CN110869391A - 用BET抑制剂,Bcl-2抑制剂和抗CD20抗体的组合疗法 - Google Patents
用BET抑制剂,Bcl-2抑制剂和抗CD20抗体的组合疗法 Download PDFInfo
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- CN110869391A CN110869391A CN201880045781.2A CN201880045781A CN110869391A CN 110869391 A CN110869391 A CN 110869391A CN 201880045781 A CN201880045781 A CN 201880045781A CN 110869391 A CN110869391 A CN 110869391A
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Abstract
本发明涉及用BET抑制剂,Bcl‑2抑制剂和抗CD20抗体对DLBCL的组合疗法。
Description
发明领域
本发明涉及用BET抑制剂,Bcl-2抑制剂和抗CD20抗体的癌症的,特别是DLBCL的组合疗法。
发明背景
B细胞淋巴瘤比T细胞淋巴瘤常见得多,而且占据所有非霍奇金淋巴瘤(NHL)的大约85%。弥漫性大B细胞淋巴瘤(DLBCL)是最常见形式的NHL,占据美国约30%的新诊断NHL病例。DLBCL在男性和女性中均发生,虽然它在男性中略微更加常见。虽然DLBCL可以在儿童期发生,但是它的发生率一般随年龄而升高,而且大致一半的患者超过60岁。
DLBCL是一种攻击性(快速生长)淋巴瘤,可以在淋巴结中或在淋巴系统外部,在胃肠道,睾丸,甲状腺,皮肤,乳房,骨,或脑中发生。通常,DLBCL的第一个体征是由淋巴结肿大引起的颈,腋下,或腹股沟中的无痛,快速肿胀。对于一些患者,肿胀可能是痛苦的。其它症状可以包括盗汗,发烧,和无法解释的体重减轻。患者可以注意到疲劳,厌食,呼吸短促,或疼痛。
外遗传失调在多种血液学恶性中看到的驱动异常基因表达样式中发挥重要作用。由于许多外遗传改变是可逆的,因此这些因素已经作为潜在抗肿瘤靶点引起广泛关注。临床上有显著兴趣的一个特定靶点是布罗莫域和额外末端(BET)家族的蛋白,其包括BRD2,BRD3,BRD4,和睾丸特异性BRDT。布罗莫域(BRD)是对于结合乙酰化基序,包括染色质内的乙酰化的组蛋白蛋白质具有高亲和力的蛋白质结构域。BET家族的蛋白结合乙酰化的染色质并调节基因转录。
BET蛋白和乙酰化的染色质之间的相互作用的选择性抑制已经在急性白血病,淋巴瘤,和多发性骨髓瘤(MM)的临床前模型中导致显著活性。靶向BET蛋白能特异性靶向癌基因和对疾病发生和进展至关紧要的基因的转录(Onco Targets Ther.2016;9)
Bcl-2蛋白在许多疾病中,特别是在癌症,白血病,免疫和自身免疫疾病中发挥作用。Bcl-2蛋白据说牵涉膀胱癌,脑癌,乳腺癌,骨髓癌,宫颈癌,慢性淋巴细胞性白血病,结肠直肠癌,食管癌,肝细胞癌,成淋巴细胞性白血病,滤泡性淋巴瘤,T细胞或B细胞起源的淋巴样恶性,黑素瘤,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。在免疫系统的各种癌症和病症中Bcl-2蛋白的过表达与对化疗的抗性,临床结局,疾病进展,总体预后或其组合有关。
CD20分子(又称作人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.et al.,J.Biol.Chem.264(1989)11282-11287;及Einfeld,D.A.et al.,EMBO J.7(1988)711-717;Tedder,T.F.etal.,Proc.Natl.Acad.Sci.U.S.A.85(1988)208-212;Stamenkovic,I.et al.,J.Exp.Med.167(1988)1975-1980;Tedder,T.F.et al.,J.Immunol.142(1989)2560-2568)。CD20在大于90%的B细胞非霍奇金(Hodgkin)氏淋巴瘤(NHL)上表达(Anderson,K.C.etal.,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.et al.,J.Immunol.135(1985)973-979)。
存在两种不同类型的抗CD20抗体,在它们的CD20结合模式和生物学活性中显著不同(Cragg,M.S.et al.,Blood 103(2004)2738-2743;和Cragg,M.S.et al.,Blood 101(2003)1045-1052)。I型抗CD20抗体主要利用补体来杀死靶细胞,而II型抗体主要经由直接诱导细胞死亡来运转。
I型和II型抗CD20抗体和它们的特征在例如Klein et al.,mAbs 5(2013)22-33中综述。II型抗CD20抗体并不将CD20定位于脂筏,显示低CDC(补体依赖性裂解)活性,只显示与I型抗CD20抗体相比约一半的对B细胞的结合能力,且诱导同型聚集和直接细胞死亡。与之形成对比,I型抗体将CD20定位于脂筏,显示高CDC活性,完全的对B细胞的结合能力,和仅仅较弱的对同型聚集和直接细胞死亡的诱导。
单克隆抗体的细胞介导的效应器功能可以通过工程化改造其寡糖组分来增强,如记载于P.et al.,Nature Biotechnol.17(1999)176-180及US 6,602,684。IgG1型抗体(即在癌症免疫疗法中最常使用的抗体)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.et al.,Glycobiology 5(1995)813-822;Jefferis,R.et al.,Immunol.Rev.163(1998)59-76;Wright,A.and Morrison,S.L.,TrendsBiotechnol.15(1997)26-32)。P.et al.,Nature Biotechnol.17(1999)176-180及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)在中国仓鼠卵巢(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C1q(P.et al.,NatureBiotechnol.17(1999)176-180;Davies,J.et al.,Biotechnol.Bioeng.74(2001)288-294;Mimura,Y.et al.,J.Biol.Chem.276(2001)45539-45547;Radaev,S.et al.,J.Biol.Chem.276(2001)16478-16483;Shields,R.L.et al.,J.Biol.Chem.276(2001)6591-6604;Shields,R.L.et al.,J.Biol.Chem.277(2002)26733-26740;Simmons,L.C.etal.,J.Immunol.Methods 263(2002)133-147)。
已经报告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.et al.,Clin.Cancer Res.12(2006)2879-2887;Natsume,A.et al.,J.Immunol.Methods 306(2005)93-103;Satoh,M.et al.,Expert Opin.Biol.Ther.6(2006)1161-1173;Kanda,Y.et al.,Biotechnol.Bioeng.94(2006)680-688;Davies,J.etal.,Biotechnol.Bioeng.74(2001)288-294)。
发明概述
令人惊讶地发现BET抑制剂与Bcl-2抑制剂和抗CD20抗体的组合显示显著增强的针对DLBCL的功效,引起明显肿瘤消退和治疗停止后肿瘤再生长延迟。令人惊讶地,这种三重组合的肿瘤消退大于叠加,即优于由三种成分中每一种分开诱导的累积肿瘤消退。
如此,本发明特别涉及:
供作为药物使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体;
供在DLBCL的治疗中使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该BET抑制剂是2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫杂-5,7,8,9a-四氮杂-环戊并[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙酰胺(RG6146),INCB-054329,INCB-057643,GSK525762,GS-5829,CPI-0610,比拉瑞塞(Birabresib),PLX51107,ABBV-075,BI 894999,FT-1101,ZEN-3694,GSK-2820151或BMS-986158;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该BET抑制剂是2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫杂-5,7,8,9a-四氮杂-环戊并[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙酰胺(RG6146);
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该Bcl-2抑制剂是维奈托克(venetoclax),navitoclax,奥巴克拉(obatoclax),S-055746或PNT-2258;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该Bcl-2抑制剂是维奈托克;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该抗CD20抗体是I型抗CD20抗体,或其中Fc区中至少40%的N连接的寡糖是非岩藻糖基化的II型抗CD20抗体;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该II型抗CD20抗体是人源化B-Ly1抗体;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该II型抗CD20抗体是奥滨尤妥珠单抗;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该I型抗CD20抗体是利妥昔单抗;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该抗CD20抗体是利妥昔单抗或奥滨尤妥珠单抗;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该抗CD20抗体是利妥昔单抗;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该抗CD20抗体是奥滨尤妥珠单抗;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其包含一种或多种另外的其它细胞毒剂,化疗剂或抗癌剂;
供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其包含增强所述药剂的效果的电离辐射;
一种药学组合物,其包含BET抑制剂,Bcl-2抑制剂和抗CD20抗体和一种或多种药学可接受赋形剂;
一种药学组合物,其包含BET抑制剂,Bcl-2抑制剂和抗CD20抗体和一种或多种药学可接受赋形剂,用于治疗DLBCL;
BET抑制剂,Bcl-2抑制剂和抗CD20抗体制造用于治疗DLBCL的药物的用途;
BET抑制剂,Bcl-2抑制剂和抗CD20抗体用于治疗DLBCL的用途;
一种治疗DLBCL的方法,其包括将BET抑制剂,Bcl-2抑制剂和抗CD20抗体施用于有需要的患者;
一种试剂盒,其包含BET抑制剂,Bcl-2抑制剂和抗CD20抗体,用于同时,分开或顺序施用所述BET抑制剂,Bcl-2抑制剂和抗CD20抗体;
依照本发明的试剂盒,其用于治疗DLBCL;
依照本发明的药学组合物,用途,方法或试剂盒,其中该BET抑制剂是2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫杂-5,7,8,9a-四氮杂-环戊并[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙酰胺(RG6146),INCB-054329,INCB-057643,GSK525762,GS-5829,CPI-0610,比拉瑞塞(Birabresib),PLX51107,ABBV-075,BI 894999,FT-1101,ZEN-3694,GSK-2820151或BMS-986158;
依照本发明的药学组合物,用途,方法或试剂盒,其中该BET抑制剂是RG6146;
依照本发明的药学组合物,用途,方法或试剂盒,其中该Bcl-2抑制剂是维奈托克,navitoclax,奥巴克拉,S-055746或PNT-2258;
依照本发明的药学组合物,用途,方法或试剂盒,其中该Bcl-2抑制剂是维奈托克;
依照本发明的药学组合物,用途,方法或试剂盒,其中该抗CD20抗体是I型抗CD20抗体,或其中Fc区中至少40%的N连接的寡糖是非岩藻糖基化的II型抗CD20抗体;
依照本发明的药学组合物,用途,方法或试剂盒,其中该II型抗CD20抗体是人源化B-Ly1抗体;
依照本发明的药学组合物,用途,方法或试剂盒,其中该II型抗CD20抗体是奥滨尤妥珠单抗;
依照本发明的药学组合物,用途,方法或试剂盒,其中该I型抗CD20抗体是利妥昔单抗;
依照本发明的药学组合物,用途,方法或试剂盒,其中该抗CD20抗体是利妥昔单抗或奥滨尤妥珠单抗;
依照本发明的药学组合物,用途,方法或试剂盒,其中该抗CD20抗体是利妥昔单抗;和
依照本发明的药学组合物,用途,方法或试剂盒,其中该抗CD20抗体是奥滨尤妥珠单抗。
如此,供依照本发明使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体是组合施用的(或共施用的)。
如此,本发明涉及供依照本发明组合使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体。
如此,本发明涉及供作为药物组合使用,特别是供DLBCL的治疗中组合使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体。
在一个实施方案中,该BET抑制剂是选自WO 2011/143669中描述的化合物的化合物。WO 2011/143669中还公开了生成所述BET抑制剂的方法。
最优选地,该BET抑制剂是如下式中的2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫杂-5,7,8,9a-四氮杂-环戊并[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙酰胺或其盐。WO 2011/143669的实施例JQ35描述了制备它的方法。
下式描绘了优选的BET抑制剂:
上文BET抑制剂还称作RG6146,JQ35或TEN-010。
在一个实施方案中,该Bcl-2抑制剂是选自WO 2010/138588中描述的化合物的化合物。WO 2010/138588中还公开了生成所述Bcl-2抑制剂的方法。
最优选地,该Bcl-2抑制剂是如下式中的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。WO 2010/138588的实施例5描述了用于制备所述Bcl-2抑制剂的方法。
下式描绘了优选的Bcl-2抑制剂:
上文Bcl-2抑制剂还命名为ABT-199,GDC-0199或维奈托克。
该抗CD20抗体可以是I型抗CD20抗体或II型抗CD20抗体。
利妥昔单抗是特别优选的抗CD20抗体。它是I型抗CD20抗体。它是一种针对人CD20抗原的含有人γ1鼠恒定域的遗传工程嵌合单克隆抗体。此嵌合抗体含有人γ1恒定域,并且在1998年4月7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细胞非霍奇金氏淋巴瘤患者。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.et al.,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。
该II型抗CD20抗体是通过Fc区中的糖基化的修饰得到有利改造的。在一个具体的实施方案中,该II型抗CD20抗体是工程化改造成具有与非工程化改造的抗体相比Fc区中升高比例的非岩藻糖基化的寡糖。抗体的Fc区中升高比例的非岩藻糖基化的寡糖导致具有升高的效应器功能的抗体。
在一个更加具体的实施方案中,该II型抗CD20抗体的Fc区中至少约40%,约45%,约50%,约55%,约60%,约65%,约70%,约75%,约80%,约85%,约90%,约95%或约100%,优选至少约40%的N连接的寡糖是非岩藻糖基化的。
在一个实施方案中,该II型抗CD20抗体的Fc区中介于约40%和约80%之间的N连接的寡糖是非岩藻糖基化的。在一个实施方案中,该II型抗CD20抗体的Fc区中介于约40%和约60%之间的N连接的寡糖是非岩藻糖基化的。
在另一个具体的实施方案中,该II型抗CD20抗体工程化改造成具有与非工程化改造的抗体相比Fc区中升高比例的两分型寡糖。在一个更加具体的实施方案中,该II型抗CD20抗体的Fc区中至少约10%,约15%,约20%,约25%,约30%,约35%,约40%,约45%,约50%,约55%,约60%,约65%,约70%,约75%,约80%,约85%,约90%,约95%或约100%,优选至少约40%的N连接的寡糖是两分型的。在一个实施方案中,该抗CD20抗体的Fc区中介于约40%和约80%之间的N连接的寡糖是两分型的。在一个实施方案中,该II型抗CD20抗体的Fc区中介于约40%和约60%之间的N连接的寡糖是两分型的。
有利的是,该抗CD20抗体是人源化B-Ly1抗体。
在一个实施方案中,该人源化B-Ly1抗体具有选自SEQ ID 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)的组的重链可变区(VH)。
在一个具体的实施方案中,此类可变域选自由SEQ ID NO:3,SEQ ID NO:4,SEQ IDNO:7,SEQ ID NO:9,SEQ ID NO:11,SEQ ID NO:13和SEQ ID NO:15(WO 2005/044859和WO2007/031875的B-HH2,BHH-3,B-HH6,B-HH8,B-HL8,B-HL11和B-HL13)组成的组。
在一个具体的实施方案中,该人源化B-Ly1抗体具有SEQ ID NO:7(WO 2005/044859和WO 2007/031875的B-HH6)的重链可变区(VH)。
在一个具体的实施方案中,该人源化B-Ly1抗体具有SEQ ID NO:20(WO 2005/044859和WO 2007/031875的B-KV1)的轻链可变区(VL)。
在一个具体的实施方案中,该人源化B-Ly1抗体具有SEQ ID NO:7(WO 2005/044859和WO 2007/031875的B-HH6)的重链可变区(VH)和SEQ ID NO:20(WO 2005/044859和WO 2007/031875的B-KV1)的轻链可变区(VL)。
而且,在一个实施方案中,该人源化B-Ly1抗体是IgG1抗体。
依照本发明,此类人源化B-Ly1抗体优选是依照WO 2005/044859,WO 2004/065540,WO 2007/031875,Umana,P.et al.,Nature Biotechnol.17(1999)176-180和WO99/154342中描述的规程在Fc区中糖工程化改造(GE)的。
在一个实施方案中,该糖工程化改造的人源化B-Ly1是B-HH6-B-KV1 GE。
在一个实施方案中,该抗CD20抗体是奥滨尤妥珠单抗(recommended INN,WHODrug Information,Vol.26,No.4,2012,p.453)。如本文中使用的,奥滨尤妥珠单抗与GA101同义且以前称作afutuzumab(recommended INN,WHO Drug Information,Vol.23,No.2,2009,p.176;Vol.22,No.2,2008,p.124)。商品名是GAZYVA或GAZYVARO。WHO药物信息文件替换所有先前的版本(例如Vol.25,No.1,2011,p.75-76)。
在一个实施方案中,该II型抗CD20抗体以10-8M至10-13M的KD结合CD20。
在本发明的一个特定方面,该II型抗CD20抗体是IgG1同种型的。
在本发明的一个特定方面,该II型抗CD20抗体是人源化B-Ly1抗体。
在一个特别优选的实施方案中,该II型抗CD20抗体是奥滨尤妥珠单抗。
附图简述
图1:与媒介,单一和双重疗法相比,用RG6146,维奈托克和奥滨尤妥珠单抗的三重组合的疗法的抗肿瘤功效(第10-50天)。
图2:与媒介,单一和双重疗法相比,用RG6146,维奈托克和奥滨尤妥珠单抗的三重组合治疗后的肿瘤生长延迟。
图3:与媒介,单一和双重疗法相比,用RG6146,维奈托克和利妥昔单抗的三重组合的疗法的抗肿瘤功效(第10-28天)。
发明详述
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,如单克隆抗体,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。如本文中所使用的,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生成的,所述杂交瘤包含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.et al.,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.etal.,Nature 332(1988)323-327;及Neuberger,M.S.et al.,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。
如本文中所使用的,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.and van de Winkel,J.G.,Curr.Opin.in Chem.Biol.5(2001)368-374)。基于此类技术,可以生成针对极其多种靶物的人抗体。人抗体的例子记载于例如Kellermann,S.A.et al.,Curr.Opin.Biotechnol.13(2002)593-597。
如本文中所使用的,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。
如本文中使用的,术语“双或多特异性抗体”涉及具有针对至少两种不同位点的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而另一针对任何其它抗原。在某些实施方案中,双特异性抗体可结合CD20的两种不同表位。双特异性抗体还可用于将细胞毒剂定位至表达CD20的细胞。双特异性抗体可以作为全长抗体或抗体片段来制备。
术语“全长抗体”,“完整抗体”,和“全抗体”在本文中可互换使用,指具有与天然抗体结构实质性相似的结构或具有含有如本文中定义的Fc区的重链的抗体。
“抗体片段”指除了完整抗体以外的分子,其包含完整抗体中结合与完整抗体结合的抗原的一部分。抗体片段的例子包括但不限于Fv,Fab,Fab’,Fab’-SH,F(ab’)2,双抗体,线性抗体,单链抗体分子(例如scFv),和自抗体片段形成的多特异性抗体。如本文中使用的,术语“抗体片段”还涵盖单域抗体。
术语“Fc域”或“Fc区”在本文中用于定义免疫球蛋白重链中至少含有恒定区的一部分的C端区域。该术语包括天然序列Fc区和变体Fc区。虽然IgG重链的Fc区的边界可以略微变化,但是人IgG重链Fc区通常定义为自Cys226或Pro230延伸至重链的羧基末端。然而,由宿主细胞生成的抗体可能经历翻译后切割,自重链的C端切除一个或多个,特别是一个或两个氨基酸。因此,通过表达编码全长重链的特定核酸分子由宿主细胞生成的抗体可包括全长重链,或者它可包括全长重链的切割变体(在本文中也称作“切割变体重链”)。在重链的最终两个C端氨基酸是甘氨酸(G446)和赖氨酸(K447,编号方式依照Kabat EU索引)的情况下可能就是这种情况。因此,Fc区的C端赖氨酸(Lys447),或C端甘氨酸(Gly446)和赖氨酸(K447)可以存在或不存在。除非本文中另外说明,Fc区或恒定区中氨基酸残基的编号方式依照EU编号系统,也称作EU索引,如描述于Kabat et al.,Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,MD,1991(还可参见上文)。如本文中使用的,Fc域的“亚基”指形成二聚体Fc域的两条多肽之一,即构成免疫球蛋白重链中能够稳定自身联合的C端恒定区的多肽。例如,IgG Fc域的亚基包含IgG CH2和IgG CH3恒定域。
如本文中所使用的,在表征抗体时,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法中,优选地在等离振子共振测定法(BIAcore,GE-HealthcareUppsala,Sweden)中抗体对肿瘤抗原的表位的结合。结合亲和力通过术语ka(来自抗体/抗原复合物的抗体的结合速率常数),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,优选地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,优选地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。
如本文中所使用的,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)。
如本文中所使用的,“可变区”(轻链可变区(VL),重链可变区(VH))意为直接牵涉抗体结合抗原的轻链和重链对之每种。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可以形成连接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 et al.,Sequences of Proteins of Immunological Interest,第5版,PublicHealth Service,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同种型的(优选地IgG1同种型的)抗体。在Asn297处发生人IgG1或IgG3的糖基化,作为以多至两个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,如本文中所使用的,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 et al.,Sequences of Proteins of Immunological Interest,第5版,PublicHealth Service,National Institutes of Health,Bethesda,MD(1991)中报告的EU索引,通过提及而将其明确收入本文)。
CD20(又称为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.et al.,J.Biol.Chem.264(1989)11282-11287;Tedder,T.F.et al.,Proc.Natl.Acad.Sci.U.S.A.85(1988)208-212;Stamenkovic,I.et al.,J.Exp.Med.167(1988)1975-1980;Einfeld,D.A.et al.,EMBO J.7(1988)711-717;Tedder,T.F.et al.,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。此初生蛋白质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同一蛋白质的两种转录物变体。
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。可以通过下列一项或多项机制而发生对表达CD20的细胞的杀死: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)可以依照Cragg,M.S.et al.,Blood 103(2004)2738-2743;及Cragg,M.S.et al.,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
I型抗CD20抗体的例子包括例如利妥昔单抗(rituximab)(一种具有85%或更高量的岩藻糖的非无岩藻糖基化抗体),HI47 IgG3(ECACC,杂交瘤),2C6IgG1(如WO 2005/103081中公开的),2F2 IgG1(如WO 2004/035607和WO 2005/103081中公开的),2H7 IgG1(如WO 2004/056312中公开的),ofatumumab,veltuzumab,ocrelizumab,ocaratuzumab,PRO131921和ublituximab.
II型抗CD20抗体的例子包括例如人源化B-Ly1抗体,人源化B-Ly1抗体IgG1(一种嵌合的人源化IgG1抗体,如WO 2005/044859中公开的),奥滨尤妥珠单抗(obinutuzumab),托西莫单抗(tositumumab)(B1),11B8 IgG1(如WO 2004/035607中公开的),和AT80 IgG1。典型地,IgG1同种型的II型抗CD20抗体显示特征性的CDC特性。与IgG1同种型的I型抗体相比,II型抗CD20抗体具有降低的CDC(若为IgG1同种型的话)。
术语“效应器功能”在提及抗体使用时指那些可归于抗体的Fc区的生物学活性,它们随抗体同种型而变化。抗体效应器功能的例子包括:C1q结合和补体依赖性细胞毒性(CDC),Fc受体结合,抗体依赖性细胞介导的细胞毒性(ADCC),抗体依赖性细胞吞噬(ADCP),细胞因子分泌,免疫复合物介导的抗原呈递细胞的抗原摄取,细胞表面受体(例如B细胞受体)的下调,和B细胞活化。
升高的效应器功能可以通过本领域已知的方法来测量。本文中描述了一种合适的用于测量ADCC的测定法。评估感兴趣分子的ADCC活性的体外测定法的其它例子描述于美国专利No.5,500,362;Hellstrom et al.,Proc Natl Acad Sci USA 83,7059-7063(1986);Hellstrom et al.,Proc Natl Acad Sci USA82,1499-1502(1985);美国专利No.5,821,337;和Bruggemann et al.,J Exp Med 166,1351-1361(1987)。或者,可以采用非放射活性测定法方法(参见例如用于流式细胞术的ACTITM非放射活性细胞毒性测定法(CellTechnology,Inc.,Mountain View,CA);和CytoTox 非放射活性细胞毒性测定法(Promega,Madison,WI))。对于此类测定法有用的效应细胞包括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。或者/另外,可以在体内评估感兴趣分子的ADCC活性,例如在动物模型中,诸如公开于Clynes et al.,Proc Natl Acad Sci USA 95,652-656(1998)。对Fc受体的结合可以例如通过ELISA或通过使用标准仪器,诸如BIAcore仪器(GE Healthcare)的表面等离振子共振(SPR)来容易地测定,而Fc受体可以诸如通过重组表达来获得。依照一个特定的实施方案,对活化性Fc受体的结合亲和力于25℃使用T100机器(GEHealthcare)通过表面等离振子共振测量。或者,抗体对Fc受体的结合亲和力可以使用已知表达特定Fc受体的细胞系来评估,诸如表达FcγIIIa受体的NK细胞。也可以进行C1q结合测定法以确定抗体是否能够结合C1q且因此具有CDC活性。参见例如WO 2006/029879和WO2005/100402中的C1q和C3c结合ELISA。为了评估补体活化,可以实施CDC测定法(参见例如Gazzano-Santoro et al.,J Immunol Methods 202,163(1996);Cragg et al.,Blood101,1045-1052(2003);和Cragg and Glennie,Blood 103,2738-2743(2004))。
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自4000ng/ml连续稀释至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细胞: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溶解的百分比,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。
可以通过所述抗体的糖工程化来获得“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.etal.,Nature Biotechnol.17(1999)176-180及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溶解。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%或更多的肿瘤细胞溶解(细胞死亡),则发现CDC。优选地,用经51Cr或Eu标记的肿瘤细胞及释放的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。
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.and 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WO2007/031875中。
依照本发明的术语“BET抑制剂”指以约0.001μM至约2μM的IC50阻止BET蛋白活性的药剂。
依照本发明的术语“Bcl-2抑制剂”指以约0.001μM至约2μM的IC50阻止Bcl-2蛋白活性的药剂。
“盐”指化合物作为药学可接受盐的盐。此类盐例如与碱金属(钾,钠,等等)的盐,与碱土金属(钙,镁,等等)的盐,铵盐,与药学可接受有机胺的盐(四甲基胺,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,等等),和酸加成盐(无机酸盐(氢氯化物,氢溴化物,氢碘化物,硫酸盐,磷酸盐,硝酸盐,等等)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/反式丁烯二酸盐,马来酸盐/顺式丁烯二酸盐,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,羟乙磺酸盐,葡糖醛酸盐,葡萄糖酸盐,等等))。
“IC50”指抑制50%的特定测量活性所需要的特定化合物的浓度。
寡糖组分可以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,药动学,和特定(specific)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。可以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,而其它寡糖结构可以被抗体结合,并触发不想要的免疫反应(Jenkins,N.et al.,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质的能力,它是用于生成治疗性糖蛋白的卓越的宿主(Cumming,D.A.et al.,Glycobiology 1(1991)115-130;Jenkins,N.et al.,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,不想要的免疫相互作用,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国仓鼠卵巢(CHO)细胞。在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。它们可以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。新近,还已经测试了自转基因动物的生成(Jenkins,N.et al.,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,其中每种同种型拥有独特的一批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.and 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,并且可以包括高甘露糖的,多分支的及双触角的复合寡糖(Wright,A.and 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形存在。同样地,已经显示了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.et al.,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,不想要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.et al.,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使用的抗体)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.et al.,Glycobiology 5(1995)813-822;Jefferis,R.et al.,Immunol.Rev.163(1998)59-76;Wright,A.and Morrison,S.L.,Trends Biotechnol.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)在中国仓鼠卵巢(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.et al.,Nature Biotechnol.17(1999)176-180;及WO 99/154342,在此通过提及而收录其全部内容)。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少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.etal.,Nature Biotechnol.17(1999)176-180)。所述研究第一次显示了可以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找到的水平。
术语“治疗方法”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”或“共施用”指在一种或几种配制剂中施用依照本发明的BET抑制剂,Bcl-2抑制剂和抗CD20抗体。共施用可以是同时的或者以任意次序顺序的,其中优选地,存在着两种(或所有)活性剂同时施加其生物学活性的时段。在顺序共施用三种治疗剂时,可以例如在同一天在三次分开的施用中施用所有药剂,或者可以在第1天施用药剂之一,而且可以在第2天至第7天,或者在第2天至第4天共施用第二种和第三种。如此,在一个实施方案中,术语“顺序地”意指在第一组分的剂量后7天或4天内;而术语“同时地”意指同一时间或同一天。术语“共施用”就抗CD20抗体,Bcl-2抑制剂和BET抑制剂的维持剂量而言意指若治疗周期对于所有药物都是合适的,例如每周,则可以同时共施用维持剂量。或者,例如,可以每第一至第三天施用Bcl-2抑制剂和BET抑制剂,而且可以每周施用抗CD20抗体。或者,在一天内或在几天内顺序共施用维持剂量。
不证自明的是,以“治疗有效量”(或仅为“有效量”)对患者施用抗体和抑制剂,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。
BET抑制剂,Bcl-2抑制剂和抗CD20抗体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。
优选地皮下施用BET抑制剂。
优选地以介于约0.3mg/kg/d和约0.65mg/kg/d之间的剂量施用BET抑制剂。
优选地每3周连续14天(即给药2周,停药1周)每天施用BET抑制剂。
优选地以介于约0.3mg/kg/d和约0.65mg/kg/d之间的剂量皮下施用BET抑制剂。
优选地每3周连续14天(即给药2周,停药1周)以介于约0.3mg/kg/d和约0.65mg/kg/d之间的剂量皮下施用BET抑制剂。
优选地BET抑制剂是RG6146。
BET抑制剂,特别是RG6146的施用可以中断长达3周,即1,2或3周。
优选地口服施用Bcl-2抑制剂。
优选地以介于约400mg/d至约800mg/d之间的剂量施用Bcl-2抑制剂。
优选地以介于约400mg/d和约800mg/d之间的剂量口服施用Bcl-2抑制剂。
优选地每天(即每日)施用Bcl-2抑制剂。这称作连续施用。
优选地以介于约400mg/d和约800mg/d之间的剂量每天口服施用Bcl-2抑制剂。
优选地Bcl-2抑制剂是维奈托克。
优选地静脉内施用抗CD20抗体。
优选地以约375mg/m2(体表面积剂量给药)的剂量施用抗CD20抗体。
优选地每周(即一周一次)施用抗CD20抗体。
优选地以约375mg/m2(体表面积剂量给药)的剂量静脉内施用抗CD20抗体。
优选地以约375mg/m2(体表面积剂量给药)的剂量每周静脉内施用抗CD20抗体,即约375mg/m2一周一次。
例如,对于平均体型或体表面积的成人,抗CD20抗体的剂量可以是约10mg/kg。
抗CD20抗体优选是利妥昔单抗或奥滨尤妥珠单抗,更加优选是利妥昔单抗。
优选地在同一天启动BET抑制剂,Bcl-2抑制剂和抗CD20抗体的施用周期。
取决于疾病的类型和严重性,可以施用下面的量:约0.3mg/kg/d至约0.65mg/kg/dBET抑制剂,优选RG6146;约400mg/d至约800mg/d Bcl-2抑制剂,优选维奈托克;和约375mg/m2(体表面积剂量给药)抗CD20抗体,优选利妥昔单抗。
一种特别有利的组合是约0.3mg/kg/d至约0.65mg/kg/d BET抑制剂,优选RG6146,每天,每3周连续14天(即给药2周,停药1周);约400mg/d至约800mg/d Bcl-2抑制剂,优选维奈托克,连续(即每日);约375mg/m2(体表面积剂量给药)抗CD20抗体,优选利妥昔单抗,每周(即一周一次)。
又一种特别有利的组合是约0.3mg/kg/d至约0.65mg/kg/d BET抑制剂,优选RG6146,皮下,每天,每3周连续14天(即给药2周,停药1周);约400mg/d至约800mg/d Bcl-2抑制剂,优选维奈托克,口服,连续(即每日);约375mg/m2(体表面积剂量给药)抗CD20抗体,优选利妥昔单抗,静脉内,每周(即一周一次)。
或者,可以如下以6个28天周期施用抗CD20抗体,特别是II型抗CD20抗体,特别是奥滨尤妥珠单抗:周期1第1,8和15天约1000mg;周期2-6第1天约1000mg。
还优选地静脉内施用奥滨尤妥珠单抗。
取决于疾病的类型和严重性,如此还可以施用下面的量:约0.3mg/kg/d至约0.65mg/kg/d BET抑制剂,优选RG6146;约400mg/d至约800mg/d Bcl-2抑制剂,优选维奈托克;和28天周期第1,8和15天约1000mg抗CD20抗体,优选奥滨尤妥珠单抗。
一种特别有利的组合是约0.3mg/kg/d至约0.65mg/kg/d BET抑制剂,优选RG6146,每天,每3周连续14天(即给药2周,停药1周);约400mg/d至约800mg/d Bcl-2抑制剂,优选维奈托克,连续(即每日);周期1(28天周期)第1,8和15天约1000mg抗CD20抗体,优选奥滨尤妥珠单抗和周期2-6(28天周期)第1天约1000mg抗CD20抗体,优选奥滨尤妥珠单抗。
又一种特别有利的组合是约0.3mg/kg/d至约0.65mg/kg/d BET抑制剂,优选RG6146,皮下,每天,每3周连续14天(即给药2周,停药1周);约400mg/d至约800mg/d Bcl-2抑制剂,优选维奈托克,口服,连续(即每日);周期1(28天周期)第1,8和15天约1000mg抗CD20抗体,优选奥滨尤妥珠单抗,皮下和周期2-6(28天周期)第1天约1000mg抗CD20抗体,优选奥滨尤妥珠单抗,皮下。
在上述剂量给药方案中,BET抑制剂,特别是RG6146的施用,可以中断长达3周,即1,2或3周。
在上述剂量给药方案中,Bcl-2抑制剂,特别是维奈托克的施用可以中断长达3周,即1,2或3周。
推荐剂量可以随何时存在有别的共施用化疗剂而变化。
本发明可用于预防或降低患有DLBCL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,本发明可用于提高患者组中的响应率。
在本发明的上下文中,可以使用另外的其它细胞毒剂,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。
此类另外的药剂包括例如: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(leukeran)),顺铂(cisplatin)(CisP;例如),白消安(busulfan)(例如,马利兰(myleran)),美法仑(melphalan),卡莫司汀(carmustine)(BCNU),链脲菌素(streptozotocin),三乙烯三聚氰胺(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(vepesid)),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(Xeloda)),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(adriamycin)),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,诸如帕西他赛(paclitaxel)(例如泰素(taxol))和帕西他赛衍生物,细胞抑制剂,糖皮质激素诸如地塞米松(dexamethasone)(DEX;例如地卡特隆(decadron))和皮质类固醇诸如泼尼松(prednisone),核苷酶抑制剂诸如羟基脲,氨基酸消减酶(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。也可以使用下列药剂作为另外的药剂:氨磷汀(arnifostine)(例如),更生霉素(dactinomycin),双氯乙基甲胺(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(gemzar)),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(taxotere)),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),托泊替康(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),睾内酪(testolactone),硫鸟嘌呤(thioguanine),塞替派(thiotepa),尿嘧啶芥(uracil mustard),长春瑞滨(vinorelbine)或苯丁酸氮芥(chlorambucil)。
上文所描述的细胞毒剂和抗癌剂及抗增殖性靶物特异性抗癌药物,如蛋白质激酶抑制剂在化学疗法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效力及关于控制施用路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以随通过使用组织培养方法测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以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,可以降低多至约一个数量级的浓度或量。如此,实际剂量会取决于内科医生的判断,患者的状况,和治疗方法的效力,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,可以实施有效量的电离辐射和/或可以使用放射性药物。放射源可以是在所治疗的患者外部或内部。在来源在患者外部时,疗法称为外部束放射疗法(EBRT)。在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以选自下组,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。
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,即对靶区域投递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)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10-80Gy的总剂量。在本发明的一个优选的实施方案中,在用本发明的组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(任选地有额外的化学治疗剂或抗癌剂),依靠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WO99/60023中。
如本文中所使用的,“药学可接受载体”或“药学可接受赋形剂”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,涵盖其在本发明的组合物中的使用。也可以将补充性活性化合物掺入组合物中。
可以通过用药学可接受的无机或有机载体或赋形剂加工依照本发明的BET抑制剂,Bcl-2抑制剂和抗CD20抗体来获得药物组合物。可以使用乳糖,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中不需要载体。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,药物组合物可以含有防腐剂,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。它们也可以含有其它治疗上有价值的物质。
可以通过将具有期望纯度的抗体与任选的药学可接受载体,赋形剂或稳定剂(Remington’s Pharmaceutical Sciences第16版,Osol,A.编(1980))混合以冻干配制剂或水溶液形式制备仅抗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;氯化己烷双胺;苯扎氯铵,苄索氯铵;酚,丁醇或苯甲醇;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,诸如血清清蛋白,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,和其它碳水化合物,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,海藻糖或山梨糖醇;成盐反荷离子诸如钠;金属复合物(例如,Zn-蛋白质复合物);和/或非离子型表面活性剂诸如TWEENTM,PLURONICSTM或聚乙二醇(PEG)。
BET抑制剂和Bcl-2抑制剂的药物组合物包括那些适合于口服,鼻,表面(包括含服和舌下),直肠,阴道和/或胃肠外施用的。组合物可以以单位剂量形式方便呈现,并且可以通过药学领域公知的任何方法来制备。可以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,及特定施用模式而有所变化。可以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BET抑制剂和Bcl-2抑制剂的所述量。一般地,在100%里,此量的范围会是约1%至约90%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抑制剂或BET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,可以如下制备药物组合物,即使Bcl-2抑制剂或BET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。适合于口服施用的药物组合物可以为胶囊,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抑制剂或BET抑制剂作为活性成分)的形式。Bcl-2抑制剂或BET抑制剂也可以以推注,药糖剂或糊剂施用。
在本发明的又一些实施方案中,将BET抑制剂,Bcl-2抑制剂和抗CD20抗体以一种,两种或三种分开的药物组合物配制。
活性成分还可以包载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),在胶状药物投递系统中(例如脂质体,清蛋白微球体,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.编(1980)。
可以制备持续释放制剂。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半透性基质,该基质是定型产品的形式,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-乙醇酸共聚物和醋酸亮丙瑞林构成的可注射微球体),及聚-D-(-)-3-羟基丁酸。
要用于体内施用的配制剂必须是无菌的。这容易通过过滤流过无菌滤膜来实现。
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(B-HH2至B-HH9,B-HL8,和B-HL10至B-HL17)的重链可变区(VH)的氨基酸序列
SEQ ID NO:20人源化B-Ly1抗体B-KV1的轻链可变区(VL)的氨基酸序列
实施例
提供下面的实施例和附图以说明本发明,它们不具有限制特征。
实施例1:体内抗肿瘤功效
针对WSU-DLCL2异种移植物(CD20+)评估与Bcl-2抑制剂维奈托克(GDC-0199)和BET抑制剂RG6146组合的CD20特异性抗体奥滨尤妥珠单抗或利妥昔单抗的体内抗肿瘤功效。
测试药剂
作为来自Roche(Basel,Switzerland)的储液提供CD20抗体奥滨尤妥珠单抗或利妥昔单抗。抗体缓冲液包括组氨酸。在注射前自储液在缓冲液中适当稀释抗体溶液。作为来自Roche(Basel,Switzerland)的粉末提供BET抑制剂RG6146并在使用前重悬浮。由Genentech(South San Francisco,USA)提供Bcl-2抑制剂GDC-0199并在使用前配制。
细胞系和培养条件
原始的WSU-DLCL2人B细胞NHL细胞系(DLBCL)购自DSMZ(Braunschweig,Germany)。依照方案由TAP CompacT CellBase细胞培养机器人进行用于移植的肿瘤细胞的扩充。在5%CO2的水饱和气氛中于37℃在RPMI 1640培养基,FCS 10%和L-Glutamin 2mM中例行培养肿瘤细胞系。用胰蛋白酶/EDTA 1x实施培养物传代,每周两次分拆,传代3用于移植。
动物
依照承诺的指导方针以12小时明亮/12小时黑暗的日周期在无特定病原体条件下维持到达时6-7周龄的雌性SCID米色小鼠。实验研究方案得到当地政府的审查和批准。到达后将动物在动物设施中维持一周以适应新环境和进行观察。定期进行连续健康监测。随意提供节食食物和高压灭菌水。
监测
每天控制动物的临床症状和不良反应检测。为了贯穿实验监测,记录动物的体重。
动物的处理
在随机化后当中值肿瘤尺寸为约150mm3时开始图1中展示的动物研究处理。每周一次,在第10,17,24和31天,以10mg/kg,ip,作为单一药剂和组合施用CD20抗体奥滨尤妥珠单抗。在同一天施用相应的媒介。在第10-18,21-25和28-32天以30mg/kg作为单一药剂和组合进行BET抑制剂RG6146 ip处理。最后,在第10-18,21-25和28-32天作为单一药剂和组合以100mg/kg口服给予Bcl-2抑制剂维奈托克(GDC-0199)。
在随机化后当中值肿瘤尺寸为约130mm3时开始图3中展示的研究中的动物处理。每周一次,在第10,17和24天,以10mg/kg,ip,作为单一药剂和组合施用CD20抗体利妥昔单抗。在同一天施用相应的媒介。在第11-17天以30mg/kg作为单一药剂和组合进行BET抑制剂RG6146 ip处理。最后,在第11-17天作为单一药剂和组合以100mg/kg口服给予bcl-2抑制剂维奈托克(GDC-0199)。
抗肿瘤功效
对于图1中显示的研究,用Matrigel将WSU-DLCL2人弥漫性大B细胞淋巴瘤(DLBCL)细胞(CD20+)皮下接种到雌性SCID米色小鼠上。10天后将携带肿瘤的小鼠随机化至指定的研究组且化合物处理启动。用媒介对照,用30mg/kg的BET抑制剂RG6146,用10mg/kg的抗CD20抗体奥滨尤妥珠单抗或用100mg/kg的Bcl-2抑制剂维奈托克(GDC-0199)作为单一药剂处理携带肿瘤的动物。另外,用RG6146和维奈托克,或RG6146和奥滨尤妥珠单抗或奥滨尤妥珠单抗和维奈托克的双重组合处理三个组。最后,一个研究组接受BET抑制剂RG6146,CD20抗体奥滨尤妥珠单抗和Bcl-2抑制剂维奈托克(GDC-0199)的三重组合。结果是,所有作为单一药剂给予的化合物展现显著的针对WSU-DLCL2异种移植物的抗肿瘤功效。更加详细地,用BET抑制剂RG6146处理导致与对照相比46%的针对WSU-DLCL2异种移植物的肿瘤生长抑制(TGI)。在用Bcl-2抑制剂维奈托克处理后注意到相似的功效(49%TGI),而用抗CD20抗体奥滨尤妥珠单抗处理后实现作为单一药剂最强的功效(TGI84%)。然而,对包括BET抑制剂RG6146加CD20抗体奥滨尤妥珠单抗加Bcl-2抑制剂维奈托克的三重组合组观察到卓越的功效。更加详细地,三重组合办法实质性诱导肿瘤消退,其达到最终75%及22%完全肿瘤缓解。与此对比,相应的双重组合研究臂效率较低且转化为肿瘤停滞(TGI约100%)。值得注意地,在研究随访中,在处理中止后,在40天后对三重组合观察到肿瘤再生长的实质性2倍延迟。与此对比,相应的双重组合方案在约20天后达到肿瘤再生长。
结果在图1-2和表2-4中显示。
表2:RG6146,维奈托克和奥滨尤妥珠单抗的功效(第10-50天)
表2列出图1中绘图的中值肿瘤体积数据。
表3:RG6146,维奈托克和奥滨尤妥珠单抗的功效(第36天)
TCR:处理对对照比;pTCR:非参数肿瘤对照比;CI:置信区间
表4:肿瘤生长延迟(直至第10-50天)
*肿瘤生长延迟是直至相对肿瘤体积再次达到100%(第10天,开始时100%)的时间(天数)。
表5:RG6146,维奈托克和利妥昔单抗的功效(第11-28天)
表5列出图3中绘图的中值肿瘤体积数据。
表6:RG6146,维奈托克和利妥昔单抗的功效(第28天)
TCR:处理对对照比;pTCR:非参数肿瘤对照比;CI:置信区间
如本文中公开的且也附在序列表中,下面的序列是本发明的一部分:
序列
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
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
鼠单克隆抗CD20抗体B-Ly1的轻链可变区(VL)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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 I le 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)的重链可变区(VH)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 I le 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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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 I le 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)的重链可变区(VH)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)的重链可变区(VH)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)的重链可变区(VH)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的轻链可变区(VL)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> 豪夫迈·罗氏有限公司(F. Hoffmann-La Roche Ltd.)
<120> 用BET抑制剂, Bcl-2抑制剂和抗CD20抗体的组合疗法
<130> P34351
<160> 20
<170> PatentIn version 3.5
<210> 1
<211> 112
<212> PRT
<213> 人
<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> 人
<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
<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
<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
<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
<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
<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
<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
<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
<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
<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
<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
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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
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Thr Leu Val Thr Val Ser Ser
115
<210> 13
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
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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
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Thr Leu Val Thr Val Ser Ser
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<210> 14
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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
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Thr Leu Val Thr Val Ser Ser
115
<210> 15
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly
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Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
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Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
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Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
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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
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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115
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<211> 119
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<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
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Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
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Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
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Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
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Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
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Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
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Arg Thr Val
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Claims (22)
1.供作为药物使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体。
2.供在DLBCL的治疗中使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体。
3.供依照权利要求1或2使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该BET抑制剂是2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫杂-5,7,8,9a-四氮杂-环戊并[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙酰胺(RG6146)。
4.供依照权利要求1至3任一项使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该Bcl-2抑制剂是维奈托克(venetoclax)。
5.供依照权利要求1至4任一项使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该抗CD20抗体是I型抗CD20抗体,或其中Fc区中至少40%的N连接的寡糖是非岩藻糖基化的II型抗CD20抗体。
6.供依照权利要求5使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该II型抗CD20抗体是人源化B-Ly1抗体。
7.供依照权利要求5或6使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该II型抗CD20抗体是奥滨尤妥珠单抗(obinutuzumab)。
8.供依照权利要求5使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,其中该I型抗CD20抗体是利妥昔单抗(rituximab)。
9.供依照权利要求1至8任一项使用的BET抑制剂,Bcl-2抑制剂和抗CD20抗体,包含一种或多种另外的其它细胞毒剂,化疗剂或抗癌剂。
10.一种药学组合物,其包含BET抑制剂,Bcl-2抑制剂和抗CD20抗体和一种或多种药学可接受赋形剂。
11.BET抑制剂,Bcl-2抑制剂和抗CD20抗体制造用于治疗DLBCL的药物的用途。
12.BET抑制剂,Bcl-2抑制剂和抗CD20抗体用于治疗DLBCL的用途。
13.一种治疗DLBCL的方法,其包括将BET抑制剂,Bcl-2抑制剂和抗CD20抗体施用于有需要的患者。
14.一种试剂盒,其包含BET抑制剂,Bcl-2抑制剂和抗CD20抗体,用于同时,分开或顺序施用所述BET抑制剂,Bcl-2抑制剂和抗CD20抗体。
15.依照权利要求15的试剂盒,其用于DLBCL的治疗。
16.依照权利要求11至16任一项的药学组合物,用途,方法或试剂盒,其中该BET抑制剂是2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫杂-5,7,8,9a-四氮杂-环戊并[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙酰胺(RG6146)。
17.依照权利要求11至17任一项的药学组合物,用途,方法或试剂盒,其中该Bcl-2抑制剂是维奈托克。
18.依照权利要求11至18任一项的药学组合物,用途,方法或试剂盒,其中该抗CD20抗体是I型抗CD20抗体,或其中Fc区中至少40%的N连接的寡糖是非岩藻糖基化的II型抗CD20抗体。
19.依照权利要求19的药学组合物,用途,方法或试剂盒,其中该II型抗CD20抗体是人源化B-Ly1抗体。
20.依照权利要求19的药学组合物,用途,方法或试剂盒,其中该II型抗CD20抗体是奥滨尤妥珠单抗。
21.依照权利要求19的药学组合物,用途,方法或试剂盒,其中该I型抗CD20抗体是利妥昔单抗。
22.说明书中描述的发明。
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US201762537127P | 2017-07-26 | 2017-07-26 | |
US62/537,127 | 2017-07-26 | ||
PCT/EP2018/070001 WO2019020606A1 (en) | 2017-07-26 | 2018-07-24 | POLYTHERAPY WITH BET INHIBITOR, BCL-2 INHIBITOR AND ANTI-CD20 ANTIBODY |
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CN110869391A true CN110869391A (zh) | 2020-03-06 |
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US (1) | US20200237905A1 (zh) |
EP (1) | EP3658584A1 (zh) |
JP (1) | JP2020528061A (zh) |
CN (1) | CN110869391A (zh) |
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CA3137454A1 (en) * | 2019-04-29 | 2020-11-05 | Immunogen, Inc. | Therapeutic combinations comprising anti-cd123 immunoconjugates |
WO2020234445A1 (en) * | 2019-05-23 | 2020-11-26 | F. Hoffmann-La Roche Ag | Combination therapy with a bet inhibitor and a bcl-2 inhibitor |
CA3160417A1 (en) * | 2019-12-06 | 2021-06-10 | Loxo Oncology, Inc. | Dosing of a bruton's tyrosine kinase inhibitor |
CN115427443A (zh) * | 2020-04-24 | 2022-12-02 | 豪夫迈·罗氏有限公司 | 巯基化合物及其衍生物的酶和途径调节 |
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- 2018-07-24 CN CN201880045781.2A patent/CN110869391A/zh active Pending
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US20200237905A1 (en) | 2020-07-30 |
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TW201909900A (zh) | 2019-03-16 |
WO2019020606A1 (en) | 2019-01-31 |
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