或响应的持续时间所测量的。在一个优选的实施方案中,本发明可用于提高一组患者中的响应率。
在本发明的上下文中,可在I型抗CD20抗体或无岩藻糖基化抗CD20 抗体及所述Bcl-2抑制剂和所述MDM2抑制剂的癌症联合治疗中使用额外的其它细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物或电离辐射(例如细胞因子)。合适地,此类分子以对于意图的目的有效的量组合存在。在一个实施方案中,所述I型抗CD20抗体,优选利妥昔单抗或所述无岩藻糖基化抗CD20抗体,优选无岩藻糖基化人源化B-Ly1抗体,更优选奥滨尤妥珠单抗,及所述Bcl-2抑制剂和所述MDM2抑制剂联合治疗在没有所述额外的细胞毒剂、化疗剂或抗癌剂、或增强此类额外药剂的效果的化合物的情况中使用。
此类额外药剂包括例如:烷化剂或具有烷基化作用的药剂,诸如环磷酰胺(cyclophosphamide)(CTX;例如苯丁酸氮芥(chlorambucil) (CHL;例如瘤可宁顺铂(cisplatin)(CisP;例如白消安(busulfan)(例如马利兰美法仑(melphalan)、卡莫司汀 (carmustine)(BCNU)、链脲菌素(streptozotocin)、三乙撑密胺 (triethylenemelamine)(TEM)、丝裂霉素C(mitomycinC),等等;抗代谢物,诸如甲氨蝶呤(methotrexate)(MTX)、依托泊苷(etoposide)(VP16;例如凡毕士6-巯嘌呤(6-mercaptopurine)(6MP)、6-硫鸟嘌呤(6-thiocguanine) (6TG)、阿糖胞苷(cytarabine)(Ara-C)、5-氟尿嘧啶(5-fluorouracil)(5-FU)、卡培他滨(capecitabine)(例如希罗达达卡巴嗪(dacarbazine)(DTIC),等等;抗生素,诸如放线菌素D(actinomycin D)、多柔比星(doxorubicin) (DXR;例如阿霉素柔红霉素(daunorubicin)(道诺霉素 (daunomycin))、博来霉素(bleomycin)、光神霉素(mithramycin),等等;生物碱,诸如长春花生物碱诸如长春新碱(vincristine)(VCR)、长春碱(vinblastine),等等;及其它抗肿瘤剂,诸如紫杉醇(paclitaxel)(例如泰素和紫杉醇衍生物、细胞生长抑制剂、糖皮质激素诸如地塞米松(dexamethasone)(DEX;例如地卡特隆和皮质类固醇诸如泼尼松(prednisone)、核苷酶抑制剂诸如羟基脲、氨基酸消耗酶(amino acid depleting enzyme)诸如天冬酰胺酶、甲酰四氢叶酸(leucovorin)和其它叶酸衍生物、和相似的多种多样的抗肿瘤剂。也可使用下列药剂作为额外的药剂:氨磷汀(arnifostine)(例如更生霉素(dactinomycin)、二氯甲基二乙胺(mechlorethamine)(氮芥)、链佐星(streptozocin)、环磷酰胺(cyclophosphamide)、洛莫司汀(lomustine) (CCNU)、多柔比星脂质体(doxorubicin lipo)(例如吉西他滨 (gemcitabine)(例如健择柔红霉素脂质体(daunorubicin lipo)(例如丙卡巴肼(procarbazine)、丝裂霉素(mitomycin)、多西他赛(docetaxel)(例如泰索帝阿地白介素(aldesleukin)、卡铂 (carboplatin)、奥沙利铂(oxaliplatin)、克拉屈滨(cladribine)、喜树碱 (camptothecin)、CPT 11(伊立替康(irinotecan))、10-羟基7-乙基-喜树碱(SN38)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、异环磷酰胺(ifosfamide)、伊达比星(idarubicin)、美司钠(mesna)、干扰素β、干扰素α、米托蒽醌(mitoxantrone)、拓扑替康(topotecan)、亮丙瑞林(leuprolide)、甲地孕酮(megestrol)、美法仑 (melphalan)、巯嘌呤、普卡霉素(plicamycin)、米托坦(mitotane)、培门冬酶 (pegaspargase)、喷司他丁(pentostatin)、哌泊溴烷(pipobroman)、普卡霉素 (plicamycin)、他莫昔芬(tamoxifen)、替尼泊苷(teniposide)、睾内酯 (testolactone)、硫鸟嘌呤(thioguanine)、塞替派(thiotepa)、尿嘧啶氮芥(uracil mustard)、长春瑞滨(vinorelbine)、苯丁酸氮芥(chlorambucil)。在一个实施方案中,所述无岩藻糖基化抗CD20抗体及所述Bcl-2抑制剂和所述MDM2抑制剂联合治疗在没有此类额外的药剂的情况中使用。
上文所描述的细胞毒剂和抗癌剂以及抗增殖性靶标特异性抗癌药物,像蛋白激酶抑制剂在化疗方案中的使用一般在癌症疗法领域中得到充分表征,并且其在本文中的使用归入关于监测耐受性和有效性及关于控制施用途径和剂量的相同考虑,伴有一些调整。例如,细胞毒剂的实际剂量可随通过使用组织培养方法确定的患者的培养细胞应答而变化。一般地,与在没有额外的其它药剂的情况中使用的量相比,剂量会是降低的。
有效细胞毒剂的典型剂量可在制造商推荐的范围中,并且在通过体外应答或动物模型中的应答指示的情况中,可降低多至约一个数量级的浓度或量。如此,实际剂量会取决于医师的判断、患者的状况、和治疗方法的有效性,其基于原代培养的恶性细胞或组织培养组织样品的体外响应性,或合适的动物模型中观察到的响应。
在本发明的上下文中,除了表达CD20的癌症的I型抗CD20抗体或无岩藻糖基化抗CD20抗体及所述Bcl-2抑制剂和所述MDM2抑制剂联合治疗外,可实施有效量的电离辐射和/或可使用放射性药物。放射源可在所治疗的患者外部或内部。当来源在患者外部时,疗法称为外部束放射疗法(EBRT)。当放射源在患者内部时,治疗称作近程疗法(BT)。本发明的上下文中使用的放射性原子可选自下组,包括但不限于镭、钇-90、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘-123、碘-131和铟-111。也有可能用此类放射性同位素标记抗体。在一个实施方案中,所述I型抗CD20抗体或无岩藻糖基化抗CD20抗体及所述Bcl-2抑制剂和所述MDM2抑制剂联合治疗在没有此类电离辐射的情况中使用。
放射疗法是一种用于控制不可切除的或不能手术的肿瘤和/或肿瘤转移的标准治疗。已经在组合放射疗法与化学疗法时看到改善的结果。放射疗法基于如下的原则,即对靶区域递送的高剂量放射会导致肿瘤和正常组织两者中的生殖细胞(reproductive cell)的死亡。放射剂量方案一般在放射吸收剂量 (Gy)、时间和分级方面限定,并且必须由肿瘤学家小心限定。患者接受的放射量会取决于各种考虑因素,但是两项最重要的是肿瘤相对于身体的其它重要结构或器官的位置和肿瘤已经扩散的程度。经历放射疗法的患者的一种典型治疗过程会是在1至6周时段里的治疗日程表,以单一每日分数约1.8至 2.0Gy一周5天对患者施用10至80Gy的总剂量。在本发明的一个优选的实施方案中,在用本发明的联合治疗和放射治疗人患者中的肿瘤时存在着协同。换言之,在与放射组合时(任选有额外的化学治疗剂或抗癌剂),借助于构成本发明组合的药剂对肿瘤生长的抑制得到增强。例如,辅助放射疗法的参数包含在WO 99/60023中。
依照已知的方法通过静脉内施用(以推注或者通过在一段时间里连续输注),通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内或鞘内途径对患者施用I型抗CD20抗体或无岩藻糖基化抗CD20抗体。在一个实施方案中,静脉内或皮下施用抗体。
依照已知的方法通过静脉内施用(以推注或者通过在一段时间里连续输注),口服、通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、或鞘内路径对患者施用Bcl-2抑制剂和MDM2抑制剂。在一个实施方案中,静脉内或口服施用所述Bcl-2抑制剂和所述MDM2抑制剂。
本文使用的“药学上可接受的载体”意图包括与药学施用相容的任何和所有材料,包括溶剂、分散介质、涂层材料、抗细菌和抗真菌剂、等张和吸收延迟剂、和与药学施用相容的其它材料和化合物。除非任何常规的介质或药剂与活性化合物不相容,否则涵盖其在本发明的组合物中的使用。还可将补充性活性化合物掺入组合物中。
药物组合物:
可通过用药学上可接受的无机或有机载体加工依照本发明的抗CD20 抗体和/或Bcl-2抑制剂和MDM2抑制剂来获得药物组合物。可使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等,例如用于片剂、包衣片剂、锭剂和硬明胶胶囊的此类载体。适合于软明胶胶囊的载体是例如植物油、蜡、脂肪、半固体和液体多元醇等。然而,根据活性物质的性质,通常在软明胶胶囊的情况下不需要载体。适合于生成溶液和糖浆剂的载体是例如水、多元醇、甘油、植物油等。适合于栓剂的载体是例如天然的或硬化的油、蜡、脂肪、半液体或液体多元醇等。
此外,药物组合物可含有防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、增甜剂、着色剂、香料、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们也可含有其它治疗上有价值的物质。
在本发明的一个实施方案中,所述组合物包含所述I型抗CD20抗体(优选利妥昔单抗)或所述无岩藻糖基化抗CD20抗体(其中岩藻糖的量是60%或更少)(优选无岩藻糖基化人源化B-Ly1抗体,更优选奥滨尤妥珠单抗)及所述 Bcl-2抑制剂和所述MDM2抑制剂两者,其用于治疗癌症,特别是表达CD20 的癌症(优选淋巴瘤或淋巴细胞性白血病,更优选B细胞非霍奇金淋巴瘤 (NHL)、套细胞淋巴瘤(MCL)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、B细胞弥漫性大细胞淋巴瘤(DLCL)、伯基特淋巴瘤、毛细胞白血病、滤泡性淋巴瘤、多发性骨髓瘤、边缘区淋巴瘤、移植后淋巴增殖性病症(PTLD)、HIV相关淋巴瘤、瓦尔登斯特伦巨球蛋白血症或原发性CNS 淋巴瘤)。
所述药物组合物可进一步包含一种或多种药学上可接受的载体。
本发明进一步提供了例如在癌症中使用的药物组合物,其包含(i)第一有效量的具有60%或更小的岩藻糖量的I型抗CD20抗体(优选利妥昔单抗)或无岩藻糖基化抗CD20抗体(优选无岩藻糖基化人源化B-Ly1抗体),和(ii)第二有效量的Bcl-2抑制剂和MDM2抑制剂。任选地,此类组合物包含药学上可接受的载体和/或赋形剂。
通过将具有期望纯度的抗体与任选的药学上可接受的载体、赋形剂或稳定剂(Remington’s Pharmaceutical Sciences第16版,Osol,A.编(1980))混合以冻干制剂或水溶液形式制备依照本发明使用的仅I型抗CD20抗体或无岩藻糖基化抗CD20抗体的药物组合物,供贮存。可接受的载体、赋形剂或稳定剂在所采用的剂量和浓度对于接受者无毒,并且包括缓冲剂诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如氯化十八烷基二甲基苄基铵;氯化六甲双胺;苯扎氯铵、苄索氯铵;酚、丁醇或苄醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(小于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物诸如聚乙烯吡咯烷酮;氨基酸诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖及其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂诸如EDTA;糖诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子诸如钠;金属络合物(例如Zn-蛋白质络合物);和/或非离子型表面活性剂诸如 TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
Bcl-2抑制剂和MDM2抑制剂的药物组合物可与上文对I型抗CD20抗体或无岩藻糖基化抗CD20抗体描述的药物组合物类似。
小分子Bcl-2抑制剂和MDM2抑制剂的药物组合物包括那些适合于口服、经鼻、经表面(包括含服和舌下)、经直肠、经阴道和/或胃肠外施用。组合物可以单位剂量形式方便呈现,并且可通过药学领域公知的任何方法来制备。可与载体材料组合以生成单一剂量形式的活性成分量会随所治疗的宿主以及特定施用模式而有所变化。可与载体材料组合以生成单一剂量形式的活性成分量一般会是产生治疗效果的Bcl-2抑制剂和MDM2抑制剂的所述量。一般地,在100%里,此量的范围会是约1%至约99%的活性成分,优选约 5%至约70%,最优选约10%至约30%。制备这些组合物的方法包括下列步骤:使Bcl-2抑制剂和MDM2抑制剂与载体及任选一种或多种辅助成分进行结合。一般地,如下制备BTK抑制剂的药物组合物:使Bcl-2抑制剂和MDM2 抑制剂与液体载体或细碎的固体载体,或两者一致且密切地结合,然后在必要时,使产物成形。适合于口服施用的组合物可为胶囊、扁囊剂、囊剂、丸剂、片剂、锭剂(使用调味基材,通常为蔗糖和阿拉伯胶或黄蓍胶得到)、粉末、颗粒,或者作为水性或非水性液体中的溶液或悬浮液,或者作为水包油或油包水液体乳剂,或者作为酏剂或糖浆剂,或者作为软锭剂(pastille)(使用惰性基材,诸如明胶和甘油、或蔗糖和阿拉伯胶得到)和/或作为漱口剂等等 (每种含有预先确定量的Bcl-2抑制剂和MDM2抑制剂作为活性成分)的形式。Bcl-2抑制剂和MDM2抑制剂也可以推注、药糖剂或糊剂施用。
在本发明的又一个实施方案中,将I型抗CD20抗体或无岩藻糖基化抗CD20抗体及Bcl-2抑制剂和MDM2抑制剂配制成两种分开的药物组合物。
活性成分也可包埋于例如通过凝聚技术或通过界面聚合制备的微胶囊中(例如分别是羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊),在胶状药物递送系统中(例如脂质体、白蛋白微球体、微乳剂、纳米颗粒和纳米胶囊),或在粗滴乳状液中。此类技术披露于例如Remington’s Pharmaceutical Sciences,第16版,Osol,A.(ed.)(1980)。
可制备持续释放制剂。持续释放制剂的合适例子包括含有抗体的固体疏水性聚合物的半透性基质,该基质是定型制品的形式,例如薄膜或微胶囊。持续释放基质的例子包括聚酯、水凝胶(例如聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(US 3,773,919)、L-谷氨酸和L-谷氨酸γ-乙酯的共聚物、不可降解的乙烯-乙酸乙烯、可降解的乳酸-乙醇酸共聚物诸如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和乙酸亮丙瑞林构成的可注射微球体)、及聚-D-(-)-3-羟基丁酸。
要用于体内施用的制剂必须是无菌的。这容易通过过滤流过无菌滤膜来实现。
优选地,所述I型抗CD20抗体是利妥昔单抗或所述无岩藻糖基化抗 CD20抗体是人源化B-Ly1抗体且所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物且所述MDM2抑制剂是 4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物,且所述癌症是表达CD20的癌症,优选淋巴瘤或淋巴细胞性白血病。
一个实施方案是用于治疗癌症的药物组合物,其包含用占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖的量无岩藻糖基化的I型抗CD20抗体或人源化B-Ly1抗体的组合,及4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1- 基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物和4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基 -5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物,其中所述癌症是表达CD20的癌症,优选淋巴瘤或淋巴细胞性白血病。
本发明进一步提供了一种用于治疗癌症的方法,包括对需要此类治疗的患者施用(i)第一有效量的具有60%或更小的I型抗CD20抗体或岩藻糖量的无岩藻糖基化抗CD20抗体(优选无岩藻糖基化人源化B-Ly1抗体),和(ii)第二有效量的Bcl-2抑制剂和MDM2抑制剂。
在一个实施方案中,岩藻糖的量在40%至60%之间。
优选地,所述癌症是表达CD20的癌症.
优选地,所述表达CD20的癌症是淋巴瘤或淋巴细胞性白血病。
优选地,I型抗CD20抗体是利妥昔单抗。
优选地,所述无岩藻糖基化抗CD20抗体是II型抗CD20抗体。
优选地,所述抗体是如本文所披露的人源化B-Ly1抗体。
优选地,所述抗体是奥滨尤妥珠单抗。
优选地,所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物。
优选地,所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3- 甲氧基-苯甲酸或其盐或多晶型物。
优选地,所述I型抗CD20抗体是利妥昔单抗或所述无岩藻糖基化抗 CD20抗体是人源化B-Ly1抗体且所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物且所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物,且所述癌症是表达CD20的癌症,优选淋巴瘤或淋巴细胞性白血病。
本文使用的术语“患者”优选指出于任何目的需要用I型抗CD20抗体或无岩藻糖基化抗CD20抗体治疗的人(例如罹患表达CD20的癌症的患者),且更优选需要此类治疗以治疗癌症、或癌前状况或损伤的人。然而,术语“患者”也可指非人动物,优选哺乳动物诸如犬、猫、马、牛、猪、绵羊和非人灵长类,等等。
本发明进一步包括在治疗癌症中使用的具有60%或更小的岩藻糖量的I 型抗CD20抗体或无岩藻糖基化抗CD20抗体及Bcl-2抑制剂和MDM2抑制剂。
优选地,所述I型抗CD20抗体是利妥昔单抗。
优选地,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。
优选地,所述无岩藻糖基化人源化B-Ly1抗体是奥滨尤妥珠单抗。
优选地,所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物且所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯 -2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物。
优选地,所述I型抗CD20抗体是利妥昔单抗或所述无岩藻糖基化抗 CD20抗体是人源化B-Ly1抗体,更优选奥滨尤妥珠单抗,且所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H- 吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物且所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物,且所述癌症是表达CD20的癌症,优选淋巴瘤或淋巴细胞性白血病。
提供以下实施例和图以帮助理解本发明,其真正的范围在所附权利要求书中列出。应当理解,可在不背离本发明精神的前提下对列出的规程做出修改。
序列表
SEQ ID NO:1 鼠单克隆抗CD20抗体B-Ly1的重链可变区(VH)的氨基酸序列。
SEQ ID NO:2 鼠单克隆抗CD20抗体B-Ly1的轻链可变区(VL)的氨基酸序列。
SEQ ID NO:3-19 人源化B-Ly1抗体的重链可变区(VH)的氨基酸序列 (B-HH2至B-HH9、B-HL8、和B-HL10至B-HL17)。
SEQ ID NO:20 人源化B-Ly1抗体的轻链可变区(VL)的氨基酸序列B-KV1。
实验规程
实施例1:
实施例
体内抗肿瘤效力
评价CD20特异性抗体奥滨尤妥珠单抗与bcl-2抑制剂GDC-0199和 MDM2抑制剂RG7388的组合针对DOHH2DLBCL异种移植物(CD20+, p53wt)的体内抗肿瘤效力。本文使用的奥滨尤妥珠单抗与RO5072759和 B-HH6-B-KV1GE同义使用。本文使用的所述bcl-2抑制剂GDC-0199是以下化学化合物:4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l- 基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物形式。本文使用的所述MDM2抑制剂RG7388是以下化学化合物: 4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物形式。
测试药剂
CD20抗体奥滨尤妥珠单抗以来自Roche,Basel,Switzerland的储备溶液形式提供。抗体缓冲液包含组氨酸。在注射之前,将抗体溶液从储备溶液适当稀释在缓冲液中。MDM2(4)抑制剂来自Roche,Basel,Switzerland的SDP 制剂形式提供,并在使用之前重悬浮。Bcl-2抑制剂GDC-0199由GNE,SSF, USA提供并在使用之前配制。
细胞系和培养条件
在NCI建立原始的DOHH-2人B细胞NHL细胞系(DLBCL),并从ATCC (Manassas,VA,USA)购买。依据实验方案,通过TAP CompacT CellBase细胞培养机器人进行用于移植的肿瘤细胞的扩增。肿瘤细胞系在如下条件常规培养:RPMI 1640培养基,FCS 10%和L-谷氨酰胺2mM,37℃,5%CO2的水饱和气氛。用胰蛋白酶/EDTA 1次裂解每周两次进行培养传代,第2次传代用于移植。
动物
根据承诺的指导原则,将达到6-7周龄的雌性SCID米色小鼠维持在无特定病原体的条件下,每天循环12小时光照/12小时黑暗。实验研究方案经地方政府审查并批准。到达后,将动物维持在动物设施中一周以适应新的环境并进行观察。定期进行持续的健康监测。随意提供食物和蒸压水。
监测
每天控制动物的临床症状并检测不良反应。为了监测整个实验,记录动物的体重。
动物的治疗
随机化后开始动物治疗,中位肿瘤大小约200mm3。在第13、21和27 天,以每周1次10mg/kg的单一药剂和组合形式施用CD20抗体奥滨尤妥珠单抗。在同一天施用相同的媒介物。在第13-17、20-24和27-29天,以30mg/kg 口服治疗的单一药剂和组合形式施用MDM2(4)抑制剂RG7388。最后,在第13-29天,以100mg/kg的单一药剂和组合形式口服给予bcl-2抑制剂 GDC-0199。
抗肿瘤效力
将DOHH-2人弥漫性大B细胞淋巴瘤(DLBCL)细胞(CD20+,p53wt)与基质胶皮下注射(s.c.)接种到雌性SCID米色小鼠上。荷瘤小鼠在13天后被随机分配到指定的研究组并开始化合物治疗。荷瘤动物用媒介物对照、30 mg/kg MDM2(4)抑制剂RO5503781(RG7388)、10mg/kg抗CD20抗体奥滨尤妥珠单抗或bcl-2抑制剂GDC-0199(100mg/kg)作为单剂进行处理。此外,一个研究组接受MDM2抑制剂RG7388、CD20抗体奥滨尤妥珠单抗和bcl-2 抑制剂GDC-0199的三重组合。结果是,作为单一药剂给予的所有化合物对 DOHH-2异种移植物展示出显著的抗肿瘤效力。更详细地,与对照相比,用 MDM2(4)抑制剂RO5503781(RG7388)处理导致对p53wt DOHH2异种移植物的56%肿瘤生长抑制。用bcl-2抑制剂GDC-0199(60%TGI)处理后注意到类似的效力,而用抗CD20抗体奥滨尤妥珠单抗治疗后实现作为单一药剂的最佳效力,达到几乎肿瘤停滞(TGI 90%)。然而,对于包含MDM2抑制剂 RG7388+CD20抗体奥滨尤妥珠单抗+bcl-2抑制剂GDC-0199的三重组合,观察到优越的效力。更详细地,三重组合方法基本上早期诱导肿瘤消退,据此最终达到90%,其中30%完全肿瘤消退。三重组合的强效力与各个单一药剂组相比协同性更好。
表2
实施例2
CD20特异性抗体奥滨尤妥珠单抗(obinuzumab)与bcl-2抑制剂 GDC-0199和MDM2抑制剂RG7388的组合。
还是在该实施例中,使用CD20特异性抗体奥滨尤妥珠单抗与bcl-2抑制剂GDC-0199和MDM2抑制剂RG7388的组合。本文使用的奥滨尤妥珠单抗与RO5072759和B-HH6-B-KV1GE同义使用。本文使用的所述bcl-2 抑制剂GDC-0199是以下化学化合物:4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1- 烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢 -2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物形式。本文使用的所述MDM2抑制剂RG7388是以下化学化合物:4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2- 二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物形式。
II型抗CD20抗体RO5072759(B-HH6-B-KV1GE)、Bcl-2特异性抑制剂GDC-0199(Abt-199,RG7601)和MDM2拮抗剂RG7388(RO5503781)的组合治疗的抗肿瘤活性。
测试药剂
II型抗CD20抗体B-HH6-B-KV1GE(=人源化B-Ly1,糖工程化改造的 B-HH6-B-KV1,参见WO 2005/044859和WO 2007/031875)以来自GlycArt, Schlieren,Switzerland的于组氨酸、海藻糖和聚山梨酯20缓冲液中的储备溶液形式提供。在体内应用之前,将抗体用PBS稀释。
Bcl-2抑制剂GDC-0199获自Genentech Inc.,CA,USA。
MDM2(4)拮抗剂RG7388(RO5503781)由小分子工艺研究和开发组 (SmallMolecule Process Research and Development unit),Hoffmann-La Roche, Basel,Switzerland提供。
细胞系和培养条件
将人Z138套细胞淋巴瘤细胞系在补充有10%胎牛血清(PAA Laboratories,Austria)和2mM L-谷氨酰胺的DMEM中于37℃在5%CO2的水饱和气氛中培养。对于体内异种移植物实验,将细胞与基质胶共注射。
动物
根据指导原则(GV-Solas;Felasa;TierschG),将达到4-5周龄的雌性SCID 米色小鼠(购自Charles River,Sulzfeld,Germany)维持在动物设施的检疫区一周,然后维持在无特定病原体的条件下,每天循环12小时光照/12小时黑暗。实验研究方案经Roche和地方政府审查并批准(Regierung von Oberbayern; registration no.55.2-1-54-2531.2-26-09)。随意提供食物(KLIBA NAFAG 3807) 和水(过滤的)。
监测
每天监测动物的临床症状并检测不良反应。在实验期间,每周检查两次动物的体重,并通过卡尺测量肿瘤体积。
动物的治疗
在肿瘤细胞接种后18天的随机化当天开始动物治疗。人源化II型抗 CD20抗体RO5072759B-HH6-B-KV1GE(奥滨尤妥珠单抗)作为单一药剂 q7d每周一次(第18、25、32天)腹膜内注射施用,持续3周,剂量为0.5mg/kg。 bcl-2抑制剂GDC-0199每天一次(从第18天至第36天)口服给予,历时19 天,剂量为100mg/kg。MDM2拮抗剂RG7388(RO5503781)每天一次口服给予,历时5天,剂量为100mg/kg(活性化合物),从第18天至第22天,并且历经第12天以80mg/kg(活性化合物)的剂量从第25天至第36天施用。在第23天和第24天没有治疗。在联合组中,RO5072759B-HH6-B-KV1GE、 MDM2(4)和GDC-0199以相同剂量并在同一天施用。相应的媒介物在同一天施用。
在第32天的肿瘤生长抑制(TGI)
使用RO5072759、GDC-0199或RG7388(RO5503781)的单一疗法治疗分别导致47%、53%或67%的肿瘤生长抑制。RO5072759与GDC-0199或 RG7388(RO5503781)的组合产生85%或86%的肿瘤生长抑制。RG7388 (RO5503781)与GDC-0199的组合和三重组合在肿瘤细胞接种后第32天显示肿瘤消退(TGI>100%)。
为了阐明各种治疗的长期效果,进行事件发生时间(time-to-event)分析直至肿瘤细胞接种后第125天。直至第125天(研究终止),三重组合导致所有动物中的完全肿瘤缓解。RG7388(RO5503781)和RO5072759的组合导致5 个无肿瘤动物(10个中的5个)。用次最佳剂量0.5mg/kg RO5072759测定单药治疗在研究结束时导致2只无肿瘤动物。
表3中示出每组的“中位事件发生时间”参数。
表3:事件发生时间分析的结果总结
*中位事件发生时间是半数动物已发生时间的时间(天数)
如本文所公开且也附在序列表中,以下序列是本发明的一部分:
序列
SEQ ID NO:1
鼠类单克隆抗CD20抗体B-Ly1的重链(VH)可变区的氨基酸序列
Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys AlaSer Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Lys Leu Arg Pro Gly GlnGly Leu Glu Trp Ile Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn GlyLys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr MetGln Leu Thr Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Leu Cys Ala Arg Asn ValPhe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
SEQ ID NO:2
鼠类单克隆抗CD20抗体B-Ly1的轻链(VL)可变区的氨基酸序列
Asn Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser LysSer Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro GlyGln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro AspArg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile Ser Arg Val GluAla Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr PheGly Gly Gly Thr Lys Leu Glu Ile Lys Arg
SEQ ID NO:3
人源化B-Ly1抗体(B-HH2)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:4
人源化B-Ly1抗体(B-HH3)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:5
人源化B-Ly1抗体(B-HH4)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala SerVal Lys Val Ser Cys Lys Val Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:6
人源化B-Ly1抗体(B-HH5)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Ser TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:7
人源化B-Ly1抗体(B-HH6)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:8
人源化B-Ly1抗体(B-HH7)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Ser TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:9
人源化B-Ly1抗体(B-HH8)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:10
人源化B-Ly1抗体(B-HH9)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala SerVal Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:11
人源化B-Ly1抗体(B-HL8)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:12
人源化B-Ly1抗体(B-HL10)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:13
人源化B-Ly1抗体(B-HL11)的重链(VH)可变区的氨基酸序列
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:14
人源化B-Ly1抗体(B-HL12)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:15
人源化B-Ly1抗体(B-HL13)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:16
人源化B-Ly1抗体(B-HL14)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:17
人源化B-Ly1抗体(B-HL15)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:18
人源化B-Ly1抗体(B-HL16)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly SerLeu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:19
人源化B-Ly1抗体(B-HL17)的重链(VH)可变区的氨基酸序列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly SerLeu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn TrpVal Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly AspGly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp LysSer Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser
SEQ ID NO:20
人源化B-Ly1抗体B-KV1的轻链(VL)可变区的氨基酸序列
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly GluPro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile ThrTyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr GlnMet Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly ThrAsp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr CysAla Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile LysArg Thr Val。
序列表
<110> F. Hoffmann-La Roche AG
<120> 抗CD20抗体与Bcl-2抑制剂和MDM2抑制剂的组合疗法
<130> P32901
<130> 31861
<150> EP 15169199.5
<151> 2015-05-26
<160> 20
<170> PatentIn version 3.5
<210> 1
<211> 112
<212> PRT
<213> Mus sp.
<220>
<221> MISC_FEATURE
<223> 鼠类单克隆抗CD20抗体B-Ly1的重链(VH)可变区的氨基酸序列
<400> 1
Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys
1 5 10 15
Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Lys Leu
20 25 30
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Phe Pro Gly Asp
35 40 45
Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr
50 55 60
Ala Asp Lys Ser Ser Asn Thr Ala Tyr Met Gln Leu Thr Ser Leu Thr
65 70 75 80
Ser Val Asp Ser Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly
85 90 95
Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
100 105 110
<210> 2
<211> 103
<212> PRT
<213> Mus sp.
<220>
<221> MISC_FEATURE
<223> 鼠类单克隆抗CD20抗体B-Ly1的轻链(VL)可变区的氨基酸序列
<400> 2
Asn Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser
1 5 10 15
Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu
20 25 30
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn
35 40 45
Leu Val Ser Gly Val Pro Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr
50 55 60
Asp Phe Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
65 70 75 80
Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly
85 90 95
Thr Lys Leu Glu Ile Lys Arg
100
<210> 3
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH2)的重链(VH)可变区的氨基酸序列
<400> 3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 4
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH3)的重链(VH)可变区的氨基酸序列
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 5
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH4)的重链(VH)可变区的氨基酸序列
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 6
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH5)的重链(VH)可变区的氨基酸序列
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 7
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH6)的重链(VH)可变区的氨基酸序列
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 8
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH7)的重链(VH)可变区的氨基酸序列
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 9
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH8)的重链(VH)可变区的氨基酸序列
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 10
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH9)的重链(VH)可变区的氨基酸序列
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 11
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL8)的重链(VH)可变区的氨基酸序列
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 12
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL10)的重链(VH)可变区的氨基酸序列
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 13
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL11)的重链(VH)可变区的氨基酸序列
<400> 13
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 14
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL12)的重链(VH)可变区的氨基酸序列
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 15
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL13)的重链(VH)可变区的氨基酸序列
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 16
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL14)的重链(VH)可变区的氨基酸序列
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 17
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL15)的重链(VH)可变区的氨基酸序列
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 18
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL16)的重链(VH)可变区的氨基酸序列
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 19
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL17)的重链(VH)可变区的氨基酸序列
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 20
<211> 115
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体B-KV1的轻链(VL)可变区的氨基酸序列
<400> 20
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val
115
Claims (26)
1.一种抗CD20抗体,其与Bcl-2抑制剂和MDM2抑制剂组合用于治疗癌症。
2.根据权利要求1所述的抗体,其特征在于,所述抗CD20抗体是I型抗CD20抗体或具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体。
3.根据权利要求1至2中任一项所述的抗体,其特征在于,所述癌症是表达CD20的癌症。
4.根据权利要求1至3中任一项所述的抗体,其特征在于,所述表达CD20的癌症是淋巴瘤或淋巴细胞性白血病。
5.根据权利要求1至4中任一项所述的抗体,其特征在于,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。
6.根据权利要求1至5中任一项所述的抗体,其特征在于,所述无岩藻糖基化抗CD20抗体是奥滨尤妥珠单抗。
7.根据权利要求1至5中任一项所述的抗体,其特征在于,所述I型抗CD20抗体是利妥昔单抗。
8.根据权利要求1至7中任一项所述的抗体,其特征在于,所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺。
9.根据权利要求1至7中任一项所述的抗体,其特征在于,所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸。
10.根据权利要求1至9中任一项所述的抗体,其特征在于,施用一种或多种额外的其它细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物或电离辐射。
11.一种药物组合物,包含I型抗CD20抗体或具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的人源化B-Ly1抗体,与4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺和4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐的组合,其用于治疗癌症。
12.一种治疗罹患癌症的患者的方法,包括向需要此类治疗的患者施用I型抗CD20抗体或具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体与Bcl-2抑制剂和MDM2抑制剂的组合。
13.根据权利要求12所述的方法,其特征在于,所述癌症是表达CD20的癌症。
14.根据权利要求12至13中任一项所述的方法,其特征在于,所述表达CD20的癌症是淋巴瘤或淋巴细胞性白血病。
15.根据权利要求12至14中任一项所述的方法,其特征在于,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。
16.根据权利要求12至15中任一项所述的方法,其特征在于,所述I型抗CD20抗体是利妥昔单抗。
17.根据权利要求12至16中任一项所述的方法,其特征在于,所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物。
18.根据权利要求12至17中任一项所述的方法,其特征在于,所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物。
19.根据权利要求12至18中任一项所述的方法,其特征在于,施用一种或多种额外的其它细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物或电离辐射。
20.I型抗CD20抗体或具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体与Bcl-2抑制剂和MDM2抑制剂的组合在制备用于治疗癌症的药物中的用途。
21.根据权利要求20所述的用途,其特征在于,所述癌症是表达CD20的癌症。
22.根据权利要求20至21中任一项所述的用途,其特征在于,所述表达CD20的癌症是淋巴瘤或淋巴细胞性白血病。
23.根据权利要求20至22中任一项所述的用途,其特征在于,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。
24.根据权利要求20至23中任一项所述的用途,其特征在于,所述Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-l-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-N-({4-[(四氢-2H-吡喃-4-基甲基)氨基]-3-[(三氟甲基)磺酰基]苯基}磺酰基)苯甲酰胺或其盐或多晶型物。
25.根据权利要求20至24中任一项所述的用途,其特征在于,所述MDM2抑制剂是4-{[(2R,3S,4R,5S)-4-(4-氯-2-氟-苯基)-3-(3-氯-2-氟-苯基)-4-氰基-5-(2,2-二甲基-丙基)-吡咯烷-2-羰基]-氨基}-3-甲氧基-苯甲酸或其盐或多晶型物。
26.根据权利要求20至25中任一项所述的用途,其特征在于,施用一种或多种额外的其它细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物或电离辐射。
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US20180206726A1 (en) | 2016-12-07 | 2018-07-26 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
US20210138213A1 (en) | 2017-03-30 | 2021-05-13 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immune modulatory agent released using an ingestible device |
WO2019101789A1 (en) * | 2017-11-22 | 2019-05-31 | Nordic Nanovector Asa | Radioimmunoconjugates in combination with other drugs as treatment against nhl |
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