CN112424225B - 抗pd-l1抗体及其用途 - Google Patents
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- CN112424225B CN112424225B CN201980023860.8A CN201980023860A CN112424225B CN 112424225 B CN112424225 B CN 112424225B CN 201980023860 A CN201980023860 A CN 201980023860A CN 112424225 B CN112424225 B CN 112424225B
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Abstract
本公开文本提供了结合T细胞共抑制剂配体程序性死亡配体l(PD‑L1)蛋白的抗体及其使用方法。在本公开文本的各种实施方案中,所述抗体是结合PD‑L1的完全人抗体。在某些实施方案中,本公开文本提供了多特异性抗原结合分子,其包含结合PD‑L1的第一结合特异性和结合肿瘤细胞抗原、感染细胞特异性抗原、或T细胞共抑制剂的第二结合特异性。在一些实施方案中,本公开文本的抗体可用于抑制或中和PD‑L1活性,从而提供治疗诸如癌症或病毒感染的疾病或障碍的手段。
Description
技术领域
本申请涉及抗PD-L1抗体或其抗原结合片段、编码其的核酸、其治疗组合物、及其用于增强T细胞功能以上调细胞介导的免疫应答以及治疗T细胞功能异常障碍(诸如肿瘤免疫)和治疗癌症的用途。
背景技术
T细胞介导针对抗原的免疫应答的能力需要两种不同的信号传导相互作用(Viglietta,V.等人(2007)Neurotherapeutics 4:666-675;Korman,A.J.等人(2007)Adv.Immunol.90:297-339)。首先,将已排列在抗原呈递细胞(APC)表面上的抗原呈递到抗原特异性天然CD4+ T细胞。这种呈递经由T细胞受体(TCR)递送信号,所述T细胞受体指导T细胞启动对所呈递抗原特异的免疫应答。其次,通过APC与不同T细胞表面分子之间的相互作用介导的各种共刺激和抑制性信号触发T细胞的激活和增殖以及最终它们的抑制。
免疫系统受到共刺激和共抑制性配体和受体的网络的严格控制。这些分子为T细胞激活提供第二信号,并且提供正信号和负信号的平衡网络,以最大化针对感染的免疫应答,同时限制对自身的免疫(Wang,L.等人(Epub 2011年3月7日)J.Exp.Med.208(3):577-92;Lepenies,B.等人(2008)Endocrine,Metabolic&Immune Disorders-Drug Targets 8:279-288)。共刺激信号的例子包括APC的B7.1(CD80)和B7.2(CD86)配体与CD4 T淋巴细胞的CD28和CTLA-4受体之间的结合(Sharpe,A.H.等人(2002)Nature Rev.Immunol.2:116-126;Lindley,P.S.等人(2009)Immunol.Rev.229:307-321)。B7.1或B7.2与CD28的结合刺激T细胞活化,而B7.1或B7.2与CTLA-4的结合抑制这种激活(Dong,C.等人(2003)Immunolog.Res.28(l):39-48;Greenwald,R.J.等人(2005)Ann.Rev.Immunol.23:515-548)。CD28在T细胞表面上组成性表达(Gross,J.等人(1992)J.Immunol.149:380-388),而CTLA-4表达在T细胞激活后快速上调(Linsley,P.等人(1996)Immunity 4:535-543)。
CD28受体的其他配体包括一组相关B7分子,也称为“B7超家族”(Coyle,A.J.等人(2001)Nature Immunol.2(3):203-209;Sharpe,A.H.等人(2002)Nature Rev.Immunol.2:116-126;Collins,M.等人(2005)Genome Biol.6:223.1-223.7;Korman,A.J.等人(2007)Adv.Immunol.90:297-339)。B7超家族的若干成员是已知的,包括B7.1(CD80)、B7.2(CD86)、诱导型共刺激配体(ICOS-L)、程序性死亡-1配体(PD-Ll;B7-H1)、程序性死亡-2配体(PD-L2;B7-DC)、B7-H3、B7-H4和B7-H6(Collins,M.等人(2005)Genome Biol.6:223.1-223.7)。
程序性死亡1(PD-1)蛋白是T细胞调节物的CD28/CTLA-4扩展家族的抑制性成员(Okazaki等人(2002)Curr Opin Immunol 14:391779-82;Bennett等人(2003)J.Immunol.170:711-8)。CD28家族的其他成员包括CD28、CTLA-4、ICOS和BTLA。已经鉴定了PD-1的两种细胞表面糖蛋白配体,即程序性死亡配体1(PD-Ll)和程序性死亡配体2(PD-L2)。已经显示PD-Ll和PD-L2在与PD-1结合后下调T细胞激活和细胞因子分泌(Freeman等人(2000)J Exp Med 192:1027-34;Latchman等人(2001)Nat Immunol 2:261-8;Carter等人(2002)Eur J Immunol 32:634-43;Ohigashi等人(2005)Clin Cancer Res 11:2947-53)。
PD-Ll(也称为分化簇274(CD274)或B7同源物1(B7-H1))是40kDa的1型跨膜蛋白。PD-Ll与在激活的T细胞、B细胞和髓系细胞上存在的其受体PD-1结合,以调控激活或抑制。PD-Ll和PD-L2两者都是与PD-1结合但不与CD28或CTLA-4结合的B7同源物(Blank等人(2005)Cancer Immunol Immunother.54:307-14)。PD-Ll与在T细胞上的其受体PD-1的结合递送抑制IL-2产生和T细胞增殖的TCR介导的激活的信号。所述机制涉及抑制ZAP70磷酸化及其与CD3C的缔合(Sheppard等人(2004)FEB S Lett.574:37-41)。PD-1信号传导会减弱由TCR信号传导产生的PKC-Θ激活环磷酸化,这是转录因子NF-κΒ和AP-1的激活以及IL-2产生所必需的。PD-Ll还结合共刺激分子CD80(B7-1),但不结合CD86(B7-2)(Butte等人(2008)Mol Immunol.45:3567-72)。
已经显示PD-Ll在细胞表面上的表达通过IFN-γ刺激上调。已经在许多癌症(包括人肺癌、卵巢癌和结肠癌以及各种骨髓瘤)中发现了PD-Ll表达,并且通常与不良预后相关联(Iwai等人(2002)PNAS 99:12293-7;Ohigashi等人(2005)Clin Cancer Res 11:2947-53;Okazaki等人(2007)Intern.Immun.19:813-24;Thompson等人(2006)Cancer Res.66:3381-5)。已经表明PD-Ll通过增加抗原特异性T细胞克隆的细胞凋亡而在肿瘤免疫中发挥作用(Dong等人(2002)Nat Med 8:793-800)。还已经表明PD-Ll可能与肠粘膜炎症有关,并且PD-Ll的抑制会抑制与结肠炎相关联的消耗性疾病(Kanai等人(2003)J Immunol 171:4156-63)。
鉴于免疫检查点途径在调节免疫应答中的重要性,需要开发新型试剂来调控免疫抑制蛋白(诸如PD-Ll)的激活,从而导致免疫系统的激活。此类药剂可以用于例如癌症免疫疗法和其他病症(诸如慢性感染)的治疗。
发明内容
本公开文本提供了抗PD-L1抗体,包括编码此类抗体的核酸和含有此类抗体的组合物,及其用于增强T细胞功能以上调细胞介导的免疫应答以及治疗T细胞功能异常障碍(包括感染(例如,急性和慢性)和肿瘤免疫)的用途。
在一方面,本文提供了一种分离的抗体或其抗原结合片段,其包含以下HVR_L1、HVR_L2和/或HRV_L3中的一种或多种,或包含HVR_L1、HVR_L2和HRV_L3中的全部三个(或与其具有至少85%序列同一性的序列):
(1)具有选自以下的氨基酸序列的HVR_L1:
(a)RASQX1X2X3X4X5LA(SEQ ID NO:1),其中:
X1:G S
X2:I V
X3:E G S
X4:K P S
X5:F W Y
(b)RASX1SVDFX2GX3SFLX4(SEQ ID NO:2),其中:
X1:E Q
X2:F H Y
X3:I K
X4:A D
(c)X1ASQX2IPX3FLX4(SEQ ID NO:3),其中:
X1:Q R
X2:D S T
X3:K S T
X4:A N
(d)RASQGX1SX2X3LA(SEQ ID NO:4),其中:
X1:I V
X2:P S
X3:W Y
以及
(e)RASQX1IPSFLN(SEQ ID NO:5),其中:
X1:S T
(2)具有选自以下的氨基酸序列的HVR_L2:
(a)DASX1X2X3X4GX5(SEQ ID NO:6),其中:
X1:N S
X2:L R
X3:A E
X4:S T
X5:I V
(b)AASX1LQSGV(SEQ ID NO:7),其中:
X1:S T
以及
(c)DASNX1X2TGX3(SEQ ID NO:8),其中:
X1:L R
X2:A E
X3:I V
(3)具有选自以下的氨基酸序列的HVR_L3:
(a)YCQQYDX1WPYT(SEQ ID NO:9),其中:
X1:A H S Y
(b)YCQX1YX2SWPRX3FT(SEQ ID NO:10),其中:
X1:H Q
X2:G I S T V
X3:G L Q R V
(c)YCQQYDX1WPYT(SEQ ID NO:11),其中:
X1:A S
以及
(d)YCQHYX1SWPRQFT(SEQ ID NO:12),其中:
X1:I T
在一些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:13-39和94-102的氨基酸序列的HVR_L1、具有选自SEQ ID NO:40-66和103-111的氨基酸序列的HVR_L2、和/或具有选自SEQ ID NO:67-93和112-120的氨基酸序列的HVR_L3。
在某些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:13-39的氨基酸序列的HVR_L1、具有选自SEQ ID NO:40-66的氨基酸序列的HVR_L2、和/或具有选自SEQID NO:67-93的氨基酸序列的HVR_L3。在实施方案中,此类抗体或其片段与人和猴PD-L1具有交叉反应性。
在某些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:94-102的氨基酸序列的HVR_L1、具有选自SEQ ID NO:103-111的氨基酸序列的HVR_L2、和/或具有选自SEQ ID NO:112-120的氨基酸序列的HVR_L3。在实施方案中,此类抗体或其片段与人、猴和小鼠PD-L1具有交叉反应性。
在某些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:121-125的氨基酸序列的VL:
DIQLTQSPSSLSASVGDRVTITCRASQX1X2X3X4X5LAWYQQKPGKAPKLLIYDASX6X7X8X9GX10PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDX11WPYTFGQGTKVEIKR(SEQ ID NO:121),其中:
X1:G S
X2:I V
X3:E G S
X4:K P S
X5:F W Y
X6:N S
X7:L R
X8:A E
X9:S T
X10:I V
X11:A S Y
DIQLTQSPSSLSASVGDRVTITCRASX1SVDFX2GX3SFLX4WYQQKPGKAPKLLIYDASX5X6X7X8GX9PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDX10WPYTFGQGTKVEIKR(SEQ ID NO:122),其中:
X1:E Q
X2:F H Y
X3:I K
X4:A D
X5:N S
X6:L R
X7:A E
X8:S T
X9:I V
X10:A H S Y
DIQLTQSPSSLSASVGDRVTITCX1ASQX2IPX3FLX4WYQQKPGKAPKLLIYAASX5LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQX6YX7SWPRX8FTFGQGTKVEIKR(SEQ ID NO:123),其中:
X1:Q R
X2:D S T
X3:K S T
X4:A N
X5:S T
X6:H Q
X7:G I S T V
X8:G L Q R V
DIQLTQSPSSLSASVGDRVTITCRASQGX1SX2X3LAWYQQKPGKAPKLLIYDASNX4X5TGX6PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDX7WPYTFGQGTKVEIKR(SEQ ID NO:124),其中:
X1:I V
X2:P S
X3:W Y
X4:L R
X5:A E
X6:I V
X7:A S
DIQLTQSPSSLSASVGDRVTITCRASQX1IPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYX2SWPRQFTFGQGTKVEIKR(SEQ ID NO:125),其中:
X1:S T
X2:I T
在一些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:121-122和124的氨基酸序列的VL,所述VL可以与人和猴PD-L1具有交叉反应性。
在一些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:123和125的氨基酸序列的VL,所述VL可以与人、猴和小鼠PD-L1具有交叉反应性。
在各种实施方案中,所述抗体或其片段还可以包含具有选自SEQ ID NO:164和167的氨基酸序列的HVR_H1、具有选自SEQ ID NO:165和168的氨基酸序列的HVR_H2、和/或具有选自SEQ ID NO:166和169的氨基酸序列的HVR_H3。
在一些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:126-127的氨基酸序列的VH。
在一些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:128-163的氨基酸序列的VL。
在一些实施方案中,所述抗体或其片段以如通过表面等离子体共振测量的100nM或更小、优选50nM或更小、更优选10nM或更小的KD结合人PD-L1。
另一方面涉及一种药物组合物,其包含本文公开的抗体或其片段中的一种或多种和药学上可接受的载体。
另一方面涉及一种用于在有需要的受试者中治疗癌症和/或减少肿瘤生长的方法,其包括向所述受试者施用治疗有效量的本文公开的抗体或其片段中的一种或多种。
本文还提供了一种诊断治疗组合物,其包含本文公开的抗体或其片段中的一种或多种和诊断成像剂,其中优选地所述诊断成像剂是放射性核素标记。
另一方面涉及一种用于在有需要的受试者中诊断和治疗癌症的方法,其包括向所述受试者施用有效量的本文公开的诊断治疗组合物。
本文还提供了一种体外检测PD-L1的方法,其包括用多聚甲醛固定细胞,并且用本文公开的抗体或其片段中的一种或多种对所述细胞进行免疫染色。
在某些实施方案中,所述抗体或其抗原结合片段具有与SEQ ID NO:1-169中的一种或多种至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的同一性的序列。
在又另一方面,本文公开的任一种抗体还可以包含人或鼠恒定区。人恒定区可以选自IgG1、IgG2、IgG3和IgG4。在一些实施方案中,人恒定区是IgG1。鼠恒定区可以选自IgG1、IgG2A、IgG2B和IgG3。在一些实施方案中,鼠恒定区是IgG2A。
在另一方面,本文提供了一种分离的抗体或其抗原结合片段,其与选自本文公开的抗PD-L1抗体中的任一种的参考抗体竞争与人PD-L1蛋白结合。在一些实施方案中,所述抗体或片段具有以下特性中的一种或多种:(a)在37℃下以如在表面等离振子体共振测定中测量的小于约310pM的结合解离平衡常数(KD)结合单体PD-L1;(b)在25℃下以在表面等离振子体共振测定中小于约180pM的KD结合单体人PD-L1;(c)在37℃下以如在表面等离振子体共振测定中测量的小于约15pM的KD结合二聚体人PD-L1;以及(d)在25℃下以在表面等离振子体共振测定中小于约8pM的KD结合二聚体人PD-L1。
在又另一方面,提供了编码本文公开的任一种序列的核酸。所述核酸还可以包含适用于表达编码先前描述的任一种抗PD-L1抗体的核酸的载体。在一些实施方案中,所述载体与适用于表达核酸的宿主细胞一起提供或在所述宿主细胞内提供。所述宿主细胞可以是真核细胞或原核细胞。在一些实施方案中,真核细胞是哺乳动物细胞,诸如中国仓鼠卵巢(CHO)。
本文还提供了一种双特异性或多特异性抗体或其抗原结合分子或其片段,其包含特异性结合PD-L1的第一抗原结合特异性和特异性结合选自例如以下的抗原的第二抗原结合特异性:肿瘤细胞特异性抗原、对病毒感染的细胞特异性的抗原、和T细胞共抑制剂。肿瘤细胞特异性抗原可以是以下中的一种或多种:CA9、CA125、黑素瘤相关抗原(MAGE)、癌胚抗原(CEA)、波形蛋白、肿瘤-M2-PK、前列腺特异性抗原(PSA)、MART-1、和CA19-9。病毒感染的细胞可以被选自以下中的一种或多种的病毒感染:人免疫缺陷病毒(HIV)、丙型肝炎病毒(HCV)、人乳头瘤病毒(HPV)、淋巴细胞性脉络丛脑膜炎病毒(LCMV)、和猿猴免疫缺陷病毒(SIV)。T细胞共抑制剂可以是以下中的一种或多种:LAG 3、TIM3、B7-1、CTLA-4、BTLA、CD28、2B4、LY108、TIGIT、ICOS、和CD160。在一些实施方案中,双特异性或多特异性抗体可以用于治疗选自以下中的一种或多种的癌症:肾细胞癌、结直肠癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、非小细胞肺癌和黑素瘤。在某些实施方案中,双特异性或多特异性抗体可以用于治疗由选自以下中的一种或多种的病毒引起的病毒感染:HIV、HPV、HBV、HCV、LCMV和SIV。
在又另一方面,本公开文本提供了一种制造抗PD-L1抗体或其抗原结合片段的方法,其包括在适于产生先前描述的抗PD-L1抗体或其抗原结合片段中的任一种的条件下培养含有呈适用于表达的形式的编码此类抗体或片段的核酸的宿主细胞,以及回收所述抗体或片段。
在又另一方面,本公开文本提供了一种抗PD-L1组合物,其包含如本文提供的抗PD-L1抗体或其抗原结合片段(或双特异性或多特异性抗体)和至少一种药学上可接受的载体。
在又另一方面,本发明提供了一种制品,其包括封闭治疗有效量的本文公开的抗PD-L1组合物的容器和指示用于治疗T细胞功能异常障碍的用途的包装插页。
在又另一方面,本公开文本提供了一种制品,其包括以上描述的任一种抗PD-L1组合物与至少一种BNCA分子的组合。在一方面,所述BNCA分子是抗体、抗原结合抗体片段、BNCA寡肽、BNCA RNAi或BNCA小分子。在另一方面,B7负共刺激分子选自:CTLA-4、PD-1、PD-L1、PD-L2、B7.1、B7-H3和B7-H4。
在又另一方面,本文提供了一种制品,其包括以上描述的任一种抗PD-L1组合物与化疗剂的组合。在一个实施方案中,所述化疗剂是吉西他滨。
在又另一方面,本公开文本提供了一种制品,其包括以上描述的任一种抗PD-L1抗体与正共刺激分子的一种或多种激动剂的组合。在一个实施方案中,正共刺激分子是B7家族共刺激分子。在另一个实施方案中,正共刺激分子选自:CD28、CD80、CD86、ICOS/ICOSL。在再另一个实施方案中,正共刺激分子是TNFR家族共刺激分子。在另一个实施方案中,TNFR共刺激分子选自:OX40/OX40L,4-1BB/4-1BBL,CD27/CD27L,CD30/CD30L和HVEM/LIGHT,及其可溶性片段、构建体和激动剂抗体。
在又另一方面,本公开文本提供了一种制品,其包括以上描述的任一种抗PD-L1抗体(或双特异性或多特异性抗体)与一种或多种抗生素的组合。在一方面,所述抗生素选自抗病毒剂、抗细菌剂、抗真菌剂、抗原生动物剂。
在一些实施方案中,所述抗病毒剂选自逆转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂、进入或融合抑制剂、成熟抑制剂、病毒释放抑制剂、免疫应答增强剂、抗病毒协同增强剂、疫苗、肝激动剂和草药疗法。在再另一方面,所述组合包含一种或多种类别的抗病毒剂。
在又另一方面,本公开文本提供了一种制品,其包括以上描述的任一种抗PD-L1抗体(或双特异性或多特异性抗体)以及一种或多种疫苗。
在又另一方面,本公开文本提供了一种增强T细胞功能的方法,其包括施用有效量的以上描述的任一种抗PD-L1抗体或组合物(或双特异性或多特异性抗体)。在一个实施方案中,抗PD-L1抗体或组合物使功能异常的T细胞变得无功能异常。
在又另一方面,本公开文本提供了一种治疗T细胞功能异常障碍的方法,其包括施用治疗有效量的以上描述的任一种抗PD-L1抗体或组合物(或双特异性或多特异性抗体)。在一个特定实施方案中,T细胞功能异常障碍是感染或肿瘤免疫。感染可以是急性或慢性的。在一些实施方案中,慢性感染是持续性的、潜伏性的或缓慢的。在再另一个实施方案中,慢性感染由选自细菌、病毒、真菌和原生动物的病原体引起。在另一个实施方案中,宿主中的病原体水平降低。
在又另一个实施方案中,所述方法还包括用疫苗进行的治疗。在又另一个实施方案中,所述方法还包括用抗生素进行的治疗。在又另一个实施方案中,病原体是细菌,并且所述方法还包括施用抗细菌剂。在又另一个实施方案中,细菌选自:分枝杆菌属(Mycobacterium spp.)、沙门氏菌属(Salmonella spp.)、李斯特菌属(Listeria spp.)、链球菌属(Streptococcus spp.)、嗜血杆菌属(Haemophilus spp.)、奈瑟氏菌属(Neisseriaspp.)、克雷伯氏菌属(Klebsiella spp.)、疏螺旋体属(Borrelia spp.)、脆弱拟杆菌(Bacterioides fragillis)、密螺旋体属(Treponema spp.)和幽门螺杆菌(Helicobacterpylori)。在又另一个实施方案中,病原体是病毒,并且所述方法还包括施用抗病毒剂。在又另一方面,病毒选自:乙型肝炎病毒、丙型肝炎病毒、单纯疱疹病毒-I、单纯疱疹病毒-II、人免疫缺陷病毒-I、人免疫缺陷病毒-II、巨细胞病毒、EB(Eppstein Barr)病毒、人乳头瘤病毒、人噬T淋巴细胞病毒-I、人噬T淋巴细胞病毒-II、水痘带状疱疹病毒。在又另一个实施方案中,病原体是真菌,并且所述方法还包括施用抗真菌剂。在又另一个实施方案中,所述障碍选自:曲霉菌病、芽生菌病、白色念珠菌病、粗球孢子菌病(coccidioiodmycosisimmitis)、组织胞浆菌病、类球孢子菌病(paracoccidioiomycosis)、微孢子虫病。在又另一个实施方案中,病原体是原生动物,并且所述方法还包括施用抗原生动物剂。在又另一个实施方案中,所述障碍选自:利什曼病、疟原虫病(即,疟疾)、隐孢子虫病、弓形虫病、锥虫病、和蠕虫(helminth)感染,包括由吸虫(例如,血吸虫病)、绦虫(例如,包虫病)和线虫(例如,旋毛虫病(trchinosis)、蛔虫病(ascariasis)、丝虫病(filariosis)和类圆线虫病(strongylodiosis))引起的那些。
在又另一方面,T细胞功能异常障碍是肿瘤免疫。在又另一个实施方案中,将PD-L1抗体或组合物与治疗方案组合,所述治疗方案还包括选自以下的传统疗法:放射疗法、化疗、靶向疗法、免疫疗法、激素疗法、血管生成抑制和姑息疗护。在又另一个特定实施方案中,化疗选自:吉西他滨、环磷酰胺、阿霉素、紫杉醇、顺铂。在又另一个特定实施方案中,肿瘤免疫由选自以下的癌症产生:乳腺癌、肺癌、结肠癌、卵巢癌、黑素瘤、膀胱癌、肾癌、肝癌、唾液腺癌、胃癌(stomach cancer)、胶质瘤、甲状腺癌、胸腺癌、上皮癌、头颈癌、胃癌(gastric cancer)和胰腺癌。
本文还提供了一种药物组合物,其包含本文公开的抗PD-L1抗体或其片段、如PCT国际申请号PCT/CN2017/098332(通过引用以其整体并入本文)中公开的抗CD137抗体或其抗原结合片段以及药学上可接受的载体。抗CD137抗体或其片段可以包含以下HVR_H1、HVR_H2、HVR_H3、HVR_L1、HVR_L2和/或HRV_L3:
(1)具有选自以下的氨基酸序列的HVR_H1:
(a)X1TFX2X3YX4IHWV(SEQ ID NO.:172),其中:
X1:F或Y
X2:S或T
X3:G或N或S
X4:A或G或W
其中优选地X2是S和/或X4是W;
(b)YSIX1SGX2X3WX4WI(SEQ ID NO.:173),其中:
X1:S或T
X2:H或Y
X3:H或Y
X4:A或D或G或N或S或T
其中优选地X4是A、D、G、N或S;以及
(c)FSLSTX1GVX2VX3WI(SEQ ID NO.:174),其中:
X1:G或S
X2:A或G
X3:A或G或S或T
其中优选地X3是A或G或S;
(2)具有选自以下的氨基酸序列的HVR_H2:
(a)LALIDWX1X2DKX3YSX4SLKSRL(SEQ ID NO.:175),其中:
X1:A或D或Y
X2:D或G
X3:R或S或Y
X4:P或T;
(b)IGX1IYHSGX2TYYX3PSLKSRV(SEQ ID NO.:176),其中:
X1:D或E
X2:N或S
X3:N或S;以及
(c)VSX1ISGX2GX3X4TYYADSVKGRF(SEQ ID NO.:177),其中:
X1:A或G或S或V或Y
X2:A或D或S或Y
X3:D或G或S
X4:S或T
其中优选地X1是G或S或V或Y;
(3)具有氨基酸序列ARX1GX2X3X4VX5GDWFX6Y(SEQ ID NO.:178)的HVR_H3,其中:
X1:E或G
X2:E或S
X3:D或T
X4:A或T或V
X5:A或I或L或T或V
X6:A或D或G;
(4)具有氨基酸序列X1ASQX2X3X4X5X6X7X8(SEQ ID NO.:179)的HVR_L1,其中:
X1:Q或R
X2:D或G或S
X3:I或V
X4:G或R或S或T
X5:P或R或S或T
X6:A或D或F或S或V或Y
X7:L或V
X8:A或G或N
其中优选地X6是A或F或S或V或Y和/或X8是A或G;
(5)具有氨基酸序列X1ASX2X3X4X5GX6(SEQ ID NO.:180)的HVR_L2,其中:
X1:A或D
X2:N或S或T
X3:L或R
X4:A或E或Q
X5:S或T
X6:I或V
其中优选地X2是N或S;
(6)具有选自以下的氨基酸序列的HVR_L3:
(a)YCQQX1YX2X3X4T(SEQ ID NO.:181),其中:
X1:A或G或S或Y
X2:Q或S或Y
X3:I或L或T或Y
X4:I或S或V或W;
其中优选地:
X1:A或G
X2:S或Y
X3:I或L或T
X4是W;以及
(b)YCX1QX2X3X4X5PX6T(SEQ ID NO.:182),其中:
X1:E或Q
X2:P或S或Y
X3:D或L或S或T或Y
X4:D或E或H或S或T
X5:D或L或T或W
X6:L或P或R或V。
另一方面涉及一种用于在有需要的受试者中治疗癌症和/或减少肿瘤生长的方法,其包括向所述受试者施用治疗有效量的本文公开的抗PD-L1抗体或其片段和以上提及的抗CD137抗体或其抗原结合片段。
附图说明
图1示出了针对在哺乳动物细胞表面上表达的人、猴和小鼠PD-L1的示例性抗体的基于流式细胞术的结合测定。它还示出了示例性抗体对PD-L1的结合特异性,但对如图顶部所指示的其他免疫检查点分子没有特异性。
图2通过基于流式细胞术的测定示出了示例性抗体完全阻断PD-L1与其配体PD1的结合。
图3通过BLI测定示出了示例性抗体完全阻断PD-L1与其配体PD1的结合。
图4通过ELISA测定示出了示例性抗体完全阻断PD-L1与其配体PD1的结合。
图5示出了一种示例性抗体TY21421以约1nM的EC50与在哺乳动物细胞表面上表达的人PD-L1结合。
图6示出了一种示例性抗体TY21421与用多聚甲醛固定的细胞表面PD-L1结合。
图7示出了一种示例性抗体TY21421在Promega PD1/PD-L1报告基因测定中是有效的。
图8示出了在DC-MLR测定中示例性抗体刺激DC-CD4+ T细胞释放IFN-γ。
图9示出了在MLR测定中一种示例性抗体TY21421有效刺激IL2和IFN-γ释放。
图10示出了相比于参考抗体Tecentriq,一种示例性抗体TY21421具有ADCC作用。
图11示出了两种示例性交叉反应性抗体在H22小鼠肝癌模型中的抗肿瘤功效。
图12示出了两种示例性交叉反应性抗体在MC38小鼠结肠癌模型中的抗肿瘤功效。
图13示出了TY21421和交叉反应性抗CD137抗体的组合在LL/2小鼠肺癌模型中的增强的抗肿瘤功效。
图14示出了TY21421和交叉反应性抗CD137抗体的组合在3LL小鼠肺癌模型中的增强的抗肿瘤功效。
图15示出了64Cu-TY21421在具有MC38异种移植物的小鼠中的PET/CT成像和生物分布分析。(A)在注射64Cu-TY21421后0.5小时、12小时、24小时、36小时、48小时和62小时处具有MC38异种移植物的小鼠的代表性PET/CT图像。(B)在注射后0.5小时、12小时、24小时、36小时、48小时和62小时处小鼠肿瘤、肝脏、肌肉、脑和肺中64Cu-TY21421摄取的平均时程(n=4)。(C)在注射后12h、24h和48h处64Cu-TY21421摄取的平均(n=3)生物分布和时程。
图16示出了在评定不同肿瘤中的PD-L1表达水平中传统PET探针18F-FDG与PD-L1特异性探针64Cu-TY21421之间的比较。(A)携带MC38和4T1异种移植物的小鼠中18F-FDG和64Cu-TY21421的代表性PET图像。(B)在NU/NU小鼠中的MC38和4T1肿瘤中18F-FDG和64Cu-TY21421的平均(n=4)摄取。
图17示出了在注射后12小时携带BGC823和U87MG肿瘤异种移植物的Nu/Nu小鼠中64Cu-TY21421的微PET成像。F
具体实施方式
除非另有指示,否则本公开文本的实践将采用分子生物学(包括重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术,所述技术都在本领域的技术范围内。此类技术在诸如以下的文献中充分解释:Molecular Cloning:A Laboratory Manual,第二版(Sambrook等人,1989);Oligonucleotide Synthesis(M.J.Gait编,1984);Animal CellCulture(R.I.Freshney编,1987);Methods in Enzymology(Academic Press,Inc.);Current Protocols in Molecular Biology(F.M.Ausubel等人编1987,和定期更新);PCR:The Polymerase Chain Reaction,(Mullis等人编,1994);A Practical Guide toMolecular Cloning(Perbal Bernard V.,1988);Phage Display:A Laboratory Manual(Barbas等人,2001)。
宿主免疫的机制,包括淋巴细胞发育和激活、T细胞及其功能、免疫应答、免疫球蛋白超家族的共刺激(包括B7.1(CD80)/B7.2(CD86)-CD28/CTLA-4(CD152)T细胞共刺激途径、ICOS/ICOSL信号传导、PD-1途径等)和TNFR家族共刺激剂综述于美国专利号8,217,419的第11-24栏中,将所述专利通过引用以其整体并入。程序性死亡-1/程序性死亡配体-1(PD-1/PD-L1)途径及其在癌症疗法中的影响由例如以下文献综述:Ohaegbulam等人,Humancancer immunotherapy with antibodies to the PD-1and PD-L1 pathway,Trends inMolecular Medicine,第21卷,第1期,第24-33页,2015年1月(DOI:dx.doi.org/10.1016/j.molmed.2014.10.009)和Dolan等人,PD-1Pathway Inhibitors:Changing theLandscape of Cancer Immunotherapy,Cancer Control,2014年7月,第21卷,第3期,第231-237页,将所述参考文献通过引用以其整体并入。
在一方面,本公开文本提供了抗PD-L1抗体,使得对通过PD-L1进行的信号传导的拮抗(包括阻断PD-L1与PD-1相互作用,从而防止PD-L1向T细胞和其他抗原呈递细胞发送负共刺激信号)可能响应于感染(例如,急性和慢性)和肿瘤免疫而增强免疫力。此外,本公开文本的抗PD-L1抗体可以与PD-1:PD-L1信号传导的其他组分的拮抗剂,例如抗PD-1和抗PD-L2抗体组合。
定义
为方便起见,在此收集了在说明书、实施例和所附权利要求中使用的某些术语。除非另外定义,否则本文所用的全部技术和科学术语具有与本公开文本所属领域的普通技术人员通常所理解的相同的含义。
如本文所用,以下术语和短语旨在具有以下含义:
本文使用的冠词“一个/种”(“a”和“an”)是指一个/种或多于一个/种(即,至少一个/种)所述冠词的语法宾语。通过举例的方式,“元件”意指一个元件或多于一个元件。
如本文所用,术语“约”意指本技术领域技术人员容易知道的相应值的普通误差范围,例如,在20%内、更优选在10%内、并且最优选在5%内。
术语“诊断治疗剂”是指将诊断和治疗能力组合的双功能剂。例如,诊断治疗剂可以将疗法和诊断成像的方式组合起来。在某些实施方案中,本文描述的诊断治疗剂在相同剂量中同时递送治疗药物和诊断成像剂。通过将这些特征组合在一种药物中,诊断治疗剂可以克服当前在不同的成像剂与治疗剂之间存在的生物分布和选择性方面不希望的差异。此外,在此方面,本公开文本的诊断治疗剂使医师能够在一个包装中对癌症进行成像并且监测肿瘤、递送动力学和治疗药物的有效性,并且由此对疗法及其对个体患者的剂量进行微调。在一些实施方案中,诊断治疗剂可以是放射性核素标记的药剂(例如,本文公开的抗体),其具体地允许诊断受试者的疾病(例如,癌症)并且然后使用相同或紧密相关的药剂来治疗所述疾病。
在免疫功能异常的背景下,“功能异常”是指免疫对抗原刺激的应答性降低的状态。所述术语包括可能发生抗原识别的耗竭和/或无能两者的共同要素,但随后的免疫应答对控制感染或肿瘤生长是无效的。
“T细胞功能异常障碍”是特征在于对抗原刺激的应答性降低的T细胞的障碍或病症。在一个具体实施方案中,T细胞功能异常障碍是与通过PD-1进行的信号传导的不适当增加特别相关联的障碍。在另一个实施方案中,T细胞功能异常障碍是其中T细胞是无能的或具有降低的分泌细胞因子、增殖或执行细胞溶解活性的能力的障碍。在一个特定方面,降低的应答性导致对表达免疫原的病原体或肿瘤的控制无效。特征在于T细胞功能异常的T细胞功能异常障碍的例子包括未解决的急性感染、慢性感染和肿瘤免疫。
“增强T细胞功能”意指诱导、导致或刺激T细胞以具有持续或扩大的生物功能,或者更新或重新激活耗竭或失活的T细胞。增强T细胞功能的例子包括:相对于干预之前的此类水平,从CD8+ T细胞分泌γ-干扰素增加、增殖增加、抗原应答性(例如,病毒或病原体清除)增加。在一个实施方案中,增强水平为至少50%,可替代地60%、70%、80%、90%、100%、120%、150%、200%。测量这种增强的方式是本领域普通技术人员已知的。
“慢性感染”是指其中感染因子(例如,病原体,诸如病毒、细菌、原生动物寄生虫、真菌等)已在感染宿主中诱导免疫应答但在急性感染期间尚未从此宿主清除或消除的感染。慢性感染可以是持续性的、潜伏性的或缓慢的。虽然急性感染典型地在几天或几周内被免疫系统解决(例如,流感),但持续性感染可能在相对低的水平下持续数月、数年、数十年或一生(例如,乙型肝炎)。相比之下,潜伏性感染的特征在于长期无症状活性,其被一段时间的快速增加的高级别感染和升高的病原体水平不时打断(例如,单纯疱疹)。最后,缓慢感染是特征在于以下的感染:疾病症状的逐渐且连续增加,诸如长期潜伏,接着在临床症状发作之后开始延长和渐进的临床过程。与潜伏性感染和持续性感染不同,缓慢感染可能不以病毒增殖的急性期开始(例如,小核糖核酸病毒感染、绵羊脱髓鞘性脑蛋白炎病(visnavirus)、羊痒病、克-雅氏病)。能够诱导慢性感染的示例性感染因子包括病毒(例如,巨细胞病毒、EB病毒、乙型肝炎病毒、丙型肝炎病毒、I型和II型单纯疱疹病毒、1型和2型人免疫缺陷病毒、人乳头瘤病毒、1型和2型人嗜T淋巴细胞病毒、水痘带状疱疹病毒等)、细菌(例如,结核分枝杆菌、李斯特菌属、肺炎克雷伯氏菌、肺炎链球菌、金黄色葡萄球菌、疏螺旋体属、幽门螺杆菌等)、原生动物寄生虫(例如,利什曼原虫属(Leishmania spp.)、恶性疟原虫(Plasmodium falciparum)、血吸虫属(Schistosoma spp.)、弓形虫属(Toxoplasmaspp.)、锥虫属(Trypanosoma spp.)、Taenia carssiceps等)和真菌(例如,曲霉属(Aspergillus spp.)、白色念珠菌(Candida albicans)、粗球孢子菌(Coccidioidesimmitis)、荚膜组织胞浆菌(Histoplasma capsulatum)、卡氏肺孢子虫(Pneumocystiscarinii)等)。另外的感染因子包括朊病毒或错误折叠蛋白,其通过在这些组织中进一步传播蛋白质错误折叠而影响大脑或神经元结构,导致形成淀粉样斑块,所述淀粉样斑块引起细胞死亡、组织损伤和最终死亡。由朊病毒感染引起的疾病的例子包括:克-雅氏病及其变种、Gerstmann-Straussler-Scheinker综合征(GSS)、致命性家族性失眠(sFI)、库鲁病、羊痒病、牛的牛海绵状脑病(BSE)(又称为“疯牛”病)和各种其他动物形式的脑病[例如,传染性貂脑病(TME),白尾鹿、麋鹿和黑尾鹿的慢性消耗性疾病(CWD),猫海绵状脑病,安氏林羚、大羚羊和扭角林羚的外来有蹄类动物脑病(EUE),鸵鸟的海绵状脑病]。
“肿瘤免疫”是指肿瘤逃避免疫识别和清除的过程。因此,作为治疗性概念,当此类逃避减弱时,肿瘤免疫“得以治疗”,并且肿瘤被免疫系统识别和攻击。肿瘤识别的例子包括肿瘤结合、肿瘤缩小和肿瘤清除。
“B7负共刺激拮抗剂”(“BNCA”)是一种减少、阻断、抑制、废除或干扰由或通过在B7家族成员介导的T淋巴细胞上表达的细胞表面蛋白介导的负共刺激信号的药剂。在一方面,BNCA可以单独或与本公开文本的抗PD-1抗体组合使功能异常的T细胞变得无功能异常。在另一方面,BNCA可以是抑制B7负共刺激分子的核酸或蛋白质合成、表达、信号传导和/或表达后处理的药剂。在再另一方面,BNCA是减少、阻断、抑制、废除或干扰由B7负共刺激分子进行的信号转导的抗体、抗原结合抗体片段、BNCA寡肽、BNCA RNAi或BNCA小分子。示例性B7负共刺激分子包括:CTLA-4、PD-L1、PD-1、B7.1(在T细胞上表达)、PD-L2、B7-H3和B7-H4。
“正共刺激激动剂”是增加、增强、加强或促进由或通过在T淋巴细胞上表达的细胞表面蛋白介导的共刺激信号的分子。在一方面,正共刺激分子可以是激活正共刺激途径的细胞外结构域、可溶性构建体或激动剂抗体。示例性正共刺激分子包括B7超家族分子,例如B7.1、B7.2、CD28和ICOS/ICOSL。另外的例子包括TNFR家族共刺激分子,例如OX40/OX40L、41-BB/41-BBL、CD27/CD27L、CD30/CD30L和HVEM/LIGHT。
“小分子”或“有机小分子”是具有低于约500道尔顿的分子量的分子。
术语“抗生素”包括特异性抑制或扼除微生物(诸如病毒、细菌、真菌或原生动物)的生长,但在所施用的浓度和给药间隔下对宿主无致命性的任何分子。如本文所用,术语抗生素包括抗细菌剂、抗病毒剂、抗真菌剂和抗原生动物剂。在一个特定方面,抗生素在所施用的浓度和给药间隔下对宿主无毒。抗细菌抗生素或抗细菌剂可以大体上分为杀细菌性(即,直接杀死)或抑细菌性(即,防止分裂)。抗细菌抗生素可以进一步细分为窄谱(即,仅影响一小类细菌子集,例如革兰氏阴性等)或广谱(即,影响广泛的一类)。抗生素的例子包括:(i)氨基糖苷,例如阿米卡星、庆大霉素、卡那霉素、新霉素、奈替米星、链霉素、妥布霉素、巴龙霉素;(ii)安莎霉素,例如格尔德霉素、除莠霉素;(iii)碳头孢烯,例如氯碳头孢;(iv)碳青霉烯,例如ertapenum、多尼培南、亚胺培南/西司他丁、美罗培南;(v)头孢菌素(第一代),例如头孢羟氨苄、头孢唑啉、头孢噻吩、头孢氨苄;(vi)头孢菌素(第二代),例如头孢克洛(ceflaclor)、头孢孟多、头孢西丁、头孢丙烯、头孢呋辛;(vi)头孢菌素(第三代),例如头孢克肟、头孢地尼、头孢托仑、头孢哌酮、头孢噻肟、头孢泊肟、头孢他啶、头孢布烯、头孢唑肟、头孢曲松;(vii)头孢菌素(第四代),例如头孢吡肟;(viii)头孢菌素(第五代),例如头孢吡普(ceftobiprole);(ix)糖肽,例如替考拉宁、万古霉素;(x)大环内酯,例如阿奇霉素(axithromycin)、克拉霉素、地红霉素(dirithromycine)、红霉素、罗红霉素、三乙酰竹桃霉素、泰利霉素、壮观霉素;(xi)单环菌素,例如氨曲南;(xii)青霉素,例如阿莫西林、氨苄青霉素、阿洛西林(axlocillin)、羧苄青霉素、氯唑西林、双氯西林、氟氯西林、美洛西林、甲氧西林、萘夫西林、苯唑西林、青霉素、哌拉西林、替卡西林;(xiii)抗生素多肽,例如杆菌肽、粘菌素、多粘菌素B;(xiv)喹诺酮,例如环丙沙星、依诺沙星、加替沙星、左氧氟沙星、洛美沙星、莫西沙星、诺氟沙星(norfloxacin)、奥氟沙星(orfloxacin)、曲伐沙星;(xv)磺酰胺,例如磺胺米隆、百浪多息、磺胺醋酰、磺胺甲噻二唑、磺胺、柳氮磺吡啶、磺胺异噁唑、甲氧苄啶、甲氧苄啶-磺胺甲噁唑(TMP-SMX);(xvi)四环素,例如去甲金霉素、多西环素、米诺环素、土霉素、四环素;以及(xvii)其他,诸如洒尔佛散(arspenamine)、氯霉素、克林霉素、林可霉素、乙胺丁醇、磷霉素、夫西地酸、呋喃唑酮、异烟肼、利奈唑酮、甲硝唑、莫匹罗星、呋喃妥因、平板霉素、吡嗪酰胺、奎奴普丁/达福普汀、利福平/利福平(rifampin/rifampicin)或替硝唑。
术语“抗病毒剂”包括抑制或扼除病毒的生长、发病和/或存活的任何分子。这包括抗逆转录病毒药物,诸如(1)逆转录酶抑制剂,包括例如:(a)核苷类似物逆转录酶抑制剂(NRTI)(例如,阿昔洛韦/阿昔洛韦(aciclovir/acyclovir)西多福韦、叠氮胸苷/齐多夫定(AZT,/>)、去羟肌苷(ddI,/>扎西他滨(ddC,/>);司他夫定(d4T,/>拉米夫定(3TC,/>);阿巴卡韦恩曲他滨/>溴夫定/>恩替卡韦/>碘苷;viramidine(由Valeant Pharmaceuticals生产的他立韦林(taribavirin))、胞嘧啶核苷类似物聚合酶抑制剂PCI-6130和由Pharmasset/Roche生产的前药变体(例如,R7128);由Merck/Isis Pharmaceuticals生产的核苷类似物抑制剂-MK-0608;(b)核苷酸类似物逆转录酶抑制剂(NtRTI)(例如,泰诺福韦/>阿德福韦/> 福米韦生/>(c)非核苷逆转录酶抑制剂(NNRTI),依法韦仑奈韦拉平/>地拉夫定/>依曲韦林/>洛韦胺;由ViroChem Pharma生产的HCV RNA依赖性RNA聚合酶的非核苷抑制剂VCH-759,由Pfizer生产的HCV聚合酶抑制剂的非核苷抑制剂PF-868554;以及(d)聚合酶抑制剂,包括:由Boehringer Ingelheim生产的丙型肝炎病毒的RNA依赖性RNA聚合酶BILB-1941,由Roche生产的RNA聚合酶抑制剂R1626;由AchillionPharmaceuticals生产的复制酶抑制剂ACH-0137171,R7128-由Roche/Pharmasset生产的聚合酶抑制剂,ABT-333和ABT-072-由Abbott生产的聚合酶抑制剂,由Boehringer Ingelheim生产的BI 207127聚合酶抑制剂,PSI-7851-由Pharmasset生产的聚合酶抑制剂,ANA598-由Anadys Pharmaceuticals生产的聚合酶抑制剂,MK-3281-由Merck生产的聚合酶抑制剂,IDX184-由Idenix生产的聚合酶抑制剂,GSK 625433-由Glaxo Smith Kline生产的聚合酶抑制剂,INX-189-由Inhibitex生产的聚合酶抑制剂,NM283-由Idenix生产的聚合酶抑制剂,HCV796-由Wyeth生产的聚合酶抑制剂,GL60667和GS9190-由Gilead生产的聚合酶抑制剂,由Pfizer生产的PF-00868554 0聚合酶抑制剂,VCH759、VCH916、VX222和VX759-由Virochem生产的聚合酶抑制剂,IDX184和IDX375-由Idenix生成的聚合酶抑制剂,BMS650032-由Bristol Myers Squibb生产的聚合酶抑制剂;(2)蛋白酶抑制剂,包括例如:沙奎那韦/>利托那韦/>茚地那韦奈非那韦/>安普那韦/>洛匹那韦阿扎那韦/>膦沙那韦/>替普那韦(tipranavir)/>达芦那韦/>telapravir(VX-950);由Vertex Pharmaceuticals生产的第二代HCV蛋白酶抑制剂-VX-500和VX-813;由Intermune/Roche生产的NS3/4A蛋白酶抑制剂-ITMN-191/R-7227,波普瑞韦(由Schering-Plough生产的博赛泼维蛋白酶抑制剂-SCH 503034),由Medivir/Tibotec生产的HCV NS3/4A蛋白酶抑制剂-TMC435/TMC435350,由Achillion生产的ACH-1625蛋白酶抑制剂。药品,ACH-806-由Achillion/Gilead生产的蛋白酶抑制剂,BI201335和BILN 2061-由Boehringer Ingelheim生产的蛋白酶抑制剂,SCH 900518/SP900518(那拉匹韦)-由Schering-Plough生产的蛋白酶抑制剂,MK-7009-由Merck生产的蛋白酶抑制剂,BMS-650032、BMS-790052和BMS-791325-由Bristol Myeres Squibb生产的蛋白酶抑制剂,R7227-由Roche生产的蛋白酶抑制剂,PHX1766-由Phenomix生产的蛋白酶抑制剂,AVL-181-由Avila Therapeutics生产的蛋白酶抑制剂,胆绿素(biliverdin),CTS-1027-由Roche Biosciences生产的蛋白酶抑制剂,VX985-由Vertex生产的蛋白酶抑制剂,VCH-759和VCH-917-由Virochem/Vertex生产的蛋白酶抑制剂,IDX-136和316-由Idenix生产的蛋白酶抑制剂,ABT-450-由Abbott生产的蛋白酶抑制剂,VBY 376-由Virobay生产的蛋白酶抑制剂;(3)整合酶抑制剂,包括例如:拉替拉韦/>埃替格韦;(4)核苷类似物/核苷酸类似物抑制剂的组合疗法,立普妥(泰诺福韦+embricitabine+依法韦仑),双汰芝(拉米夫定+齐多夫定),(5)进入或融合抑制剂,包括例如:maraviroc,恩夫韦肽(enfuvirtide),二十二醇(docosanol),抗CD4抗体,抗gp120抗体,抗CCR5抗体,HCV NS5a拮抗剂:(a)由Arrow Therapeutics生产的A-831、A-689和AZD 2836,(b)由Bristol Myers Squibb生产的BMS-790052和BMS-824393,(c)由GlaxoSmith Kline生产的GSK-625433,(d)NS4a拮抗剂ACH-1095;(5)成熟抑制剂,包括例如:bevirimat和vivecon;(6)病毒释放抑制剂,包括例如:扎那米韦/>奥司他韦/>阿比朵尔(arbidol);(7)免疫应答增强剂,包括例如干扰素-α(例如,由Biolex Therapeutics生产的BLX-883和BLX 883CR,由Nautilus Biotech生产的belerofon,由LG Life Sciences生产的长效IFN-α、IFN-αSR,由Flamel Technologies生产的长效IFN-α2b CR和IFN-α2b XL,聚乙二醇化的IFN-α(例如,PEG-IFN-α-2a,PEG-IFN-α2b,/>),IFN-α2b人血清白蛋白融合蛋白);干扰素-β,包括IFN-β-1b/>干扰素-γ,干扰素-λ,聚乙二醇化的干扰素-λ(例如,由ZymoGenetics/Novo Nordisk生产的PEG-rIL-29),干扰素-ω/白细胞II干扰素(例如,Intarcia Therapeutics),toll样受体7激动剂,包括由Anadys Pharmaceuticals生产的咪喹莫特、艾沙托立宾及其前药变体(例如,ANA-975和ANA-971),由Implicit Bioscience生产的oglufanide(IM862,L-Glu-L-Trp-OH)及其脂质或糖基缀合的变体,NOV-205(例如,/>-由Novelos Therapeutics,Inc.生产的肽抗病毒剂/>),由Enzo Biochem生产的抗病毒剂EHC18,γ-D-谷氨酰胺基-L-色氨酸(例如,SCV-07,SciClone Pharmaceuticals/Verta),aloferon(例如,aloferon-1-HGVSGHGQHGVHG,aloferon-2-GVSGHGQHGVHG),由Coley Pharmaceuticals/Actilon生产的TLR-9激动剂CPG 10101;(8)抗病毒协同作用增强剂,即单独具有小的或没有抗病毒特性,但是增强其他抗病毒剂的作用-例如,氯喹啉(choroquine)、葡萄柚汁、羟基脲、来氟米特、麦考酚酸、白藜芦醇、利托那韦(ritonavi);以及其他抗病毒药物,诸如金刚烷胺、依度尿苷、泛昔洛韦/>喷昔洛韦、膦甲酸盐(fascarnet)、膦酰乙酸盐(fosfonet)、更昔洛韦/>加德西(gardasil)、伊巴他滨、immunovir、吗啉胍、nexavir、帕拉米韦(peramivir)、普来可那立、鬼臼毒素、利巴韦林、金刚乙胺、曲氟尿苷、三协唯、曲金刚胺、特鲁瓦达(truvada)、伐昔洛韦、缬更昔洛韦、阿糖腺苷、和干扰素增强剂(诸如由Transition Therapeutics生产的EMZ702,二盐酸组胺);以及(9)各种或未分类的抗病毒剂,诸如:由KeminPharmaceuticals生产的KPE-02003002(青蒿醇(Artenimol)),米托蒽醌-由AntipodeanPharmaceuticals生产的辅酶Q10抗氧化剂激动剂,α-葡糖苷酶I抑制剂(例如,由MigenixPharmaceuticals生产的MX-3253-西戈斯韦(celgosivir),澳粟精胺,糖皮质激素拮抗剂(例如,HCV IRES抑制剂、米非司酮、由VGX Pharmaceuticals生产的VGX-410C),肝激动剂(例如,由Phynova Pharmaceuticals生产的PYN17),源自传统草药疗法的抗病毒剂,例如由Phynova Pharmaceuticals生产的PYN18,半胱天冬酶抑制剂(例如,LB-84451-由LG LifeSciences生产、emricasan-由Pfizer生产的PF-03491390/IDN-6556),通过阻止与亲环蛋白A结合而抑制病毒复制的环孢菌素类似物(例如,由Novartis生产的SDZ NIM 911、由Debiopharm生产的Debio-025)。
术语“抗真菌剂”包括抑制或扼除真菌的生长、发病和/或存活的任何分子。例如,这包括例如(1)聚烯抗真菌药,诸如那他霉素、龟裂杀菌素(rimocidin)、非律平、制霉菌素、两性霉素B、坎底辛(candicin);(2)咪唑,诸如咪康唑、酮康唑益康唑、联苯苄唑、布康唑、芬替康唑、异康唑、奥昔康唑、舍他康唑/>硫康唑、噻康唑;(3)三唑,诸如氟康唑、伊曲康唑、艾沙康唑、雷夫康唑、泊沙康唑、伏立康唑、特康唑;(4)烯丙胺,诸如特比萘芬/>阿莫罗芬、萘替芬/>布替萘芬(LOTRIMIN);(5)棘球白素,诸如阿尼芬净;卡泊芬净;米卡芬净;以及具有抗真菌特性的其他物质,诸如苯甲酸、cicclopix、氟胞嘧啶、灰黄霉素、龙胆紫、卤普罗近、托萘酯 十一烯酸、茶树油-ISO 4730(白千层油,松油烯-4-醇型)、香茅油、柠檬草、橙油、玫瑰草油、绿叶刺蕊草、柠檬姚金娘、印度楝树种子油、椰子油。
术语“抗原生动物剂”或“抗原生动物的药剂”包括抑制或扼除原生动物生物体的生长、发病和/或存活的任何分子。示例性抗原生动物剂包括:(1)抗疟疾剂,例如奎宁(quinine)、quinimax、奎尼丁、quinimax、氯喹羟氯喹阿莫地喹、乙胺嘧啶/>磺胺多辛、氯胍、甲氟喹卤泛群、伯氨喹、青蒿素及其衍生物(例如,蒿甲醚、青蒿琥酯、双氢青蒿素、蒿乙醚)、克林霉素及其组合;(2)蛋白酶抑制剂和以下药物:苄硝唑(benznidaole)、布帕伐醌、卡巴胂、氯碘羟喹、双硫仑、依氟鸟氨酸、依米丁、呋喃唑酮、锑酸葡甲胺、美拉胂醇、甲硝唑/>米替福新、硝呋替莫、硝唑尼特、奥硝唑、硫酸巴龙霉素、喷他脒、乙胺嘧啶/>塞克硝唑、替硝唑。
如本文所用,术语“疫苗”包括当接种到宿主中时针对特定病原体诱导保护性免疫的任何非致病性免疫原。疫苗可以采取许多形式。疫苗可以是与病原体共享重要抗原但本身不致病的完整生物体(例如,牛痘)。疫苗也可以由杀死的疫苗(例如,索尔克(Salk)脊髓灰质炎疫苗)或减毒的疫苗(丧失产生疾病的能力-例如Sabin脊髓灰质炎疫苗)制备。疫苗也可以由从致病生物体分离的纯化大分子制备。例如,含有非活性形式的可溶性细菌毒素的类毒素疫苗(例如,破伤风和白喉)导致产生抗毒素抗体,但对完整细菌没有免疫性。亚单位疫苗(例如,乙型肝炎)仅含有从感兴趣的病原体分离的单一免疫原性蛋白。半抗原缀合疫苗将从感兴趣的病原体中分离的某些碳水化合物或多肽表位附接到免疫原性载体,诸如破伤风类毒素。这些策略基本上使用表位作为半抗原来诱导抗体产生,其然后识别天然病原体中的相同表位。然而,为了最大效力,此类疫苗必须包含B细胞和T细胞的细胞表位,并且必须选择T细胞表位以确保它们可以被识别、呈递并且被宿主个体的免疫系统应答。
可以与抗PD-L1抗体组合用于本文描述的方法的抗病毒疫苗的例子包括:由Pevion Biotech.生产的HCV疫苗(virasome),由Transgene viron设计来增强针对NS3、NS4和NS5B的细胞(细胞毒性T淋巴细胞CD4+和CD8+)免疫应答的TG4040(MVA-HCV,-由Inovio Biomedical生产的密码子优化的NS3/4a DNA疫苗,由Novartis生产的HCV/CpG疫苗,GI-5005-由Globeimmune生产的HCV疫苗,IC41,由Intercell生产的具有HCV CD4和CD8 T表位的合成肽与聚精氨酸组合的混合物。
如果作为与佐剂的混合物来施用,则可以增强宿主对免疫原的应答。免疫佐剂通过以下方式中的一种或多种来发挥作用:(1)延长免疫原的保留时间;(2)增加免疫原的有效尺寸(并且从而促进吞噬作用和向巨噬细胞的呈递);(3)刺激巨噬细胞或其他免疫细胞向注射位点的流入,或(4)促进局部细胞因子产生和其他免疫活性。示例性佐剂包括:完全弗氏佐剂(CFA);铝盐;和分枝杆菌衍生的蛋白质,诸如胞壁酰二肽或三肽。
术语“抗体”包括单克隆抗体(包括具有免疫球蛋白Fc区的全长抗体)、具有多表位特异性的抗体组合物、多特异性抗体(例如,双特异性抗体、双抗体和单链分子)以及抗体片段(例如,Fab、F(ab')2和Fv)。术语“免疫球蛋白”(Ig)在本文中与“抗体”可互换使用。
基本的4链抗体单元是异四聚体的糖蛋白,其由两条相同的轻(L)链和两条相同的重(H)链构成。IgM抗体由5个基本的异四聚体单元连同另外的称为J链的多肽组成,并且含有10个抗原结合位点,而IgA抗体包含2-5个基本的4链单元,其可以聚合以与J链相组合形成多价组合体(assemblage)。在IgG的情况下,4链单元通常为约150,000道尔顿。每条L链通过一个共价二硫键与H链连接,而两条H链通过一个或多个二硫键相互连接,这取决于H链同种型。每条H和L链还具有规则间隔的链内二硫桥键。每条H链在N末端具有可变结构域(VH),随后是每条α和γ链的三个恒定结构域(CH)以及μ和ε同种型的四个CH结构域。每条L链在N末端具有可变结构域(VL),随后是在其另一端的恒定结构域。VL与VH对齐并且CL与重链的首个恒定结构域(CHI)对齐。据信特定的氨基酸残基在轻链与重链可变结构域之间形成界面。VH和VL的配对一起形成单个抗原结合位点。关于不同类别抗体的结构和特性,参见例如Basic and Clinical Immunology,第8版,Daniel P.Sties,Abba I.Terr和TristramG.Parsolw(编),Appleton&Lange,Norwalk,Conn.,1994,第71页和第6章。基于它们恒定结构域的氨基酸序列,可以将来自任何脊椎动物物种的L链分配到两种清楚区分的类型(称为κ和λ)之一。取决于其重链(CH)的恒定结构域的氨基酸序列,可以将免疫球蛋白分配到不同的类别或同种型。存在五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别称为α、δ、ε、γ和μ的重链。基于CH序列和功能的差异相对较小,γ和α类别被进一步分为亚类,例如,人表达以下亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgA2。
“分离的”抗体是已经从其产生环境的组分(例如,天然的或重组的)中鉴定、分离和/或回收的抗体。优选地,分离的多肽不与来自其产生环境的所有其他组分缔合。其产生环境的污染组分(诸如由重组转染细胞产生的组分)是典型地会干扰抗体的研究、诊断或治疗用途的材料,并且可包括酶、激素和其他蛋白质溶质或非蛋白质溶质。在优选的实施方案中,多肽将被纯化:(1)至按重量计大于95%的抗体,如通过例如Lowry方法确定的,并且在一些实施方案中,至按重量计大于99%;(1)至通过使用旋转杯测序仪足以获得N末端或内部氨基酸序列的至少15个残基的程度,或(3)至使用考马斯蓝或优选银染在非还原或还原条件下通过SDS-PAGE测得的同质性。分离的抗体包括重组细胞内的原位抗体,因为抗体的天然环境的至少一种组分将不存在。然而,分离的多肽或抗体通常将通过至少一个纯化步骤来制备。
抗体的“可变区”或“可变结构域”是指抗体重链或轻链的氨基末端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”。这些结构域通常是抗体中最可变的部分(相对于同一类别的其他抗体)并且含有抗原结合位点。在一些实施方案中,轻链可变区是κ型,并且可以被称为“VK”。
术语“可变的”是指可变结构域的某些区段在抗体间的序列差异很大的事实。V结构域介导抗原结合并且限定特定抗体对其特定抗原的特异性。然而,可变性不在可变结构域的整个跨度上均匀地分布。相反,在轻链可变结构域和重链可变结构域两者中,所述可变性均集中在称为高变区(HVR)的三个片段中。可变结构域的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区,主要采用由三个HVR连接的β-折叠构型,所述HVR形成连接β-折叠结构的环并且在一些情况下形成β-折叠结构的一部分。每条链中的HVR通过FR区紧密靠近地保持在一起,并且与来自另一条链的HVR一起有助于抗体的抗原结合位点的形成(参见Kabat等人,Sequences of Immunological Interest,第5版,National Institute of Health,Bethesda,Md.(1991))。虽然恒定结构域并不直接参与抗体与抗原的结合,但是表现出各种效应子功能,诸如抗体参与抗体依赖性细胞毒性。
术语“全长抗体”、“完整抗体”或“整个抗体”可互换使用,以指代基本上完整形式的抗体,与抗体片段相反。具体地,整个抗体包括具有重链和轻链(包括Fc区)的抗体。恒定结构域可以是天然序列恒定结构域(例如,人天然序列恒定结构域)或其氨基酸序列变体。在一些情况下,完整抗体可以具有一种或多种效应子功能。
术语“Fc区”用于限定免疫球蛋白重链的C末端区域。“Fc区”可以是天然序列Fc区或变体Fc区。尽管免疫球蛋白重链的Fc区的边界可以变化,但是人IgG重链Fc区通常被定义为从位置Cys226或从Pro230处的氨基酸残基延伸至其羧基末端。“天然序列Fc区”包含与在自然界中发现的Fc区的氨基酸序列相同的氨基酸序列。天然序列人Fc区包括天然序列人IgG1 Fc区(非A同种异型和A同种异型);天然序列人IgG2 Fc区;天然序列人IgG3 Fc区;和天然序列人IgG4 Fc区以及其天然存在的变体。由于至少一个如本文定义的“氨基酸修饰”,“变体Fc区”包含与天然序列Fc区的氨基酸序列不同的氨基酸序列。变体Fc区与天然序列Fc区或亲本抗体的Fc区相比在天然序列Fc区中或在亲本抗体的Fc区中可以具有至少一个氨基酸取代,并且可以具有例如约一个至约十个氨基酸取代或约一个至约五个氨基酸取代。变体Fc区可以具有与天然序列Fc区和/或与亲本抗体的Fc区至少约80%同一性,并且可以具有与其至少约90%同一性,或具有与其至少约95%同一性。
“抗体片段”或“抗原结合片段”包含完整抗体的一部分,优选完整抗体的抗原结合区和/或可变区。抗体片段的例子包括Fab、Fab'、F(ab')2和Fv片段;双抗体;线性抗体(参见美国专利号5,641,870,实施例2;Zapata等人,Protein Eng.8(10):1057-1062[1995]);单链抗体分子及由抗体片段形成的多特异性抗体。抗体的木瓜蛋白酶消化产生两个相同的抗原结合片段,称为“Fab”片段,和残留的“Fc”片段,这一名称反映了容易结晶的能力。Fab片段由整条L链连同H链的可变区结构域(VH)和一条重链的首个恒定结构域(CH1)组成。就抗原结合而言,每个Fab片段是单价的,即,它具有单个抗原结合位点。抗体的胃蛋白酶处理产生单个大的F(ab')2片段,其大致对应于具有不同抗原结合活性的两个二硫键连接的Fab片段,并且仍然能够交联抗原。Fab'片段与Fab片段的不同之处在于在CH1结构域的羧基末端具有一些另外的残基,包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH是本文中Fab'的名称,其中恒定结构域的一个或多个半胱氨酸残基带有游离巯基。F(ab')2抗体片段最初是作为Fab'片段对产生的,它们之间具有铰链半胱氨酸。抗体片段的其他化学偶联也是已知的。
Fc片段包含通过二硫键保持在一起的两条H链的羧基末端部分。抗体的效应子功能由Fc区中的序列决定,所述区域也通过存在于某些类型的细胞上的Fc受体(FcR)来识别。
“Fv”是含有完全抗原识别和结合位点的最小抗体片段。此片段由处于紧密、非共价缔合的一个重链可变区结构域和一个轻链可变区结构域的二聚体组成。从这两个结构域的折叠产生六个高变环(从H链和L链各自产生3个环),所述高变环恭喜用于抗原结合的氨基酸残基并且为抗体赋予抗原结合特异性。然而,甚至单个可变结构域(或仅包含三个对抗原具有特异性的HVR的Fv的一半)具有识别和结合抗原的能力,尽管亲和力低于整个结合位点。
“单链Fv”(也缩写为“sFv”或“scFv”)是包含连接到单条多肽链中的VH和VL抗体结构域的抗体片段。优选地,sFv多肽还包含在VH与VL结构域之间的多肽接头,其使sFv能够形成用于抗原结合的所需结构。关于sFv的综述,参见Pluckthun in The Pharmacology ofMonoclonal Antibodies,第113卷,Rosenburg和Moore编,Springer-Verlag,New York,第269-315页(1994)。
本公开文本的抗体的“功能片段”包含完整抗体的一部分,通常包括所述完整抗体的抗原结合或可变区或保留或具有修饰的FcR结合能力的抗体的Fc区。抗体片段的例子包括线性抗体、单链抗体分子和由抗体片段形成的多特异性抗体。
术语“双抗体(diabody)”是指通过以下方式制备的小抗体片段:构建具有在VH与VL结构域之间的短接头(约5-10个残基)的sFv片段(参见前段),使得实现V结构域的链间而非链内配对,从而产生二价片段,即具有两个抗原结合位点的片段。双特异性双抗体是两个“交叉”sFv片段的异二聚体,其中两种抗体的VH和VL结构域存在于不同的多肽链上。双抗体更详细地描述在例如EP 404,097;WO 93/11161;Hollinger等人,Proc.Natl.Acad.Sci.USA90:6444-6448(1993)。
本文的抗体具体包括“嵌合”抗体(免疫球蛋白),其中重链和/或轻链的一部分与源自特定物种或属于特定抗体类别或亚类的抗体中的对应序列相同或同源,而所述重链和/或轻链的其余部分与源自另一物种或属于另一种抗体类别或亚类的抗体以及此类抗体的片段中的对应序列相同或同源,只要它们展现出所需的生物活性(美国专利号4,816,567;Morrison等人,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。本文中感兴趣的嵌合抗体包括抗体,其中所述抗体的抗原结合区衍生自通过例如用目的抗原免疫猕猴产生的抗体。如本文所用,“人源化抗体”用作“嵌合抗体”的子集。
非人(例如,鼠)抗体的“人源化”形式是含有衍生自非人免疫球蛋白的最小序列的嵌合抗体。在一个实施方案中,人源化抗体是人免疫球蛋白(受体抗体),其中来自受体的HVR(下文定义)的残基被具有所需特异性、亲和力和/或能力的来自诸如小鼠、大鼠、兔或非人灵长类动物的非人物种(供体抗体)的HVR的残基替代。在一些情况下,人免疫球蛋白的框架(“FR”)残基被对应的非人残基替代。此外,人源化抗体可以包含在受体抗体或供体抗体中未发现的残基。可以进行这些修饰以进一步完善抗体性能,诸如结合亲和力。通常,人源化抗体将包含基本上所有至少一个(并且典型地两个)可变结构域,其中所有或基本上所有高变环对应于非人免疫球蛋白序列的那些,并且所有或基本上所有FR区是人免疫球蛋白序列的那些,尽管所述FR区可以包括一个或多个单独的FR残基取代,所述FR残基取代改进抗体性能,诸如结合亲和力、异构化、免疫原性等。FR中这些氨基酸取代的数量典型地是在H链中不超过6并且在L链中不超过3。所述人源化抗体任选地也将包含免疫球蛋白恒定区(Fc)的至少一部分,典型地是人免疫球蛋白恒定区的至少一部分。关于进一步的细节,参见例如Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature 332:323-329(1988);以及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。还参见例如Vaswani和Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions23:1035-1038(1995);Hurle和Gross,Curr.Op.Biotech.5:428-433(1994);和美国专利号6,982,321和7,087,409。
“人抗体”是这样的抗体,其具有对应于由人产生的抗体的氨基酸序列的氨基酸序列和/或已经使用任何用于制备人抗体的技术(如本文公开的)来制备。人抗体的这种定义特别排除了包含非人抗原结合残基的人源化抗体。人抗体可以使用本领域已知的各种技术(包括噬菌体展示文库)产生。Hoogenboom和Winter,J.Mol.Biol.,227:381(1991);Marks等人,J.Mol.Biol.,222:581(1991)。描述在Cole等人,Monoclonal Antibodies and CancerTherapy,Alan R.Liss,第77页(1985);Boerner等人,J.Immunol.,147(1):86-95(1991)中的方法也可用于制备人单克隆抗体。还参见van Dijk和van de Winkel,Curr.Opin.Pharmacol.,5:368-74(2001)。人抗体可以通过将抗原施用给已经过修饰以响应于抗原激发产生此类抗体但是其内源性基因座被禁用的转基因动物来制备,所述转基因动物例如免疫化的异种小鼠(参见例如,美国专利号6,075,181和6,150,584,其关于XENOMOUSETM技术)。还参见例如,Li等人,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006),其关于通过人B细胞杂交瘤技术生成人抗体。
当在本文中使用时,术语“高变区”、“HVR”或“HV”是指抗体可变结构域的区域,其在序列上是高变的和/或形成结构上确定的环。通常,抗体包含六个HVR:三个在VH中(H1、H2、H3),并且三个在VL中(L1、L2、L3)。在天然抗体中,H3和L3显示出六个HVR的最多的多样性,并且据信H3在将良好的特异性赋予给抗体方面尤其发挥独特的作用。参见例如,Xu等人,Immunity 13:37-45(2000);Johnson和Wu,在Methods in Molecular Biology 248:1-25(Lo编,Human Press,Totowa,N.J.,2003)中。事实上,仅由重链组成的天然存在的骆驼科动物抗体在不存在轻链时是有功能的且稳定的。参见例如,Hamers-Casterman等人,Nature363:446-448(1993);Sheriff等人,Nature Struct.Biol.3:733-736(1996)。
本文使用并且涵盖许多HVR描绘。Kabat互补决定区(CDR)是以序列可变性为基础的,并且是最常用的(Kabat等人,Sequences of Proteins of Immunological Interest,第5版Public Health Service,National Institutes of Health,Bethesda,Md.(1991))。Chothia替代地是指结构化环的位置(Chothia和Lesk,J.Mol.Biol.196:901-917(1987))。AbM HVR表示Kabat HVR和Chothia结构环之间的折衷,并由Oxford Molecular的AbM抗体建模软件使用。“接触(contact)”HVR是基于对可用的复杂晶体结构的分析。来自这些HVR中的每个的残基在以下指出。
环 | Kabat | AbM | Chothia | 接触 |
L1 | L24-L34 | L24-L34 | L26-L32 | L30-L36 |
L2 | L50-L56 | L50-L56 | L50-L52 | L46-L55 |
L3 | L89-L97 | L89-L97 | L91-L96 | L89-L96 |
H1(Kabat编号) | H31-H35B | H26-H35B | H26-H32 | H30-H35B |
H1(Chothia编号) | H31-H35 | H26-H35 | H26-H32 | H30-H35 |
H2 | H50-H65 | H50-H58 | H53-H55 | H47-H58 |
H3 | H95-H102 | H95-H102 | H96-H101 | H93-H101 |
在一些实施方案中,重链的三个HVR在本文中被称为HVR_H1、HVR_H2和HVR_H3,并且轻链的三个HVR被称为HVR_L1、HVR_L2和HVR_L3,其定义根据如下所示的“ADG”编号系统。每个VH和VL由三个HVR和四个FW(框架区)构成,按照以下顺序从氨基末端到羧基末端排列:FW1、HVR1、FW2、HVR2、FW3、HVR3、FW4。对于比较,Yvonne Chen等人(Selection andAnalysis of an Optimized Anti-VEGF Antibody:Crystal Structure of an Affinity-matured Fab in Complex with Antigen,J.Mol.Biol.(1999)293,865-881)的Kabat CDR定义也在以下示出。
HVR可以包含如下的“扩展HVR(extended HVR)”:VL中的24-36或24-34(L1)、46-56或50-56(L2)和89-97或89-96(L3),以及VH中的26-35(H1)、50-65或49-65(H2)和93-102、94-102或95-102(H3)。对于这些定义中的每一个,可变结构域残基是根据同上的Kabat等人来编号。
表述“如Kabat中的可变结构域残基编号”或“如Kabat中的氨基酸位置编号”及其变体是指同上的Kabat等人中的用于抗体的编译的重链可变结构域或轻链可变结构域的编号系统。使用此编号系统,实际线性氨基酸序列可以包含较少或额外的氨基酸,所述氨基酸对应于可变结构域的FR或HVR的缩短或对其进行的插入。例如,重链可变结构域可以包含在H2的残基52之后的单个氨基酸插入(根据Kabat的残基52a)和在重链FR残基82之后插入的残基(例如,根据Kabat的残基82a、82b和82c等)。通过在抗体序列同源性区域与“标准”Kabat编号序列比对,可以确定给定抗体的残基的Kabat编号。
“框架”或“FR”残基是除如本文定义的HVR残基之外的那些可变结构域残基。“人共有框架”或“受体人框架”是表示选择人免疫球蛋白VL或VH框架序列中最常出现的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列的选择来自可变结构域序列的亚组。通常,序列亚组是如Kabat等人,Sequences of Proteins of Immunological Interest,第5版PublicHealth Service,National Institutes of Health,Bethesda,Md.(1991)中的亚组。例子包括,对于VL,亚组可以是如同上的Kabat等人中的亚组κI、κII、κIII或κIV。另外,对于VH,所述亚组可以是如同上的Kabat等人中的亚组I、亚组II、或亚组III。可替代地,人共有框架可以衍生自以上,其中特定残基,诸如当通过将供体框架序列与各个人框架序列的集合比对而基于其与供体框架的同源性选择人框架残基时。“衍生自”人免疫球蛋白框架或人共有框架的受体人框架可以包含其相同的氨基酸序列,或者它可以含有预先存在的氨基酸序列变化。在一些实施方案中,预先存在的氨基酸变化的数量是10或更小、9或更小、8或更小、7或更小、6或更小、5或更小、4或更小、3或更小或者2或更小。
在例如Fc区的指定位置处的“氨基酸修饰”是指指定残基的取代或缺失,或指定残基相邻的至少一个氨基酸残基的插入。与指定残基“相邻”的插入意指在其一至两个残基内插入。插入可以是指定残基的N末端或C末端。本文中的优选氨基酸修饰是取代。
“亲和力成熟的”抗体是在其一个或多个HVR中具有一种或多种改变的抗体,所述改变与不具有那些改变的亲本抗体相比导致抗体对抗原的亲和力的改进。在一个实施方案中,亲和力成熟抗体对于靶抗原具有纳摩尔或甚至皮摩尔亲和力。通过本领域已知的程序产生亲和力成熟的抗体。例如,Marks等人,Bio/Technology 10:779-783(1992)描述了通过VH结构域和VL结构域改组的亲和力成熟。HVR和/或框架残基的随机诱变通过以下进行描述,例如:Barbas等人Proc Nat.Acad.Sci.USA91:3809-3813(1994);Schier等人Gene 169:147-155(1995);Yelton等人J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):3310-9(1995);以及Hawkins等人,J.Mol.Biol.226:889-896(1992)。
如本文所用,术语“特异性结合”、或“对……具有特异性”是指可测量且可再现的相互作用,诸如靶标与抗体之间的结合,其决定在包括生物分子在内的异质分子群存在时靶标的存在。例如,特异性结合靶标(其可以是表位)的抗体是以比它结合其他靶标更大的亲和力、亲合力、更容易、和/或更长的持续时间结合此靶标的抗体。在一些实施方案中,抗体与不相关靶标的结合程度小于抗体与靶标结合的约10%,如例如通过放射免疫测定法(RIA)测量的。在某些实施方案中,特异性结合靶标的抗体具有≤1μM、≤100nM、≤10nM、≤1nM或≤0.1nM的解离常数(Kd)。在某些实施方案中,抗体特异性结合蛋白质上的表位,其在来自不同物种的蛋白质中是保守的。在另一个实施方案中,特异性结合可以包括但不需要专一结合。
“阻断”抗体或“拮抗剂”抗体是抑制或降低其结合抗原的生物活性的抗体。在一些实施方案中,阻断抗体或拮抗剂抗体基本上或完全抑制抗原的生物活性。本公开文本的抗PD-L1抗体阻断通过PD-1进行的信号传导,从而从功能异常状态恢复T细胞对抗原刺激的功能应答。
“激动剂”或激活抗体是通过其结合的抗原增强或启动信号传导的抗体。在一些实施方案中,激动剂抗体在不存在天然配体的情况下引起或激活信号传导。
“抗体效应子功能”是指那些归因于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的生物学活性并且随抗体同种型而变化。抗体效应子功能的例子包括:C1q结合和补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如,B细胞受体)下调;和B细胞激活。“减少或最小化的”抗体效应子功能意指与野生型或未修饰的抗体相比效应子功能降低至少50%(可替代地60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)。抗体效应子功能可由本领域普通技术人员容易地确定和测量。在一个优选的实施方案中,补体结合、补体依赖性细胞毒性和抗体依赖性细胞毒性的抗体效应子功能受到影响。在本公开文本的一些实施方案中,效应子功能通过恒定区中消除糖基化的突变(例如“无效应子的突变”)而消除。在一方面,无效应子的突变是CH2区中的N297A或DANA突变(D265A+N297A)。Shields等人,J.Biol.Chem.276(9):6591-6604(2001)。可替代地,导致效应子功能降低或消除的另外的突变包括:K322A和L234A/L235A(LALA)。可替代地,可以通过生产技术来降低或消除效应子功能,所述生产技术诸如在不糖基化的宿主细胞(例如,大肠杆菌)中表达或者在导致对促进效应子功能无效或效力较低的改变的糖基化模式的宿主细胞中表达(例如,Shinkawa等人,J.Biol.Chem.278(5):3466-3473(2003)。
“抗体依赖性细胞介导的细胞毒性”或“ADCC”是指其中结合到某些细胞毒性细胞(例如,自然杀伤(NK)细胞、嗜中性粒细胞和巨噬细胞)上存在的Fc受体(FcR)上的分泌Ig使得这些细胞毒性效应细胞能够与携带抗原的靶细胞特异性结合并且随后用细胞毒素杀死靶细胞的细胞毒性形式。所述抗体“武装”细胞毒性细胞,而且是通过此机制杀死靶细胞所要求的。用于介导ADCC的原代细胞,NK细胞仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。FcR在造血细胞上的表达在Ravetch和Kinet,Annu.Rev.Immunol.9:457-92(1991)第464页的表3中进行概述。为了评定感兴趣的分子的ADCC活性,可以进行体外ADCC测定,诸如美国专利号5,500,362或5,821,337所描述的。用于此类测定的有用效应细胞包括外周血单核细胞(PBMC)和天然杀伤(NK)细胞。可替代地或另外地,可以在体内(例如在动物模型中,诸如Clynes等人,PNAS USA95:652-656(1998)中公开的动物模型中)评定感兴趣的分子的ADCC活性。
除非本文另有指示,否则免疫球蛋白重链中残基的编号是同上的Kabat等人中的EU索引的编号。“如Kabat中的EU索引”是指人IgG1 EU抗体的残基编号。
“补体依赖性细胞毒性”或“CDC”是指在补体存在下靶细胞的裂解。经典补体途径的激活通过补体系统的第一组分(C1q)与结合其同源抗原的(适当亚类的)抗体的结合来启动。为了评定补体激活,可以进行CDC测定,例如,如Gazzano-Santoro等人,J.Immunol.Methods 202:163(1996)中所描述。具有改变的Fc区氨基酸序列并且C1q结合能力升高或降低的抗体变体描述于美国专利号6,194,551B1和WO 99/51642。将这些专利出版物的内容具体地通过引用并入本文。还参见Idusogie等人J.Immunol.164:4178-4184(2000)。
“结合亲和力”通常是指分子(例如,抗体)的单个结合位点与其结合配偶体(例如,抗原)之间的非共价相互作用的总和的强度。除非另有指示,否则如本文所用,“结合亲和力”是指内在结合亲和力,其反映结合对(例如,抗体和抗原)的成员之间的1:1相互作用。分子X对其配偶体Y的亲和力通常可以表示为解离常数(Kd)。亲和力可以通过本领域已知的常见方法(包括本文所描述的那些)测量。低亲和力抗体通常缓慢地结合抗原并且倾向于容易解离,而高亲和力抗体通常更快地结合抗原并且倾向于保持更长时间的结合。测量结合亲和力的多种方法是本领域已知的,其中任何方法都可以用于本公开文本的目的。用于测量结合亲和力的具体说明性和示例性实施方案描述如下。
在一个实施方案中,根据本公开文本的“Kd”或“Kd值”通过用抗体的Fab形式和抗原分子进行的放射标记的抗原结合测定(RIA)来测量,如通过以下测定所描述,所述测定通过在滴定系列的未标记抗原的存在下用最小浓度的(125I)标记的抗原平衡Fab,然后用抗Fab抗体涂覆的板捕获结合的抗原来测量Fab对抗原的溶液结合亲和力(Chen等人,(1999)J.Mol.Biol293:865-881)。为了建立测定条件,将微滴定板(Dynex)用在50mM碳酸钠(pH9.6)中的5ug/ml的捕获抗Fab抗体(Cappel Labs)涂覆过夜,并且随后在室温(大约23℃)下用在PBS中的2%(w/v)牛血清白蛋白封闭2至5小时。在非吸附板(Nunc#269620)中,将100pM或26pM[125I]-抗原与感兴趣的Fab的连续稀释液混合(与Presta等人,(1997)CancerRes.57:4593-4599中的抗VEGF抗体Fab-12的评定一致,)。然后将感兴趣的Fab孵育过夜;然而,孵育可以持续更长的时间段(例如,65小时)以确保达到平衡。此后,将所述混合物转移到捕获板中,以在室温下孵育1小时。然后去除溶液,并且用在PBS中的0.1%Tween-20将板洗涤八次。当板已干燥时,添加150ul/孔的闪烁体(MicroScint-20;Packard),并且在Topcountγ计数器(Packard)上对板进行10分钟计数。选择给出小于或等于20%最大结合的每种Fab的浓度用于竞争性结合测定。
根据另一个实施方案,通过使用表面等离子体共振测定,在25℃下使用或/>仪器(BIAcore,Inc.,皮斯卡塔韦,新泽西州)以固定的抗原CM5芯片以约10个响应单位(RU)测量Kd。简而言之,根据供应商的说明书,用N-乙基-N'-(3-二甲基氨基丙基)-碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)激活羧甲基化葡聚糖生物传感器芯片(CM5,BIAcore Inc.)。在以5μL/分钟的流速注射前,将抗原用10mM乙酸钠(pH 4.8)稀释至5μg/ml(约0.2μM)以获得大约10个响应单位(RU)的偶联蛋白。在抗原注射后,注射1M乙醇胺以封闭未反应基团。针对动力学测量,在25℃下,以大约25μL/min的流速,将Fab的两倍连续稀释液(0.78nM至500nM)注射到具有0.05%TWEEN 20TM表面活性剂的PBS(PBST)中。通过同时拟合缔合和解离传感器图,使用简单一对一朗缪尔结合模型(/>评价软件3.2版)计算缔合速率(k缔合)和解离速率(k解离)。平衡解离常数(Kd)被计算为比率k解离/k缔合。参见例如,Chen等人,J.Mol.Biol.293:865-881(1999)。如果通过上述表面等离子体共振测定测得的缔合速率超过106M-1s-1,则可以通过使用荧光猝灭技术确定缔合速率,所述荧光淬灭技术在25℃下,在递增浓度的抗原的存在下,测量在pH 7.2的PBS中20nM抗抗原抗体(Fab形式)的荧光发射强度的增加或减少(激发=295nm;发射=340nm,16nm带通),如在带搅拌比色皿的光谱仪(诸如装有停流计(stop-flow)的分光光度计(Aviv Instruments)或8000系列SLM-AMINCOTM分光光度计(ThermoSpectronic))中所测量的。
根据本公开文本的“缔合速率(on-rate)”、“缔合速率(rate of association)”、“缔合速率(association rate)”或“k缔合”也可以如上所描述在25℃下使用或/>系统(BIAcore,Inc.,皮斯卡塔韦,新泽西州)以固定的抗原CM5芯片以约10个响应单位(RU)来确定。简而言之,根据供应商的说明书,用N-乙基-N'-(3-二甲基氨基丙基)-碳二亚胺盐酸盐(ECD)和N-羟基琥珀酰亚胺(NHS)激活羧甲基化葡聚糖生物传感器芯片(CM5,BIAcore Inc.)。在以5μl/min的流速注射前,将抗原用10mM乙酸钠(pH 4.8)稀释至5μg/ml(0.2mM)以获得大约10个响应单位(RU)的偶联蛋白。在注射抗原之后,添加1M乙醇胺以封闭未反应的基团。对于动力学测量,在25℃下,以大约25ul/min的流速,将Fab的两倍连续稀释液(0.78nM至500nM)注射到具有0.05%Tween 20的PBS(PBST)中。通过同时拟合缔合和解离传感器图,使用简单一对一朗缪尔结合模型(BIAcore评价软件3.2版)计算缔合速率(k缔合)和解离速率(k解离)。平衡解离常数(Kd)被计算为比率k解离/k缔合。参见例如,Chen,Y.等人,(1999)J.Mol.Biol 293:865-881。然而,如果通过上述表面等离子体共振测定测得的缔合速率超过106M-1S-1,则优选通过使用荧光猝灭技术确定缔合速率,所述荧光淬灭技术在25℃下,在递增浓度的抗原的存在下,测量在pH 7.2的PBS中20nM抗抗原抗体(Fab形式)的荧光发射强度的增加或减少(激发=295nm;发射=340nm,16nm带通),如在带搅拌比色皿的光谱仪(诸如装有停流计(stop-flow)的分光光度计(Aviv Instruments)或8000系列SLM-Aminco分光光度计(ThermoSpectronic))中所测量的。
如本文所用,短语“基本上减少”或“基本上不同”表示两个数值(通常一个与分子相关联并且另一个与参考/比较物分子相关联)之间的足够高的差异程度,使得本领域技术人员将认为在由所述值(例如,Kd值)测量的生物学特征的背景下这两个值之间的差异具有统计学显著性。根据参考/比较物分子的值,所述两个值之间的差异是例如大于约10%、大于约20%、大于约30%、大于约40%和/或大于约50%。
如本文所用,术语“基本上相似”或“基本上相同”表示两个数值(例如,一个与本公开文本的抗体相关联并且另一个与参考/比较物抗体相关联)之间足够高的相似度,使得本领域技术人员认为这两个值之间的差异在由所述值(例如,Kd值)测量的生物学特征的背景下具有很小或者没有生物学和/或统计学显著性。根据参考/比较物值,所述两个值之间的差异是例如小于约50%、小于约40%、小于约30%、小于约20%和/或小于约10%。
术语“交叉竞争(cross-compete)”、“交叉竞争(cross-competition)”、“交叉阻断(cross-block)”、“交叉阻断(cross-blocked)”和“交叉阻断(cross-blocking)”在本文中可互换使用,意指抗体或其片段直接或通过变构调控间接干扰本公开文本的抗PD-L1抗体与靶人PD-L1的结合的能力。可以使用竞争结合测定法确定抗体或其片段能够干扰另一种抗体或其片段与靶标结合的程度,以及因此根据本公开文本是否可以说其交叉阻断或交叉竞争。一种特别合适的定量交叉竞争测定法使用基于FACS或AlphaScreen的方法来测量标记的(例如,加His标签的、生物素化的或放射标记的)抗体或其片段与另一种抗体或其片段之间关于它们结合靶标的竞争。通常,交叉竞争抗体或其片段是例如一种抗体,其将在交叉竞争测定中结合靶标,使得在测定期间并且在第二抗体或其片段存在的情况下,根据本公开文本的免疫球蛋白单可变结构域或多肽的记录置换是以给定量存在的待测试的潜在交联抗体或其片段的最大理论置换(例如,需要交联的冷(例如,未标记)抗体或其片段的置换)的多达100%(例如,在基于FACS的竞争测定中)。优选地,交叉竞争抗体或其片段具有在10%与100%之间、更优选在50%至100%之间的记录置换。
关于肽、多肽或抗体序列的“氨基酸序列同一性百分比(%)”和“同源性”定义为在用以实现最大百分比序列同一性并且不将任何保守取代视为序列同一性的一部分而比对序列和引入缺口(如果需要)后,候选序列中与特定肽或多肽序列中的氨基酸残基相同的氨基酸残基的百分比。用于确定氨基酸序列同一性百分比的目的的比对能以本领域技术范围内的各种方式实现,例如使用公众可用的计算机软件,诸如BLAST、BLAST-2、ALIGN或MEGALIGNTM(DNASTAR)软件。本领域技术人员可以确定用于测量比对的适当参数,包括为了在被比较的序列的全长上实现最大比对所需要的任何算法。然而,对于本文的目的,使用由Genentech,Inc.编写的ALIGN-2序列比较计算机程序生成氨基酸序列同一性%值。已将ALIGN-2的源代码与用户文档一起提交到美国版权局(U.S.Copyright Office)(华盛顿特区,20559),并且在美国版权局以美国版权注册号TXU510087进行了注册。ALIGN-2程序通过加利福尼亚州南旧金山的Genentech,Inc.可公开获得。应在UNIX操作系统、优选数字UNIXV4.0D上编译使用ALIGN-2程序。所有序列比较参数均由ALIGN-2程序设置并且不改变。
在ALIGN-2用于氨基酸序列比较的情形下,给定氨基酸序列A对于、与或相对于给定氨基酸序列B的氨基酸序列同一性%(其可以可替代地措词为给定氨基酸序列A具有或包含对于、与或相对于给定氨基酸序列B的某一氨基酸序列同一性%)如下计算:
分数X/Y乘100
其中X是由序列比对程序ALIGN-2在此程序的A和B比对中评分为相同匹配的氨基酸残基数,并且其中Y是B中的氨基酸残基总数。应当理解,若氨基酸序列A的长度与氨基酸序列B的长度不相等,则A相对于B的氨基酸序列同一性%将不等于B相对于A的氨基酸序列同一性%。
除非另有特别说明,否则本文所用的所有氨基酸序列同一性%值均如前段中所述的使用ALIGN-2计算机程序获得。
编码本文的抗体的“分离的”核酸分子是已经鉴定且与生成它的环境中通常与之相关的至少一种污染核酸分子分开的核酸分子。优选地,分离的核酸不与和产生环境相关的所有组分缔合。编码本文中的多肽和抗体的分离的核酸分子呈其在自然界中存在的形式或状态以外的形式。因此,分离的核酸分子区别于天然存在于细胞中的编码本文中的多肽和抗体的核酸。
术语“控制序列”是指在特定宿主生物体中表达可操作地连接的编码序列所必需的DNA序列。适合于原核生物的控制序列例如包括启动子、任选地操纵子序列和核糖体结合位点。已知真核细胞利用启动子、多腺苷酸化信号和增强子。
当核酸被放置成与另一核酸序列有功能关系时,其为“可操作地连接”。例如,如果前序列或分泌前导序列的DNA表达为参与多肽分泌的前蛋白,则它与多肽的DNA可操作地连接;如果启动子或增强子影响序列的转录,则它与编码序列可操作地连接;或者如果核糖体结合位点被定位以便于翻译,则它与编码序列可操作地连接。通常,“可操作地连接”意指被连接的DNA序列是连续的,并且在分泌前导序列的情况下,是连续的并且处于阅读相。然而,增强子不必是连续的。通过在方便的限制性位点处的连接来实现连接。如果不存在此类位点,则根据常规实践使用合成的寡核苷酸衔接子或接头。
“宿主”旨在包括可以是或已经是载体的受体或用于掺入外源核酸分子、多核苷酸和/或蛋白质的任何个体病毒或细胞或其培养物。它还旨在包括单个病毒或细胞的后代。由于天然、偶然或刻意突变,所述后代可能不一定与初始亲代细胞完全相同(在形态或基因组或总DNA补体方面)。所述病毒可以是噬菌体。细胞可以是原核的或真核的,并且包括但不限于细菌细胞、酵母细胞、昆虫细胞、动物细胞和哺乳动物细胞(例如鼠、大鼠、猿猴或人细胞)。
如本文所用,术语“载体”是指能够转运与它连接的另一个核酸的核酸分子。载体包括任何遗传元件,诸如质粒、噬菌体载体、噬菌粒、转座子、粘粒、染色体、人工染色体、附加体、病毒、病毒体等,其在与适当的控制元件缔合时能够进行复制(例如,含有复制起点,其作为DNA序列,允许通过募集复制机器蛋白来实现复制的启动)并且可以将基因序列转移到宿主中或宿主之间。一种类型的载体是附加体,即能够进行染色体外复制的核酸。另一种类型的载体是设计成与宿主细胞的遗传物质重组的整合载体。载体可以既是自主复制的又是整合的,并且载体的特性可以根据细胞环境而不同(即,载体可以在一种宿主细胞类型中自主复制,并且在另一种宿主细胞类型中完全整合)。载体通常含有一个或少量限制性核酸内切酶识别位点和/或用于位点特异性重组的位点。可以将外源DNA片段切割并且在这些位点处连接到载体中。载体可以含有适用于鉴定转化或转染细胞的标记物。例如,标记物可以提供抗生素抗性、荧光、酶促以及其他性状。作为第二个例子,标记物可以补充营养缺陷型缺陷,或提供培养基中没有的关键营养物质。
“稳定的”配制品是其中蛋白质在储存时基本上保持其物理和化学稳定性以及完整性的配制品。用于测量蛋白质稳定性的各种分析技术在本领域中是可用的,并且在以下进行综述:Peptide and Protein Drug Delivery,247-301,Vincent Lee编,MarcelDekker,Inc.,纽约市,纽约州,Pubs.(1991)和Jones,A.Adv.Drug Delivery Rev.10:29-90(1993)。可以在选定的温度下在选定的时间段内测量稳定性。对于快速筛选,可以将配制品在40℃下保持2周至1个月,此时测量稳定性。当配制品待在2℃-8℃下储存时,通常所述配制品应在30℃或40℃下稳定至少1个月和/或在2℃-8℃下稳定至少2年。当配制品待在30℃下储存时,通常所述配制品应在30℃下稳定至少2年和/或在40℃下稳定至少6个月。例如,在储存期间的聚集程度可以用作蛋白质稳定性的指标。因此,“稳定的”配制品可以是其中小于约10%并且优选小于约5%的蛋白质作为聚集体存在于配制品中的配制品。在其他实施方案中,可以确定配制品在储存期间聚集体形成的任何增加。
“重构的”配制品是通过将冻干的蛋白质或抗体配制品溶解在稀释剂中使得蛋白质完全分散而制备的配制品。重构的配制品适用于向待用感兴趣的蛋白质治疗的患者施用(例如,皮下施用),并且在本公开文本的某些实施方案中,可以是适用于肠胃外或静脉内施用的配制品。
“等渗”配制品是具有与人血液基本上相同的渗透压的配制品。等渗配制品通常具有约250至350mOsm的渗透压。术语“低渗的”描述渗透压低于人血液的渗透压的配制品。对应地,术语“高渗的”用于描述渗透压高于人血液的渗透压的配制品。等渗性可以使用例如蒸气压或冰冻型渗透压计来测量。由于添加盐和/或缓冲液,本公开文本的配制品是高渗的。
如本文所用的“载体”包括药学上可接受的载体、赋形剂或稳定剂,它们在所采用的剂量和浓度下对暴露于其的细胞或哺乳动物是无毒的。生理上可接受的载体经常是水性pH缓冲溶液。生理学上可接受的载体的例子包括缓冲液,诸如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸;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、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨糖醇;成盐反离子,诸如钠;和/或非离子型表面活性剂,诸如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。
“包装插页”是指通常包括在商业药剂包装中的说明书,所述说明书包含通常包括在商业药剂包装中的关于适应症的信息,所述说明书包含关于适应症、用途、剂量、施用、禁忌症、与包装产品组合的其他药剂、和/或有关使用此类药剂的警告等的信息。
“药学上可接受的酸”包括在其配制的浓度和方式下无毒的无机酸和有机酸。例如,合适的无机酸包括盐酸、高氯酸、氢溴酸、氢碘酸、硝酸、硫酸、磺酸、亚磺酸、磺胺酸、磷酸、碳酸等。合适的有机酸包括直链和支链烷基、芳族、环状、脂环族、芳脂族、杂环、饱和、不饱和的单、二和三羧酸,包括例如甲酸、乙酸、2-羟基乙酸、三氟乙酸、苯乙酸、三甲基乙酸、叔丁基乙酸、邻氨基苯甲酸、丙酸、2-羟基丙酸、2-氧代丙酸、丙二酸(propandioic)、环戊烷丙酸、环戊烷丙酸、3-苯基丙酸、丁酸、丁二酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、2-乙酰氧基-苯甲酸、抗坏血酸、肉桂酸、月桂基硫酸、硬脂酸、粘康酸、扁桃酸、琥珀酸、扑酸、富马酸、苹果酸、马来酸、羟基马来酸、丙二酸(malonic)、乳酸、柠檬酸、酒石酸、乙醇酸、糖酸(glyconic)、葡萄糖酸、丙酮酸、乙醛酸、草酸、甲磺酸、琥珀酸、水杨酸、邻苯二甲酸、palmoic、棕榈酸、硫氰酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、萘-2-磺酸、对甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-甲酸、葡糖庚糖、4,4'-亚甲基双-3-(羟基-2-烯-1-甲酸)、羟基萘甲酸。
“药学上可接受的碱”包括在其配制的浓度和方式下无毒的无机碱和有机碱。例如,合适的碱包括由形成无机碱的金属(诸如锂、钠、钾、镁、钙、铵、铁、锌、铜、锰、铝)、N-甲基葡糖胺、吗啉、哌啶形成的那些,和有机无毒碱,包括伯胺、仲胺和叔胺、经取代的胺、环胺和碱性离子交换树脂[例如,N(R')4+(其中R'独立地是H或C1-4烷基,例如铵,Tris)],例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、三甲胺、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、多胺树脂等。特别优选的有机无毒碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。可用于本公开文本的另外的药学上可接受的酸和碱包括衍生自氨基酸(例如,组氨酸、甘氨酸、苯丙氨酸、天冬氨酸、谷氨酸、赖氨酸和天冬酰胺)的那些。
“药学上可接受的”缓冲液和盐包括衍生自以上指示的酸和碱的酸和碱加成盐的那些。具体的缓冲液和/或盐包括组氨酸、琥珀酸盐和乙酸盐。
“药学上可接受的糖”是这样的分子,当与感兴趣的蛋白质组合时,所述分子在储存时显著防止或减少蛋白质的化学和/或物理不稳定性。当旨在将配制品冻干并且然后重构时,“药学上可接受的糖”也可以被称为“冻干保护剂”。示例性糖及其对应的糖醇包括:氨基酸,诸如谷氨酸一钠或组氨酸;甲胺,诸如甜菜碱;易溶(lyotropic)盐,诸如硫酸镁;多元醇,诸如三元或更高分子量的糖醇,例如丙三醇(glycerin)、右旋糖酐、赤藓糖醇、甘油(glycerol)、阿拉伯糖醇、木糖醇、山梨糖醇和甘露糖醇;丙二醇;聚乙二醇;及其组合。另外的示例性冻干保护剂包括丙三醇和明胶,以及以下糖:蜜二糖(mellibiose)、松三糖、棉子糖、甘露三糖和水苏糖。还原糖的例子包括葡萄糖、麦芽糖、乳糖、麦芽酮糖、异麦芽酮糖和乳果糖。非还原糖的例子包括选自糖醇和其他直链多元醇的多羟基化合物的非还原性糖苷。优选的糖醇是单糖苷,尤其是通过还原诸如乳糖、麦芽糖、乳果糖和麦芽酮糖的二糖获得的那些化合物。糖苷侧基可以是葡糖苷或半乳糖苷。糖醇的另外例子是葡萄糖醇、麦芽糖醇、乳糖醇和异麦芽酮糖。优选的药学上可接受的糖是非还原糖海藻糖或蔗糖。将药学上可接受的糖以“保护量”添加到配制品中(例如,冻干前),这意味着蛋白质在储存期间(例如,在重构和储存之后)基本上保持其物理和化学稳定性和完整性。
本文中感兴趣的“稀释剂”是这样的稀释剂,它是药学上可接受的(对于向人施用而言是安全且无毒的)并且可用于制备液体配制品(诸如冻干后重构的配制品)。稀释剂的例子包括无菌水、注射用抑细菌水(BWFI)、pH缓冲溶液(例如,磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液(Ringer's solution)或右旋糖溶液。在替代性实施方案中,稀释剂可以包括盐和/或缓冲液的水溶液。
“防腐剂”是可以添加到本文的配制品中以降低细菌活性的化合物。防腐剂的添加可以例如促进多用途(多剂量)配制品的生产。潜在的防腐剂的例子包括十八烷基二甲基苄基氯化铵、氯化六甲双铵、苯扎氯铵(烷基苄基二甲基氯化铵的混合物,其中烷基是长链化合物)和苄索氯铵。其他类型的防腐剂包括芳族醇,诸如苯酚、丁醇和苯甲醇;烷基对羟基苯甲酸酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚、间苯二酚、环己醇、3-戊醇和间甲酚。本文最优选的防腐剂是苯甲醇。
“治疗”是指被设计来改变所治疗的个体或细胞的自然过程的临床干预,并且可以用于预防而进行或在临床病理过程中进行。希望的治疗效果包括预防疾病的发生或复发、预防转移、降低疾病进展速率、改善或缓解疾病状态、和缓和或预后改善。在一些实施方案中,本公开文本的抗体用于延迟疾病或障碍的发展。如果减轻了与T细胞功能异常障碍相关联的一种或多种症状,则例如使用本公开文本的凋亡抗PD-L1抗体成功“治疗了”受试者。
“有效量”是指至少在必需的剂量和时间上有效实现所需的或指示的效果(包括治疗或预防结果)的量。例如,本公开文本的抗PD-L1抗体的有效量至少是导致抑制从PD-L1的信号传导(通过T细胞上的PD-1或其他APC上的B7.1或两者)的最小浓度。
“治疗有效量”至少是实现对特定障碍的可测量改善或预防所需的最小浓度。本文的治疗有效量可以根据诸如患者的疾病状态、年龄、性别和体重及所述抗体在个体中引发所需应答的能力的因素而变化。治疗有效量也是其中治疗上有益的效果超过抗体的任何毒性或有害影响的量。例如,本公开文本的抗PD-L1抗体的治疗有效量至少是导致抑制T细胞功能异常障碍的至少一种症状的最小浓度。
“预防有效量”指在必需的剂量和时间上有效实现所需的预防结果的量。例如,本公开文本的抗PD-L1抗体的预防有效量至少是防止或减弱T细胞功能异常障碍的至少一种症状的发展的最小浓度。
“长期”施用是指与短期模式相反,以连续模式施用一种或多种药剂,从而将初始治疗效果(活性)维持较长一段时间。“间歇”施用指不是无间断连续进行,而是本质上周期性的治疗。
用于治疗目的的“哺乳动物”是指被分类为哺乳动物的任何动物,包括人、家畜和农场动物,以及动物园、体育或宠物动物,诸如狗、马、兔、牛、猪、仓鼠、沙鼠、小鼠、雪貂、大鼠、猫等。优选地,哺乳动物是人。
术语“药物配制品”是指呈使得活性成分的生物活性有效的形式并且不含对将被施用所述配制品的受试者具有不可接受的毒性的另外组分的配制品。此类配制品是无菌的。
“无菌”配制品是无菌的或不含所有活微生物及其孢子。
“自身免疫障碍”是由个体自身组织或器官产生并且针对个体自身组织或器官的疾病或障碍,或其共分离(co-segregation)或表现或者由此产生的病症。自身免疫疾病可以是器官特异性疾病(即,免疫应答特异性地针对器官系统,诸如内分泌系统、造血系统、皮肤、心肺系统、胃肠和肝脏系统、肾脏系统、甲状腺、耳朵、神经肌肉系统、中枢神经系统等)或可以影响多器官系统的全身性疾病(例如,系统性红斑狼疮(SLE)、类风湿性关节炎(RA)、多肌炎等)。优选的此类疾病包括自身免疫性风湿性障碍(例如像RA、斯耶格伦氏综合征、硬皮病、狼疮(诸如SLE和狼疮性肾炎)、多肌炎-皮肌炎、冷球蛋白血症、抗磷脂抗体综合征和银屑病性关节炎)、自身免疫性胃肠和肝脏障碍(例如像炎性肠病(例如,溃疡性结肠炎和克罗恩氏病)、自身免疫性胃炎和恶性贫血、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎和乳糜泻)、血管炎(例如像ANCA阴性血管炎和ANCA相关血管炎,包括丘-施二氏(Churg-Strauss)血管炎、韦格纳(Wegener's)肉芽肿病和显微镜下多血管炎)、自身免疫性神障碍(例如像多发性硬化症、眼阵挛肌阵挛综合征、重症肌无力、视神经脊髓炎、帕金森氏病、阿尔茨海默病和自身免疫性多发性神经病)、肾障碍(例如像肾小球肾炎、古德帕斯彻氏(Goodpasture's)综合征和贝格尔氏(Berger's)病)、自身免疫性皮肤障碍(例如像银屑病、荨麻疹、麻疹、寻常型天疱疮、大疱性类天疱疮和皮肤红斑狼疮)、血液学障碍(例如像血小板减少性紫癜、血栓性血小板减少性紫癜、输血后紫癜和自身免疫性溶血性贫血)、动脉粥样硬化、葡萄膜炎、自身免疫性听觉疾病(例如像内耳病和听力损失)、贝切特氏(Behcet's)病、雷诺氏(Raynaud's)综合征、器官移植和自身免疫性内分泌障碍(例如像糖尿病相关自身免疫性疾病,诸如胰岛素依赖型糖尿病(IDDM)、艾迪生(Addison's)病和自身免疫性甲状腺疾病(例如格雷夫斯(Graves’)病和甲状腺炎))。更优选的此类疾病包括例如RA、溃疡性结肠炎、ANCA相关血管炎、狼疮、多发性硬化症、斯耶格伦氏综合征、格雷夫斯病、IDDM、恶性贫血、甲状腺炎和肾小球肾炎。
如本文所用,术语“免疫缀合物”或“抗体-药物缀合物”是指抗体或其抗原结合片段与另一种药剂(诸如化疗剂、毒素、免疫治疗剂、成像探针等)连接。连接可以是共价键或诸如通过静电力产生的非共价相互作用。为了形成免疫缀合物,可以采用本领域已知的各种接头。另外,免疫缀合物可以以融合蛋白的形式提供,所述融合蛋白可以由编码所述免疫缀合物的多核苷酸表达。如本文所用,“融合蛋白”是指通过最初编码单独蛋白质(包括肽和多肽)的两个或更多个基因或基因片段的连接而产生的蛋白质。融合基因的翻译产生具有源自每种原始蛋白质的功能特性的单个蛋白质。
如本文所用,术语“细胞毒性剂”是指抑制或阻止细胞功能和/或引起细胞破坏的物质。所述术语包括放射性同位素(例如,At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32和Lu的放射性同位素);以及毒素,诸如小分子毒素或细菌、真菌、植物或动物来源的酶促活性毒素或其片段。
“化疗剂”是可用于治疗癌症的化合物。“化疗剂”的例子包括:烷基化剂,诸如噻替派和环磷酰胺烷基磺酸盐,诸如白消安、英丙舒凡和哌泊舒凡;氮丙啶,诸如苯并多巴(benzodopa)、卡波醌、美妥替哌(meturedopa)和尿烷亚胺(uredopa);乙撑亚胺(ethylenimines)和甲基蜜胺(methylamelamines),包括六甲蜜胺、三乙撑密胺、三乙撑磷酰胺、三乙撑硫代磷酰胺和三羟甲蜜胺;多聚乙酰(acetogenins)(尤其是布拉它辛和布拉它辛酮(bullatacinone));δ-9-四氢大麻酚(屈大麻酚,/>);β-拉帕酮(lapachone);拉帕醇;秋水仙碱;桦木酸;喜树碱(包括合成类似物拓朴替康CPT-11(依立替康,/>)、乙酰化喜树碱、东莨菪亭(scopolectin)、以及9-氨基喜树碱);苔藓抑素;培美曲塞;callystatin;CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);鬼臼毒素;鬼臼酸;替尼泊苷;隐藻素(cryptophycin)(尤其是隐藻素1和隐藻素8);海兔毒素;多卡米星(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);艾榴素(eleutherobin);水鬼蕉碱;TLK-286;CDP323(一种口服α-4整合素抑制剂);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥,诸如苯丁酸氮芥、萘氮芥(chlomaphazine)、氯磷酰胺、雌莫司汀、异环磷酰胺、二氯甲基二乙胺、盐酸甲氧氮芥、美法仑、新恩比兴(novembichin)、苯芥胆甾醇、松龙苯芥、三芥环磷酰胺(trofosfamide)、尿嘧啶氮芥;亚硝基脲(nitrosurea),诸如卡莫司汀、氯脲霉素、福泰氮芥、罗氮芥、尼莫司汀、以及雷莫司汀(ranimnustine);抗生素,诸如烯二炔类抗生素(例如,加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωll(参见例如,Nicolaou等人,Angew.Chem.Intl.Ed.Engl.,33:183-186(1994));烯二炔蒽环类抗生素(dynemicin),包括烯二炔蒽环类抗生素A;埃斯波霉素(esperamicin);以及新制癌菌素生色团和相关色素蛋白稀二炔类抗生素生色团)、阿克拉霉素、放线菌素(actinomycin)、安曲霉素、重氮丝氨酸、博来霉素、放线菌素、carabicin、洋红霉素(caminomycin)、嗜癌菌素(carzinophilin)、色霉素、更生菌素(dactinomycin)、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、阿霉素(包括/>吗啉代-阿霉素、氰基吗啉代-阿霉素、2-吡咯啉-阿霉素、阿霉素HCl脂质体注射剂/>和脱氧阿霉素)、表柔比星、依索比星、伊达比星、马塞罗霉素(marcellomycin)、丝裂霉素类(诸如丝裂霉素C)、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、紫菜霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核霉素、乌苯美司、净司他丁、佐柔比星;抗代谢物,诸如氨甲蝶呤、吉西他滨/>替加氟/>卡培他滨/>埃博霉素和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、氨甲蝶呤、喋罗呤、三甲曲沙;嘌呤类似物,诸如福达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷和伊马替尼(2-苯基氨基嘧啶衍生物),以及其他c-Kit抑制剂;抗肾上腺药,诸如氨鲁米特、米托坦、曲洛司坦;叶酸补偿剂,诸如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基酮戊酸;恩尿嘧啶;安吖啶;bestrabucil;比生群;依达曲沙(edatraxate);defofamine;秋水仙胺;地吖醌;依氟鸟氨酸;依利醋铵;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登木素生物碱,诸如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;尼曲吖啶(nitraerine);喷司他丁;异丙嗪(phenamet);吡柔比星;洛索蒽醌;2-乙基酰肼;丙卡巴肼;/>多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生;利索新;西佐喃(sizofuran);锗螺胺;细交链胞菌酮酸;三亚胺醌;2,2',2″-三氯三乙胺;单端孢霉烯族化合物(特别是T-2毒素、verracurin A、杆孢菌素A和蛇形菌素(anguidine));乌拉坦;长春地辛/>达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;派泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);噻替哌;紫杉烷类,例如紫杉醇紫杉醇的白蛋白工程化的纳米颗粒配制品(ABRAXANETM)和多西他塞苯丁酸氮芥;6-硫鸟嘌呤;巯嘌呤;氨甲蝶呤;铂类似物,诸如顺铂和卡铂;长春花碱/>铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱奥沙利铂;leucovovin;长春瑞滨/>诺安托(novantrone);依达曲沙;道诺霉素;氨基蝶呤;伊班膦酸盐;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇,诸如视黄酸;任何上述物质的药学上可接受的盐、酸或衍生物;以及上述物质中的两种或更多种的组合,诸如CHOP(环磷酰胺、阿霉素、长春新碱和泼尼松龙组合疗法的缩写)和FOLFOX(使用奥沙利铂(ELOXATINTM)与5-FU和leucovovin组合的治疗方案的缩写)。可与本公开文本的抗PD-L1抗体组合使用的特别优选的化疗剂尤其在肿瘤免疫治疗中是吉西他滨。
此定义中还包括抗激素剂,其用来调节、减少、阻断或抑制可以促进癌症生长的激素的作用,并且经常呈系统性或全身治疗的形式。它们本身可以是激素。例子包括抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(tamoxifen)(包括他莫昔芬)、雷洛昔芬/>屈洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、凯奥昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬抗黄体酮;雌激素受体下调剂(ERD);雌激素受体拮抗剂,诸如氟维司群功能为抑制或关闭卵巢的药剂,例如促黄体生成激素释放激素(LHRH)激动剂,诸如乙酸亮丙瑞林(/>和/>)、乙酸戈舍瑞林(goserelinacetate)、乙酸布舍瑞林(buserelin acetate)和曲普瑞林(tripterelin);抗雄激素,诸如氟他胺(flutamide)、尼鲁米特(nilutamide)和比卡鲁胺(bicalutamide);以及抑制调节肾上腺中雌激素产生的酶芳香酶的芳香酶抑制剂,例如像4(5)-咪唑、氨鲁米特、乙酸甲地孕酮/>依西美坦/>福美司坦(formestanie)、法曲唑(fadrozole)、伏氯唑/>来曲唑/>以及阿那曲唑此外,化疗剂的这种定义包括双膦酸盐,诸如氯膦酸盐(clodronate)(例如,/>或/>)、依替膦酸盐/>NE-58095、唑来膦酸(zoledronic acid)/唑来膦酸盐/>阿仑膦酸盐/>帕米膦酸盐/>替洛膦酸盐/>或利塞膦酸盐/>以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,特别是抑制参与异常细胞增殖的信号传导路径中的基因表达的反义寡核苷酸,例如像PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R);疫苗,诸如/>疫苗和基因疗法疫苗,例如疫苗、/>疫苗和/>疫苗;拓扑异构酶1抑制剂抗雌激素,诸如氟维司群;Kit抑制剂,诸如伊马替尼或EXEL-0862(酪氨酸激酶抑制剂);EGFR抑制剂,诸如厄洛替尼或西妥昔单抗;抗VEGF抑制剂,诸如贝伐单抗;arinotecan;rmRH(例如,/>);拉帕替尼和二甲苯磺酸拉帕替尼(ErbB-2和EGFR双酪氨酸激酶小分子抑制剂,也称为GW572016);17AAG(格尔德霉素衍生物,其是热休克蛋白(Hsp)90毒物),以及上述任一种药物的药学上可接受的盐、酸或衍生物。
“生长抑制剂”是指抑制细胞生长的化合物或组合物,所述细胞的生长取决于体外或体内的受体激活。因此,所述生长抑制剂包括显著降低处于S期的受体依赖性细胞的百分比的抑制剂。生长抑制剂的例子包括阻断细胞周期进程(在除了S期以外的阶段处)的药剂,诸如诱导G1停滞和M期停滞的药剂。经典的M期阻滞剂包括长春花和长春花生物碱(长春新碱和长春花碱)、紫杉烷、和拓扑异构酶II抑制剂,诸如阿霉素、表柔比星、柔红霉素、依托泊苷以及博来霉素。使G1停滞的那些药剂还深入至S期停滞,所述药剂例如DNA烷基化剂,诸如他莫昔芬、泼尼松、达卡巴嗪、盐酸氧氮芥、顺铂、氨甲蝶呤、5-氟尿嘧啶以及阿糖胞苷。另外的信息可以见于The Molecular Basis of Cancer,Mendelsohn和Israel编,第1章,标题为“Cell cycle regulation,oncogenes,and antineoplastic drugs”Murakami等人(WBSaunders:Philadelphia,1995),尤其是第13页。紫杉烷(紫杉醇和多西他赛)是均源自紫杉树的抗癌药。源自欧洲紫衫的多西他赛(Rhone-Poulenc Rorer公司)是紫杉醇(/>Bristol-Myers Squibb公司)的半合成类似物。
术语“细胞因子”是由一个细胞群释放的作为细胞间介体作用于另一种细胞的蛋白质的通用术语。此类细胞因子的例子是淋巴细胞因子、单核细胞因子;白介素(IL),诸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-11、IL-12、IL-13、IL-15...IL-35,包括rIL-2;肿瘤坏死因子,诸如TNF-α或TNF-β;和其他多肽因子,包括LIF和kit配体(KL),而术语“白介素”现在基本上已经成为细胞因子的同义词。如本文所用,术语细胞因子包括来自天然来源或来自重组细胞培养物的蛋白质和天然序列细胞因子的生物学活性等效物,包括合成产生的小分子实体及其药学上可接受的衍生物和盐。细胞因子可以在预期靶标的近端位置上进行分类,其中自分泌是指对分泌其的同一细胞的作用,旁分泌是指限于向其中分泌细胞因子的紧邻区域的作用,并且内分泌是指在身体的远区中的作用。免疫细胞因子还可以根据它们是否增强以下应答进行分类:I型应答(例如,IFN-γ、TGF-β等),I型应答有利于细胞免疫;或II型应答(IL-4、IL-10、IL-13等),II型应答有利于抗体或体液免疫。免疫细胞因子在共刺激、成熟、增殖、激活、炎症、生长、分化、细胞因子产生和分泌、各种免疫细胞的存活中发挥作用。
如本文所使用,在免疫学、癌症免疫疗法、药理学、重组核酸技术、抗体工程化、以及分子和细胞生物学领域中使用的其他术语将通常被适用领域的普通技术人员所理解。
抗体文库及其筛选
噬菌体(噬菌粒)展示(在本文中也称为噬菌体展示)可以用作在例如通过序列设计和/或随机化生成的文库中生成和筛选许多不同的潜在变体抗体的方便且快速的方法。然而,技术人员可使用用于制备和筛选改变的抗体的其他方法。
噬菌体(噬菌粒)展示(在本文中,在一些情况下也称为噬菌体展示)可以用作在通过序列随机化生成的文库中生成和筛选许多不同的潜在变体抗体的方便且快速的方法。然而,技术人员可使用用于制备和筛选改变的抗体的其他方法。
噬菌体(噬菌粒)展示技术为生成和选择结合配体(诸如抗原)的新型蛋白提供了强大的工具。使用噬菌体(噬菌粒)展示技术允许生成大的蛋白质变体文库,可以将其针对以高亲和力结合靶分子的那些序列进行快速分选。通常将编码变体多肽的核酸与编码病毒外壳蛋白(诸如基因III蛋白或基因VIII蛋白)的核酸序列融合。已经开发出单价噬菌粒展示系统,其中编码蛋白质或多肽的核酸序列与编码基因III蛋白的一部分的核酸序列融合。(Bass,S.,Proteins,8:309(1990);Lowman和Wells,Methods:A Companion to Methods inEnzymology,3:205(1991))。在单价噬菌粒展示系统中,基因融合体以低水平表达,并且野生型基因III蛋白也被表达,使得保留了颗粒的感染性。生成肽文库和筛选那些文库的方法已在许多专利中公开(例如,美国专利号5,723,286、美国专利号5,432,018、美国专利号5,580,717、美国专利号5,427,908和美国专利号5,498,530)。
已经以许多种方式制备了抗体或抗原结合多肽的文库,所述方式包括通过插入随机DNA序列改变单基因或通过克隆相关基因家族。用于使用噬菌体(噬菌粒)展示来展示抗体或抗原结合片段的方法已经描述于美国专利号5,750,373、5,733,743、5,837,242、5,969,108、6,172,197、5,580,717和5,658,727中。然后针对具有所需特征的抗体或抗原结合蛋白的表达筛选文库。
在一个实施方案中,如PCT国际申请号PCT/CN2017/098333和PCT/CN2017/098299中所描述制备和筛选重链和轻链文库,将所述文献通过引用以其整体并入本文。
在本领域中已经很好地建立了将选择的氨基酸取代到模板核酸中的方法,本文描述了其中的一些。例如,可以使用Kunkel方法来取代高变区残基。参见例如,Kunkel等人,Methods Enzymol.154:367-382(1987)。
寡核苷酸的序列包含一个或多个设计的密码子集,用于待改变的高变区残基。密码子集是一组用于编码所需变体氨基酸的不同核苷酸三联体序列。密码子集可以使用符号表示,以指定具体核苷酸或核苷酸的等摩尔混合物,根据IUB代码如下文所示。
重组制剂
本公开文本还提供了一种编码抗PD-L1抗体的分离的核酸、包含这种核酸的载体和宿主细胞、以及用于产生抗体的重组技术。
为了重组产生抗体,分离编码它的核酸,并且将其插入可复制载体中以用于进一步克隆(DNA扩增)或用于根据常规重组DNA技术表达。在如上所描述进行文库筛选之后,使用常规程序容易地推断或在其他方面分离编码抗体的DNA并且测序(例如,通过使用能够与编码抗体重链和轻链的基因特异性结合的寡核苷酸探针)。本领域已知的许多载体可用于克隆DNA。载体的选择部分地取决于待使用的宿主细胞。通常,优选的宿主细胞是原核或真核(通常是哺乳动物)起源的。一旦克隆,就可以使用本领域熟知的方法表达和纯化抗体。
表位作图和相关技术
本公开文本包括抗PD-L1抗体,其与在PD-L1分子的一个或多个结构域中存在的一个或多个氨基酸相互作用,所述结构域包括例如细胞外(IgV样)结构域、细胞外IgC样结构域、跨膜结构域和细胞内结构域。与抗体结合的表位可以由位于PD-L1分子的任何上述结构域内的3个或更多个(例如,3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个或更多个)氨基酸的单个连续序列组成(例如,结构域中的线性表位)。可替代地,表位可以由位于PD-L1分子的上述结构域之一或两个内的多个非连续氨基酸(或氨基酸序列)组成(例如,构象表位)。
可以使用本领域普通技术人员已知的各种技术来确定抗体是否与多肽或蛋白质内的“一个或多个氨基酸相互作用”。示例性技术包括例如常规交叉阻断测定,诸如在Antibodies,Harlow和Lane(Cold Spring Harbor Press,Cold Spring Harbor,NY)中所描述的技术。其他方法包括丙氨酸扫描突变分析、肽印迹分析(Reineke(2004)MethodsMol.Biol.248:443-63)、肽切割分析晶体学研究和NMR分析。此外,可以采用诸如表位切除、表位提取和抗原的化学修饰的方法(Tomer(2000)Prot.Sci.9:487-496)。可以用于鉴定与抗体相互作用的多肽内的氨基酸的另一种方法是通过质谱法检测的氢/氘交换。一般而言,氢/氘交换方法涉及对感兴趣的蛋白质进行氘标记,接着将抗体与氘标记的蛋白质结合。接下来,将蛋白质/抗体复合物转移到水中,并且在被抗体复合物保护的氨基酸内的可交换质子以比在不是界面的一部分的氨基酸内的可交换质子慢的速率经历氘向氢反向交换。其结果是,形成蛋白质/抗体界面的一部分的氨基酸可以保留氘,并且因此与不包括在界面中的氨基酸相比展现出相对较高的质量。在抗体解离之后,使靶蛋白经受蛋白酶切割和质谱分析,从而揭示氘标记的残基,其对应于与抗体相互作用的特定氨基酸。参见例如,Ehring(1999)Analytical Biochemistry 267:252-259;Engen和Smith(2001)Anal.Chem.73:256A-265A。
术语“表位”是指B细胞和/或T细胞对其产生应答的在抗原上的位点。B细胞表位可以由通过蛋白质的三级折叠并列的连续氨基酸或非连续氨基酸两者形成。由连续氨基酸形成的表位典型地在暴露于变性溶剂时得以保持,而通过三级折叠形成的表位典型地在用变性溶剂处理时丧失。表位典型地包括独特空间构象中的至少3个,并且更通常至少5个或8-10个氨基酸。修饰辅助谱分析(MAP),也称为基于抗原结构的抗体谱分析(ASAP)是这样的方法,所述方法根据每种抗体与化学或酶促修饰的抗原表面的结合谱的相似性对大量针对同一抗原的抗体进行分类(参见US 2004/0101920,将其具体地通过引用以其整体并入本文)。每个类别可以反映独特的表位,其与另一类别代表的表位明显不同或部分重叠。此技术允许快速过滤遗传上相同的抗体,使得表征可以集中在遗传上不同的抗体上。当用于杂交瘤筛选时,MAP可以有助于鉴定产生具有所需特征的mAb的罕见杂交瘤克隆。MAP可以用于将本公开文本的抗体分类为结合不同表位的抗体组。
通过使用本领域已知的常规方法,人员可以容易地确定抗体是否与参考抗PD-L1抗体结合相同的表位,或与所述参考抗体竞争结合。例如,为了确定测试抗体是否与本公开文本的参考抗PD-L1抗体结合相同的表位,允许参考抗体在饱和条件下结合PD-L1蛋白或肽。接下来,评定测试抗体结合PD-L1分子的能力。如果在与参考抗PD-L1抗体饱和结合后测试抗体能够结合PD-L1,则可以得出结论,所述测试抗体与参考抗PD-L1抗体结合不同的表位。在另一方面,如果在与参考抗PD-L1抗体饱和结合后测试抗体不能结合PD-L1蛋白,则所述测试抗体可以结合与本公开文本的参考抗PD-L1抗体所结合的表位相同的表位。
为了确定抗体是否与参考抗PD-L1抗体竞争结合,以两个方向进行以上描述的结合方法:在第一方向中,允许参考抗体在饱和条件下结合PD-L1蛋白,接着评定测试抗体与PD-L1分子的结合。在第二方向上,允许测试抗体在饱和条件下结合PD-L1分子,接着评定参考抗体与PD-L1分子的结合。如果在两个方向上,只有第一(饱和)抗体能够结合PD-L1分合,则可以得出结论,测试抗体和参考抗体竞争结合PD-L1。如本领域普通技术人员将理解的,与参考抗体竞争结合的抗体可能未必与参考抗体结合相同的表位,而是可能通过结合重叠或相邻表位而在空间上阻断参考抗体的结合。
如果一种抗体竞争性地抑制(阻断)另一种抗体与抗原的结合,则两种抗体结合相同或重叠的表位。即,1、5、10、20或100倍过量的一种抗体将另一种抗体的结合抑制至少50%,优选地75%、90%或甚至99%,如在竞争性结合测定中测量的(例如参见,Junghans等人,Cancer Res.199050:1495-1502)。可替代地,如果抗原中基本上所有的减少或消除一种抗体的结合的氨基酸突变减少或消除了另一种抗体的结合,则两种抗体具有相同的表位。如果减少或消除一种抗体结合的一些氨基酸突变减少或消除了另一种抗体的结合,则两种抗体具有重叠的表位。
然后可以进行另外的常规实验(例如,肽突变和结合分析),以确认观察到的测试抗体结合的缺乏实际上是由于与参考抗体结合相同的表位,或者空间阻断(或另一种现象)是否是造成观察到的结合缺乏的原因。可以使用ELISA、RIA、表面等离振子共振、流式细胞术或本领域可用的任何其他定量或定性抗体结合测定法进行此类实验。
抗体和片段
在一些实施方案中,本文提供了一种分离的抗体或其抗原结合片段,其包含以下HVR_L1、HVR_L2和/或HRV_L3中的一种或多种:
(1)具有选自以下的氨基酸序列的HVR_L1:
(a)RASQX1X2X3X4X5LA(SEQ ID NO:1),其中:
X1:G S
X2:I V
X3:E G S
X4:K P S
X5:F W Y
(b)RASX1SVDFX2GX3SFLX4(SEQ ID NO:2),其中:
X1:E Q
X2:F H Y
X3:I K
X4:A D
(c)X1ASQX2IPX3FLX4(SEQ ID NO:3),其中:
X1:Q R
X2:D S T
X3:K S T
X4:A N
(d)RASQGX1SX2X3LA(SEQ ID NO:4),其中:
X1:I V
X2:P S
X3:W Y
以及
(e)RASQX1IPSFLN(SEQ ID NO:5),其中:
X1:S T
(2)具有选自以下的氨基酸序列的HVR_L2:
(a)DASX1X2X3X4GX5(SEQ ID NO:6),其中:
X1:N S
X2:L R
X3:A E
X4:S T
X5:I V
(b)AASX1LQSGV(SEQ ID NO:7),其中:
X1:S T
以及
(c)DASNX1X2TGX3(SEQ ID NO:8),其中:
X1:L R
X2:A E
X3:I V
(3)具有选自以下的氨基酸序列的HVR_L3:
(e)YCQQYDX1WPYT(SEQ ID NO:9),其中:
X1:A H S Y
(f)YCQX1YX2SWPRX3FT(SEQ ID NO:10),其中:
X1:H Q
X2:G I S T V
X3:G L Q R V
(g)YCQQYDX1WPYT(SEQ ID NO:11),其中:
X1:A S
以及
(h)YCQHYX1SWPRQFT(SEQ ID NO:12),其中:
X1:I T
在某些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:13-39和94-102的氨基酸序列的HVR_L1、具有选自SEQ ID NO:40-66和103-111的氨基酸序列的HVR_L2、和/或具有选自SEQ ID NO:67-93和112-120的氨基酸序列的HVR_L3。在一些实施方案中,包含具有选自SEQ ID NO:13-39的氨基酸序列的HVR_L1、具有选自SEQ ID NO:40-66的氨基酸序列的HVR_L2和/或具有选自SEQ ID NO:67-93的氨基酸序列的HVR_L3的抗体或其片段与人和猴PD-L1具有交叉反应性。在某些实施方案中,包含具有选自SEQ ID NO:94-102的氨基酸序列的HVR_L1、具有选自SEQ ID NO:103-111的氨基酸序列的HVR_L2和/或具有选自SEQID NO:112-120的氨基酸序列的HVR_L3的抗体或其片段与人、猴和小鼠PD-L1具有交叉反应性。
>B14033-HVR_L1
RASQGIGSFLA(SEQ ID NO:13)
>B14614-HVR_L1
RASESVDFYGKSFLD(SEQ ID NO:14)
>B14615-HVR_L1
RASQSVDFYGKSFLA(SEQ ID NO:15)
>B14617-HVR_L1
RASESVDFFGKSFLA(SEQ ID NO:16)
>B14622-HVR_L1
RASQSVDFYGKSFLD(SEQ ID NO:17)
>B14627-HVR_L1
RASQSVSSWLA(SEQ ID NO:18)
>B14631-HVR_L1
RASESVDFFGKSFLA(SEQ ID NO:19)
>B14633-HVR_L1
RASESVDFHGISFLA(SEQ ID NO:20)
>B14634-HVR_L1
RASQSVSPYLA(SEQ ID NO:21)
>B14638-HVR_L1
RASQSVGSIYLG(SEQ ID NO:22)
>B14642-HVR_L1
RASQSVDFYGKSFLA(SEQ ID NO:23)
>B14644-HVR_L1
RASESVDFYGKSFLA(SEQ ID NO:24)
>B14645-HVR_L1
RASQSVDFYGKSFLD(SEQ ID NO:25)
>B14650-HVR_L1
RASESVDFYGKSFLD(SEQ ID NO:26)
>B14651-HVR_L1
RASESVDFHGKSFLA(SEQ ID NO:27)
>B14652-HVR_L1
RASQGVSPWLA(SEQ ID NO:28)
>B14654-HVR_L1
RASQSVSPYLA(SEQ ID NO:29)
>B14658-HVR_L1
RASQSVDFHGKSFLD(SEQ ID NO:30)
>B14665-HVR_L1
RASQSVDFYGKSFLA(SEQ ID NO:31)
>B14673-HVR_L1
RASESVDFYGKSFLA(SEQ ID NO:32)
>B14674-HVR_L1
RASQSIEKWLA(SEQ ID NO:33)
>B14681-HVR_L1
RASQSVDFHGISFLD(SEQ ID NO:34)
>B14689-HVR_L1
RASQSVDFYGKSFLD(SEQ ID NO:35)
>B14690-HVR_L1
RASQSVDFHGISFLD(SEQ ID NO:36)
>B13002-HVR_L1
RASQGVSSYLA(SEQ ID NO:37)
>B13004-HVR_L1
RASQGISPWLA(SEQ ID NO:38)
>B13005-HVR_L1
RASQSVSSYLA(SEQ ID NO:39)
>B14033-HVR_L2
DASSLESGV(SEQ ID NO:40)
>B14614-HVR_L2
DASNRATGI(SEQ ID NO:41)
>B14615-HVR_L2
DASSLESGV(SEQ ID NO:42)
>B14617-HVR_L2
DASSLESGV(SEQ ID NO:43)
>B14622-HVR_L2
DASNRATGI(SEQ ID NO:44)
>B14627-HVR_L2
DASSLESGV(SEQ ID NO:45)
>B14631-HVR_L2
DASNLETGV(SEQ ID NO:46)
>B14633-HVR_L2
DASNRATGI(SEQ ID NO:47)
>B14634-HVR_L2
DASNLETGV(SEQ ID NO:48)
>B14638-HVR_L2
DASNRATGI(SEQ ID NO:49)
>B14642-HVR_L2
DASSLESGV(SEQ ID NO:50)
>B14644-HVR_L2
DASNRATGI(SEQ ID NO:51)
>B14645-HVR_L2
DASNLETGV(SEQ ID NO:52)
>B14650-HVR_L2
DASNRATGI(SEQ ID NO:53)
>B14651-HVR_L2
DASNRATGI(SEQ ID NO:54)
>B14652-HVR_L2
DASSLESGV(SEQ ID NO:55)
>B14654-HVR_L2
DASNRATGI(SEQ ID NO:56)
>B14658-HVR_L2
DASNRATGI(SEQ ID NO:57)
>B14665-HVR_L2
DASSLESGV(SEQ ID NO:58)
>B14673-HVR_L2
DASSLESGV(SEQ ID NO:59)
>B14674-HVR_L2
DASSLESGV(SEQ ID NO:60)
>B14681-HVR_L2
DASNRATGI(SEQ ID NO:61)
>B14689-HVR_L2
DASSLESGV(SEQ ID NO:62)
>B14690-HVR_L2
DASNLETGV(SEQ ID NO:63)
>B13002-HVR_L2
DASNLETGV(SEQ ID NO:64)
>B13004-HVR_L2
DASNRATGI(SEQ ID NO:65)
>B13005-HVR_L2
DASNLETGV(SEQ ID NO:66)
>B14033-HVR_L3
YCQQYDYWPYT(SEQ ID NO:67)
>B14614-HVR_L3
YCQQYDSWPYT(SEQ ID NO:68)
>B14615-HVR_L3
YCQQYDHWPYT(SEQ ID NO:69)
>B14617-HVR_L3
YCQQYDSWPYT(SEQ ID NO:70)
>B14622-HVR_L3
YCQQYDSWPYT(SEQ ID NO:71)
>B14627-HVR_L3
YCQQYDSWPYT(SEQ ID NO:72)
>B14631-HVR_L3
YCQQYDHWPYT(SEQ ID NO:73)
>B14633-HVR_L3
YCQQYDHWPYT(SEQ ID NO:74)
>B14634-HVR_L3
YCQQYDAWPYT(SEQ ID NO:75)
>B14638-HVR_L3
YCQQYDSWPYT(SEQ ID NO:76)
>B14642-HVR_L3
YCQQYDAWPYT(SEQ ID NO:77)
>B14644-HVR_L3
YCQQYDYWPYT(SEQ ID NO:78)
>B14645-HVR_L3
YCQQYDAWPYT(SEQ ID NO:79)
>B14650-HVR_L3
YCQQYDHWPYT(SEQ ID NO:80)
>B14651-HVR_L3
YCQQYDHWPYT(SEQ ID NO:81)
>B14652-HVR_L3
YCQQYDAWPYT(SEQ ID NO:82)
>B14654-HVR_L3
YCQQYDAWPYT(SEQ ID NO:83)
>B14658-HVR_L3
YCQQYDSWPYT(SEQ ID NO:84)
>B14665-HVR_L3
YCQQYDSWPYT(SEQ ID NO:85)
>B14673-HVR_L3
YCQQYDSWPYT(SEQ ID NO:86)
>B14674-HVR_L3
YCQQYDAWPYT(SEQ ID NO:87)
>B14681-HVR_L3
YCQQYDHWPYT(SEQ ID NO:88)
>B14689-HVR_L3
YCQQYDHWPYT(SEQ ID NO:89)
>B14690-HVR_L3
YCQQYDSWPYT(SEQ ID NO:90)
>B13002-HVR_L3
YCQQYDAWPYT(SEQ ID NO:91)
>B13004-HVR_L3
YCQQYDSWPYT(SEQ ID NO:92)
>B13005-HVR_L3
YCQQYDAWPYT(SEQ ID NO:93)
>B14032-HVR_L1
QASQDIPTFLA(SEQ ID NO:94)
>B15012-HVR_L1
RASQTIPSFLN(SEQ ID NO:95)
>B15014-HVR_L1
RASQDIPKFLA(SEQ ID NO:96)
>B15016-HVR_L1
RASQTIPSFLN(SEQ ID NO:97)
>B15022-HVR_L1
RASQSIPSFLN(SEQ ID NO:98)
>B15024-HVR_L1
RASQSIPTFLN(SEQ ID NO:99)
>B15041-HVR_L1
RASQSIPSFLN(SEQ ID NO:100)
>B15074-HVR_L1
RASQTIPSFLN(SEQ ID NO:101)
>B15082-HVR_L1
RASQTIPSFLN(SEQ ID NO:102)
>B14032-HVR_L2
AASSLQSGV(SEQ ID NO:103)
>B15012-HVR_L2
AASTLQSGV(SEQ ID NO:104)
>B15014-HVR_L2
AASTLQSGV(SEQ ID NO:105)
>B15016-HVR_L2
AASSLQSGV(SEQ ID NO:106)
>B15022-HVR_L2
AASTLQSGV(SEQ ID NO:107)
>B15024-HVR_L2
AASTLQSGV(SEQ ID NO:108)
>B15041-HVR_L2
AASSLQSGV(SEQ ID NO:109)
>B15074-HVR_L2
AASTLQSGV(SEQ ID NO:110)
>B15082-HVR_L2
AASSLQSGV(SEQ ID NO:111)
>B14032-HVR_L3
YCQQYVSWPRGFT(SEQ ID NO:112)
>B15012-HVR_L3
YCQHYSSWPRGFT(SEQ ID NO:113)
>B15014-HVR_L3
YCQHYVSWPRQFT(SEQ ID NO:114)
>B15016-HVR_L3
YCQHYTSWPRQFT(SEQ ID NO:115)
>B15022-HVR_L3
YCQQYSSWPRLFT(SEQ ID NO:116)
>B15024-HVR_L3
YCQHYVSWPRLFT(SEQ ID NO:117)
>B15041-HVR_L3
YCQHYISWPRQFT(SEQ ID NO:118)
>B15074-HVR_L3
YCQHYISWPRVFT(SEQ ID NO:119)
>B15082-HVR_L3
YCQHYGSWPRRFT(SEQ ID NO:120)
在一些实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:121-125的氨基酸序列的VL:
DIQLTQSPSSLSASVGDRVTITCRASQX1X2X3X4X5LAWYQQKPGKAPKLLIYDASX6X7X8X9GX10PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDX11WPYTFGQGTKVEIKR(SEQ ID NO:121),其中
X1:G S
X2:I V
X3:E G S
X4:K P S
X5:F W Y
X6:N S
X7:L R
X8:A E
X9:S T
X10:I V
X11:A S Y
DIQLTQSPSSLSASVGDRVTITCRASX1SVDFX2GX3SFLX4WYQQKPGKAPKLLIYDASX5X6X7X8GX9PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDX10WPYTFGQGTKVEIKR(SEQ ID NO:122),其中:
X1:E Q
X2:F H Y
X3:I K
X4:A D
X5:N S
X6:L R
X7:A E
X8:S T
X9:I V
X10:A H S Y
DIQLTQSPSSLSASVGDRVTITCX1ASQX2IPX3FLX4WYQQKPGKAPKLLIYAASX5LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQX6YX7SWPRX8FTFGQGTKVEIKR(SEQ ID NO:123),其中:
X1:Q R
X2:D S T
X3:K S T
X4:A N
X5:S T
X6:H Q
X7:G I S T V
X8:G L Q R V
DIQLTQSPSSLSASVGDRVTITCRASQGX1SX2X3LAWYQQKPGKAPKLLIYDASNX4X5TGX6PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDX7WPYTFGQGTKVEIKR(SEQ ID NO:124),其中:
X1:I V
X2:P S
X3:W Y
X4:L R
X5:A E
X6:I V
X7:A S
DIQLTQSPSSLSASVGDRVTITCRASQX1IPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYX2SWPRQFTFGQGTKVEIKR(SEQ ID NO:125),其中:
X1:S T
X2:I T
在一些实施方案中,包含具有选自SEQ ID NO:121-122和124的氨基酸序列的VL的抗体或其片段与人和猴PD-L1具有交叉反应性。在某些实施方案中,包含具有选自SEQ IDNO:123和125的氨基酸序列的VL的抗体或其片段与人、猴和小鼠PD-L1具有交叉反应性。
在各种实施方案中,所述抗体或其片段还可以包含具有选自SEQ ID NO:164和167的氨基酸序列的HVR_H1、具有选自SEQ ID NO:165和168的氨基酸序列的HVR_H2、和/或具有选自SEQ ID NO:166和169的氨基酸序列的HVR_H3:
YTFSNYGIHWV(SEQ ID NO:164)
IGWIYPSGGGTKYAQKFQGRV(SEQ ID NO:165)
AREGGGYGYALDY(SEQ ID NO:166)
YSISSGYYWGWI(SEQ ID NO:167)
IGIIYPSGGGTNYAQKFQGRV(SEQ ID NO:168)
ARGGGLGFDY(SEQ ID NO:169)
在一些实施方案中,所述抗体或其片段还包含具有选自SEQ ID NO:126-127的氨基酸序列的VH。在实施方案中,所述抗体或其片段可以包含具有选自SEQ ID NO:128-163的氨基酸序列的VL。这些序列可以呈Fab的形式。
>B14032-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B14032-VL
DIQLTQSPSSLSASVGDRVTITCQASQDIPTFLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYVSWPRGFTFGQGTKVEIKR(SEQ ID NO:128)
>B14033-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14033-VL
DIQLTQSPSSLSASVGDRVTITCRASQGIGSFLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDYWPYTFGQGTKVEIKR(SEQ ID NO:129)
>B14614-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14614-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFYGKSFLDWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:130)
>B14615-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14615-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFYGKSFLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:131)
>B14617-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14617-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFFGKSFLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:132)
>B14622-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14622-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFYGKSFLDWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:133)
>B14627-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14627-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVSSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:134)
>B14631-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14631-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFFGKSFLAWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:135)
>B14633-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14633-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFHGISFLAWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:136)
>B14634-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14634-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVSPYLAWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:137)
>B14638-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14638-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVGSIYLGWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:138)
>B14642-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14642-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFYGKSFLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:139)
>B14644-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14644-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFYGKSFLAWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDYWPYTFGQGTKVEIKR(SEQ ID NO:140)
>B14645-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14645-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFYGKSFLDWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:141)
>B14650-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14650-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFYGKSFLDWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:142)
>B14651-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14651-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFHGKSFLAWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:143)
>B14652-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14652-VL
DIQLTQSPSSLSASVGDRVTITCRASQGVSPWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:144)
>B14654-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14654-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVSPYLAWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:145)
>B14658-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14658-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFHGKSFLDWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:146)
>B14665-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14665-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFYGKSFLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:147)
>B14673-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14673-VL
DIQLTQSPSSLSASVGDRVTITCRASESVDFYGKSFLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:148)
>B14674-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14674-VL
DIQLTQSPSSLSASVGDRVTITCRASQSIEKWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:149)
>B14681-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14681-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFHGISFLDWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:150)
>B14689-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14689-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFYGKSFLDWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDHWPYTFGQGTKVEIKR(SEQ ID NO:151)
>B14690-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B14690-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVDFHGISFLDWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:152)
>B15012-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15012-VL
DIQLTQSPSSLSASVGDRVTITCRASQTIPSFLNWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYSSWPRGFTFGQGTKVEIKR(SEQ ID NO:153)
>B15014-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15014-VL
DIQLTQSPSSLSASVGDRVTITCRASQDIPKFLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYVSWPRQFTFGQGTKVEIKR(SEQ ID NO:154)
>B15016-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15016-VL
DIQLTQSPSSLSASVGDRVTITCRASQTIPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYTSWPRQFTFGQGTKVEIKR(SEQ ID NO:155)
>B15022-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15022-VL
DIQLTQSPSSLSASVGDRVTITCRASQSIPSFLNWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSSWPRLFTFGQGTKVEIKR(SEQ ID NO:156)
>B15024-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15024-VL
DIQLTQSPSSLSASVGDRVTITCRASQSIPTFLNWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYVSWPRLFTFGQGTKVEIKR(SEQ ID NO:157)
>B15041-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15041-VL
DIQLTQSPSSLSASVGDRVTITCRASQSIPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYISWPRQFTFGQGTKVEIKR(SEQ ID NO:158)
>B15074-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15074-VL
DIQLTQSPSSLSASVGDRVTITCRASQTIPSFLNWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYISWPRVFTFGQGTKVEIKR(SEQ ID NO:159)
>B15082-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>B15082-VL
DIQLTQSPSSLSASVGDRVTITCRASQTIPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYGSWPRRFTFGQGTKVEIKR(SEQ ID NO:160)
>B13002-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B13002-VL
DIQLTQSPSSLSASVGDRVTITCRASQGVSSYLAWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:161)
>B13004-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B13004-VL
DIQLTQSPSSLSASVGDRVTITCRASQGISPWLAWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:162)
>B13005-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>B13005-VL
DIQLTQSPSSLSASVGDRVTITCRASQSVSSYLAWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:163)
在一些实施方案中,可以将以上序列中的一个或多个转化为IgG,诸如IgG1、IgG2、IgG3和IgG4。示例性IgG序列可以具有以下VH和/或VL:
>TY21418-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>TY21418-VL
DIQLTQSPSSLSASVGDRVTITCRASQGVSSYLAWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDAWPYTFGQGTKVEIKR(SEQ ID NO:161)
>TY21419-VH
EVQLVESGGGLVQPGGSLRLSCAASGYTFSNYGIHWVRQAPGKGLEWIGWIYPSGGGTKYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCAREGGGYGYALDYWGQGTLVTVSS(SEQ ID NO:126)
>TY21419-VL
DIQLTQSPSSLSASVGDRVTITCRASQGISPWLAWYQQKPGKAPKLLIYDASNRATGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDSWPYTFGQGTKVEIKR(SEQ ID NO:162)
>TY21420-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>TY21420-VL
DIQLTQSPSSLSASVGDRVTITCRASQTIPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYTSWPRQFTFGQGTKVEIKR(SEQ ID NO:155)
>TY21421-VH
EVQLVESGGGLVQPGGSLRLSCAASGYSISSGYYWGWIRQAPGKGLEWIGIIYPSGGGTNYAQKFQGRVTISRDNSKNTLYLQLNSLRAEDTAVYYCARGGGLGFDYWGQGTLVTVSS(SEQ ID NO:127)
>TY21421-VL
DIQLTQSPSSLSASVGDRVTITCRASQSIPSFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHYISWPRQFTFGQGTKVEIKR(SEQ ID NO:158)
在一些实施方案中,抗体或其抗原结合片段可以包含以下HVR区序列中的一个或多个(例如,在IgG中):
>TY21418-HVR_H1
YTFSNYGIHWV(SEQ ID NO:164)
>TY21418-HVR_H2
IGWIYPSGGGTKYAQKFQGRV(SEQ ID NO:165)
>TY21418-HVR_H3
AREGGGYGYALDY(SEQ ID NO:166)
>TY21418-HVR_L1
RASQGVSSYLA(SEQ ID NO:37)
>TY21418-HVR_L2
DASNLETGV(SEQ ID NO:64)
>TY21418-HVR_L3
YCQQYDAWPYT(SEQ ID NO:91)
>TY21419-HVR_H1
YTFSNYGIHWV(SEQ ID NO:164)
>TY21419-HVR_H2
IGWIYPSGGGTKYAQKFQGRV(SEQ ID NO:165)
>TY21419-HVR_H3
AREGGGYGYALDY(SEQ ID NO:166)
>TY21419-HVR_L1
RASQGISPWLA(SEQ ID NO:38)
>TY21419-HVR_L2
DASNRATGI(SEQ ID NO:65)
>TY21419-HVR_L3
YCQQYDSWPYT(SEQ ID NO:92)
>TY21420-HVR_H1
YSISSGYYWGWI(SEQ ID NO:167)
>TY21420-HVR_H2
IGIIYPSGGGTNYAQKFQGRV(SEQ ID NO:168)
>TY21420-HVR_H3
ARGGGLGFDY(SEQ ID NO:169)
>TY21420-HVR_L1
RASQTIPSFLN(SEQ ID NO:97)
>TY21420-HVR_L2
AASSLQSGV(SEQ ID NO:106)
>TY21420-HVR_L3
YCQHYTSWPRQFT(SEQ ID NO:115)
>TY21421-HVR_H1
YSISSGYYWGWI(SEQ ID NO:167)
>TY21421-HVR_H2
IGIIYPSGGGTNYAQKFQGRV(SEQ ID NO:168)
>TY21421-HVR_H3
ARGGGLGFDY(SEQ ID NO:169)
>TY21421-HVR_L1
RASQSIPSFLN(SEQ ID NO:100)
>TY21421-HVR_L2
AASSLQSGV(SEQ ID NO:109)
>TY21421-HVR_L3
YCQHYISWPRQFT(SEQ ID NO:118)
在某些情况下,使用抗体片段而不是整个抗体具有优势。较小的片段尺寸允许快速清除,并且可能导致改善对实体瘤的可及性。
已经开发了用于产生抗体片段的多种技术。传统上,这些片段是通过完整抗体的蛋白水解消化而衍生的(参见例如,Morimoto等人,J Biochem Biophys.Method.24:107-117(1992);以及Brennan等人,Science 229:81(1985))。然而,现在可以直接由重组宿主细胞产生这些片段。Fab、Fv和scFv抗体片段都可以在大肠杆菌中表达并且由大肠杆菌分泌,从而允许容易地产生大量的这些片段。可以从上文讨论的抗体噬菌体文库中分离抗体片段。可替代地,可以直接从大肠杆菌回收Fab'-SH片段并且将其化学偶联以形成F(ab')2片段(Carter等人,Bio/Technology 10:163-167(1992))。根据另一种方法,可以直接从重组宿主细胞培养物分离F(ab')2片段。具有增加的体内半衰期的Fab和F(ab')2描述于美国专利号5,869,046。在其他实施方案中,选择的抗体是单链Fv片段(scFv)。参见WO 93/16185;美国专利号5,571,894和美国专利号5,587,458。所述抗体片段也可以是“线性抗体”,例如,如美国专利号5,641,870中所描述的。此类线性抗体片段可以是单特异性的或双特异性的。
双特异性和多特异性抗体
双特异性抗体(BsAb)是对至少两种不同的表位(包括同一蛋白质或另一种蛋白质上的那些表位)具有结合特异性的抗体。可替代地,一条臂可以结合靶蛋白,并且另一条臂可以与结合淋巴细胞上的触发分子(诸如T细胞受体分子(例如,CD3),或IgG的Fc受体(FcγR),诸如FcγR1(CD64)、FcγRII(CD32)和FcγRIII(CD16))的臂组合,以便使细胞防御机制集中并且定位到表达靶抗原的细胞。此类抗体可以衍生自全长抗体或抗体片段(例如,F(ab')2双特异性抗体)。
双特异性抗体还可以用于将细胞毒剂定位到表达靶抗原的细胞。此类抗体具有结合所需抗原的一条臂和结合细胞毒性剂(例如,皂草素、抗干扰素-α、长春花生物碱、蓖麻毒素A链、氨甲蝶呤或放射性同位素半抗原)的另一条臂。已知的双特异性抗体的例子包括抗ErbB2/抗FcgRIII(WO 96/16673)、抗ErbB2/抗FcgRI(美国专利号5,837,234)、抗ErbB2/抗CD3(美国专利号5,821,337)。
用于制备双特异性抗体的方法是本领域已知的。全长双特异性抗体的传统产生基于两条免疫球蛋白重链/轻链对的共表达来进行,其中所述两条链具有不同的特异性。Millstein等人,Nature,305:537-539(1983)。由于免疫球蛋白重链和轻链的随机分配,这些杂交瘤(四源杂交瘤(quadromas))产生10种不同的抗体分子的潜在混合物,其中仅一种具有正确的双特异性结构。正确分子的纯化(其通常通过亲和色谱步骤进行)是相当麻烦的,并且产物产率很低。WO 93/08829中和Traunecker等人,EMBO J.,10:3655-3659(1991)中公开了相似的程序在。
根据不同的方法,将具有所需结合特异性(抗体抗原组合位点)的抗体可变结构域融合到免疫球蛋白恒定结构域序列。融合体优选地具有免疫球蛋白重链恒定结构域,其包含铰链区、CH2区和CH3区的至少一部分。优选的是使含有轻链结合所必需的位点的第一重链恒定区(CH1)存在于至少一种融合体中的。将编码免疫球蛋白重链融合体和(如果需要的话)免疫球蛋白轻链的DNA插入到单独表达载体中,并且共转染到合适的宿主生物体中。当构建中所使用的不等比率的三条多肽链提供最佳产率时,这在实施方案中为调整三个多肽片段的相互比例提供极大的灵活性。然而,当相等比率的至少两条多肽链的表达产生高产率时或当比率不是特别重要时,可能将两条或全部三条多肽链的编码序列插入一个表达载体中。
在此方法的优选的实施方案中,双特异性抗体由一条臂中的具有第一结合特异性的杂合免疫球蛋白重链和另一条臂中的杂合免疫球蛋白重链-轻链对(提供第二结合特异性)构成。发现此不对称结构有助于所需的双特异性化合物与不想要的免疫球蛋白链组合分离,因为免疫球蛋白轻链仅存在于双特异性分子的一半中提供容易的分离方法。这种方法公开在WO 94/04690中。关于生成双特异性抗体的进一步细节参见例如Suresh等人,Methods in Enzymology 121:210(1986)。
根据WO 96/27011或美国专利号5,731,168中所描述的另一种方法,一对抗体分子之间的界面可以经过工程化以便使从重组细胞培养物回收的异源二聚体的百分比最大化。优选的界面包含抗体恒定结构域的CH3区的至少一部分。在此方法中,将来自第一抗体分子的界面的一条或多条小氨基酸侧链用较大的侧链(例如,酪氨酸或色氨酸)替代。通过用较小的氨基酸侧链(例如,丙氨酸或苏氨酸)替代大氨基酸侧链,在第二抗体分子的界面上产生具有与一条或多条大侧链相同或相似尺寸的补偿性“腔”。这提供了用于相对于其他不想要的最终产物(诸如同源二聚体)增加异源二聚体的产率的机制。
用于从抗体片段生成双特异性抗体的技术描述在文献中。例如,双特异性抗体可以使用化学键联来制备。Brennan等人,Science 229:81(1985)描述了一种程序,其中将完整抗体进行蛋白水解裂解以生成F(ab')2片段。在二硫醇络合剂亚砷酸钠的存在下还原这些片段,以稳定邻近的二硫醇并且防止形成分子间二硫化物。然后将所生成的Fab'片段转化为硫代硝基苯甲酸(TNB)衍生物。然后将一种Fab'-TNB衍生物再转化为Fab'-TNB衍生物以形成双特异性抗体。所产生的双特异性抗体可以用作用于选择性固定酶的药剂。
可以直接从大肠杆菌回收Fab'片段并且将其化学偶联以形成双特异性抗体。Shalaby等人,J.Exp.Med.175:217-225(1992)描述了完全人源化双特异性抗体F(ab')2分子的产生。单独地从大肠杆菌分泌每个Fab'片段并且使其在体外经受定向化学偶联以形成双特异性抗体。由此形成的双特异性抗体能够结合到过表达ErbB2受体的细胞和正常人类T细胞,并且触发人类细胞毒性淋巴细胞针对人类乳腺肿瘤靶标的裂解活性。
也已描述了用于直接从重组细胞培养物制备和分离二价抗体片段的各种技术。例如,已使用亮氨酸拉链产生二价异源二聚体。Kostelny等人,J.Immunol.,148(5):1547-1553(1992)。将来自Fos和Jun蛋白的亮氨酸拉链肽通过基因融合连接到两种不同抗体的Fab'部分。将抗体同源二聚体在铰链区还原以形成单体,并且然后再氧化以形成抗体异源二聚体。Hollinger等人,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)所描述的“双抗体”技术为制造双特异性/二价抗体片段提供了替代性机制。所述片段包含通过接头连接到轻链可变结构域(VL)的重链可变结构域(VH),所述接头太短而不允许同一链上的两个结构域之间进行配对。因此,迫使一个片段的VH结构域和VL结构域与另一个片段的互补VL结构域和VH结构域配对,从而形成两个抗原结合位点。还已报道了用于通过使用单链Fv(sFv)二聚体制造双特异性/二价抗体片段的另一种策略。参见Gruber等人,J.Immunol.,152:5368(1994)。
考虑了具有超过两个价态的抗体。例如,可以制备三特异性抗体。Tutt等人,J.Immunol.147:60(1991)。
示例性双特异性抗体可以结合给定分子上的两个不同表位。可替代地,可以将抗蛋白臂与结合白细胞上的触发分子(诸如T细胞受体分子(例如,CD2、CD3、CD28或B7),或IgG的Fc受体(FcγR),诸如FcγRI(CD64)、FcγRII(CD32)和FcγRIII(CD16))的臂组合,以便使细胞防御机制集中到表达特定蛋白质的细胞。双特异性抗体也可以用于将细胞毒性剂定位到表达特定蛋白质的细胞。此类抗体具有蛋白质结合臂和结合细胞毒性剂或放射性核素螯合剂(诸如EOTUBE、DPTA、DOTA或TETA)的臂。另一种感兴趣的双特异性抗体结合感兴趣的蛋白质并且还结合组织因子(TF)。
免疫缀合物
本公开文本涵盖一种缀合至治疗性部分(诸如细胞毒素或化疗剂)以治疗癌症的人抗PD-L1抗体(“免疫缀合物”)。如本文所用,术语“免疫缀合物”是指与细胞毒素、放射性剂、细胞因子、干扰素、靶标或报告部分、酶、毒素、肽或蛋白质或治疗剂化学或生物连接的抗体。抗体可以在分子的任何位置处与细胞毒素、放射活性剂、细胞因子、干扰素、靶标或报告部分、酶、毒素、肽或治疗剂连接,只要它能够结合其靶标即可。免疫缀合物的例子包括抗体药物缀合物和抗体-毒素融合蛋白。在一个实施方案中,所述药剂可以是针对PD-L1的第二不同抗体。在某些实施方案中,抗体可以缀合至对肿瘤细胞或病毒感染的细胞具有特异性的药剂。可以缀合至抗PD-L1抗体的治疗部分的类型将考虑待治疗的病症和待实现的所需治疗效果。用于形成免疫缀合物的合适药剂的例子是本领域已知的;参见例如WO 05/103081。
效应子功能工程化
可能需要关于Fc效应子功能修饰本公开文本的抗体,例如以便修饰(例如,增强或消除)抗体的抗原依赖性细胞介导的细胞毒性(ADCC)和/或补体依赖性细胞毒性(CDC)。在一个优选的实施方案中,抗PD-L1抗体的Fc效应子功能被降低或消除。这可以通过在抗体的Fc区中引入一个或多个氨基酸取代来实现。可替代地或另外地,可以将一个或多个半胱氨酸残基引入所述Fc区中,从而允许在此区中形成链间二硫键。由此生成的同源二聚体抗体可以具有改善的内化能力和/或增加的补体介导的细胞杀伤和抗体依赖性细胞毒性(ADCC)。参见Caron等人,J.Exp Med.176:1191-1195(1992)和Shopes,B.J.Immunol.148:2918-2922(1992)。还可以使用异双功能交联剂制备具有增强的抗肿瘤活性的同源二聚体抗体,如Wolff等人,Cancer Research 53:2560-2565(1993)中所描述。可替代地,可以对抗体进行工程化,其具有双Fc区并且从而可以具有增强的补体裂解和ADCC能力。参见Stevenson等人,Anti-Cancer Drug Design 3:219-230(1989)。
为了增加抗体的血清半衰期,人员可以将补救受体结合表位掺入抗体(尤其是抗体片段)中,如例如美国专利号5,739,277中所描述。如本文所用,术语“补救受体结合表位”是指IgG分子(例如,IgG1、IgG2、IgG3或IgG4)的Fc区中负责增加IgG分子的体内血清半衰期的表位。
其他氨基酸序列修饰
考虑了本文描述的抗体的一种或多种氨基酸序列修饰。例如,可能需要改善抗体的结合亲和力和/或其他生物特性。通过将适当的核苷酸变化引入抗体核酸中或通过肽合成来制备抗体的氨基酸序列变体。此类修饰包括例如抗体的氨基酸序列内的残基的缺失、和/或插入和/或取代。进行缺失、插入和取代的任何组合以得到最终构建体,条件是最终构建体具有所需的特征。氨基酸变化还可以改变抗体的翻译后过程,诸如改变糖基化位点的数量或位置。
用于鉴定抗体的作为优选诱变位置的某些残基或区域的可用方法被称为“丙氨酸扫描诱变”,如由Cunningham和Wells在Science,244:1081-1085(1989)中所描述的。在此,鉴定残基或靶残基组(例如,带电荷的残基,诸如arg、asp、his、lys和glu)并且用中性或带负电的氨基酸(最优选地丙氨酸或聚丙氨酸)替代以影响氨基酸抗原的相互作用。然后通过在取代位点处针对其引入另外的或其他变体来完善对取代展示功能敏感性的那些氨基酸位置。因此,尽管用于引入氨基酸序列变异的位点是预先决定的,然而突变本身的本质不必预先决定。例如,为了分析给定位点处的突变的性能,在靶标密码子或区域处进行ala扫描或随机诱变,并且针对所需活性筛选所表达的抗体变体。
氨基酸序列插入包括氨基和/或羧基末端融合,长度范围从一个残基到含有一百个或更多个残基的多肽,以及单个或多个氨基酸残基的序列内插入。末端插入的例子包括具有N末端甲硫氨酰基残基的抗体或融合到细胞毒性多肽的抗体。所述抗体分子的其他插入变体包括将所述抗体的N末端或C末端与酶(例如,用于ADEPT)或增加所述抗体的血清半衰期的多肽融合。
变体的另一种类型是氨基酸取代变体。这些变体在抗体分子中具有被不同的残基替代的至少一个氨基酸残基。对于取代诱变最感兴趣的位点包括高变区,但是也考虑了FR改变。保守取代以标题“优选取代”示出在以下表1中。如果此类取代导致生物活性改变,则可以引入在表1中命名为“示例性取代”或如参考氨基酸类别在以下进一步描述的更多实质性变化,并且筛选产物。
表1.氨基酸取代
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对抗体的生物特性的实质性修饰通过选择取代来实现,所述取代对其维持以下方面的影响显著不同:(a)取代区域中的多肽主链的结构,例如呈折叠或螺旋构象;(b)分子在靶位点处的电荷或疏水性;或(c)侧链体积。基于共同的侧链特性,将天然存在的残基分为以下组:
(1)疏水性:正亮氨酸、Met、Ala、Val、Leu、Ile;
(2)中性亲水性:Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)碱性:Asn、Gln、His、Lys、Arg;
(5)影响链取向的残基:Gly、Pro;以及
(6)芳族:Trp、Tyr、Phe。
非保守取代将需要将这些类别中的一类的成员更换成另一类别。
也可以通常用丝氨酸来取代不参与维持抗体的适当构象的任何半胱氨酸残基,以改善分子的氧化稳定性并且防止异常交联。相反地,可以向抗体添加一个或多个半胱氨酸键以改善其稳定性(尤其是在抗体是诸如Fv片段的抗体片段的情况下)。
特别优选类型的取代变体涉及取代亲本抗体(例如,人源化或人抗体)的一个或多个高变区残基。通常,选择用于进一步开发的所得变体相对于生成所述变体的亲本抗体将具有改善的生物特性。用于生成此类取代变体的便利方法涉及使用噬菌体展示进行的亲和力成熟。简而言之,使若干高变区位点(例如,6-7个位点)突变以在每个位点处生成所有可能的氨基取代。由此生成的抗体变体从丝状噬菌体颗粒以单价方式展示,作为与包装在每个颗粒内的M13的基因III产物的融合体。然后对噬菌体展示的变体筛选如本文公开的其生物活性(例如,结合亲和力)。为了针对修饰鉴定候选高变区位点,可以进行丙氨酸扫描诱变以鉴定对抗原结合有显著贡献的高变区残基。可替代地或另外,可能有益的是,分析抗原-抗体复合物的晶体结构以鉴定抗体与其靶标(例如,PD-L1,B7.1)之间的接触点。此类接触残基和邻近残基是根据本文详述的技术进行取代的候选位点。一旦生成此类变体,就使这组变体经受如本文所描述的筛选,并且可以选择在一个或多个相关测定中具有优异特性的抗体以用于进一步开发。
抗体的另一种类型的氨基酸变体改变抗体的原始糖基化模式。改变意指使抗体中存在的一个或多个碳水化合物部分缺失、和/或添加抗体中不存在的一个或多个糖基化位点。
抗体的糖基化典型地是N连接或O连接的。N连接是指碳水化合物部分与天冬酰胺残基的侧链附接。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除了脯氨酸之外的任何氨基酸)是用于将碳水化合物部分酶促附接到天冬酰胺侧链的识别序列。因此,在多肽中存在这些三肽序列中的任一个产生了潜在的糖基化位点。O连接的糖基化是指糖N-乙酰半乳糖胺、半乳糖或木糖中的一种附接到羟基氨基酸,最常见的是丝氨酸或苏氨酸,虽然也可使用5-羟基脯氨酸或5-羟基赖氨酸。
向抗体添加糖基化位点便利地通过以下方式来实现:改变氨基酸序列,使得其含有以上所描述的三肽序列中的一个或多个(对于N连接的糖化位点)。也可以通过向原始抗体的序列添加一个或多个丝氨酸或苏氨酸残基或用一个或多个丝氨酸或苏氨酸残基取代来进行改变(对于O连接的糖基化位点)。
编码本公开文本的抗体的氨基酸序列变体的核酸分子可以通过本领域已知的多种方法来制备。这些方法包括但不限于从天然来源分离(在天然存在氨基酸序列变体的情况中),或者通过对较早制备的变体或非变体形式进行寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来制备。
其他抗体修饰
可以将本公开文本的抗体进一步修饰以含有本领域已知的且易于获得的额外非蛋白质部分。优选地,适于使抗体衍生化的部分是水溶性聚合物。水溶性聚合物的非限制性例子包括但不限于聚乙二醇(PEG)、乙二醇/丙二醇的共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊环、聚-1,3,6-三噁烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或无规共聚物)、和葡聚糖或聚(n-乙烯基吡咯烷酮)聚乙二醇、聚丙二醇均聚物、聚氧化丙烯/氧化乙烯共聚物、聚氧乙基化多元醇(例如,甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛由于其在水中的稳定性而可以在制备中具有优势。所述聚合物可以具有任何分子量,并且可以是分支或未分支的。附接到抗体的聚合物的数量可以变化,并且如果附接多于一种聚合物,则它们可以是相同或不同的分子。通常,用于衍生化的聚合物的数量和/或类型可以基于包括但不限于有待改善的抗体的具体特性或功能、抗体衍生物是否将在限定条件下用于疗法中等考虑因素来确定。此类技术和其他合适的配制品公开在Remington:The Science and Practice of Pharmacy,第20版,Alfonso Gennaro编,PhiladelphiaCollege of Pharmacy and Science(2000)中。
抗体的治疗用途
本公开文本的抗体可用于治疗、预防和/或改善疾病或障碍或病症,诸如癌症、自身免疫疾病或病毒感染和/或用于改善与此类疾病、障碍或病症相关联的至少一种症状。在本公开文本的一些实施方案中,本文描述的抗体可用于治疗患有原发性或复发性癌症的受试者,所述癌症包括例如肾细胞癌、前列腺癌、卵巢癌、肾癌、结直肠癌、胃癌、乳腺癌、头颈癌、非小细胞肺癌、脑癌、多发性骨髓瘤和黑素瘤。所述抗体可以用于治疗癌症的早期或晚期症状。在一个实施方案中,本公开文本的抗体或其片段可以用于治疗转移性癌症。所述抗体可用于减少或抑制或缩减实体瘤和血液癌的肿瘤生长。在某些实施方案中,抗体可以用于预防肿瘤复发。在某些实施方案中,用本公开文本的抗体或其抗原结合片段进行的治疗可以导致受试者的肿瘤的超过50%消退、超过60%消退、超过70%消退、超过80%消退或超过90%消退。在某些实施方案中,抗体可以用于增加患有癌症的受试者的存活。
在某些实施方案中,本公开文本的抗体可用于治疗患有慢性病毒感染的受试者。在一些实施方案中,本公开文本的抗体可用于降低宿主中的病毒滴度和/或拯救耗竭的T细胞。在一个实施方案中,本公开文本的抗体或其抗原结合片段可以以治疗剂量施用于被人免疫缺陷病毒(HIV)或人乳头瘤病毒(HPV)或乙型/丙型肝炎病毒(HBV/HCV)感染的患者。在一个相关实施方案中,本公开文本的抗体或其抗原结合片段可以用于治疗猿猴受试者(诸如食蟹猴)的猿猴免疫缺陷病毒(SIV)感染。在另一个实施方案中,本公开文本的抗体或其片段可以用于治疗淋巴细胞性脉络丛脑膜炎病毒(LCMV)的慢性病毒感染。
在某些实施方案中,可以以治疗有效量向患有癌症或病毒感染的受试者施用本公开文本的阻断抗体。
在某些实施方案中,本公开文本的抗体可用于治疗自身免疫疾病,包括但不限于斑秃、自身免疫性肝炎、乳糜泻、格雷夫斯病、格林-巴利综合征(Guillain-Barresyndrome)、桥本氏病(Hashimoto's disease)、溶血性贫血、炎性肠病、炎性肌病、多发性硬化症、原发性胆汁性肝硬化、银屑病、类风湿性关节炎、硬皮病、斯耶格伦氏综合征、系统性红斑狼疮、白癜风、自身免疫性胰腺炎、自身免疫性荨麻疹、自身免疫性血小板减少性紫癜、克罗恩氏病、I型糖尿病、嗜酸性筋膜炎、嗜酸性胃肠炎、古德帕斯彻氏综合征、重症肌无力、银屑病性关节炎、风湿热、溃疡性结肠炎、血管炎和韦格纳肉芽肿病。在某些实施方案中,本公开文本的激活抗体可以用于治疗患有自身免疫疾病的受试者。
可以施用本公开文本的一种或多种抗体以缓解或预防或降低疾病或障碍的一种或多种症状或状况的严重性。
本文还考虑将本公开文本的一种或多种抗体预防性地用于处于发展疾病或障碍(诸如癌症和慢性病毒感染)风险的患者。
在本公开文本的另一个实施方案中,本发明的抗体用于制备用于治疗患有癌症、自身免疫疾病或病毒感染的患者的药物组合物。在本公开文本的另一个实施方案中,本发明的抗体用作与本领域技术人员已知的可用于治疗癌症、自身免疫疾病或病毒感染的任何其他药剂或任何其他疗法的辅助疗法。
组合疗法
组合疗法可以包括本公开文本的抗PD-L1抗体和可以有利地与本公开文本的抗体或与本公开文本的抗体的生物学活性片段组合的任何另外的治疗剂。
本公开文本的抗体可以与一种或多种用于治疗癌症的抗癌药物或疗法协同组合,所述癌症包括例如肾细胞癌、卵巢癌、前列腺癌、结直肠癌、非小细胞肺癌和黑素瘤。本文考虑将本公开文本的抗PD-L1抗体与免疫刺激和/或免疫支持疗法组合使用以抑制肿瘤生长和/或增强癌症患者的存活。免疫刺激疗法包括直接免疫刺激疗法,以通过对受抑制的免疫细胞“放松抑制”或“加大油门”激活免疫应答来加强免疫细胞活性。例子包括靶向其他检查点受体、疫苗接种和佐剂。免疫支持方式可以通过促进免疫原性细胞死亡、炎症来增加肿瘤的抗原性或具有其他促进抗肿瘤免疫应答的间接作用。
例子包括放射、化疗、抗血管生成剂、和手术。
在各种实施方案中,本公开文本的一种或多种抗体可以与以下物质组合来治疗癌症:针对PD-L1的第二抗体、针对PD-1的抗体(例如,纳武单抗)、LAG-3抑制剂、CTLA-4抑制剂(例如,伊匹单抗)、TIM3抑制剂、BTLA抑制剂、TIGIT抑制剂、CD47抑制剂、另一种T细胞共抑制剂或配体的拮抗剂(例如,针对CD-28、2B4、LY108、LAIR1、ICOS、CD160或VISTA的抗体)、吲哚胺-2,3-双加氧酶(IDO)抑制剂、血管内皮生长因子(VEGF)拮抗剂[例如,“VEGF-Trap”,诸如如在US 7,087,41 1中列出的阿柏西普或其他抑制VEGF的融合蛋白,或抗VEGF抗体或其抗原结合片段(例如,贝伐单抗或雷珠单抗)或VEGF受体的小分子激酶抑制剂(例如,舒尼替尼、索拉非尼或帕唑帕尼)]、Ang2抑制剂(例如,奈伐苏单抗(nesvacumab))、转化生长因子β(TGF3)抑制剂、表皮生长因子受体(EGFR)抑制剂(例如,厄洛替尼、西妥昔单抗)、共刺激受体的激动剂(例如,糖皮质激素诱导的TNFR相关蛋白的激动剂)、肿瘤特异性抗原(例如,CA9、CA125、黑素瘤相关抗原3(MAGE3)、癌胚抗原(CEA)、波形蛋白、肿瘤M2-PK、前列腺特异性抗原(PSA)、粘蛋白-1、MART-1和CA19-9)的抗体、疫苗(例如,卡介苗(一种癌症疫苗))、增加抗原呈递的佐剂(例如,粒细胞-巨噬细胞集落刺激因子)、双特异性抗体(例如,CD3xCD20双特异性抗体、PSMAxCD3双特异性抗体)、细胞毒素、化疗剂(例如,达卡巴嗪、替莫唑胺、环磷酰胺、多西他赛、阿霉素、柔红霉素、顺铂、卡铂、吉西他滨、氨甲蝶呤、米托蒽醌、奥沙利铂、紫杉醇和长春新碱)、环磷酰胺、放射疗法、IL-6R抑制剂(例如,萨瑞鲁单抗)、IL-4R抑制剂(例如,度匹鲁单抗)、IL-10抑制剂、细胞因子(诸如IL-2、IL-7、IL-21和IL-15)、抗体-药物缀合物(ADC)(例如,抗CD19-DM4 ADC和抗DS6-DM4 ADC)、抗炎药(例如,皮质类固醇和非甾体类抗炎药)、膳食补充剂(诸如抗氧化剂)或任何姑息疗护。在某些实施方案中,本公开文本的抗PD-L1抗体可以与包括树突细胞疫苗、溶瘤病毒、肿瘤细胞疫苗等的癌症疫苗组合使用以加强抗肿瘤应答。可以与本公开文本的抗PD-L1抗体组合使用的癌症疫苗的例子包括针对黑素瘤和膀胱癌的MAGE3疫苗、针对乳腺癌的MUC1疫苗、针对脑癌(包括多形性胶质母细胞瘤)的EGFRv3(例如,Rindopepimut)、或ALVAC-CEA(针对CEA+癌症)。在某些实施方案中,本公开文本的抗PD-L1抗体可以与膳食补充剂(诸如抗氧化剂)或任何姑息疗护组合使用以治疗癌症。
在某些实施方案中,本公开文本的抗PD-L1抗体可以在产生长期持久的抗肿瘤应答和/或增强癌症患者的存活的方法中与放射疗法组合施用。在一些实施方案中,本公开文本的抗PD-L1抗体可以在向癌症患者施用放射疗法之前、同时或之后施用。例如,可以一个或多个剂量对肿瘤病变施用放射疗法,接着施用一个或多个剂量的本公开文本的抗PD-L1抗体。在一些实施方案中,可以对肿瘤病变局部施用放射疗法以增强患者肿瘤的局部免疫原性(辅助放射)和/或杀死肿瘤细胞(消融放射),接着全身性施用本公开文本的抗PD-L1抗体。例如,可以与本公开文本的抗PD-L1抗体的全身性施用一起向患有脑癌(例如,多形性胶质母细胞瘤)的患者施用颅内放射。在某些实施方案中,本公开文本的抗PD-L1抗体可以与放射疗法和化疗剂(例如,替莫唑胺)或VEGF拮抗剂(例如,阿柏西普)组合施用。
本公开文本的抗体或其片段可以与本领域已知的一种或多种抗病毒药物组合施用,所述抗病毒药物包括但不限于齐多夫定、拉米夫定、阿巴卡韦、利巴韦林、洛匹那韦、依法韦仑、可比司他、泰诺福韦、利匹韦林和皮质类固醇。在一些实施方案中,本公开文本的抗PD-L1抗体可以与LAG3抑制剂、CTLA-4抑制剂、PD-1抑制剂或另一种T细胞共抑制剂的任何拮抗剂组合施用以治疗慢性病毒感染。
本公开文本的抗体或其片段可以与本领域已知的任何药物或疗法(例如,皮质类固醇和其他免疫抑制剂)组合用于治疗自身免疫疾病或障碍,包括但不限于斑秃、自身免疫性肝炎、乳糜泻、格雷夫斯病、格林-巴利综合征、桥本氏病、溶血性贫血、炎性肠病、炎性肌病、多发性硬化症、原发性胆汁性肝硬化、银屑病、类风湿性关节炎、硬皮病、斯耶格伦氏综合征、系统性红斑狼疮、白癜风、自身免疫性胰腺炎、自身免疫性荨麻疹、自身免疫性血小板减少性紫癜、克罗恩氏病、I型糖尿病、嗜酸性筋膜炎、嗜酸性胃肠炎、古德帕斯彻氏综合征、重症肌无力、银屑病性关节炎、风湿热、溃疡性结肠炎、血管炎和韦格纳肉芽肿病。
可以在本公开文本的抗PD-L1抗体的施用之前、同时或之后施用一种或多种另外的治疗活性组分。出于本公开文本的目的,此类施用方案被认为是将抗PD-L1抗体与第二治疗活性组分“组合”施用。
可以在本公开文本的抗PD-L1抗体的施用之前向受试者施用一种或多种另外的治疗活性组分。例如,如果第一组分在第二组分的施用之前1周、之前72小时、之前60小时、之前48小时、之前36小时、之前24小时、之前12小时、之前6小时、之前5小时、之前4小时、之前3小时、之前2小时、之前1小时、之前30分钟、之前15分钟、之前10分钟、之前5分钟或之前小于1分钟施用,则可以认为第一组分在第二组分“之前”施用。在其他实施方案中,可以在本公开文本的抗PD-L1抗体的施用之后向受试者施用一种或多种另外的治疗活性组分。例如,如果第一组分在第二组分的施用之后1分钟、之后5分钟、之后10分钟、之后15分钟、之后30分钟、之后1小时、之后2小时、之后3小时、之后4小时、之后5小时、之后6小时、之后12小时、之后24小时、之后36小时、之后48小时、之后60小时、之后72小时施用,则可以认为第一组分在第二组分“之后”施用。在又其他实施方案中,可以与本公开文本的抗PD-L1抗体的施用同时向受试者施用一种或多种另外的治疗活性组分。出于本公开文本的目的,“同时”施用包括例如以单一剂型(例如,共同配制的)向受试者施用抗PD-L1抗体和另外的治疗活性组分,或以单独剂型在彼此约30分钟或更短内向受试者施用。如果以单独剂型施用,则每种剂型可以经由相同的途径施用(例如,抗PD-L1抗体和另外的治疗活性组分两者可以静脉内、皮下等施用);可替代地,每种剂型可以经由不同的途径施用(例如,抗PD-L1抗体可以静脉内施用,并且另外的治疗活性组分可以皮下施用)。在任何情况下,出于本公开文本的目的,以单一剂型、通过相同的途径以单独剂型、或通过不同途径以单独剂型施用组分均被认为是“同时施用”。出于本公开文本的目的,在施用另外的治疗活性组分“之前”、“同时”或“之后”(如以上在本文中所定义的那些术语)施用抗PD-L1抗体被认为是抗PD-L1抗体与另外的治疗活性组分“组合”施用。
本公开文本包括其中使用多种剂量组合将本公开文本的抗PD-L1抗体与如在本文其他地方描述的一种或多种另外的治疗活性组分共同配制的药物组合物。
在其中将本公开文本的抗PD-L1抗体与VEGF拮抗剂(例如,VEGF trap,诸如阿柏西普)组合施用(包括施用包含抗PD-L1抗体和VEGF拮抗剂的共配制品)的示例性实施方案中,可以使用多种剂量组合将单独的组分施用于受试者和/或共同配制。例如,可以将抗PD-L1抗体以选自以下的量施用于受试者和/或包含在共配制品中:0.01mg、0.02mg、0.03mg、0.04mg、0.05mg、0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg、5.0mg、6.0mg、7.0mg、8.0mg、9.0mg和10.0mg;并且可以将VEGF拮抗剂(例如,VEGF trap,诸如阿柏西普)以选自以下的量施用于受试者和/或包含在共配制品中:0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、1.1mg、1.2mg、1.3mg、1.4mg、1.5mg、1.6mg、1.7mg、1.8mg、1.9mg、2.0mg、2.1mg、2.2mg、2.3mg、2.4mg、2.5mg、2.6mg、2.7mg、2.8mg、2.9mg和3.0mg。可以根据本文其他地方公开的任何施用方案向受试者施用组合/共配制品,所述施用方案包括例如每周两次、每周一次、每2周一次、每3周一次、每月一次、每2个月一次、每3个月一次、每4个月一次、每5个月一次、每6个月一次等。
抗体的诊断用途
本公开文本的抗PD-L1抗体可以用于检测和/或测量例如用于诊断目的的样品中的PD-L1。一些实施方案考虑了本公开文本的一种或多种抗体在测定中检测疾病或障碍(诸如癌症、自身免疫疾病或慢性病毒感染)的用途。用于PD-L1的示例性诊断测定可以包括例如使从患者获得的样品与本公开文本的抗PD-L1抗体接触,其中将所述抗PD-L1抗体用可检测的标记或报告分子标记或用作捕获配体以从患者样品中选择性分离PD-L1。可替代地,未标记的抗PD-L1抗体可以与本身可检测地标记的第二抗体组合用于诊断应用。可检测的标记或报告分子可以是放射性同位素,诸如3H、14C、32P、35S或125l;荧光或化学发光部分,诸如异硫氰酸荧光素或罗丹明;或酶,诸如碱性磷酸酶、β-半乳糖苷酶、辣根过氧化物酶、或荧光素酶。可以用于检测或测量样品中的PD-L1的特定示例性测定包括酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)和荧光激活细胞分选(FACS)。
可以用于根据本公开文本的PD-L1诊断测定的样品包括可从患者获得的处在正常或病理状况下的含有可检测量的PD-L1蛋白或其片段的任何组织或液体样品。
通常,将测量从健康患者(例如,未患癌症或自身免疫疾病的患者)获得的特定样品中的PD-L1水平以初步建立基线或标准PD-L1水平。然后可以将此基线PD-L1水平与从怀疑具有癌症相关病症或与这种病症相关联的症状的个体获得的样品中测量的PD-L1水平进行比较。
对PD-L1具有特异性的抗体可以不含另外的标记或部分,或者它们可以含有N末端或C末端标记或部分。在一个实施方案中,标记或部分是生物素。在结合测定中,标记(如果有的话)的位置可以确定肽相对于与肽结合的表面的取向。例如,如果表面涂覆有抗生物素蛋白,则含有N末端生物素的肽将被取向成使得肽的C末端部分将在所述表面的远端。
本公开文本的方面涉及所公开的抗体作为用于预测患者的癌症或自身免疫障碍的预后的标记物的用途。本公开文本的抗体可以在诊断测定中用于评估患者的癌症的预后并且预测存活。
药物配制品
通过将具有所需纯度的活性成分与任选的药学上可接受的载体、赋形剂或稳定剂(Remington:The Science and Practice of Pharmacy,第20版,Lippincott Williams&Wiklins,Pub.,Gennaro编,Philadelphia,Pa.2000)混合来制备治疗配制品,供贮存用。可接受的载体、赋形剂或稳定剂在所采用的剂量和浓度下对受体是无毒的,而且包括缓冲液、抗氧化剂(包括抗坏血酸、甲硫氨酸、维生素E、偏亚硫酸氢钠);防腐剂、等渗调节剂、稳定剂、金属复合物(例如,Zn-蛋白质复合物);螯合剂(诸如EDTA)和/或非离子表面活性剂。
当治疗剂是抗体片段时,特异性结合靶蛋白的结合结构域的最小抑制片段是优选的。例如,基于抗体的可变区序列,可以设计保留结合靶蛋白序列的能力的抗体片段或甚至肽分子。此类肽可以化学合成和/或通过重组DNA技术生产(参见例如,Marasco等人,Proc.Natl.Acad.Sci.USA 90:7889-7893[1993])。
缓冲液用于将pH控制在优化治疗有效性的范围内,尤其如果稳定性是pH依赖性的话。缓冲液优选以约50mM至约250mM范围的浓度存在。适于与本公开文本一起使用的缓冲液包括有机酸和无机酸两者及其盐。例如,柠檬酸盐、磷酸盐、琥珀酸盐、酒石酸盐、富马酸盐、葡糖酸盐、草酸盐、乳酸盐、乙酸盐。另外,缓冲液可以由组氨酸和三甲胺盐(诸如Tris)构成。
添加防腐剂以延缓微生物生长,并且典型地以0.2%-1.0%(w/v)的范围存在。用于本公开文本的合适防腐剂包括十八烷基二甲基苄基氯化铵;六甲氯铵;苯扎卤铵(例如,苯扎氯铵、苯扎溴铵、苯扎碘铵)、苄索氯铵;硫柳汞、苯酚、丁醇或苄基醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇、3-戊醇和间甲酚。
存在张力剂(有时称为“稳定剂”),以调节或维持组合物中液体的张力。当与大的带电生物分子(诸如蛋白质和抗体)一起使用时,它们通常被称为“稳定剂”,因为它们可以与氨基酸侧链的带电基团相互作用,从而减少分子间和分子内相互作用的可能性。考虑到其他成分的相对量,张力剂能以0.1%至25%重量,优选1%至5%的任何量存在。优选的张力剂包括多元糖醇,优选三元糖醇或更高级糖醇,诸如丙三醇、赤藓糖醇、阿拉伯糖醇、木糖醇、山梨糖醇和甘露糖醇。
另外的赋形剂包括可以充当以下中的一种或多种的药剂:(1)增量剂,(2)溶解度增强剂,(3)稳定剂以及(4)防止变性或粘附到容器壁上的药剂。此类赋形剂包括:多元糖醇(上面列举的);氨基酸,诸如丙氨酸、甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸、赖氨酸、鸟氨酸、亮氨酸、2-苯丙氨酸、谷氨酸、苏氨酸等;有机糖或糖醇,诸如蔗糖、乳糖、乳糖醇、海藻糖、水苏糖、甘露糖、山梨糖、木糖、核糖、核糖醇、肌肉肌糖、肌肉肌醇、半乳糖、半乳糖醇、甘油、环醇(例如肌醇)、聚乙二醇;含硫还原剂,诸如脲、谷胱甘肽、硫辛酸、硫代乙醇酸钠、硫代甘油、α-单硫代甘油和硫代硫酸钠;低分子量蛋白质,诸如人血清白蛋白、牛血清白蛋白、明胶或其他免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;单糖(例如,木糖、甘露糖、果糖、葡萄糖;二糖(例如,乳糖、麦芽糖、蔗糖);三糖,诸如棉子糖;以及多糖,诸如糊精或葡聚糖。
存在非离子表面活性剂或洗涤剂(也称为“润湿剂”)以帮助溶解治疗剂以及保护治疗性蛋白免受搅动诱导的聚集,这也允许配制品暴露于剪切表面应力而不引起所述活性治疗蛋白或抗体的变性。非离子表面活性剂以约0.05mg/ml至约1.0mg/ml、优选约0.07mg/ml至约0.2mg/ml的范围存在。
合适的非离子表面活性剂包括聚山梨醇酯(20、40、60、65、80等),泊洛沙姆(polyoxamer)(184、188等),多元醇,/>聚氧乙烯脱水山梨糖醇单醚(/>等),聚桂醇400,聚烃氧40硬脂酸酯,聚氧乙烯氢化蓖麻油10、50和60,单硬脂酸甘油酯,蔗糖脂肪酸酯,甲基纤维素和羧甲基纤维素。可以使用的阴离子洗涤剂包括十二烷基硫酸钠、二辛基磺基琥珀酸钠和二辛基磺酸钠。阳离子洗涤剂包括苯扎氯铵或苄索氯铵。
为了配制品用于体内施用,它们必须是无菌的。通过无菌滤膜过滤,可以使得所述配制品变成无菌的。通常将本文中的治疗性组合物置入具有无菌存取口的容器中,例如具有皮下注射针可刺穿的塞子的静脉内溶液袋或小瓶。
施用途径是根据已知且可接受的方法,诸如通过单次或多次推注或者以合适的方式长时间输注,例如通过皮下、静脉内、腹膜内、肌肉内、动脉内、病灶内或关节内途径注射或输注,局部施用,吸入或通过持续释放或延长释放方式。
本文中的配制品还可以含有多于一种的所治疗特定适应症所必需的活性化合物,优选彼此没有不利影响的活性互补的那些。可替代地或另外地,所述组合物可以包含细胞毒剂、细胞因子或生长抑制剂。此类分子适合地以对预期目的有效的量组合存在。
活性成分也可以包埋在例如通过凝聚技术或通过界面聚合制备的微胶囊(例如分别为羟甲基纤维素或明胶-微胶囊以及聚-(甲基丙烯酸甲酯)微胶囊)中、包埋在胶体药物递送系统中(例如脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)、或包埋在粗乳液中。此类技术在同上的Remington's Pharmaceutical Sciences第18版中公开。
通过使用无毒的“水溶性多价金属盐”,可以增强本文描述的蛋白质和抗体的稳定性。例子包括Ca2+、Mg2+、Zn2+、Fe2+、Fe3+、Cu2+、Sn2+、Sn4+、Al2+和Al3+。可以与以上多价金属阳离子形成水溶性盐的示例性阴离子包括由无机酸和/或有机酸形成的那些阴离子。此类水溶性盐在水中(在20℃下)具有至少约20mg/ml、可替代地至少约100mg/ml、可替代地至少约200mg/ml的溶解度。
可以用于形成“水溶性多价金属盐”的合适的无机酸包括盐酸、乙酸、硫酸、硝酸、硫氰酸和磷酸。可以使用的合适的有机酸包括脂族羧酸和芳族酸。在此定义内的脂族酸可以被定义为饱和或不饱和的C2-9羧酸(例如,脂族单、二和三羧酸)。例如,在此定义内的示例性单羧酸包括以下饱和C2-9单羧酸:乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸壬酸和capryonic酸,以及以下不饱和C2-9单羧酸:丙烯酸、丙炔酸(propriolic)甲基丙烯酸、巴豆酸和异巴豆酸。示例性二羧酸包括以下饱和C2-9二羧酸:丙二酸、琥珀酸、戊二酸、己二酸和庚二酸,而不饱和C2-9二羧酸包括马来酸、富马酸、柠康酸和中康酸。示例性三羧酸包括饱和C2-9三羧酸:丙三羧酸和1,2,3-丁烷三羧酸。另外,此定义的羧酸还可以含有一个或两个羟基以形成羟基羧酸。示例性羟基羧酸包括乙醇酸、乳酸、甘油酸、亚酒石酸、苹果酸、酒石酸和柠檬酸。此定义内的芳族酸包括苯甲酸和水杨酸。
可以用于帮助稳定本公开文本的包封多肽的常用水溶性多价金属盐包括例如:(1)卤化物的无机酸金属盐(例如,氯化锌、氯化钙)、硫酸盐、硝酸盐、磷酸盐和硫氰酸盐;(2)脂族羧酸金属盐(例如,乙酸钙、乙酸锌、丙酸钙、乙醇酸锌、乳酸钙、乳酸锌和酒石酸锌);以及(3)苯甲酸盐(例如,苯甲酸锌)和水杨酸盐的芳族羧酸金属盐。
药物剂量
本公开文本的药物组合物的剂量和所需药物浓度可以根据设想的特定用途而变化。确定施用的适当剂量或途径完全在普通技术人员的范围内。动物实验为针对人类疗法的有效剂量的确定提供可靠的指导。有效剂量的种间类推可以遵循Mordenti,J.和Chappell,W.“The Use of Interspecies Scaling in Toxicokinetics,”InToxicokinetics and New Drug Development,Yacobi等人编,Pergamon Press,纽约1989,第42-46页中制定的原则进行。
在使用体内施用本文描述的多肽或抗体时,正常剂量可以根据施用途径从约10ng/kg哺乳动物体重/天变化至约100mg/kg哺乳动物体重/天或更多、优选约1mg/kg/天变化至10mg/kg/天。关于具体的剂量和递送方法的指导提供在文献中;参见例如,美国专利号4,657,760;5,206,344;或5,225,212。在本公开文本的范围内,不同的配制品对于不同的治疗和不同的障碍是有效的,并且旨在治疗特定器官或组织的施用可能需要以不同于针对另一种器官或组织的方式的方式进行递送。此外,剂量可以通过一个或多个单独的施用或通过连续输注来施用。对于若干天或更长时间内的重复施用,取决于病症,持续进行治疗,直至实现所需的疾病症状抑制。然而,其他剂量方案可以是有用的。容易通过常规技术和测定来监测此疗法的进展。
配制品的施用
根据已知方法将本公开文本的配制品(包括但不限于重构配制品和液体配制品)施用于需要用抗PD-L1抗体治疗的哺乳动物(优选是人),所述已知方法诸如作为大丸剂进行静脉内施用或通过在一段时间内进行连续输注(通过肌肉内、腹膜内、脑脊液内、皮下、关节内、滑膜内、鞘内、口服、局部或吸入途径)。
在优选实施方案中,通过皮下(即,在皮肤下)施用向哺乳动物施用配制品。出于此类目的,可以使用注射筒注射配制品。然而,用于施用配制品的其他装置是可用的,诸如注射装置(例如,INJECT-EASETM和GENJECTTM装置);注射器笔(诸如GENPENTM);自动注射器装置,无针装置(例如,MEDIJECTORTM和BIOJECTORTM);以及皮下贴片递送系统。
在一个具体的实施方案中,本公开文本涉及用于单剂施用单位的试剂盒。此类试剂盒包括治疗性蛋白质或抗体的水性配制品的容器,包括单室或多室预装填注射筒。示例性预装填注射筒可以从Vetter GmbH(拉芬斯堡(Ravensburg),德国)获得。
蛋白质的适当剂量(“治疗有效量”)将取决于例如待治疗的病症、病症的严重性和病程、是否出于预防或治疗目的施用所述蛋白质、先前的疗法、患者的临床病史和对抗PD-L1抗体的应答、所用配制品的形式、以及主治医师的判断。可以将抗PD-L1抗体一次或通过一系列治疗适当地施用于患者,并且可以在从诊断开始的任何时间施用于患者。抗PD-L1抗体可以作为单独的治疗施用或与可用于治疗所讨论的病症的其他药物或疗法联合施用。
对于抗PD-L1抗体,用于向患者施用的初始候选剂量可以在约0.1-20mg/kg的范围内,其可以采取一个或多个单独施用的形式。然而,其他剂量方案可以是有用的。容易通过常规技术来监测此类疗法的进展。
根据本公开文本的某些实施方案,可以在定义的时程内向受试者施用多个剂量的抗PD-LI抗体(或包含抗PD-L1抗体和本文提及的任何另外的治疗活性剂的组合的药物组合物)。根据本公开文本的此方面的方法包括向受试者依次施用多个剂量的本公开文本的抗PD-L1抗体。如本文所用,“依次施用”意指将每个剂量的抗PD-L1抗体在不同时间点施用于受试者,例如,以预定间隔(例如,数小时、数天、数周或数月)隔开的不同日期。本公开文本包括这样的方法,所述方法包括依次向患者施用单一初始剂量的抗PD-L1抗体,接着施用一个或多个二级剂量的抗PD-LI抗体,并且任选地接着施用一个或多个三级剂量的抗PD-L1抗体。抗PD-L1抗体可以以在0.1mg/kg至约100mg/kg之间的剂量施用。
术语“初始剂量”、“二级剂量”和“三级剂量”是指施用本公开文本的抗PD-L1抗体的时间顺序。因此,“初始剂量”是在治疗方案开始时施用的剂量(也称为“基线剂量”);“二级剂量”是在初始剂量之后施用的剂量;并且“三级剂量”是在二级剂量之后施用的剂量。初始、二级和三级剂量可以均含有相同量的抗PD-L1抗体,但通常在施用频率方面可以彼此不同。然而,在某些实施方案中,初始、二级和/或三级剂量中含有的抗PD-L1抗体的量在治疗过程中彼此不同(例如,适当时向上或向下调整)。在某些实施方案中,在治疗方案开始时施用两个或更多个(例如,2、3、4或5个)剂量作为“负荷剂量”,随后是在频率较小的基础上施用的后续剂量(例如,“维持剂量”)。
在根据本公开文本的某些示例性实施方案中,紧接在前的剂量后1至26(例如,1、11/2、2、21/2、3、31/2、4、41/2、5、51/2、6、61/2、7、71/2、8、81/2、9、91/2、10、101/2、11、111/2、12、121/2、13、131/2、14、141/2、15、151/2、16、161/2、17、171/2、18、181/2、19、191/2、20、201/2、21、211/2、22、221/2、23、231/2、24、241/2、25、251/2、26、261/2或更多)周施用每个二级和/或三级剂量。如本文所用,短语“紧接在前的剂量”意指在多次施用的序列中,在施用所述序列中紧接着的剂量之前向患者施用的抗PD-L1抗体的剂量(没有干预剂量)。
根据本公开文本的此方面的方法可以包括向患者施用任何数量的二级和/或三级剂量的抗PD-L1抗体。例如,在某些实施方案中,仅向患者施用单个二级剂量。在其他实施方案中,向患者施用两个或更多个(例如,2、3、4、5、6、7、8或更多个)二级剂量。同样地,在某些实施方案中,仅向患者施用单个三级剂量。在其他实施方案中,向患者施用两个或更多个(例如,2、3、4、5、6、7、8或更多个)三级剂量。
在涉及多个二级剂量的实施方案中,每个二级剂量可以以与其他二级剂量相同的频率施用。例如,可以在紧接在前的剂量后1至2周或1至2月向患者施用每个二级剂量。类似地,在涉及多个三级剂量的实施方案中,每个三级剂量可以以与其他三级剂量相同的频率施用。例如,可以在紧接在前的剂量后2至12周向患者施用每个三级剂量。在本公开文本的某些实施方案中,向患者施用二级和/或三级剂量的频率可以在治疗方案的过程中变化。施用频率也可以在治疗过程中由医师根据临床检查后个体患者的需要进行调整。
本公开文本包括施用方案,其中以第一频率(例如,每周一次、每两周一次、每三周一次、每月一次、每两月一次等)向患者施用2至6个负荷剂量,接着以较低的频率基础向患者施用两个或更多个维持剂量。例如,根据本公开文本的此方面,如果以例如每月一次的频率施用负荷剂量(例如,每月一次施用两个、三个、四个或更多个负荷剂量),则可以每五周一次、每六周一次、每七周一次、每八周一次、每十周一次、每十二周一次等向患者施用维持剂量)。
制品
在本公开文本的另一个实施方案中,提供了一种制品,其含有所述配制品并且优选地提供其使用说明书。所述制品包括容器。合适的容器包括例如瓶、小瓶(例如,双室小瓶)、注射筒(诸如单室或双室注射筒)和试管。所述容器可以用各种材料(诸如玻璃或塑料)形成。所述容器容纳所述配制品。在容器上或与容器相关联的标签可以指示用于重构和/或使用的指导。所述标签还可以指示所述配制品可用于或旨在用于皮下施用和/或用于治疗T细胞功能异常障碍。容纳所述配制品的容器可以是多次使用的小瓶,其允许重构配制品的重复施用(例如,2-6次施用)。所述制品还可以包括含有合适的稀释剂的第二容器(例如,BWFI)。在稀释剂和冻干配制品混合后,重构配制品中的最终蛋白质浓度将通常为至少50mg/ml。所述制品还可以包括从商业和用户角度来看所需的其他材料,包括其他缓冲液、稀释剂、过滤器、针、注射筒、和带有使用说明书的包装插页。
通过参考以下实施例将更全面地理解本公开文本。然而,它们不应被解读为限制本公开文本的范围。将贯穿本公开文本的所有引用特此通过引用明确并入。
在另一个实施方案中,本公开文本提供了一种制品,其包括本文描述用于在自动注射器装置中施用的配制品。自动注射器可以被描述为在激活后无需另外的来自患者或施用者的必需动作就会递送其内容物的注射装置。当递送速率必须恒定并且递送时间大于少许片刻的时候,它们特别适于治疗性配制品的自我药疗。
实施例
实施例1
特异性结合PD-L1的初级Fab的发现
采用专有噬菌粒文库来针对人抗原PD-L1-His(Sino Biological#10084-H08H)进行淘选。对抗原进行生物素化,并且根据制造商的说明书通过Dynabeads(M280,链霉亲和素,Invitrogen#60210)捕获,以用于通过KingFisher(Thermo Scientific)进行淘选。在所述过程中采用标准噬菌体淘选方案。进行三至四轮淘选,并且然后进行单菌落上清液ELISA以鉴定结合人PD-L1的初级Fab。初级中选者物定义为其ELISA信号为背景信号的至少两倍的那些。选取总计960个克隆用于上清液ELISA分析,并且发现了101个具有独特序列的克隆。基于Fab ELISA测定,可以将这些独特初级中选物分为两组:一组对人PD-L1具有特异性,而另一组与人和小鼠PD-L1交叉反应。如通过生物层干涉(BLI)测定所测量,大多数初级中选物的KD的范围是0.5nM至10nM。
应注意,在用相同抗体进行的不同测量方法中,KD值可能发生10%-20%的变化。KD的差异也可能是由PD-L1的单体或二聚体形式引起的。令人惊讶地,当将PD-L1-Fc(推测是二聚体)固定在芯片表面上时,与常规抗体相比,在相同测定中观察到的亲和力显著更高(<15pM)。
通过轻链改组,选择12个初级中选物(由7个交叉反应中选物和5个人特异性中选物组成),以用于进一步的亲和力成熟。通过噬菌体展示或酵母展示进行亲和力成熟。鉴定了总计36个对PD-L1具有增强亲和力的中选物,并且将它们分为两组:具有27个Fab中选物的一组结合人PD-L1(后来证实也结合猴PD-L1),并且具有9个Fab中选物的另一组结合来自人和小鼠的PD-L1(后来证实也结合猴PD-L1)。在大肠杆菌中表达对应于独特中选物的Fab并且将其纯化。通过BLI测定测量它们对人或小鼠PD-L1的亲和力。简而言之,使用AHC传感器(抗人IgG Fc Capture Dip和读取生物传感器)捕获PD-L1-Fc融合蛋白(SinoBiological目录号10084-H02H),并且将其浸入到含有用动力学缓冲液(10mM HEPES,150mMNaCl,3mM EDTA,0.005%v/v表面活性剂P20,pH 7.4)稀释至5-10μg/ml的纯化Fab的孔中。用数据采集(Data Acquisition)软件7.1处理采集的数据,并且将动力学数据拟合到1:1朗缪尔结合模型。表2列出了亲和力和动力学参数(减去背景)。所有VH和VL的氨基酸序列在SEQ ID NO:126-163中示出。
一组27个Fab中选物结合人和猴PD-L1。它们具有相同的VH(SEQ ID NO:126),但是具有不同的VL。
一组9个Fab中选物结合来自人、猴和小鼠的PD-L1,它们具有相同的VH(SEQ IDNO:127),但是具有不同的VL。
表2.通过ForteBio测量的Fab对人或小鼠PD-L1的亲和力
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实施例2
IgG转化和表达:TY21418、TY21419、TY21420和TY21421
选择将四种Fab:B13002、B13004、B15016和B15041转化为IgG1。其中两种(B13002和B13004)对人PD-L1具有特异性,而另外两种(B15016和B15041)与人和小鼠PD-L1交叉反应。将它们的重链和轻链分别以IgG1同种型克隆到哺乳动物表达载体pCDNA3.3(ThermoFisher Scientific,目录号K830001)中。还将参考抗体(YW243.55.S70)的重链和轻链以IgG1同种型克隆到pCDNA3.3中(参考US 8217149B2(Genentech)抗PD-L1抗体、组合物和制品)。表3示出了本文中使用的IgG。
>YW243.55.S70_VH,来自美国专利号8217149B2
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(SEQ ID NO.170)
>YW243.55.S70_VL,来自美国专利号US8217149B2
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO.171)
表3:IgG列表
将质粒对瞬时转染到HEK293F细胞中。6天之后,收获上清液,通过离心和过滤使其干净,并且将IgG用标准蛋白A亲和色谱法(MabSelect SuRe,GE Healthcare)纯化。将IgG洗脱并且中和,并且缓冲液交换到PB缓冲液(20mM磷酸钠,150mM NaCl,pH 7.0)中。通过紫外分光光度法确定蛋白质浓度,并且通过SDS-PAGE或SEC-HPLC在变性、还原和非还原条件下分析IgG纯度。
实施例3
PD-L1抗体选择性结合在哺乳动物细胞表面上表达的PD-L1
使用流式细胞术评估抗体对PD-L1的选择性。简而言之,在HEK293F细胞膜上单独地瞬时表达人、恒河猴和小鼠PD-L1以及人PD1、CTLA4、LAG3、TIM3和B7-H3。将转染的细胞在预冷的染色缓冲液(补充有2%FBS的PBS)中洗涤,然后在冰上与100nM测试抗体一起孵育1小时。将细胞用染色缓冲液洗涤两次,并且添加藻红蛋白(PE)缀合的小鼠抗人Fc抗体,并且在冰上孵育30min。将样品用染色缓冲液洗涤一次,之后通过流式细胞术进行分析。如图1所示,TY21418、TY21419、TY21420、TY21421和参考抗体强烈结合人和恒河猴PD-L1,同时仅TY21420、TY21421和参考抗体能够结合小鼠PD-L1,这与基于用纯化的Fab蛋白进行的ELISA的早期观察一致。重要的是,候选抗体TY21418、TY21419、TY21420和TY21421仅结合PD-L1,并且它们均未显示出与其他测试的免疫检查点分子的任何可见结合。
实施例4
通过抗体阻断PD1和PD-L1相互作用
为了确定候选抗体是否阻断PD-L1与其配体PD1之间的相互作用,进行三种类型的测定。它们包括流式细胞术、BLI和ELISA。所有这三种方法都证明了四种候选抗体TY21418、TY21419、TY21420和TY21421完全阻断了PD1与PD-L1的结合。
4a.如通过流式细胞术测量的PD1与PD-L1之间结合的阻断
在HEK293F细胞中瞬时表达编码全长人PD-L1的质粒。将细胞用染色缓冲液(补充有1%BSA的PBS)洗涤,并且重悬浮在含有100nM测试抗体的染色缓冲液中。在冰上孵育1小时之后,向每个孔中添加100nM生物素化的PD1-His(Sino Biological目录号10377-H08H),并且在冰上再孵育30min。将细胞用1x PBSA洗涤一次,并且添加100μL含有Alexa fluor633缀合的链霉亲和素的染色缓冲液,并在冰上孵育30min。然后将细胞洗涤一次并且通过CytoFlex流式细胞术进行分析。如图2所示,全部四种候选抗体以及参考抗体均有效地阻断PD-L1与PD1之间的结合。
4b.如通过BLI测量的PD1与PD-L1之间结合的阻断
在此测定中,将生物素化的PD-L1-His调整为4μg/ml,并且平行加载到链霉亲和素(SA)Dip和读取生物传感器上。在动力学缓冲液中平衡30秒之后,将生物传感器浸入到含有在动力学缓冲液中调节至37.5μg/ml的不同抗体的孔中。在信号达到平台之后,将生物传感器浸入到含有PD1-Fc(5μg/ml)和对应抗体(37.5μg/ml)的混合物的孔中。信号增加指示有效结合。如图3所证明,全部四种候选抗体以及参考抗体均防止PD1信号的增加,从而表明它们有效地阻断PD-L1与PD1之间的相互作用。
4c.如通过ELISA测量的PD1与PD-L1之间结合的阻断
将重组人PD1-Fc在PBS中稀释至1μg/mL,并且在4℃下涂覆在Maxisorp板上过夜。将板在37℃下在补充有3%脱脂奶的PBS中封闭1小时。洗涤之后,将总体积为100μL的50μL生物素化的PD-L1-Fc(3μg/mL)和各种浓度的测试抗体(从50μg/mL至0.195μg/mL范围内的8个1:2连续稀释液)的混合物添加到每个孔中,并且在37℃下孵育1小时。将板洗涤3次,并且将100μL HRP缀合的中性亲和素(1:1,000)添加到每个孔中,并且在37℃下孵育1小时。如先前所描述洗涤板,并且添加50μL TMB底物溶液并且在室温下孵育。通过50μL H2SO4终止各反应。如图4所示,全部四种候选抗体以及参考抗体均有效地阻断PD-L1与PD1的结合。
实施例5
抗体结合PD-L1的表征
通过Biacore测量抗体对人、恒河猴、小鼠和大鼠PD-L1的结合亲和力。结果在表4-6中总结。
5a.通过SPR测量TY21418和TY21419与人PD-L1的结合亲和力和动力学
根据制造商的指导,使用BiacoreTMT200仪器(Biacore AB,乌普萨拉,瑞典),通过表面等离振子共振(SPR)分析来检查TY21418和TY21419对人PD-L1蛋白的结合亲和力和动力学。通过以下方式将来自人抗体捕获试剂盒(GE BR-1008-39)的抗人IgG(Fc)抗体固定在CM5芯片上:根据胺偶联试剂盒(GE Biacore#BR-1000-50)的说明书,通过将其胺基团偶联到传感器芯片的羧化表面上。将固定的抗人IgG(Fc)抗体用于捕获TY21418、TY21419或参考抗体。最后,将6种浓度(3.13、6.25、12.5、25、50、100)(nM)(在运行缓冲液中稀释)的人PD-L1-His6(Sino Biological#10084-H08H)以30μI/min的流速注射300秒,并且解离时间为300秒。所使用的运行缓冲液是1×HBS-EP(10mM HEPES,150mM NaCl,3mM EDTA,0.005%v/v表面活性剂P20,pH 7.4,在25℃下)。在每种情况下,使用其中没有固定蛋白质的空白流动池进行对应的对照,以用于“背景”减去。根据制造商的指导,使用BIAcore T200评估软件(Biacore AB,乌普萨拉,瑞典)将缔合和解离曲线拟合到1:1朗缪尔结合模型。如表4所示,TY21418和TY21419均以亚纳摩尔亲和力结合人PD-L1,与参考抗体相似。然而,相比于参考抗体,在Biacore中TY21418和TY21419均未显示出与小鼠PD-L1的任何结合。
表4.TY21418和TY21419对人PD-L1的结合亲和力
5b.通过SPR测量TY21421与人PD-L1的结合亲和力和动力学
使用BiacoreTMT200仪器(Biacore AB,乌普萨拉,瑞典)通过SPR分析类似地检查TY21421对人PD-L1蛋白的结合亲和力和动力学,不同的是将人PD-L1-Fc融合蛋白直接固定在CM5芯片上至300RU,并且将在运行缓冲液(HBS-EP)中的IgG的两倍连续稀释液(0.098nM至1.563nM)在25℃下以30μI/min的流速注射300秒,接着是1,200秒的解离时间。根据制造商的指导,使用BIAcore T200评估软件(Biacore AB,乌普萨拉,瑞典)将缔合和解离曲线拟合到1:1朗缪尔结合模型。如表5所示,TY21421以极高的亲和力(KD<10pM)结合固定的人PD-L1-Fc,与参考抗体相似或稍微更好。
表5.TY21421与固定的人PD-L1-Fc的结合亲和力
5c.通过SPR测量TY21421与来自其他物种的PD-L1的结合亲和力和动力学
使用BiacoreTMT200仪器(Biacore AB,乌普萨拉,瑞典)通过SPR分析类似地检查TY21421对来自人、恒河猴(Sino Biological目录号90251-C02H)、小鼠和大鼠(SinoBiological目录号80450-R08H)的PD-L1蛋白的结合亲和力和动力学,不同的是将来自人、恒河猴、小鼠和大鼠的PD-L1-Fc融合蛋白直接固定在CM5芯片上至约500RU,并且将在运行缓冲液(HBS-EP)中的IgG的两倍连续稀释液(0.098nM至1.563nM)在25℃下以30μI/min的流速注射300秒,接着是1,200秒的解离时间。根据制造商的指导,使用BIAcore T200评估软件(Biacore AB,乌普萨拉,瑞典)将缔合和解离曲线拟合到1:1朗缪尔结合模型。如表6所示,TY21421以皮摩尔亲和力结合来自所有测试物种的固定的PD-L1,但是与来自人、恒河猴或小鼠的PD-L1相比,其对大鼠PD-L1的亲和力稍微更差(KD=20.9pM)。
表6.TY21421与来自不同物种的固定的PD-L1的结合亲和力
5d.通过流式细胞术测量TY21421对在细胞表面上表达的PD-L1的EC50
为了测量TY21421对在细胞表面上表达的PD-L1的亲和力,采用在其膜上表达PD-L1的稳定细胞系293T-002(Crownbio#C2005)。简而言之,将细胞用冷FACS缓冲液(补充有1%BSA的1xPBS)洗涤一次,并且然后用TY21421的3倍连续稀释液(从100nM开始)在冰上孵育1小时,用预冷的FACS缓冲液洗涤两次,并且用别藻蓝蛋白(APC)缀合的小鼠抗人FC抗体在冰上孵育30min。将细胞洗涤一次,之后通过流式细胞术(CytoFlex)进行分析。如图5所示,TY21421以1.08nM的EC50强烈结合在细胞表面上表达的PD-L1,
实施例6
抗体结合用多聚甲醛固定之后的细胞表面PD-L1
还检查抗体结合用多聚甲醛固定之后的细胞表面PD-L1的能力。简而言之,将10,000个表达PD-L1的HCC827人细胞(细胞库,中国科学院典型培养物保藏中心(Cell Bank,Type Culture Collection of Chinese Academy of Sciences))铺板在96孔板中。在组织培养箱中孵育过夜之后,将细胞用4%多聚甲醛固定并且用1%BSA封闭。然后将TY21421的连续稀释液添加到孔中并且在4℃下孵育过夜。用PBST洗涤之后,添加HRP缀合的抗IgG Fc抗体(Santa Cruz,sc-2005)和TMB底物,并且通过在450nm处的吸光度测量细胞结合。如图6所示,TY21421以高亲和力结合用多聚甲醛固定之后的细胞表面PD-L1,其计算EC50为0.30nM。
实施例7
使用Promega PD1/PD-L1报告基因测定进行的抗体的功能表征
使用Promega PD1/PD-L1报告基因测定来检查PD-L1抗体在激活PD-L1依赖性NFAT介导的萤光素酶表达中是否具有功能性。简而言之,将40.000个表达PD-L1的CHO细胞(Promega,目录号J1081)铺板在96孔白板的每个孔中,在37℃下孵育16-18h。然后将40,000个表达PD-1的Jurkat细胞(Promega,目录号J1121)添加到2%FBS-RPMI1640中的每个孔中。将TY21421的连续稀释液添加到培养物中,并且将板在37℃下再孵育6小时,之后测量相对发光单位(RLU)。通过其计算EC50评估抗体效力。如图7所示,TY21421有效地刺激了PD-L1依赖性信号传导途径,并且其计算EC50达到0.39nM。
实施例8
通过抗PD-L1抗体刺激CD4+ T细胞活性
在DC-MLR测定中还测试了PD-L1抗体增强T细胞活性的能力。简而言之,通过密度梯度离心从健康供体中分离PBMC,并且通过阳性选择商业试剂盒(StemCell)从PBMC中纯化CD14+单核细胞。通过在补充有10%失活FBS、1%青霉素/链霉素、20ng/mL rhGM-CSF和20ng/mL rhIL-4的RPMI 1640培养基中体外培养6天来将它们偏离到DC中,并且在第3天将培养基换成新鲜培养基。在第6天,在补充有10%失活FBS、1%青霉素/链霉素和50ng/mLrhTNF-α的RPMI 1640培养基中诱导DC成熟,进行24小时。通过从新鲜人PBMC中负分离来纯化来自另一位健康供体的CD4+ T细胞,所述新鲜人PBMC是通过在密度梯度培养基上离心来从全血制备的。然后在PD-L1抗体的连续稀释液的存在下,将成熟的DC(10,000个)与同种异体CD4+ T细胞(100,000个)共培养。5天之后,通过ELISA测量上清液中的IFN-γ细胞因子。如图8所示,即使在最低的测试浓度0.03μg/ml下,TY21418、TY21419和TY21421也显著增强了IFN-γ细胞因子的分泌。
在另一个供体对中,并且采用另一种DC成熟方法,即使用1mg/mL LPS(Sigma)和50ng/mL IFN-γ(Novoprotein)而非50ng/mL rhTNF-α,显示TY21421在刺激T细胞活性方面与参考抗体一样有效,通过释放的IL2和IFN-γ增加例示(图9)。
实施例9
通过抗PD-L1抗体进行的抗体依赖性细胞介导的细胞毒性(ADCC)
在野生型IgG1同种型中构建候选抗体。进行体外实验以证明其ADCC作用。简而言之,将来自健康供体的人外周血单核细胞(PBMC)与表达PD-L1的HCC827细胞以30:1的比率一起孵育。然后将连续稀释的TY21421或商业Tecentriq(作为ADCC的阴性对照)添加到培养物中,并且孵育4小时。通过LDH细胞毒性试剂盒(Dojindo,目录号CK12)测量乳酸脱氢酶(LDH)从靶细胞的释放来评估细胞毒性。如图10所证明,TY21421证明了有效的ADCC作用。相比之下并且与早期报告一致,Tecentriq即使在高浓度下也几乎没有ADCC作用。
实施例10
用抗PD-L1抗体处理小鼠同基因模型
与小鼠PD-L1的物种交叉反应性允许进行快速体内功能评定。TY21420和TY21421已经在多个小鼠同基因模型中进行了测试。
10a.PD-L1抗体在H22小鼠肝癌模型中展现出抗肿瘤功效
向BALB/c小鼠(每组n=8)皮下移植2×106个H22小鼠肝癌细胞。建立肿瘤之后(约100mm3),通过腹膜内注射将这些荷瘤小鼠用媒介物、TY21420(10mg/kg)或TY21421(10mg/kg)一周两次处理,长达3周。一周两次监测肿瘤生长,并且报告为随时间的平均肿瘤体积±SEM。如图11所示,TY21420和TY21421均有效抑制H22肿瘤生长。
10b.PD-L1抗体在MC38小鼠结肠癌模型中展现出抗肿瘤功效
一组9个Fab中选物结合来自人、猴和小鼠的PD-L1,它们具有相同的VH(SEQ IDNO:127),但是具有不同的VL。向C57BL/6小鼠皮下移植3×105个MC38小鼠结肠癌细胞。建立肿瘤之后(约75mm3),通过腹膜内注射将这些荷瘤小鼠用媒介物、TY21420(10mg/kg)或TY21421(10mg/kg)一周两次处理,长达3周。每周三次监测肿瘤生长,并且报告为随时间的平均肿瘤体积±SEM。如图12所示,TY21420和TY21421均有效抑制MC38肿瘤生长。
实施例11
在抗体组合的情况下增强的抗肿瘤功效
11a.在TY21421和物种交叉反应性抗CD137抗体的组合的情况下在LL/2小鼠肺癌模型中增强的抗肿瘤功效
向C57BL/6小鼠(每组n=8)皮下移植2×105个LL/2小鼠肺癌细胞。当建立肿瘤(约87mm3)时,通过腹膜内注射用同种型对照、TY21421(7.5mg/kg,一周三次×3周)或抗CD137抗体(10mg/kg,一周两次×3周)(诸如PCT国际申请号PCT/CN2017/098332中公开的那些,将所述文献通过引用以其整体并入本文)作为单一疗法或组合处理这些荷瘤小鼠。一周两次监测肿瘤生长,并且报告为随时间的平均肿瘤体积±SEM。如图13所示,作为单一疗法,TY21421或抗CD137抗体有效抑制LL/2小鼠肿瘤生长。有趣的是,当组合使用时,TY21421和抗CD137抗体在抑制LL/2小鼠肿瘤生长方面甚至更有效。
11b.在TY21421和物种交叉反应性抗CD137抗体的组合的情况下在3LL小鼠肺癌模型中增强的抗肿瘤功效
向C57BL/6小鼠(每组n=8)皮下移植2×106个3LL小鼠肺癌细胞。当建立肿瘤(约76mm3)时,通过腹膜内注射用同种型对照、TY21421(10mg/kg,一周两次×3周)或抗CD137抗体(10mg/kg,一周两次×3周)作为单一疗法或组合处理这些荷瘤小鼠。一周两次监测肿瘤生长,并且报告为随时间的平均肿瘤体积±SEM。如图14所示,作为单一疗法,TY21421或抗CD137抗体有效抑制3LL小鼠肿瘤生长。有趣的是,当组合使用时,TY21421和抗CD137抗体在抑制3LL小鼠肿瘤生长方面有效得多。
实施例12
抗PD-L1抗体作为用于癌症免疫疗法的诊断治疗剂的应用
测试小鼠交叉反应性抗PD-L1抗体TY21421作为用于癌症免疫疗法的诊断治疗剂。将抗体TY21421在PBS缓冲液中与p-SCN-Bn-NOTA(Macrocyclics,Inc.达拉斯,得克萨斯州)缀合。平均而言,每个TY21421分子缀合三个p-SCN-Bn-NOTA分子,如通过MALDI-TOF-MS所测量的。之后,将64Cu-Cu2+(北京大学肿瘤医院,北京,中国)在37℃下螯合1小时,并且通过尺寸排阻色谱法对螯合的抗体(64Cu-TY21421)分级并且储存在PBS(pH 7.4)中。
12a.64Cu-AG10130在具有MC38异种移植物的小鼠中的PET/CT成像和生物分布
将放射标记的抗PD-L1抗体64Cu-TY21421(22.2±0.2MBq)注射到具有MC38异种移植物的雌性C57BL/6小鼠中,并且在注射后0.5小时、12小时、24小时、36小时、48小时和62小时使用NanoScan PET-CT扫描仪(Mediso Medical Solutions HUN,Inc.)记录图像。通过Tera-Tomo 3D方法和Variance Reduced D.W.重建图像。通过Nucline NanoScan软件(InterViewTM FUSION,Mediso Medical Solutions HUN,Inc.)在重建的PET图像上获取三维ROI(目的区域)。
如图15中的代表性PET/CT图像中所示,如通过ROI所测量的,64Cu-TY21421在肿瘤位点中的摄取从在注射后0.5小时的2.3%±1.2%ID/g增加至在62小时的10.2%±1.7%ID/g(图15,图B)。相比之下,在相同时间内,64Cu-TY21421在肝脏和肌肉中的摄取逐渐减少(图15,图B)。因此,在注射后62小时,肿瘤/肝脏和肿瘤/肌肉的ROI比率分别稳定地增加至62.1±23.3和3.18±1.06。
接下来,在注射后12小时、24小时和48小时进行64Cu-TY21421的离体生物分布研究。向携带MC38肿瘤的雌性C57BL/6小鼠(对于每个时间点,n=3)静脉内注射64Cu-TY21421,当通过其衰变校正后,在注射后12小时、24小时和48小时,针对每只小鼠的注射剂量为0.56MBq。将肿瘤和多个小鼠器官解剖并且称重,并且通过γ计数器测量放射性。如图15的图C和表7所示,64Cu-TY21421在肿瘤、肝脏、肌肉和骨骼中的摄取与PET/CT成像一致,即在肿瘤中的摄取以时间依赖性方式增加,并且在注射后48小时变得高于肝脏和其他主要器官。
表7.64Cu-TY21421在携带MC38肿瘤的C57BL/6小鼠(n=4)中的平均生物分布。
12b.传统PET探针18F-FDG与PD-L1特异性PET探针64Cu-TY21421之间的比较
为了在传统PET探针18F-FDG与PD-L1特异性PET探针64Cu-TY21421之间进行比较和对比,向携带MC38和4T1异种移植物的小鼠注射18F-FDG(7.4MBq),并且在1小时后记录图像。之后,注射64Cu-TY21421(7.4MBq),并且在12小时后记录图像。如图16所示,未观察到在MC38和4T1肿瘤部位中18F-FDG摄取的显著差异:对于MC38异种移植物,18F-FDG摄取为5.3%±0.4%ID/g,并且对于4T1异种移植物,摄取为6.4%±0.6%ID/g(图16,图B)。相比之下,64Cu-TY21421的特异性高得多:对于表达PD-L1的MC38肿瘤,64Cu-TY21421摄取为5.6%±0.3%ID/g,并且对于不表达PD-L1的4T1肿瘤,摄取为1.3%±0.4%ID/g,相差超过四倍(图16,图B)。使用IHC特异性抗PD-L1抗体(#64988,Cell Signaling Technology),通过IHC实验确认PD-L1在MC38肿瘤中的存在及其在4T1肿瘤中的不存在。
12c.64Cu-TY21421在人癌症模型中的PET成像
还使用放射标记的抗PD-L1抗体64Cu-TY21421来评定人癌症异种移植物中的PD-L1表达水平。向Nu/Nu小鼠接种人胃癌(BGC823,National Infrastructure of Cell LineResources,中国)和人胶质母细胞瘤(U87MG,National Infrastructure of Cell LineResources,中国)异种移植物,据报道两者均具有PD-L1表达。64Cu-TY21421在BGC823和U87MG异种移植物中均展现出特异性积累(图17)。在注射后12小时,64Cu-TY21421摄取为在BGC823中4.6%±0.5%ID/g(n=3)并且在U87MG中为5.3%±0.4%ID/g(n=3)。
等效物
本公开文本尤其提供了新型抗PD-L1抗体及其用途。虽然已经讨论了主题公开文本的特定实施方案,但以上说明书是示例性而非限制性的。在审阅本说明书之后,本公开文本的许多变化对于本领域技术人员而言将变得清楚。本公开文本的全部范围应通过参考权利要求书和其等效物的全部范围以及说明书和此类变化来确定。
通过引用并入
将本文提到的所有出版物、专利和序列数据库条目都特此通过引用以其整体并入,就如同具体且单独地指示将每个单独的出版物或专利通过引用并入一样。
序列表
<110> 天演药业公司(Adagene Inc.)
<120> 抗PD-L1抗体及其用途
<130> F19W0502PCT
<150> PCT/CN2018/081096
<151> 2018-03-29
<160> 182
<170> PatentIn version 3.5
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<211> 11
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Arg Ala Ser Gln Xaa Xaa Xaa Xaa Xaa Leu Ala
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<222> (11)..(11)
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Arg Ala Ser Xaa Ser Val Asp Phe Xaa Gly Xaa Ser Phe Leu Xaa
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<223> Xaa = A或N
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Xaa Ala Ser Gln Xaa Ile Pro Xaa Phe Leu Xaa
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<223> Xaa = P或S
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Arg Ala Ser Gln Gly Xaa Ser Xaa Xaa Leu Ala
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<223> Xaa = N或S
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<222> (7)..(7)
<223> Xaa = S或T
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Asp Ala Ser Xaa Xaa Xaa Xaa Gly Xaa
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Asp Ala Ser Asn Xaa Xaa Thr Gly Xaa
1 5
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Tyr Cys Gln Gln Tyr Asp Xaa Trp Pro Tyr Thr
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Tyr Cys Gln Xaa Tyr Xaa Ser Trp Pro Arg Xaa Phe Thr
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Arg Ala Ser Gln Gly Ile Gly Ser Phe Leu Ala
1 5 10
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Arg Ala Ser Glu Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Asp
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Arg Ala Ser Gln Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Ala
1 5 10 15
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Arg Ala Ser Glu Ser Val Asp Phe Phe Gly Lys Ser Phe Leu Ala
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Arg Ala Ser Gln Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Asp
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Arg Ala Ser Gln Ser Val Ser Ser Trp Leu Ala
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Arg Ala Ser Glu Ser Val Asp Phe Phe Gly Lys Ser Phe Leu Ala
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Arg Ala Ser Glu Ser Val Asp Phe His Gly Ile Ser Phe Leu Ala
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Arg Ala Ser Gln Ser Val Ser Pro Tyr Leu Ala
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Arg Ala Ser Gln Ser Val Gly Ser Ile Tyr Leu Gly
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Arg Ala Ser Gln Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Ala
1 5 10 15
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Arg Ala Ser Glu Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Ala
1 5 10 15
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Arg Ala Ser Gln Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Asp
1 5 10 15
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Arg Ala Ser Glu Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Asp
1 5 10 15
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Arg Ala Ser Glu Ser Val Asp Phe His Gly Lys Ser Phe Leu Ala
1 5 10 15
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Arg Ala Ser Gln Gly Val Ser Pro Trp Leu Ala
1 5 10
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Arg Ala Ser Gln Ser Val Ser Pro Tyr Leu Ala
1 5 10
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Arg Ala Ser Gln Ser Val Asp Phe His Gly Lys Ser Phe Leu Asp
1 5 10 15
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Arg Ala Ser Gln Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Ala
1 5 10 15
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Arg Ala Ser Glu Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Ala
1 5 10 15
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Arg Ala Ser Gln Ser Ile Glu Lys Trp Leu Ala
1 5 10
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Arg Ala Ser Gln Ser Val Asp Phe His Gly Ile Ser Phe Leu Asp
1 5 10 15
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Arg Ala Ser Gln Ser Val Asp Phe Tyr Gly Lys Ser Phe Leu Asp
1 5 10 15
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Arg Ala Ser Gln Ser Val Asp Phe His Gly Ile Ser Phe Leu Asp
1 5 10 15
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Arg Ala Ser Gln Gly Val Ser Ser Tyr Leu Ala
1 5 10
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Arg Ala Ser Gln Gly Ile Ser Pro Trp Leu Ala
1 5 10
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Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
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<211> 9
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Asp Ala Ser Ser Leu Glu Ser Gly Val
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Asp Ala Ser Asn Arg Ala Thr Gly Ile
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Asp Ala Ser Ser Leu Glu Ser Gly Val
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Asp Ala Ser Ser Leu Glu Ser Gly Val
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Asp Ala Ser Asn Arg Ala Thr Gly Ile
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Asp Ala Ser Ser Leu Glu Ser Gly Val
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Asp Ala Ser Asn Leu Glu Thr Gly Val
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Asp Ala Ser Asn Arg Ala Thr Gly Ile
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Asp Ala Ser Asn Leu Glu Thr Gly Val
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Asp Ala Ser Asn Arg Ala Thr Gly Ile
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Asp Ala Ser Ser Leu Glu Ser Gly Val
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Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 52
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Asp Ala Ser Asn Leu Glu Thr Gly Val
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<220>
<223> 合成构建体
<400> 53
Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 54
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 54
Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 55
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 55
Asp Ala Ser Ser Leu Glu Ser Gly Val
1 5
<210> 56
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 56
Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 57
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 57
Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 58
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 58
Asp Ala Ser Ser Leu Glu Ser Gly Val
1 5
<210> 59
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 59
Asp Ala Ser Ser Leu Glu Ser Gly Val
1 5
<210> 60
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 60
Asp Ala Ser Ser Leu Glu Ser Gly Val
1 5
<210> 61
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 61
Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 62
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 62
Asp Ala Ser Ser Leu Glu Ser Gly Val
1 5
<210> 63
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 63
Asp Ala Ser Asn Leu Glu Thr Gly Val
1 5
<210> 64
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 64
Asp Ala Ser Asn Leu Glu Thr Gly Val
1 5
<210> 65
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 65
Asp Ala Ser Asn Arg Ala Thr Gly Ile
1 5
<210> 66
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 66
Asp Ala Ser Asn Leu Glu Thr Gly Val
1 5
<210> 67
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 67
Tyr Cys Gln Gln Tyr Asp Tyr Trp Pro Tyr Thr
1 5 10
<210> 68
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 68
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 69
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 69
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 70
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 70
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 71
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 71
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 72
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 72
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 73
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 73
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 74
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 74
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 75
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 75
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 76
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 76
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 77
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 77
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 78
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 78
Tyr Cys Gln Gln Tyr Asp Tyr Trp Pro Tyr Thr
1 5 10
<210> 79
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 79
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 80
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 80
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 81
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 81
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 82
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 82
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 83
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 83
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 84
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 84
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 85
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 85
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 86
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 86
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 87
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 87
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 88
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 88
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 89
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 89
Tyr Cys Gln Gln Tyr Asp His Trp Pro Tyr Thr
1 5 10
<210> 90
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 90
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 91
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 91
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 92
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 92
Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr Thr
1 5 10
<210> 93
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 93
Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr Thr
1 5 10
<210> 94
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 94
Gln Ala Ser Gln Asp Ile Pro Thr Phe Leu Ala
1 5 10
<210> 95
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 95
Arg Ala Ser Gln Thr Ile Pro Ser Phe Leu Asn
1 5 10
<210> 96
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 96
Arg Ala Ser Gln Asp Ile Pro Lys Phe Leu Ala
1 5 10
<210> 97
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 97
Arg Ala Ser Gln Thr Ile Pro Ser Phe Leu Asn
1 5 10
<210> 98
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 98
Arg Ala Ser Gln Ser Ile Pro Ser Phe Leu Asn
1 5 10
<210> 99
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 99
Arg Ala Ser Gln Ser Ile Pro Thr Phe Leu Asn
1 5 10
<210> 100
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 100
Arg Ala Ser Gln Ser Ile Pro Ser Phe Leu Asn
1 5 10
<210> 101
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 101
Arg Ala Ser Gln Thr Ile Pro Ser Phe Leu Asn
1 5 10
<210> 102
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 102
Arg Ala Ser Gln Thr Ile Pro Ser Phe Leu Asn
1 5 10
<210> 103
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 103
Ala Ala Ser Ser Leu Gln Ser Gly Val
1 5
<210> 104
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 104
Ala Ala Ser Thr Leu Gln Ser Gly Val
1 5
<210> 105
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 105
Ala Ala Ser Thr Leu Gln Ser Gly Val
1 5
<210> 106
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 106
Ala Ala Ser Ser Leu Gln Ser Gly Val
1 5
<210> 107
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 107
Ala Ala Ser Thr Leu Gln Ser Gly Val
1 5
<210> 108
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 108
Ala Ala Ser Thr Leu Gln Ser Gly Val
1 5
<210> 109
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 109
Ala Ala Ser Ser Leu Gln Ser Gly Val
1 5
<210> 110
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 110
Ala Ala Ser Thr Leu Gln Ser Gly Val
1 5
<210> 111
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 111
Ala Ala Ser Ser Leu Gln Ser Gly Val
1 5
<210> 112
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 112
Tyr Cys Gln Gln Tyr Val Ser Trp Pro Arg Gly Phe Thr
1 5 10
<210> 113
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 113
Tyr Cys Gln His Tyr Ser Ser Trp Pro Arg Gly Phe Thr
1 5 10
<210> 114
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 114
Tyr Cys Gln His Tyr Val Ser Trp Pro Arg Gln Phe Thr
1 5 10
<210> 115
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 115
Tyr Cys Gln His Tyr Thr Ser Trp Pro Arg Gln Phe Thr
1 5 10
<210> 116
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 116
Tyr Cys Gln Gln Tyr Ser Ser Trp Pro Arg Leu Phe Thr
1 5 10
<210> 117
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 117
Tyr Cys Gln His Tyr Val Ser Trp Pro Arg Leu Phe Thr
1 5 10
<210> 118
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 118
Tyr Cys Gln His Tyr Ile Ser Trp Pro Arg Gln Phe Thr
1 5 10
<210> 119
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 119
Tyr Cys Gln His Tyr Ile Ser Trp Pro Arg Val Phe Thr
1 5 10
<210> 120
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 120
Tyr Cys Gln His Tyr Gly Ser Trp Pro Arg Arg Phe Thr
1 5 10
<210> 121
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (28)..(28)
<223> Xaa = G或S
<220>
<221> 变体
<222> (29)..(29)
<223> Xaa = I或V
<220>
<221> 变体
<222> (30)..(30)
<223> Xaa = E、G或S
<220>
<221> 变体
<222> (31)..(31)
<223> Xaa = K、P或S
<220>
<221> 变体
<222> (32)..(32)
<223> Xaa = F、W或Y
<220>
<221> 变体
<222> (53)..(53)
<223> Xaa = N或S
<220>
<221> 变体
<222> (54)..(54)
<223> Xaa = L或R
<220>
<221> 变体
<222> (55)..(55)
<223> Xaa = A或E
<220>
<221> 变体
<222> (56)..(56)
<223> Xaa = S或T
<220>
<221> 变体
<222> (58)..(58)
<223> Xaa = I或V
<220>
<221> 变体
<222> (93)..(93)
<223> Xaa = A、S或Y
<400> 121
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Xaa Xaa Xaa Xaa Xaa
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Xaa Xaa Xaa Xaa Gly Xaa Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Xaa Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 122
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (27)..(27)
<223> Xaa = E或Q
<220>
<221> 变体
<222> (32)..(32)
<223> Xaa = F、H或Y
<220>
<221> 变体
<222> (34)..(34)
<223> Xaa = I或K
<220>
<221> 变体
<222> (38)..(38)
<223> Xaa = A或D
<220>
<221> 变体
<222> (57)..(57)
<223> Xaa = N或S
<220>
<221> 变体
<222> (58)..(58)
<223> Xaa = L或R
<220>
<221> 变体
<222> (59)..(59)
<223> Xaa = A或E
<220>
<221> 变体
<222> (60)..(60)
<223> Xaa = S或T
<220>
<221> 变体
<222> (62)..(62)
<223> Xaa = I或V
<220>
<221> 变体
<222> (97)..(97)
<223> Xaa = A、H、S或Y
<400> 122
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Xaa Ser Val Asp Phe Xaa
20 25 30
Gly Xaa Ser Phe Leu Xaa Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Xaa Xaa Xaa Xaa Gly Xaa Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Xaa Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 123
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (24)..(24)
<223> Xaa = Q或R
<220>
<221> 变体
<222> (28)..(28)
<223> Xaa = D、S或T
<220>
<221> 变体
<222> (31)..(31)
<223> Xaa = K、S或T
<220>
<221> 变体
<222> (34)..(34)
<223> Xaa = A或N
<220>
<221> 变体
<222> (53)..(53)
<223> Xaa = S或T
<220>
<221> 变体
<222> (90)..(90)
<223> Xaa = H或Q
<220>
<221> 变体
<222> (92)..(92)
<223> Xaa = G、I、S、T或V
<220>
<221> 变体
<222> (97)..(97)
<223> Xaa = G、L、Q、R或V
<400> 123
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Xaa Ala Ser Gln Xaa Ile Pro Xaa Phe
20 25 30
Leu Xaa Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Xaa Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Xaa Tyr Xaa Ser Trp Pro Arg
85 90 95
Xaa Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 124
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (29)..(29)
<223> Xaa = I或V
<220>
<221> 变体
<222> (31)..(31)
<223> Xaa = P或S
<220>
<221> 变体
<222> (32)..(32)
<223> Xaa = W或Y
<220>
<221> 变体
<222> (54)..(54)
<223> Xaa = L或R
<220>
<221> 变体
<222> (55)..(55)
<223> Xaa = A或E
<220>
<221> 变体
<222> (58)..(58)
<223> Xaa = I或V
<220>
<221> 变体
<222> (93)..(93)
<223> Xaa = A或S
<400> 124
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Xaa Ser Xaa Xaa
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Xaa Xaa Thr Gly Xaa Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Xaa Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 125
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (28)..(28)
<223> Xaa = S或T
<220>
<221> 变体
<222> (92)..(92)
<223> Xaa = I或T
<400> 125
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Xaa Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Xaa Ser Trp Pro Arg
85 90 95
Gln Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 126
<211> 120
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 126
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Asn Tyr
20 25 30
Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Ser Gly Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Gly Tyr Gly Tyr Ala Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 127
<211> 118
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 127
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Ile Ile Tyr Pro Ser Gly Gly Gly Thr Asn Tyr Ala Gln Lys
50 55 60
Phe Gln Gly Arg Val Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Gly Leu Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 128
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 128
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Pro Thr Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Val Ser Trp Pro Arg
85 90 95
Gly Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 129
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 129
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Tyr Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 130
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 130
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 131
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 131
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 132
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 132
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Phe
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 133
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 133
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 134
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 134
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 135
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 135
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Phe
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 136
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 136
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe His
20 25 30
Gly Ile Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 137
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 137
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Pro Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 138
<211> 109
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 138
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Gly Ser Ile
20 25 30
Tyr Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Trp Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 139
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 139
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ala Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 140
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 140
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Tyr Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 141
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 141
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ala Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 142
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 142
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 143
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 143
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe His
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 144
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 144
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ser Pro Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 145
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 145
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Pro Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 146
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 146
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe His
20 25 30
Gly Lys Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 147
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 147
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 148
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 148
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 149
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 149
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Glu Lys Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 150
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 150
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe His
20 25 30
Gly Ile Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 151
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 151
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe Tyr
20 25 30
Gly Lys Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
His Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 152
<211> 112
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 152
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Phe His
20 25 30
Gly Ile Ser Phe Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp
85 90 95
Ser Trp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 153
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 153
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Ser Ser Trp Pro Arg
85 90 95
Gly Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 154
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 154
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Pro Lys Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Val Ser Trp Pro Arg
85 90 95
Gln Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 155
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 155
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Thr Ser Trp Pro Arg
85 90 95
Gln Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 156
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 156
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Trp Pro Arg
85 90 95
Leu Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 157
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 157
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Pro Thr Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Val Ser Trp Pro Arg
85 90 95
Leu Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 158
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 158
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Ile Ser Trp Pro Arg
85 90 95
Gln Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 159
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 159
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Ile Ser Trp Pro Arg
85 90 95
Val Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 160
<211> 110
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 160
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Pro Ser Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Gly Ser Trp Pro Arg
85 90 95
Arg Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 161
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 161
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 162
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 162
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Pro Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 163
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 163
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ala Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 164
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 164
Tyr Thr Phe Ser Asn Tyr Gly Ile His Trp Val
1 5 10
<210> 165
<211> 21
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 165
Ile Gly Trp Ile Tyr Pro Ser Gly Gly Gly Thr Lys Tyr Ala Gln Lys
1 5 10 15
Phe Gln Gly Arg Val
20
<210> 166
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 166
Ala Arg Glu Gly Gly Gly Tyr Gly Tyr Ala Leu Asp Tyr
1 5 10
<210> 167
<211> 12
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 167
Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp Gly Trp Ile
1 5 10
<210> 168
<211> 21
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 168
Ile Gly Ile Ile Tyr Pro Ser Gly Gly Gly Thr Asn Tyr Ala Gln Lys
1 5 10 15
Phe Gln Gly Arg Val
20
<210> 169
<211> 10
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 169
Ala Arg Gly Gly Gly Leu Gly Phe Asp Tyr
1 5 10
<210> 170
<211> 118
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 170
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 171
<211> 108
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<400> 171
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 172
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (1)..(1)
<223> Xaa = F或Y
<220>
<221> 变体
<222> (4)..(4)
<223> Xaa = S或T
<220>
<221> 变体
<222> (5)..(5)
<223> Xaa = G、N或S
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = A、G或W
<400> 172
Xaa Thr Phe Xaa Xaa Tyr Xaa Ile His Trp Val
1 5 10
<210> 173
<211> 12
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (4)..(4)
<223> Xaa = S或T
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = H或Y
<220>
<221> 变体
<222> (8)..(8)
<223> Xaa = H或Y
<220>
<221> 变体
<222> (10)..(10)
<223> Xaa = A、D、G、N、S或T
<400> 173
Tyr Ser Ile Xaa Ser Gly Xaa Xaa Trp Xaa Trp Ile
1 5 10
<210> 174
<211> 13
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (6)..(6)
<223> Xaa = G或S
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = A或G
<220>
<221> 变体
<222> (11)..(11)
<223> Xaa = A、G、S或T
<400> 174
Phe Ser Leu Ser Thr Xaa Gly Val Xaa Val Xaa Trp Ile
1 5 10
<210> 175
<211> 20
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = A、D或Y
<220>
<221> 变体
<222> (8)..(8)
<223> Xaa = D或G
<220>
<221> 变体
<222> (11)..(11)
<223> Xaa = R、S或Y
<220>
<221> 变体
<222> (14)..(14)
<223> Xaa = P或T
<400> 175
Leu Ala Leu Ile Asp Trp Xaa Xaa Asp Lys Xaa Tyr Ser Xaa Ser Leu
1 5 10 15
Lys Ser Arg Leu
20
<210> 176
<211> 20
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (3)..(3)
<223> Xaa = D或E
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = N或S
<220>
<221> 变体
<222> (13)..(13)
<223> Xaa = N或S
<400> 176
Ile Gly Xaa Ile Tyr His Ser Gly Xaa Thr Tyr Tyr Xaa Pro Ser Leu
1 5 10 15
Lys Ser Arg Val
20
<210> 177
<211> 21
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (3)..(3)
<223> Xaa = A、G、S、V或Y
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = A、D、S或Y
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = D、G或S
<220>
<221> 变体
<222> (10)..(10)
<223> Xaa = S或T
<400> 177
Val Ser Xaa Ile Ser Gly Xaa Gly Xaa Xaa Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Gly Arg Phe
20
<210> 178
<211> 15
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (3)..(3)
<223> Xaa = E或G
<220>
<221> 变体
<222> (5)..(5)
<223> Xaa = E或S
<220>
<221> 变体
<222> (6)..(6)
<223> Xaa = D或T
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = A、T或V
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = A、I、L、T或V
<220>
<221> 变体
<222> (14)..(14)
<223> Xaa = A、D或G
<400> 178
Ala Arg Xaa Gly Xaa Xaa Xaa Val Xaa Gly Asp Trp Phe Xaa Tyr
1 5 10 15
<210> 179
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (1)..(1)
<223> Xaa = Q或R
<220>
<221> 变体
<222> (5)..(5)
<223> Xaa = D、G或S
<220>
<221> 变体
<222> (6)..(6)
<223> Xaa = I或V
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = G、R、S或T
<220>
<221> 变体
<222> (8)..(8)
<223> Xaa = P、R、S或T
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = A、D、F、S、V或Y
<220>
<221> 变体
<222> (10)..(10)
<223> Xaa = L或V
<220>
<221> 变体
<222> (11)..(11)
<223> Xaa = A、G或N
<400> 179
Xaa Ala Ser Gln Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 180
<211> 9
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (1)..(1)
<223> Xaa = A或D
<220>
<221> 变体
<222> (4)..(4)
<223> Xaa = N、S或T
<220>
<221> 变体
<222> (5)..(5)
<223> Xaa = L或R
<220>
<221> 变体
<222> (6)..(6)
<223> Xaa = A、E或Q
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = S或T
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = I或V
<400> 180
Xaa Ala Ser Xaa Xaa Xaa Xaa Gly Xaa
1 5
<210> 181
<211> 10
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (5)..(5)
<223> Xaa = A、G、S或Y
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = Q、S或Y
<220>
<221> 变体
<222> (8)..(8)
<223> Xaa = I、L、T或Y
<220>
<221> 变体
<222> (9)..(9)
<223> Xaa = I、S、V或W
<400> 181
Tyr Cys Gln Gln Xaa Tyr Xaa Xaa Xaa Thr
1 5 10
<210> 182
<211> 11
<212> PRT
<213> 人工(Artificial)
<220>
<223> 合成构建体
<220>
<221> 变体
<222> (3)..(3)
<223> Xaa = E或Q
<220>
<221> 变体
<222> (5)..(5)
<223> Xaa = P、S或Y
<220>
<221> 变体
<222> (6)..(6)
<223> Xaa = D、L、S、T或Y
<220>
<221> 变体
<222> (7)..(7)
<223> Xaa = D、E、H、S或T
<220>
<221> 变体
<222> (8)..(8)
<223> Xaa = D、L、T或W
<220>
<221> 变体
<222> (10)..(10)
<223> Xaa = L、P、R或V
<400> 182
Tyr Cys Xaa Gln Xaa Xaa Xaa Xaa Pro Xaa Thr
1 5 10
Claims (12)
1.一种分离的针对PD-L1的抗体或其抗原结合片段,其包含HVR_L1、HVR_L2和HVR_L3,其氨基酸序列分别由SEQ ID NO:100、SEQ ID NO: 109和SEQ ID NO: 118所示;以及HVR_H1、HVR_H2和HVR_H3,其氨基酸序列分别由SEQ ID NO: 167、SEQ ID NO: 168和SEQ ID NO:169所示。
2.根据权利要求1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段与人、猴和小鼠PD-L1具有交叉反应性。
3. 根据权利要求1或2所述的抗体或其抗原结合片段,其包含具有由SEQ ID NO: 127所示的氨基酸序列的VH和具有由SEQ ID NO: 158所示的氨基酸序列的VL。
4. 根据权利要求1或2所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段以如通过表面等离子体共振测量的100 nM或更小的KD结合人PD-L1。
5. 根据权利要求4所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段以如通过表面等离子体共振测量的50 nM或更小的KD结合人PD-L1。
6. 根据权利要求4所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段以如通过表面等离子体共振测量的10 nM或更小的KD结合人PD-L1。
7.根据权利要求1或2所述的抗体或其抗原结合片段,其包含人IgG1或IgG4重链恒定区Fc或其变体。
8.一种药物组合物,其包含根据权利要求1-7中任一项所述的抗体或其抗原结合片段和药学上可接受的载体。
9.根据权利要求1-7中任一项所述的抗体或其抗原结合片段在制备用于在有需要的受试者中治疗癌症和/或减少肿瘤生长的药物中的用途。
10.一种诊断治疗组合物,其包含根据权利要求1-7中任一项所述的抗体或其抗原结合片段和诊断成像剂,其中所述诊断成像剂是放射性核素标记。
11.根据权利要求10所述的诊断治疗组合物在制备用于在有需要的受试者中诊断和治疗癌症的诊断治疗剂中的用途。
12.根据权利要求1-7中任一项所述的抗体或其抗原结合片段在制备供在体外检测PD-L1的方法中使用的试剂中的用途,所述方法包括将细胞用多聚甲醛固定,并且将所述细胞用所述抗体或其抗原结合片段进行免疫染色。
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CN114225023B (zh) * | 2021-12-22 | 2022-10-18 | 宝船生物医药科技(上海)有限公司 | 抗csf-1r抗体联合抗pd-l1抗体的应用 |
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CN101248089A (zh) * | 2005-07-01 | 2008-08-20 | 米德列斯公司 | 抗程序性死亡配体1(pd-l1)的人单克隆抗体 |
WO2016000619A1 (en) * | 2014-07-03 | 2016-01-07 | Beigene, Ltd. | Anti-pd-l1 antibodies and their use as therapeutics and diagnostics |
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EP4245376A3 (en) * | 2014-10-14 | 2023-12-13 | Novartis AG | Antibody molecules to pd-l1 and uses thereof |
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- 2019-03-29 CA CA3095076A patent/CA3095076A1/en active Pending
- 2019-03-29 WO PCT/CN2019/080496 patent/WO2019185035A1/en active Application Filing
- 2019-03-29 JP JP2021501072A patent/JP7433285B2/ja active Active
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WO2017215590A1 (en) * | 2016-06-13 | 2017-12-21 | I-Mab | Anti-pd-l1 antibodies and uses thereof |
CN110337448A (zh) * | 2016-12-23 | 2019-10-15 | 瑞美德生物医药科技有限公司 | 使用与程序性死亡配体1(pd-l1)结合的抗体的免疫疗法 |
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KR20210016514A (ko) | 2021-02-16 |
CN117362436A (zh) | 2024-01-09 |
US20210122824A1 (en) | 2021-04-29 |
JP2021521267A (ja) | 2021-08-26 |
EP3774920A4 (en) | 2022-01-05 |
AU2019241345A1 (en) | 2020-10-15 |
JP7433285B2 (ja) | 2024-02-19 |
EP3774920A1 (en) | 2021-02-17 |
CA3095076A1 (en) | 2019-10-03 |
CN112424225A (zh) | 2021-02-26 |
WO2019185035A1 (en) | 2019-10-03 |
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