CN115175942A - 一种双功能融合蛋白及其用途 - Google Patents
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Abstract
本公开提供包含TGFβRII的至少一部分和抗PD‑L1抗体或其抗原结合部分的融合蛋白,产生该融合蛋白的方法,使用该融合蛋白治疗疾病或病况的方法及其用途。
Description
对相关申请的交叉引用
本申请要求2020年2月25日提交的国际专利申请PCT/CN2020/076658的优先权,其全部内容通过提述并入本文。
序列表
本申请包含电子形式的序列表,其全部内容通过引用并入本文。
技术领域
本公开一般涉及双功能融合蛋白、其制备方法和用途。
背景技术
PD-1是免疫检查点蛋白之一,是CD28家族的抑制性成员,在激活的CD4+T细胞和CD8+T细胞以及B细胞上表达。它的配体PD-L1是一种1型跨膜蛋白,据推测在抑制适应性免疫系统中起主要作用。PD-L1与PD-1的结合通过基于免疫受体酪氨酸的开关基序(ITSM)与磷酸酶(SHP-1或SHP-2)相互作用而传递抑制信号。结果,该途径抑制T细胞增殖和T细胞功能,例如细胞因子产生和细胞毒性活性。PD-1/PD-L1轴在下调免疫系统中起主要作用[1,2]。
靶向PD-1或PD-L1的单克隆抗体可以阻断PD-1/PD-L1的结合并增强针对癌细胞的免疫反应。这些药物在治疗某些癌症方面显示出巨大的潜力。几家制药公司已经开发出多种获批的靶向PD-1/PD-L1的治疗性抗体,包括Pembrolizumab(Keytruda)、Nivolumab(Opdivo)、Cemiplimab(Libtayo)、Atezolizumab(Tecentriq)、Avelumab(Bavencio)和Durvalumab(Imfinzi)。这些药物已显示可有效治疗各种类型的癌症,包括皮肤黑素瘤,非小细胞肺癌,肾癌,膀胱癌,头颈癌和霍奇金氏淋巴瘤。还在研究这些药物用于治疗许多其他类型的癌症[3]。
转化生长因子β(TGF-β)是结构相关的一类蛋白质家族,包括TGF-β、激活素/抑制素、和骨形态发生蛋白(BMP)。TGF-β家族的成员控制着许多细胞功能,包括增殖,凋亡,分化,上皮-间质转化(EMT)和迁移。TGF-β失调与癌变有关。在癌症的早期阶段,TGF-β通过抑制细胞周期进程并促进细胞凋亡而表现出肿瘤抑制作用。然而,在晚期,TGF-β发挥肿瘤促进作用,增加肿瘤侵袭性和转移。此外,TGF-β信号传导途径以协同或拮抗的方式与其他信号传导途径通信并调节细胞功能。考虑到TGF-β在肿瘤进展中的关键作用,该途径是癌症治疗的有吸引力的靶标[4]。有几种治疗工具已显示出抑制TGF-β信号传导的巨大潜力,例如TGF-β抗体、反义寡核苷酸、和TGF-β受体1(TGF-βR1)的小分子抑制剂。最后,为了开发未来的治疗方法,有必要进行进一步的研究以鉴定TGF-β与肿瘤微环境中其他信号传导途径和致癌因子的新的汇合点。
最近,已经报道了同时靶向PD1/PD-L1和TGF-β途径的治疗剂,例如含有TGFβRII细胞外结构域(ECD)和抗PD-L1抗体的双功能蛋白。但是,这种融合抗体的开发仍具有改善的空间和临床需求。在本公开中,描述了包含TGFβRII ECD和抗PD-L1抗体的新型双功能蛋白。该融合抗体蛋白显示出优异的蛋白稳定性和体内抗肿瘤活性。这些结果证明了该新型融合抗体作为用于进一步临床前研究的候选药物的巨大潜力。
发明概述
广义而言,本公开涉及提供具有改善功效的抗体和抗体类蛋白质(例如融合蛋白分子)的化合物、方法、组合物和制品。本公开提供的益处广泛地适用于抗体治疗和诊断领域,并且可以与能够与各种靶标反应的抗体联合使用。
在一个方面,本公开提供一种融合蛋白,其包含特异性结合PD-L1的抗体或其抗原结合部分融合于能够结合TGFβ的人转化生长因子β受体(TGFβR)或其部分,其中所述抗体或其抗原结合部分包含:
重链CDR1(HCDR1),其包含SEQ ID NO:1或与SEQ ID NO:1相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
HCDR2,其包含SEQ ID NO:2或与SEQ ID NO:2相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
HCDR3,其包含SEQ ID NO:3或与SEQ ID NO:3相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
轻链CDR1(LCDR1),其包含SEQ ID NO:4或与SEQ ID NO:4相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
LCDR2,其包含SEQ ID NO:5或与SEQ ID NO:5相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;和
LCDR3,其包含SEQ ID NO:6或与SEQ ID NO:6相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列。
在一些实施方案中,如本文公开的抗体或其抗原结合部分包含:
包含SEQ ID NO:1的HCDR1;包含SEQ ID NO:2的HCDR2;和包含SEQ ID NO:3的HCDR3;和
包含SEQ ID NO:4的LCDR1;包含SEQ ID NO:5的LCDR2;和SEQ ID NO:6的LCDR3。
在一些实施方案中,如本文公开的抗体或其抗原结合部分包含重链可变区(VH)和轻链可变区(VL),其中VH包含:
(A)如SEQ ID NO:7所示的氨基酸序列;
(B)与SEQ ID NO:7至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)与SEQ ID NO:7相比具有一个或多个(例如1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失、和/或取代的氨基酸序列;
和/或VL包含:
(A)如SEQ ID NO:8所示的氨基酸序列;
(B)与SEQ ID NO:8至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)与SEQ ID NO:8相比具有一个或多个(例如1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失、和/或取代的氨基酸序列。
在一些实施方案中,人TGFβR选自TGFβRII或TGFβRIII,优选TGFβRII。在一些优选的实施方案中,融合蛋白包含TGFβRII的一部分而非全长TGFβRII,该部分是TGFβRII的胞外结构域。
在一些实施方案中,如本文公开的能结合TGFβ的人TGFβR或其部分包含:
(A)与野生型人TGFβRII的氨基酸序列至少85%、至少90%、或至少95%相同的氨基酸序列;
(B)与野生型人TGFβRII胞外结构域的氨基酸序列至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)野生型人TGFβRII的部分,其保留与TGFβ的结合能力的至少75%、至少80%、至少85%、至少90%、或至少95%。
在一些实施方案中,能结合TGFβ的TGFβR或其部分包含或组成为野生型人TGFβRII的胞外结构域的氨基酸序列,即SEQ ID NO:9的氨基酸序列。
在一些实施方案中,包含在融合蛋白中的抗体或其抗原结合部分是全抗体、ScFv、Fab、F(ab’)2、或Fv片段,例如全抗体。
在一些实施方案中,抗体或其抗原结合部分包含VH区可操作地连接于重链Fc区。例如,抗体或其抗原结合部分可以是全抗体并且在重链包含VH-CH1-铰链-Fc,在轻链包含VL-CL。
在一些实施方案中,抗体或其抗原结合部分是IgG1、IgG2、IgG3或IgG4同种型,优选IgG1同种型。
在一些实施方案中,抗体或其抗原结合部分的Fc区可操作地连接于人TGFβR或其部分的N末端,任选地经由接头。接头可以是肽接头。在一些实施方案中,接头包含(G4S)n,其中n=1-4,例如n可以是1、2、3或4。
在一些实施方案中,抗体或其抗原结合部分是人源化的或全人抗体,例如全人抗体。在一些实施方案中,融合蛋白的重链和轻链分别包含SEQ ID NO:10和11。
在一个方面,本公开提供分离的核酸分子,其包含编码如上文限定的融合蛋白的抗体或其抗原结合部分和/或人TGFβR或其部分的核酸序列。
在一个方面,本公开提供包含如本文中限定的核酸分子的载体。在一个方面,本公开提供包含如本文中公开的核酸分子或载体的宿主细胞。
在一个方面,本公开提供包含如本文中公开的融合蛋白以及药学可接受的载体的药物组合物。
在一个方面,本公开提供一种产生如本文中公开的融合蛋白的方法,包括以下步骤:
-在如本文公开的宿主细胞中表达所述融合蛋白;和
-从该宿主细胞分离所述融合蛋白。
在一个方面,本公开提供一种调控受试者中免疫应答的方法,包括对所述受试者施用如本文中公开的融合蛋白或药物组合物。
在一个方面,本公开提供一种抑制受试者中与PD-1/PD-L1有关的肿瘤细胞生长的方法,包括对所述受试者施用有效量的如本文中公开的融合蛋白或药物组合物。
在一个方面,本公开提供一种预防或治疗受试者中与PD-1/PD-L1有关的癌症的方法,包括对所述受试者施用有效量的如本文中公开的融合蛋白或药物组合物。所述癌症可选自结肠癌、淋巴瘤、肺癌、肝癌、宫颈癌、乳腺癌、卵巢癌、胰腺癌、黑素瘤、胶质母细胞瘤、前列腺癌、食道癌或胃癌。在某些实施方案中,所述癌症为结肠癌或肺癌,例如NSCLC。
在一些实施方案中,如本文公开的融合蛋白与化疗剂、放疗和/或用于癌症免疫治疗的其他药剂组合施用。
在一个方面,本公开提供如本文公开的融合蛋白用于治疗或预防与PD-1/PD-L1有关的癌症。
在一个方面,本公开提供如本文公开的融合蛋白在制备用于调控受试者中与PD-1/PD-L1有关的免疫应答或抑制与PD-1/PD-L1有关的肿瘤细胞生长的药物中的用途。
在一个方面,本公开提供如本文公开的融合蛋白在制备用于治疗或预防与PD-1/PD-L1有关的癌症的药物中的用途。
在一个方面,本公开提供一种用于治疗或诊断癌症的试剂盒,其包含在容器中的如本文中公开的融合蛋白。
以上内容是一个概述,因此必要时包含细节的简化、概括和省略;因此,本领域技术人员将认识到,该概述仅是举例说明性的,并不意图以任何方式进行限制。本文所述的方法、组合物和/或装置和/或其他主题的其它方面、特征和优势将在本文所示的教导中变得明显。提供概述以简化地介绍一些选择的概念,这些概念将在下面的详细描述中进一步描述。本概述不旨在确定所要求保护的主题的关键特征或基本特征,也不旨在用作确定所要求保护的主题的范围的辅助手段。此外,贯穿本申请引用的所有参考文献、专利和公开的专利申请的内容通过引用整体并入本文。
附图简述
图1显示通过ELISA测定的,当将TGF-β固定化时(A)或将抗体固定化时(B)抗体对人TGF-β1、TGF-β2和TGF-β3的结合结果。人IgG1是同种型对照。
图2显示通过FACS测定的,抗体对表达人PD-L1(A),食蟹猴PD-L1(B)和小鼠PD-L1(C)的细胞的结合结果。
图3显示通过ELISA测定的,当将TGF-β1(A)或人PD-L1(B)固定化时抗体同时结合PD-L1和TGF-β1。
图4显示通过FACS测定的,抗体阻断PD-1对细胞表面PD-L1结合的结果。
图5A显示在RGA测定中,抗体阻断TGF-β1信号传导的结果。图5B显示在RGA测定中,抗体阻断人PD-1/PD-L1信号传导的结果。数据呈现为均值±SEM。
图6显示抗体在同种异体混合的淋巴细胞反应中的IL-2(A)和IFN-γ(B)产生结果。
图7显示通过双重结合ELISA测试和PD-L1结合FACS测试的抗体的血清稳定性结果。
图8显示抗体施用在小鼠HCC827 PBMC模型中引起的体重变化(A)和抗肿瘤功效(B)。
图9显示WT1122抗体的体内药代动力学研究结果。
发明详述
虽然本发明可以以许多不同的形式来实施,但在此公开的是验证本发明原理的其具体的举例说明性实施方案。应该强调的是,本发明不限于所举例说明的具体实施方案。此外,本文使用的任何章节标题仅用于组织目的,并不被解释为限制所描述的主题。
除非在此另外定义,否则与本发明结合使用的科学和技术术语将具有本领域普通技术人员通常理解的含义。此外,除非上下文另有要求,单数形式的术语应包括复数形式,复数形式的术语应包括单数形式。更具体地,如在本说明书和所附权利要求中所使用的,除非上下文另外明确指出,否则单数形式“一”,“一个”和“该”包括复数指示物。因此,例如,提及“一种蛋白质”包括多种蛋白质;提及“一种细胞”包括细胞的混合物等。在本申请中,除非另有说明,否则使用“或”意指“和/或”。此外,术语“包含”以及其他形式(诸如“包括”和“含有”)的使用不是限制性的。此外,说明书和所附权利要求中提供的范围包括端点和端点之间的所有值。
通常,与本文描述的细胞和组织培养、分子生物学、免疫学、微生物学、遗传学和蛋白质以及核酸化学和杂交有关的术语以及其技术是本领域众所周知和常用的术语。除非另有说明,否则本发明的方法和技术通常根据本领域公知的常规方法进行,并如在本说明书全文中引用和讨论的各种通用和更具体的参考文献中所述进行。参见例如Abbas等人,Cellular and Molecular Immunology,第6版,W.B.Saunders Company(2010);SambrookJ.&Russell D.Molecular Cloning:A Laboratory Manual,第3版,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.(2000);Ausubel等人,Short Protocols inMolecular Biology:A Compendium of Methods from Current Protocols in MolecularBiology,Wiley,John&Sons,Inc.(2002);Harlow和Lane Using Antibodies:A LaboratoryManual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.(1998);和Coligan等人,Short Protocols in Protein Science,Wiley,John&Sons,Inc.(2003)。与本文描述的分析化学、合成有机化学以及医药和药物化学有关的术语以及实验室程序和技术是本领域中众所周知和常用的那些。
定义
为了更好地理解本发明,相关术语的定义和解释提供如下。
术语“抗体”或“Ab”在本文中以最广泛含义使用,其涵盖多种抗体结构,包括多克隆抗体、单特异性和多特异性抗体(例如双特异性抗体)。天然的完整抗体通常是指包含通过共价二硫键和非共价相互作用保持在一起的两条重链(H)和两条轻链(L)多肽链的Y形四聚体蛋白。抗体的轻链可以分为κ和λ轻链。重链可分为μ、δ、γ、α和ε,它们分别将抗体的同种型定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链中,可变区通过约12个或更多个氨基酸的“J”区与恒定区连接,并且重链还包含约3个或更多个氨基酸的“D”区。每条重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1,CH2和CH3)组成。每条轻链由轻链可变区(VL)和轻链恒定区(CL)组成。VH和VL区可以进一步分为由相对保守的区域(称为框架区(FR))间隔开的高变区(称为互补决定区(CDR))。每个VH和VL由以下顺序的3个CDR和4个FR组成:从N端到C端的FR1,CDR1,FR2,CDR2,FR3,CDR3,FR4。每个重链/轻链对的可变区(VH和VL)分别形成抗原结合位点。氨基酸在各种区域或结构域中的分布遵循KabatSequences of Proteins of Immunological Interest(National Institutes ofHealth,Bethesda,Md.(1987和1991))或Chothia&Lesk(1987)J.Mol.Biol.196:901-917;Chothia等人,(1989)Nature 342:878-883中的定义。抗体可以具有不同的抗体同种型,例如IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或IgM抗体。如本文公开的包含抗PD-L1抗体或其抗原结合部分的融合蛋白也属于抗体。
术语抗体的“抗原结合部分”或“抗原结合片段”,可以在本申请的上下文中互换使用,是指包含全长抗体的片段的多肽,其保留了与全长抗体特异性结合的抗原特异性结合的能力,和/或其与全长抗体竞争结合相同的抗原。一般而言,参见FundamentalImmunology,Ch.7(Paul,W.编,第二版,Raven Press,N.Y.(1989),其出于所有目的通过引用并入本文。抗体的抗原结合片段可使用任何适合的标准技术,例如蛋白质水解消化作用或涉及编码抗体可变结构域和任选地恒定结构域的DNA的操作和表达的重组基因工程技术,衍生自例如全抗体分子。这样的DNA为已知的和/或可容易地从例如商业来源、DNA文库(包括,例如噬菌体-抗体文库)取得,或是可合成的。DNA可用化学或通过使用分子生物技术来测序和操作,例如,以将一或多个可变和/或恒定结构域排列成适合的构型,或导入密码子、产生半胱氨酸残基、修饰、增加或删除氨基酸等。
抗原结合片段的非限制性实例包括:(i)Fab片段;(ii)F(ab')2片段;(iii)Fd片段;(iv)Fv片段;(v)单链Fv(scFv)分子;(vi)dAb片段;和(vii)由模拟抗体高变区的氨基酸残基所组成的最小识别单位(例如分离的互补决定区(CDR),例如CDR3肽)或限制性FR3-CDR3-FR4肽。其他工程化的分子,例如结构域特异性抗体、单结构域抗体、结构域删除的抗体、嵌合抗体、CDR移植抗体、双抗体、三抗体、四抗体、微抗体、纳米抗体(例如单价纳米抗体、双价纳米抗体等)、小模块免疫药物(SMIP)及鲨可变IgNAR结构域,也涵盖在本文所用的表述“抗原结合片段”内。在某些实施方案中,抗体的抗原结合片段可以含有与至少一个恒定结构域共价连接的至少一个可变结构域。可变结构域和恒定结构域可以彼此直接连接或可以通过完整或部分铰链或接头区域连接。铰链区可由至少2个(例如5、10、15、20、40、60个或更多个)氨基酸组成,其导致单个多肽分子中相邻的可变和/或恒定结构域之间的柔性或半柔性连接。
如本文中使用的,术语抗体的“可变域/可变结构域”或“可变区”指包含一个或多个CDR的抗体可变区或其片段。尽管可变域可以包含完整的可变区(如HCVR或LCVR),但也可以包含少于完整的可变区而仍然保留结合抗原或形成抗原结合位点的能力。
抗体的“Fc”是指抗体的以下部分,其包含第一重链的第二(CH2)和第三(CH3)恒定区经由二硫键联合第二重链的第二和第三恒定区。Fc区还可以包含全部或部分的铰链区。抗体的Fc部分负责多种效应器功能例如ADCC和CDC,但并不在抗原结合中发挥功能。抗体经由其Fc域启动和调节效应器功能的能力是其体内保护性活性的关键部分。尽管以前认为抗体的中和活性仅仅是Fab-抗原相互作用的结果,但越来越多的证据表明其体内活性还高度依赖于IgG Fc域与其相关受体Fcγ受体(FcγR)之间的相互作用,这些受体在效应器淋巴细胞表面上表达。
术语“PD-L1”,也称为程序性死亡配体1,是一种40kDa的1型跨膜蛋白,据推测在抑制适应性免疫系统中起主要作用。PD-L1是程序性死亡1(PD-1)的主要配体。如本文所用,术语“PD-L1”在指PD-L1蛋白的氨基酸序列(例如NCBI GenBank ID:NP_054862.1所提供的)时,包括全长PD-L1蛋白,或PD-L1的胞外域(PD-L1 ECD)或含有PD-L1 ECD的片段;还包括PD-L1 ECD的融合蛋白,例如与小鼠或人的IgG Fc(mFc或hFc)融合的片段。此外,如本领域技术人员所理解的,PD-L1蛋白也将包括那些天然或人工引入氨基酸序列的突变(包括但不限于置换、缺失和/或添加)而不影响生物学功能的PD-L1蛋白。
如本文所用,术语“结合PD-L1的抗体”或“抗PD-L1抗体”包括特异性识别或结合PD-L1的抗体及其抗原结合片段。如本文所用,表述“抗PD-L1抗体”包括具有单一特异性的单价抗体,以及包含结合PD-L1的第一抗原结合位点和结合第二(靶)抗原的第二抗原结合位点的双特异性抗体。
术语“TGFβ”,即转化生长因子β(TGF-β),是属于转化生长因子超家族的多功能细胞因子,该家族包括三种不同的哺乳动物同工型(TGF-β1至3,HGNC代号TGFB1、TGFB2、TGFB3)和许多其他信号蛋白。TGFβ参与旁分泌信号传导,可以在许多不同的组织类型中发现,包括脑,心脏,肾脏,肝脏,骨骼和睾丸。TGF-β失调与癌变有关。例如,据报道在某些人肿瘤样品中PD-L1表达升高与活化的TGF-β信号传导之间存在潜在关联(Justin M.David等人Oncoimmunology.2017;6(10):e1349589)。
术语“TGFβR”,即TGFβ家族受体,可以分为I型、II型和III型三种类型。对于总共13种TGFβ超家族受体,有7种I型受体,5种II型受体和1种III型受体。如本文所用,“TGFβRII”或“TGFβ受体II”是指具有野生型人TGFβ受体2型同工型A序列(例如,NCBI参考序列(RefSeq)登录号NP-001020018),或具有野生型人TGFβ受体2型同工型B序列(例如,NCBIRefSeq登录号NP-003233的氨基酸序列)或具有与野生型氨基酸序列基本相同的序列的多肽。TGFβRII可保留野生型序列的TGFβ结合活性的至少0.1%,0.5%,1%,5%,10%,25%,35%,50%,75%,90%,95%或99%。表达的TGFβRII的多肽可能缺少信号序列。
如本文所用,术语“单克隆抗体”或“mAb”是指单分子成分的抗体分子制剂。单克隆抗体显示对特定表位的单一结合特异性和亲和力。
如本文所用,术语“人抗体”或“全人抗体”意图包括具有以下可变区的抗体,其中框架区和CDR区均衍生自人种系免疫球蛋白序列。此外,如果抗体含有恒定区,那么恒定区也衍生自人种系免疫球蛋白序列。本公开的人抗体可包括并非由人种系免疫球蛋白序列编码的氨基酸残基(例如通过体外随机的或位点特异性的诱变或通过体内体细胞突变)。然而,术语“人抗体”在本文中不意图包括其中将衍生自另一个哺乳动物物种(例如小鼠)的CDR序列嫁接到人框架区序列上的抗体。
术语“人源化抗体”意指其中衍生自另一哺乳动物物种例如小鼠的种系的CDR序列已嫁接到人框架序列上的抗体。可以在人框架序列内进行其他框架区修饰。
术语“融合蛋白”,如本文所用,是指具有两个(或更多个)共价连接在一起的部分的多肽,其中每个部分是具有不同特性的肽。该性质可以是生物学性质,例如体外或体内活性。该性质也可以是简单的化学或物理性质,例如与靶抗原的结合,反应的催化等。这两个部分可以通过单个肽键直接连接或通过包含一个或多个氨基酸残基的肽接头连接。通常,这两个部分和接头将符合阅读框地连接。在某些实施方案中,融合蛋白的两个部分分别是特异性结合PD-L1的抗原结合部分和能够结合TGFβ的人TGFβ受体(TGFβR)或其部分。这样的包含抗体的融合蛋白在本公开中也可以视为抗体(例如,称为“融合抗体”)。
术语“可操作地连接”是指两个或多个感兴趣的生物序列的并置(带有或不带有间隔区或接头)以使得它们处于允许以预期方式起作用的关系。就多肽而言,是指以允许连接的产物具有预期的生物学功能的方式连接多肽序列。例如,抗体可变区可以可操作地连接于恒定区,以便提供具有抗原结合活性的稳定产物。该术语也可以关于多核苷酸使用。举例来说,当编码多肽的多核苷酸可操作地连接于调节序列(例如启动子、增强子、沉默子序列等)时,其意指多核苷酸序列以允许调节多肽从该多核苷酸的表达的方式连接。
如本文所用,术语“Ka”旨在表示特定抗体-抗原相互作用的缔合速率,而本文所用的术语“Kd”旨在表示特定抗体-抗原相互作用的解离速率。抗体的Kd值可以使用本领域良好建立的方法来确定。如本文所用,术语“KD”旨在表示特定抗体-抗原相互作用的解离常数,其从Kd与Ka的比率(即,Kd/Ka)获得并且表示为摩尔浓度(M)。确定抗体Kd的优选方法是通过使用表面等离子体共振,优选使用生物传感器系统如系统。
如本文所用的术语IgG抗体的“高亲和力”是指针对靶抗原具有1×10-7M或更低,更优选5×10-8M或更低,甚至更优选1×10-8M或更低,甚至更优选5×10-9M或更低,和甚至更优选1×10-9M或更低的KD的抗体。
如本文所用,术语“EC50”也被称为“半数有效浓度”,是指在特定的暴露时间后诱导在基线和最大值之间的50%的应答的药物、抗体或毒剂的浓度。在本申请的上下文中,EC50的单位为“nM”。
如本文所用,“抑制结合”的能力是指抗体或融合蛋白抑制或阻断两个分子(例如PD1和PD-L1)的结合至任何可检测水平。在某些实施方案中,两个分子的结合可以被抗体或其抗原结合片段抑制至少50%。在某些实施方案中,这类抑制效果可以大于60%、大于70%、大于80%或大于90%。在某些实施方案中,本发明的融合蛋白以不超过0.1nM的IC50阻断PD1与细胞表面PD-L1的结合。
如本文所用,术语“表位”是指免疫球蛋白或抗体特异性结合的抗原部分。“表位”也被称为“抗原决定簇”。表位或抗原决定簇通常由分子例如氨基酸、碳水化合物或糖侧链的化学活性表面基团组成,并且通常具有特定的三维结构和特定的电荷特征。参见例如Epitope Mapping Protocols in Methods in Molecular Biology,Vol.66,G.E.Morris,编(1996)。
如本文所用,术语“分离的”是指通过人工方式从天然状态获得的状态。如果某种“分离的”物质或组分天然存在,则可能是因为其天然环境发生变化,或者物质与天然环境分离,或者两者兼而有之。例如,某种未分离的多核苷酸或多肽天然存在于某个活动物体内,从该天然状态分离的相同的高纯度多核苷酸或多肽被称为分离的多核苷酸或多肽。术语“分离的”既不排除混合的人造或合成物质,也不排除不影响分离的物质的活性的其他不纯物质。
如本文所用,术语“分离的抗体”旨在指基本上不含具有不同抗原特异性的其他抗体的抗体(例如,特异性结合PD-L1蛋白的分离的抗体基本上不含特异性结合除PD-L1蛋白以外的抗原的抗体)。然而,特异性结合人PD-L1蛋白的分离的抗体对其他抗原如来自其他物种的PD-L1蛋白可能具有交叉反应性。此外,分离的抗体可以基本上不含其他细胞材料和/或化学物质。
如本文所用,术语“载体”是指可以在其中插入多核苷酸的核酸媒介物。当载体允许插入其中的多核苷酸编码的蛋白质的表达时,该载体称为表达载体。该载体可以通过转化、转导或转染入宿主细胞而使携带的遗传物质元件在宿主细胞中表达。载体是本领域技术人员所熟知的,包括但不限于质粒,噬菌体,粘粒,人工染色体如酵母人工染色体(YAC),细菌人工染色体(BAC)或P1衍生人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体和动物病毒。可用作载体的动物病毒包括但不限于逆转录病毒(包括慢病毒),腺病毒,腺伴随病毒,疱疹病毒(如单纯疱疹病毒),痘病毒,杆状病毒,乳头瘤病毒,乳多空病毒(如SV40)。载体可以包含用于控制表达的多个元件,包括但不限于启动子序列,转录起始序列,增强子序列,选择元件和报道基因。另外,载体可以包含复制起点。
如本文所用,术语“宿主细胞”是指可被工程化以产生感兴趣的蛋白质、蛋白质片段或肽的细胞系统。宿主细胞包括但不限于培养细胞,例如来源于啮齿动物(大鼠,小鼠,豚鼠或仓鼠)的哺乳动物培养细胞,如CHO,BHK,NSO,SP2/0,YB2/0;或人体组织或杂交瘤细胞,酵母细胞和昆虫细胞,以及包含在转基因动物或培养组织内的细胞。该术语不仅涵盖特定的受试细胞,还涵盖这种细胞的后代。由于突变或环境影响可能在后代中发生某些修饰,这样的后代可能与亲本细胞不同,但仍包括在术语“宿主细胞”的范围内。
如本文所用,术语“同一性”是指通过比对和比较序列确定的两个或更多个多肽分子或两个或更多个核酸分子的序列之间的关系。“百分比同一性”是指比较分子中氨基酸或核苷酸之间相同残基的百分比,并基于被比较的最小分子的大小计算。对于这些计算,比对中的缺口(如果有的话)优选通过特定的数学模型或计算机程序(即“算法”)来寻址。可以用于计算比对的核酸或多肽的同一性的方法包括在Computational Molecular Biology,(Lesk,A.M.编),1988,New York:Oxford University Press;Biocomputing Informaticsand Genome Projects,(Smith,D.W.编),1993,New York:Academic Press;ComputerAnalysis of Sequence Data,Part I,(Griffin,A.M.和Griffin,H.G.编),1994,NewJersey:Humana Press;von Heinje,G.,1987,Sequence Analysis in MolecularBiology,New York:Academic Press;Sequence Analysis Primer,(Gribskov,M.和Devereux,J.编),1991,New York:M.Stockton Press;和Carillo等人,1988,SIAMJ.Applied Math.48:1073中描述的那些。
如本文所用,术语“免疫原性”是指刺激生物体中特异性抗体或致敏淋巴细胞形成的能力。它不仅指抗原刺激特定免疫细胞活化、增殖和分化以最终产生免疫效应物质如抗体和致敏淋巴细胞的性质,还指抗体或致敏T淋巴细胞的特异性免疫应答可以在用抗原刺激生物体后在生物体的免疫系统中形成。免疫原性是抗原最重要的特性。抗原是否能够成功诱导宿主中免疫应答的产生取决于三个因素:抗原的性质、宿主的反应性和免疫手段。
如本文所用,术语“转染”是指将核酸引入真核细胞特别是哺乳动物细胞的过程。用于转染的方案和技术包括但不限于脂质转染和化学和物理方法如电穿孔。许多转染技术在本领域是公知的并且在本文中公开。参见例如Graham等人,1973,Virology 52:456;Sambrook等人,2001,Molecular Cloning:A Laboratory Manual,同上;Davis等人,1986,Basic Methods in Molecular Biology,Elsevier;Chu等人,1981,Gene 13:197。在本发明的一个具体实施方案中,将人PD-L1基因转染入293F细胞。
如本文所用,术语“SPR”或“表面等离子体共振”是指并且包括允许通过检测生物传感器基质内的蛋白质浓度的改变来分析实时生物特异性相互作用的光学现象,例如使用BIAcore系统(Pharmacia Biosensor AB,Uppsala,Sweden和Piscataway,NJ)。关于详细描述,参见U.,等人(1993)Ann.Biol.Clin.51:19-26;U.,等人(1991)Biotechniques 11:620-627;Johnsson,B.,等人(1995)J.Mol.Recognit.8:125-131;和Johnnson,B.,等人(1991)Anal.Biochem.198:268-277。
如本文所用,术语“荧光激活细胞分选”或“FACS”是指专门类型的流式细胞术。它提供了根据每个细胞的特定光散射和荧光特征,将生物细胞的异质混合物以每次一个细胞分拣到两个或更多个容器中的方法(FlowMetric.“Sorting Out Fluorescence ActivatedCell Sorting”.2017-11-09)。用于进行FACS的仪器是本领域技术人员已知的并且可以对于公众是可商购获得的。这种仪器的实例包括Becton Dickinson(Foster City,CA)的FACSStar Plus、FACScan和FACSort仪器、来自Coulter Epics Division(Hialeah,FL)的EpicsC和来自Cytomation(Colorado Springs,Colorado)的MoFlo。
术语“受试者”包括任何人或非人动物,优选人。
如本文所用,术语“癌症”是指引发医学病症的任何肿瘤或恶性细胞生长、增殖或转移介导的实体瘤和非实体瘤如白血病。
本文在治疗病况的情况中使用的术语“治疗”、“处理”和“医治”一般涉及人或动物的治疗和疗法,其中实现了一些期望的治疗效果,例如,抑制病况进展,包括进展速度下降,进展速度停滞,病况消退,病况改善和病况治愈。还包括了作为预防措施(即预防)的治疗。对于癌症,“治疗”可能是指抑制或减缓肿瘤或恶性细胞生长、增殖或转移或其某种组合。对于肿瘤,“治疗”包括去除全部或部分肿瘤、抑制或减缓肿瘤生长和转移、预防或延迟肿瘤的发展或其某种组合。
如本文所用,术语“有效量”涉及活性化合物的量或包含活性化合物的材料、组合物或剂量的量,其在按照所需的治疗方案施用时有效用于产生与合理的益处/风险比相称的某些所需的治疗效果。例如,当与治疗PD-1/PD-L1相关疾病或病症联合使用时,“有效量”是指抗体或其抗原结合部分有效治疗所述疾病或病症的量或浓度。
如本文所用,关于哺乳动物中的某种疾病病况的术语“预防”、“防止”或“阻止”是指预防或延迟疾病的发作或预防其临床或亚临床症状的表现。
如本文所用,术语“药学上可接受”是指载体、稀释剂、赋形剂和/或其盐在化学和/或物理上与制剂中的其他成分相容,并且与接受者在生理学上相容。
如本文所用,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性剂相容的载体和/或赋形剂,其在本领域中是公知的(参见,例如,Remington's Pharmaceutical Sciences.Edited by Gennaro AR,第19版,Pennsylvania:Mack Publishing Company,1995),并且包括但不限于pH调节剂、表面活性剂、佐剂和离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子、阴离子或非离子表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
如本文所用,术语“佐剂”是指非特异性免疫增强剂,其在与抗原一起递送至生物体或被提前递送至有机体时可以增强生物体中的对抗原的免疫应答或改变免疫应答的类型。存在多种佐剂,包括但不限于铝佐剂(例如氢氧化铝)、弗氏佐剂(例如弗氏完全佐剂和弗氏不完全佐剂)、短小棒状杆菌、脂多糖、细胞因子等。弗氏佐剂是目前动物实验中最常用的佐剂。氢氧化铝佐剂更常用于临床试验。
包含抗PD-L1抗体和TGFβR或其部分的融合蛋白
本申请提供能特异性结合PD-L1和TGFβ(例如TGFβ1和TGFβ3)两者的融合蛋白,因此不仅靶向PD-L1抗原或表达PD-L1的细胞,还促进微环境中TGFβ的局部消耗。广义上而言,这类融合蛋白也可视为抗体,因为其能特异性结合PD-L1、拮抗PD-L1活性和阻断PD-1/PD-L1信号传导途径。该融合蛋白在本文中也可以称为“双功能性蛋白”或“TGFβ捕获-PD-L1靶向性抗体融合物”。
本文中的融合蛋白可以包含(a)特异性结合PD-L1的抗体或其抗原结合部分,和(b)能够结合TGFβ的人转化生长因子β受体(TGFβR)或其部分(也称为TGFβ捕获者),其中(a)和(b)可以经由接头融合。所述抗体或其抗原结合部分可以具有多种形式,例如全抗体、单特异性抗体、双特异性抗体、ScFv、域抗体(SdAb)、VHH、Fab、F(ab')2或Fv片段等,只要它具有与PD-L1的特异性结合亲和力。人转化生长因子β受体可以选自TGFβRII和TGFβRIII,优选TGFβRII。融合蛋白可包含野生型TGFβRII的一部分,该部分保留一些或全部的TGFβ结合能力,例如融合蛋白可包含TGFβRII的细胞外结构域(ECD)。
(a)和(b)之间的接头将特异性结合PD-L1的抗体或其抗原结合部分的C末端连接到能结合TGFβ的人转化生长因子β受体(TGFβR)或其部分的N末端或C末端。在一些实施方案中,在不存在Fc区的情况下,接头可以连接至抗体的可变结构域(例如Fab、域Ab或ScFv)的C末端;或者,在抗体是全抗体或重链抗体的情况下,接头可以连接至Fc区的C末端。
在单一药剂中将抗PD-L1和TGFβ捕获者组合引发了协同的抗肿瘤作用,这是由于同时阻断肿瘤细胞上的PD-L1和免疫细胞上的PD-1之间的相互作用,以及中和肿瘤微环境中的TGFβ。如实施例所证实的,与M7824相比,本公开的融合蛋白表现出更好的对PD-1/PD-L1信号传导途径的阻断,并更有效地增强了IFNγ的产生。
具体地,本发明的融合蛋白提供了以下一种或多种特性:
(a)能够以不超过7×10-10M的KD结合人PD-L1,以及以不超过2×10-12M的KD结合TGFβ1,如通过SPR测定的;
(b)能够以不超过2nM的EC50结合食蟹猴PD-L1,如通过FACS测定的;
(c)能够同时结合PD-L1和TGFβ1;
(d)能够实现PD-1/PD-L1信号传导阻断和TGF-β1阻断;
(e)在同种异体混合淋巴细胞反应中有力地增强IL-2和IFNγ产生;
(f)在加速稳定性研究中是稳定的;和
(g)在人血清中稳定至少14天。
特异性结合PD-L1的抗体或其抗原结合部分
在一些实施方案中,特异性结合PD-L1的抗体或其抗原结合部分包含一个或多个重链CDR(HCDR),所述重链CDR选自由以下组成的至少一组:
(i)HCDR1,其包含SEQ ID NO:1或与SEQ ID NO:1相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
(ii)HCDR2,其包含SEQ ID NO:2或与SEQ ID NO:2相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;和
(iii)HCDR3,其包含SEQ ID NO:3或与SEQ ID NO:3相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;和/或
包含一个或多个轻链CDR(LCDR),所述轻链CDR选自由以下组成的至少一组:
(i)LCDR1,其包含SEQ ID NO:4或与SEQ ID NO:4相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
(ii)LCDR2,其包含SEQ ID NO:5或与SEQ ID NO:5相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;和
(iii)LCDR3,其包含SEQ ID NO:6或与SEQ ID NO:6相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列。
在一些实施方案中,抗体或其抗原结合部分包含重链可变区(VH)和轻链可变区(VL),其中重链可变区包含(i)包含或组成为SEQ ID NO:1的HCDR1;(ii)包含或组成为SEQID NO:2的HCDR2;和(iii)包含或组成为SEQ ID NO:3的HCDR3;和/或轻链可变区包含:(i)包含或组成为SEQ ID NO:4的LCDR1;(ii)包含或组成为SEQ ID NO:5的LCDR2;和(iii)包含或组成为SEQ ID NO:6的LCDR3。
在一些实施方案中,所述重链可变区包含:(i)SEQ ID NO:7的氨基酸序列;(ii)与SEQ ID NO:7至少85%、至少90%、或至少95%相同的氨基酸序列;或(iii)与SEQ ID NO:7相比具有一个或多个氨基酸的添加、缺失、和/或取代的氨基酸序列;和/或
所述轻链可变区包含:(i)SEQ ID NO:8的氨基酸序列;(ii)与SEQ ID NO:8至少85%、至少90%、或至少95%相同的氨基酸序列;或(iii)与SEQ ID NO:8相比具有一个或多个氨基酸的添加、缺失、和/或取代的氨基酸序列。
包含上述抗体或其抗原结合部分的本公开的融合蛋白能以高亲和力结合人PD-L1。本公开的抗体对PD-L1的结合可使用本领域中确立的一种或多种技术(例如ELISA)来评估。本公开的抗体的结合特异性也可以通过监测抗体对表达PD-L1蛋白的细胞的结合(例如流式细胞术)来测定。例如,可以通过流式细胞术测定来测试抗体,其中使抗体与表达人PD-L1的细胞系反应,例如经过转染以在其细胞表面上表达PD-L1的CHO-K1或293F细胞。另外或者备选地,可以在BIAcore结合测定法中测试抗体的结合,包括结合动力学(例如KD值)。其他合适的结合测定法包括ELISA或FACS测定法,例如可使用重组PD-L1蛋白。
例如,本公开的抗体以1×10-7M或更低的KD、5×10-8M或更低的KD、2×10-8M或更低的KD、1×10-8M或更低的KD、5×10-9M或更低的KD、4×10-9M或更低的KD、3×10-9M或更低的KD、2×10-9M或更低的KD、1×10-9M或更低的KD、5×10-10M或更低的KD、1×10-10M或更低的KD结合人PD-L1蛋白,如通过表面等离子共振测量的。或者,本公开的抗体能以低于5nM、低于4nM、低于3nM、低于2nM、低于1nM或甚至低于0.5nM的EC50结合表达人或食蟹猴PD-L1的细胞系,如通过FACS测定的。
除非另有说明,否则将氨基酸分配给每个CDR可以根据以下提供的编号方案之一:Kabat等人(1991)Sequences of Proteins of Immunological Interest(第5版),USDept.of Health and Human Services,PHS,NIH,NIH Publication no.91-3242;Chothia等人,1987,PMID:3681981;Chothia等人,1989,PMID:2687698;MacCallum等人,1996,PMID:8876650;或Dubel编(2007)Handbook of Therapeutic Antibodies,第3版,Wily-VCHVerVEGF GmbH and Co.。
抗体序列中的可变区和CDR可以根据本领域已经开发的一般规则(如上所述,例如Kabat编号系统)或通过将序列与已知可变区的数据库比对来鉴定。在Kontermann和Dubel编,Antibody Engineering,Springer,New York,NY,2001和Dinarello等人,CurrentProtocols in Immunology,John Wiley and Sons Inc.,Hoboken,NJ,2000中描述了鉴定这些区域的方法。抗体序列的示例性数据库描述于并可获自www.bioinf.org.uk/abs上的“Abysis”网站(由Department of Biochemistry&Molecular Biology UniversityCollege London,London,England的A.C.Martin维护)和VBASE2网站www.vbase2.org,如Retter等人,Nucl.Acids Res.,33(Database issue):D671-D674(2005)中所述。优选使用Abysis数据库分析序列,其整合了来自Kabat、IMGT和蛋白质数据库(PDB)的序列数据与来自PDB的结构数据,参见Dr.Andrew C.R.Martin所著的书中的Protein Sequence andStructure Analysis of Antibody Variable Domains.In:Antibody Engineering LabManual(编:Duebel,S.和Kontermann,R.,Springer-VerVEGF,Heidelberg,ISBN-13:978-3540413547,也可在网站bioinforg.uk/abs上获得)。Abysis数据库网站还包括已经开发用于识别可以根据本文的教导使用的CDR的一般规则。除非另有说明,否则本文所述的所有CDR均根据Kabat的Abysis数据库网站获得。
两个氨基酸序列之间的百分比同一性可以使用E.Meyers和W.Miller的算法(Comput.Appl.Biosci.,4:11-17(1988))确定,该算法已被并入ALIGN程序(版本2.0),使用PAM120权重残基表,空位长度罚分为12,空位罚分为4。另外,两个氨基酸序列之间的百分比同一性可以通过Needleman和Wunsch的算法(J.Mol.Biol.48:444-453(1970))确定,其已并入GCG软件包(可从http://www.gcg.com获得)中的GAP程序中,使用Blossum 62矩阵或PAM250矩阵,缺口权重为16、14、12、10、8、6或4,长度权重为1、2、3、4、5或6。
另外地或可选地,本发明的蛋白质序列可以进一步用作“查询序列”来执行针对公共数据库的搜索以例如识别相关序列。这种搜索可以使用Altschul,等人(1990)J.MoI.Biol.215:403-10的XBLAST程序(版本2.0)来执行。可用XBLAST程序进行BLAST蛋白质搜索,得分=50,字长=3,以获得与本发明的抗体分子同源的氨基酸序列。为了获得用于比较目的的空位比对,可使用空位BLAST,如Altschul等人,(1997)Nucleic Acids Res.25(17):3389-3402中所述的。当使用BLAST和空位BLAST程序时,可以使用各个程序(例如,XBLAST和NBLAST)的默认参数。参见www.ncbi.nlm.nih.gov。
在其他实施方案中,CDR氨基酸序列可以是与上述相应序列中所包含的具体的CDR氨基酸序列至少90%,91%,92%,93%,94%,95%,96%,97%,98%或99%相同。在其他实施方案中,可变区的氨基酸序列可以与上述相应序列至少80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%或99%相同。
优选地,分离的抗体或其抗原结合部分的CDR包含不多于2个氨基酸或不多于1个氨基酸的保守取代。本文使用的术语“保守取代”是指氨基酸取代,其不会不利地影响或改变包含氨基酸序列的蛋白质/多肽的基本性质。例如,保守取代可以通过本领域已知的标准技术(例如定点诱变和PCR介导的诱变)引入。保守氨基酸取代包括其中氨基酸残基被具有相似侧链的另一氨基酸残基取代的取代,例如物理或功能相似的残基(例如具有相似的大小,形状,电荷,化学性质包括形成共价键或氢键的能力等)至相应的氨基酸残基的取代。本领域已经定义了具有相似侧链的氨基酸残基家族。这些家族包括具有碱性侧链的氨基酸(例如赖氨酸,精氨酸和组氨酸),具有酸性侧链的氨基酸(例如天冬氨酸和谷氨酸),具有不带电荷的极性侧链的氨基酸(例如甘氨酸,天冬酰胺,谷氨酰胺,丝氨酸,苏氨酸,酪氨酸,半胱氨酸,色氨酸),具有非极性侧链的氨基酸(例如丙氨酸,缬氨酸,亮氨酸,异亮氨酸,脯氨酸,苯丙氨酸,甲硫氨酸),具有β-分支侧链的氨基酸(例如苏氨酸,缬氨酸,异亮氨酸)和具有芳香族侧链的氨基酸(例如酪氨酸,苯丙氨酸,色氨酸,组氨酸)。因此,相应的氨基酸残基优选被来自相同侧链家族的另一个氨基酸残基取代。用于鉴定氨基酸保守取代的方法在本领域中是公知的(参见例如Brummell等人,Biochem.32:1180-1187(1993);Kobayashi等人,Protein Eng.12(10):879-884(1999);和Burks等人,Proc.Natl.Acad.Sci.USA 94:412-417(1997),其通过引用并入本文)。
包含人转化生长因子β受体(TGFβR)或其部分的TGFβ捕获者
TGFβ具有三个配体同工型,TGFβ1、2和3,它们均以同二聚体形式存在。还有三种TGFβR受体(TGFβR),分别称为I、II和III型TGFβR。TGFβRI是信号链,不能结合配体。TGFβRII以高亲和力结合配体TGFβ1和3,但不结合TGFβ2。TGFβRIII是TGFβ与其信号受体结合的阳性调节物,并以高亲和力结合所有3种TGFβ同工型。据报道,TGFβ1和TGFβ2分别在肿瘤微环境和心脏生理中起主要作用,因此中和TGFβ1而非TGFβ2的治疗剂可通过使心脏毒性最小化而不损害抗肿瘤活性而提供最佳的治疗指标。因此,选择了TGFβRII,并且TGFβRII的胞外结构域仅具有136个氨基酸残基的长度(SEQ ID No:9),这使其非常适合于构建抗体-捕获者融合蛋白。
在所述融合蛋白中,人转化生长因子β受体(TGFβR)或其部分可以包含:
(A)与野生型人TGFβRII的氨基酸序列至少85%、至少90%、或至少95%相同的氨基酸序列;
(B)与野生型人TGFβRII胞外结构域的氨基酸序列至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)野生型人TGFβRII的部分,其保留与TGFβ的结合能力的至少75%、至少80%、至少85%、至少90%、或至少95%。
在一些实施方案中,本文中的融合蛋白中包含的TGFβ捕获者是TGFβRII的胞外结构域或其部分。在一些特定的实施方案中,所述TGFβ捕获者包含或组成为如SEQ ID NO:9中所示的序列。
编码本公开的融合蛋白的核酸分子
在一些方面,本公开涉及分离的核酸分子,其包含编码以下一种或多种的核酸序列:
(i)抗体或其抗原结合部分,或抗体的VH或VL结构域;
(ii)融合蛋白的人TGFβRII或其部分;和
(iii)融合蛋白的重链或轻链。
在一些方面,本公开涉及包含编码如本文所公开的核酸序列的载体。在本发明的情况下载体可以是任何合适的载体,包括染色体、非染色体和合成的核酸载体(包含一组合适的表达控制元件的核酸序列)。这样的载体的实例包括SV40的衍生物、细菌质粒、噬菌体DNA、杆状病毒、酵母质粒、源自质粒和噬菌体DNA的组合的载体,和病毒核酸(RNA或DNA)载体。在一个实施方案中,PD-L1抗体编码核酸包含在裸DNA或RNA载体中,包括例如线性表达元件(描述于例如Sykes和Johnston,Nat Biotech 17,355-59(1997))、紧密核酸载体(描述于例如US 6,077,835和/或WO 00/70087)、质粒载体例如pBR322、pUC 19/18或pUC 118/119、"midge"最小尺寸的核酸载体(描述于例如Schakowski等人,Mol Ther 3,793-800(2001))或作为沉淀的核酸载体构建体,例如CaPO4沉淀的构建体(描述于例如WO200046147,Benvenisty和Reshef,PNAS USA 83,9551-55(1986),Wigler等人,Cell 14,725(1978)和Coraro和Pearson,SomaticCell Genetics 7,603(1981))。这样的核酸载体和其用途是本领域众所周知的(参见例如US 5,589,466和US 5,973,972)。
在一个实施方案中,载体适合在细菌细胞中表达如本文公开的融合蛋白。这样的载体的实例包括表达载体,例如BlueScript(Stratagene)、pIN载体(Van Heeke&Schuster,J Biol Chem 264,5503-5509(1989)、pET载体(Novagen,Madison WI)等)。载体还可或备选地是适合在酵母系统中表达的载体。可使用合适在酵母系统中表达的任何载体。合适的载体包括,例如包含组成型或诱导型启动子,例如α因子、醇氧化酶和PGH的载体(综述于:F.Ausubel等人编,Current Protocols in MolecularBiology,Greene Publishing andWiley InterScience New York(1987)和Grant等人,Methods in Enzymol 153,516-544(1987))。
载体还可或备选地是适合在哺乳动物细胞中表达的载体,例如,包含谷氨酰胺合成酶作为可选择标记的载体,例如描述于Bebbington(1992)Biotechnology(NY)10:169-175中的载体。
核酸和/或载体还可包含编码分泌/定位序列的核酸序列,所述序列可将多肽,例如新生的多肽链靶向周质空间或细胞培养基。这样的序列是本领域已知的,和包括分泌前导或信号肽。
表达载体可包含任何合适的启动子、增强子和其它表达促进元件或与其缔合。这样的元件的实例包括强表达启动子(例如人CMV IE启动子/增强子以及RSV、SV40、SL3-3、MMTV和HIV LTR启动子)、有效的多聚(A)终止序列、在大肠杆菌中质粒产物的复制起点、作为可选择标记的抗生素抗性基因和/或方便的克隆位点(例如,聚合接头)。核酸还可包含与组成型启动子相对的诱导型启动子,例如CMV IE。
在再一个方面,本公开涉及包含本文所述的载体的宿主细胞。因此,本发明还涉及产生本发明的融合蛋白的重组真核或原核宿主细胞,例如转染瘤。
融合蛋白可在重组的真核或原核宿主细胞例如转染瘤中表达,其产生本文定义的融合蛋白。
宿主细胞的实例包括酵母、细菌、植物和哺乳动物细胞,例如CHO、CHO-S、HEK,HEK293、HEK-293F、Expi293F、PER.C6或NS0细胞或淋巴细胞。例如,在一个实施方案中,宿主细胞可包含稳定整合至细胞基因组的第一和第二核酸构建体。在另一个实施方案中,本发明提供包含非整合核酸、例如质粒、粘粒、噬菌粒或线性表达元件的细胞,其包含上文所述的第一和第二核酸构建体。
在另一个方面,本发明涉及转基因非人动物或植物,其包含编码如本文公开的融合蛋白的重链和轻链的一组或两组的核酸,其中所述动物或植物产生所述融合蛋白。
在再一个方面,本公开涉及杂交瘤,其产生用于本文定义的融合蛋白的抗体。
在一个方面,本发明涉及表达载体,其包含
(i)核酸序列,其编码根据本文公开的任一个实施方案的抗体或其抗原结合部分,或抗体的VH或VL结构域;
(ii)核酸序列,其编码根据本文公开的任一个实施方案的融合蛋白的人TGFβRII或其部分;
(iii)核酸序列,其编码融合蛋白的重链或轻链;或
(iv)上述两种或更多种的组合。
在一个方面,本公开涉及编码序列表中所列一种或多种氨基酸序列的核酸构建体。
在一个方面,本公开涉及产生根据本文公开的任一个实施方案的融合蛋白的方法,包括培养本文公开的包含表达融合蛋白的一种或多种表达载体的宿主细胞,和从培养基纯化所述融合蛋白。在一个方面,本发明涉及包含上文定义的表达载体的宿主细胞。在一个实施方案中,宿主细胞是重组真核、重组原核或重组微生物宿主细胞。
药物组合物
在一些方面,本发明涉及药物组合物,其包含至少一种如本文所公开的融合蛋白和药学上可接受的载体。
组合物的组分
药物组合物可以任选地含有一种或多种另外的药物活性成分,例如另一种抗体或药物。本发明的药物组合物还可以与例如另一种免疫刺激剂、抗癌剂、抗病毒剂或疫苗组合施用,使得如本文公开的融合蛋白增强对抗原的免疫反应。药学上可接受的载体可以包括例如药学上可接受的液体,凝胶或固体载体,水性介质,非水性介质,抗微生物剂,等渗剂,缓冲剂,抗氧化剂,麻醉剂,悬浮/分散剂,螯合剂,稀释剂,佐剂,赋形剂或无毒的辅助物质,本领域已知的各种组分的组合或更多。
合适的组分可以包括例如抗氧化剂、填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、润滑剂、调味剂、增稠剂、着色剂、乳化剂或稳定剂如糖和环糊精。合适的抗氧化剂可包括例如甲硫氨酸,抗坏血酸,EDTA,硫代硫酸钠,铂,过氧化氢酶,柠檬酸,半胱氨酸,巯基甘油,巯基乙酸,巯基山梨糖醇,丁基甲基苯甲醚,丁基化羟基甲苯和/或丙基砷酸盐。如本发明所公开的,在包含还原抗体或其抗原结合片段的一种或多种抗氧化剂如甲硫氨酸的含有本发明公开的组合物的抗体或抗原结合片段的溶剂中,其可被氧化。氧化还原可防止或减少结合亲和力的降低,从而增强抗体稳定性并延长保质期。因此,在一些实施方案中,本发明提供了包含一种或多种抗体或其抗原结合片段和一种或多种抗氧化剂如甲硫氨酸的组合物。本发明进一步提供了多种方法,其中将抗体或其抗原结合片段与一种或多种抗氧化剂如甲硫氨酸混合。从而,抗体或其抗原结合片段可以被防止氧化,以延长其保质期和/或增加活性。
为了进一步说明,药学上可接受的载体可以包括例如含水载体,例如氯化钠注射液,林格氏注射液,等渗右旋糖注射液,无菌水注射液或右旋糖和乳酸林格氏注射液,非水性载体如植物来源的固定油,棉籽油,玉米油,芝麻油或花生油,抑细菌剂或抑真菌浓度的抗微生物剂,等渗剂如氯化钠或葡萄糖,缓冲剂如磷酸盐或柠檬酸盐缓冲剂,抗氧化剂如硫酸氢钠,局部麻醉剂如盐酸普鲁卡因,悬浮剂和分散剂如羧甲基纤维素钠,羟丙基甲基纤维素或聚乙烯吡咯烷酮,乳化剂如聚山梨酯80(TWEEN-80),隔绝剂或螯合剂如EDTA(乙二胺四乙酸)或EGTA(乙二醇四乙酸),乙二醇,聚乙二醇,丙二醇,氢氧化钠,盐酸,柠檬酸或乳酸。用作载体的抗微生物剂可以添加到包含酚或甲酚、汞制剂、苯甲醇、氯丁醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、硫柳汞、苯扎氯铵和苄索氯铵的多剂量容器中的药物组合物中。合适的赋形剂可以包括例如水,盐水,右旋糖,甘油或乙醇。合适的无毒辅助物质可包括例如润湿剂或乳化剂,pH缓冲剂,稳定剂,溶解度增强剂或诸如乙酸钠、脱水山梨糖醇单月桂酸酯、三乙醇胺油酸酯或环糊精的试剂。
施用、制剂和剂量
本发明的药物组合物可以通过各种途径体内施用至有需要的受试者,所述途径包括但不限于口服,静脉内,动脉内,皮下,肠胃外,鼻内,肌内,颅内,心内,心室内,气管内,口腔,直肠,腹膜内,皮内,局部,经皮和鞘内,或者通过植入或吸入。本发明组合物可以配制成固体、半固体、液体或气体形式的制剂;包括但不限于片剂,胶囊剂,粉剂,颗粒剂,软膏剂,溶液剂,栓剂,灌肠剂,注射剂,吸入剂和气雾剂。根据预期的应用和治疗方案可以选择合适的制剂和施用途径。
用于肠内施用的合适制剂包括硬或软的明胶胶囊,丸剂,片剂,包括包衣片剂,酏剂,混悬剂,糖浆剂或吸入剂及其控释剂型。
适用于肠胃外施用(例如通过注射)的制剂包括活性成分溶解、悬浮于其中或以其他方式提供的(例如,在脂质体或其他微粒中)的水性或非水性、等渗、无热原、无菌液体(例如溶液,混悬液)。这些液体可以另外含有其它药学上可接受的成分,例如抗氧化剂,缓冲剂,防腐剂,稳定剂,抑菌剂,悬浮剂,增稠剂和使制剂与预期接受者的血液(或其他相关体液)等渗的溶质。赋形剂的实例包括例如水,醇,多元醇,甘油,植物油等。适用于此类制剂的等渗载体的实例包括氯化钠注射液,林格溶液或乳酸林格氏注射液。类似地,特定剂量方案(包括剂量,时间和重复)将取决于具体个体和个体的病史以及诸如药代动力学(例如半衰期,清除率等)的经验考虑。
施用频率可以在治疗过程中确定和调整,并且基于减少增殖或致瘤细胞的数量,维持这种肿瘤细胞的减少,减少肿瘤细胞的增殖或延迟转移的发展。在一些实施方案中,施用的剂量可以被调节或减少以控制潜在的副作用和/或毒性。或者,本发明治疗组合物的持续连续释放制剂可能是合适的。
本领域技术人员将会理解,合适的剂量可因患者而异。确定最佳剂量通常涉及治疗益处水平与任何风险或有害副作用的平衡。所选择的剂量水平将取决于多种因素,包括但不限于特定化合物的活性,施用,施用时间,化合物清除速率,治疗持续时间,其他联合使用的药物、化合物和/或材料,病症的严重程度,以及物种,患者的性别、年龄、体重、病况、一般健康状况和以前的病史。化合物的量和施用途径最终由医生、兽医或临床医师决定,但通常选择剂量以达到实现所需效果的作用部位处的局部浓度,而不会导致实质性的有害或不利副作用。
通常,本发明的融合蛋白可以以各种范围施用。这些包括每剂量约5μg/kg体重至约100mg/kg体重;每剂量约50μg/kg体重至约5mg/kg体重;每剂量约100μg/kg体重至约10mg/kg体重。其他范围包括每剂量约100μg/kg体重至约20mg/kg体重和每剂量约0.5mg/kg体重至约20mg/kg体重。在一些实施方案中,每剂量为至少约100μg/kg体重,至少约250μg/kg体重,至少约750μg/kg体重,至少约3mg/kg体重,至少约5mg/kg体重,至少约10mg/kg体重。
无论如何,本发明的融合蛋白优选根据需要施用于有需要的受试者。本领域技术人员可以确定施用频率,例如主治医生基于所治疗病况、所治疗受试者的年龄、所治疗病况的严重程度、所治疗受试者的一般健康状况等的考虑。
在某些优选的实施方案中,涉及本发明的融合蛋白的治疗过程将包含在数周或数月的时间内施用的多剂量的所选药物产品。更具体地说,本发明的融合蛋白可以每天,每两天,每四天,每周,每十天,每两周,每三周,每月,每六周,每两个月,每十周或每三个月施用。就此而言,可以理解的是,可以基于患者响应和临床实践来改变剂量或者调整间隔。
在给予一次或多次施用的个体中也可凭经验确定所公开的治疗组合物的剂量和方案。例如,可给予个体增量剂量的如本文所述产生的治疗组合物。在选定的实施方案中,剂量可分别根据经验确定或观察到的副作用或毒性逐渐增加或减少或减轻。为了评估所选择的组合物的功效,可以如前所述跟踪特定疾病、病症或病况况的标志物。对于癌症,这些包括通过触诊或视觉观察直接测量肿瘤大小,通过X射线或其他成像技术间接测量肿瘤大小;通过直接肿瘤活组织检查和肿瘤样本的显微镜检查评估的改善;测量根据本文所述方法鉴定的间接肿瘤标志物(例如用于前列腺癌的PSA)或致瘤性抗原,疼痛或麻痹的减轻;与肿瘤相关的言语、视力、呼吸或其他失能的改善;食欲增加;或通过接受的测试测量的生活质量的提高或生存期的延长。本领域技术人员将明白,剂量将根据个体、肿瘤病况的类型、肿瘤病况的阶段、肿瘤病况是否已开始转移至个体中的其他位置以及过去使用的治疗和并行使用的治疗而变化。
用于肠胃外施用(例如静脉内注射)的相容制剂将包含浓度为约10μg/ml至约100mg/ml的本文公开的融合蛋白。在某些选定的实施方案中,融合蛋白的浓度将包括20μg/ml,40μg/ml,60μg/ml,80μg/ml,100μg/ml,200μg/ml,300μg/μg/ml,400μg/ml,500μg/ml,600μg/ml,700μg/ml,800μg/ml,900μg/ml或1mg/ml。在其他优选的实施方案中,融合蛋白的浓度将包括2mg/ml,3mg/ml,4mg/ml,5mg/ml,6mg/ml,8mg/ml,10mg/ml,12mg/ml,14mg ml,16mg/ml,18mg/ml,20mg/ml,25mg/ml,30mg/ml,35mg/ml,40mg/ml,45mg/ml,50mg/ml,60mg/ml,70mg/ml,80mg/ml,90mg/ml或100mg/ml。
本发明的应用
在一些方面,本发明提供了治疗受试者病症的方法,其包括向需要治疗的患者(例如人)施用治疗有效量的如本文公开的融合蛋白。例如,这种病症是一种癌症。
可以使用本公开提供的方法治疗或预防涉及PD-1/PD-L1的多种癌症,无论是恶性的还是良性的,以及是否是原发性的或继发性的。这些癌症可以是实体癌或血液恶性肿瘤。这些癌症的实例包括肺癌如支气管癌(例如鳞状细胞癌,小细胞癌,大细胞癌和腺癌),肺泡细胞癌,支气管腺瘤,软骨性错构瘤(非癌性)和肉瘤(癌性);心脏癌如粘液瘤,纤维瘤和横纹肌瘤;骨癌例如骨软骨瘤,软骨瘤,软骨母细胞瘤,软骨样软骨瘤,骨样骨瘤,巨细胞瘤,软骨肉瘤,多发性骨髓瘤,骨肉瘤,纤维肉瘤,恶性纤维组织细胞瘤,尤因氏肿瘤(尤因氏肉瘤)和网织细胞肉瘤;脑癌例如神经胶质瘤(例如多形性成胶质细胞瘤),间变性星形细胞瘤,星形细胞瘤,少突神经胶质瘤,成神经管细胞瘤,脊索瘤,神经鞘瘤,室管膜瘤,脑膜瘤,垂体腺瘤,松果体瘤,骨瘤,血管母细胞瘤,颅咽管瘤,脊索瘤,生殖细胞瘤,畸胎瘤,皮样囊肿和血管瘤;消化系统中的癌症如结肠癌,平滑肌瘤,表皮样癌,腺癌,平滑肌肉瘤,胃腺癌,肠脂肪瘤,肠神经纤维瘤,肠纤维瘤,大肠息肉和结肠直肠癌;肝癌如肝细胞腺瘤,血管瘤,肝细胞癌,纤维板层癌,胆管癌,肝母细胞瘤和血管肉瘤;肾癌如肾腺癌,肾细胞癌,高肾上腺瘤和肾盂的移行细胞癌;膀胱癌;血液系统癌症如急性淋巴细胞白血病(急性淋巴细胞性白血病),急性骨髓性(髓细胞性,骨髓,成髓细胞性,骨髓单核细胞性)白血病,慢性淋巴细胞性白血病(例如Sezary综合征和毛细胞性白血病),慢性髓细胞性(髓性,骨髓性,粒细胞性)淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,B细胞淋巴瘤,蕈样霉菌病和骨髓增殖性疾病(包括骨髓增生性疾病,如真性红细胞增多症,骨髓纤维化,血小板增多症和慢性粒细胞白血病);皮肤癌如基底细胞癌,鳞状细胞癌,黑素瘤,卡波西肉瘤和佩吉特氏病;头颈部癌症;与眼相关的癌症,如成视网膜细胞瘤和眼内黑素癌;男性生殖系统癌症如良性前列腺增生,前列腺癌和睾丸癌(例如精原细胞瘤,畸胎瘤,胚胎癌和绒毛膜癌);乳腺癌;女性生殖系统癌症如子宫癌(子宫内膜癌),宫颈癌(宫颈肿瘤),卵巢癌(卵巢肿瘤),外阴癌,阴道癌,输卵管癌和葡萄胎;甲状腺癌(包括乳头状,滤泡状,间变性或髓样癌);嗜铬细胞瘤(肾上腺);甲状旁腺的非癌性生长;胰腺癌;和血液学癌症例如白血病,骨髓瘤,非霍奇金淋巴瘤和霍奇金淋巴瘤。在具体的实施方案中,癌症是结肠癌。在一些其他实施方案中,癌症是肺癌,例如非小细胞肺癌(NSCLC)。
在一些实施方案中,癌症的实例包括但不限于B细胞癌,包括B细胞淋巴瘤(包括低级/滤泡性非霍奇金氏淋巴瘤(NHL);小淋巴细胞(SL)NHL;中级/滤泡性NHL;中间级别扩散性NHL;免疫母细胞NHL;高级别淋巴母细胞NHL;高级别小型非切割细胞NHL;大块疾病NHL;套细胞淋巴瘤;艾滋病相关淋巴瘤;瓦尔登斯特伦巨球蛋白血症;慢性淋巴细胞白血病(CLL);急性淋巴细胞白血病(ALL);毛细胞白血病;慢性粒细胞白血病;和移植后淋巴增生性疾病(PTLD),以及与瘢痣病相关的异常血管增生,水肿(例如与脑肿瘤相关的),B细胞增殖性病症和Meigs'综合征,更具体的例子包括但不限于复发或难治性NHL,前线低级别NHL,III/IV级NHL,化疗耐受性NHL,前体Bly成淋巴细胞性白血病和/或淋巴瘤,小淋巴细胞性淋巴瘤,B细胞慢性淋巴细胞白血病和/或幼淋巴细胞性白血病和/或小淋巴细胞性淋巴瘤,B细胞幼淋巴细胞淋巴瘤,免疫细胞瘤和/或淋巴浆细胞淋巴瘤,淋巴浆细胞性淋巴瘤,边缘区B细胞淋巴瘤,脾边缘区淋巴瘤,结外边缘区-MALT淋巴瘤,淋巴结边缘区淋巴瘤,毛细胞白血病,浆细胞瘤和/或浆细胞骨髓瘤,低级/滤泡性淋巴瘤,中级/滤泡性NHL,套细胞淋巴瘤,滤泡中心淋巴瘤(包括侵袭性前线NHL和侵袭性复发NHL),自体干细胞移植后复发或复发的NHL,原发性纵隔大B细胞淋巴瘤,原发性纵隔大B细胞淋巴瘤,原发性渗出性淋巴瘤,高级别免疫母细胞NHL,高级成淋巴细胞性NHL,高级别小非裂解性细胞NHL,庞大疾病NHL,伯基特淋巴瘤,前体(外周)大颗粒淋巴细胞白血病,蕈样肉芽肿和/或塞扎里综合征,皮肤(皮肤)淋巴瘤,间变性大细胞淋巴瘤,血管中心性淋巴瘤。
在一些实施方案中,癌症的实例进一步包括但不限于B细胞增殖性病症,其进一步包括但不限于淋巴瘤(例如B细胞非霍奇金淋巴瘤(NHL))和淋巴细胞白血病。这种淋巴瘤和淋巴细胞白血病包括例如a)滤泡性淋巴瘤,b)小的未分裂细胞淋巴瘤/伯基特淋巴瘤(包括地方性伯基特淋巴瘤,散发性伯基特氏淋巴瘤和非伯基特淋巴瘤),c)边缘区淋巴瘤(包括结外边缘区B细胞淋巴瘤(粘膜相关淋巴组织淋巴瘤,MALT),结节边缘区B细胞淋巴瘤和脾边缘区淋巴瘤),d)套细胞淋巴瘤(MCL),e)大细胞淋巴瘤(包括B细胞弥漫性大细胞淋巴瘤(DLCL)细胞淋巴瘤,免疫母细胞性淋巴瘤,原发性纵隔B细胞淋巴瘤,血管中心性淋巴瘤-肺B细胞淋巴瘤),f)毛细胞白血病,g)淋巴细胞淋巴瘤,瓦尔登斯特伦巨球蛋白血症,h)急性淋巴细胞白血病(ALL),慢性淋巴细胞白血病CLL)/小淋巴细胞性淋巴瘤(SLL),B细胞幼淋巴细胞性白血病,i)浆细胞瘤,浆细胞性骨髓瘤,多发性骨髓瘤,浆细胞瘤和/或j)霍奇金氏病。
在一些其他实施方案中,病症是自身免疫性疾病。可以用抗体或其抗原结合部分治疗的自身免疫性疾病的实例包括自身免疫性脑脊髓炎,红斑狼疮和类风湿性关节炎。抗体或其抗原结合部分也可用于治疗或预防感染性疾病,炎症性疾病(例如变应性哮喘)和慢性移植物抗宿主病。
与化疗组合使用
本文公开的融合蛋白可以与抗癌剂、细胞毒性剂或化学治疗剂组合使用。
术语“抗癌剂”或“抗增殖剂”意指可用于治疗细胞增殖性病症例如癌症的任何药剂,并且包括但不限于细胞毒性剂,细胞抑制剂,抗血管生成剂,放射疗法和放射治疗剂,靶向抗癌剂,BRM,治疗性抗体,癌症疫苗,细胞因子,激素疗法,放射疗法和抗转移剂和免疫治疗剂。应该理解的是,在如上所述的选定实施方案中,此类抗癌剂可以包含缀合物并且可以在施用之前与公开的融合蛋白缔合。更具体而言,在一些实施方案中,将选择的抗癌剂连接至抗体的不配对半胱氨酸以提供工程化缀合物。因此,这样的工程化缀合物被明确地考虑在本发明的范围内。在其他实施方案中,所公开的抗癌剂将与包含如上所述的不同治疗剂的位点特异性缀合物组合施用。
如本文所用,术语“细胞毒性剂”是指对细胞有毒并降低或抑制细胞功能和/或引起细胞破坏的物质。在一些实施方案中,该物质是源自活生物体的天然存在的分子。细胞毒性剂的实例包括但不限于,细菌(例如,白喉毒素、假单胞菌内毒素和外毒素,葡萄球菌肠毒素(Staphylococcal enterotoxin)A),真菌(例如α-八叠球菌素(sarcin),局限曲霉素(restrictocin)),植物(相思豆毒蛋白、蓖麻毒素、蒴莲根毒素、槲寄生素、美洲商陆抗病毒蛋白、皂草素、白树毒素、momoridin、天花粉蛋白、大麦毒素、油桐(Aleurites fordii)蛋白、石竹素蛋白、Phytolacca mericana蛋白(PAPI、PAPII和PAP-S)、苦瓜(Momordicacharantia)抑制剂、麻风树毒蛋白、巴豆毒素、石碱草(Saponaria officinalis)抑制剂、白树毒素、mitegellin、局限曲霉素、酚霉素、新霉素和单端孢霉烯族化合物)或动物(例如细胞毒性RNA酶,如胞外胰腺RNA酶;DNA酶I,包括其片段和/或变体)的小分子毒素或酶促活性毒素。
为了本发明的目的,“化学治疗剂”包括非特异性降低或抑制癌细胞的生长、增殖和/或存活的化学化合物(例如细胞毒性剂或细胞抑制剂)。这些化学药剂通常针对细胞生长或分裂所需的细胞内过程,因此对于通常快速生长和分裂的癌细胞特别有效。例如,长春新碱使微管解聚,从而抑制细胞进入有丝分裂。通常,化学治疗剂可以包括抑制或被设计用于抑制癌细胞或可能变成性或产生致瘤后代(例如TIC)的细胞的任何化学药剂。这些药剂通常是组合使用的,并且通常是最有效的,例如,在诸如CHOP或FOLFIRI的方案中。
可以与本发明的融合蛋白组合使用的抗癌剂(作为位点特异性缀合物的组分或未缀合状态)的实例包括但不限于烷化剂、烷基磺酸盐、氮丙啶、乙烯亚胺和甲基三聚氰胺、多聚乙酰(acetogenins)、喜树碱、苔藓抑素、卡利士他汀(callystatin)、CC-1065、克瑞托欣(cryptophycins)、多拉司他汀、多卡米星、艾榴素(eleutherobin)、水鬼蕉碱、沙克迪因(sarcodictyin)、海绵素(spongistatin)、氮芥、抗生素、烯二炔类抗生素、dynemicin、双膦酸盐、埃斯波霉素、色素蛋白烯二炔抗生素发色团、阿克拉霉素类(aclacinomysins)、放线菌素、安曲霉素、偶氮丝氨酸、博莱霉素、放线菌素C、卡拉宾辛(carabicin)、洋红霉素、嗜癌霉素、色霉素类(chromomycinis)、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、博地霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链脲菌素、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗-代谢物、埃罗替尼、威罗菲尼、克唑替尼、索拉非尼、依鲁替尼、恩杂鲁胺、叶酸类似物、嘌呤类似物、雄激素、抗-肾上腺素、叶酸补充剂如弗林酸(frolinic acid)、醋葡醛内酯、醛磷酰胺糖苷、氨基乙酰丙酸、恩尿嘧啶、安吖啶、贝斯布希(bestrabucil)、比生群、依达曲沙、迪夫法明(defofamine)、秋水仙胺、地吖醌、艾夫尼辛(elfornithine)、依利醋铵、爱波喜龙、依托格鲁、硝酸镓、羟基脲、香菇多糖、氯尼达明、美坦生类化合物(maytansinoids)、米托胍腙、米托蒽醌、莫丹摩尔(mopidanmol)、尼特林(nitraerine)、喷司他丁、蛋氨氮芥、吡柔比星、洛索蒽醌、鬼臼酸、2-乙基肼、丙卡巴肼、多糖复合物(JHS Natural Products,Eugene,OR)、雷佐生;根霉素;西佐喃;锗螺胺;替奴佐酸;三亚胺醌;2,2',2”-三氯三乙胺;单端孢霉烯类(尤其是T-2毒素、维拉库林A(verracurin A)、杆孢菌素A和蛇形菌素);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;哌泊溴烷;卡西托欣(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷类;苯丁酸氮芥(chloranbucil);吉西他滨;6-硫代鸟嘌呤;巯嘌呤;氨甲喋呤;铂类似物;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱,长春瑞滨;诺消灵;替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(Camptosar,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸;类视色素;卡培他滨;考布他汀;甲酰四氢叶酸;奥沙利铂;PKC-α、Raf、H-Ras、EGFR和VEGF-A的抑制剂(其减少细胞增殖),以及上述任一项的药学上可接受的盐、酸或衍生物。这一定义中还包括的是用于调节或抑制对肿瘤的激素作用的抗激素剂,诸如抗雌激素和选择性雌激素受体调节剂,抑制调节肾上腺中的雌激素产生的芳香酶的芳香酶抑制剂,和抗-雄激素;以及曲沙他滨(1,3-二氧杂环戊烷核苷胞嘧啶类似物);反义寡核苷酸、核酶诸如VEGF表达抑制剂和HER2表达抑制剂;疫苗,rIL-2;拓扑异构酶1抑制剂;rmRH;长春瑞滨和埃斯波霉素,以及上述任一项的药学上可接受的盐、酸或衍生物。
与放射疗法组合使用
本发明还提供了融合蛋白与放射疗法(即,用于在肿瘤细胞内局部诱导DNA损伤的任何机制,例如γ-照射、X-射线、UV-照射、微波、电子发射等)的组合。还考虑了使用放射性同位素至肿瘤细胞的定向递送的联合疗法,并且所公开的抗体可以与靶向的抗癌剂或其他靶向手段结合使用。通常,放射疗法在约1周至约2周的时间段内以脉冲方式施用。放射疗法可以对患有头颈癌的受试者施用约6至7周。任选地,放射疗法可以作为单剂量或作为多个顺序剂量施用。
药物包装和试剂盒
还提供了包含含有一个或多个剂量的抗体或其抗原结合部分的一个或多个容器的药物包装和试剂盒。在一些实施方案中,提供单位剂量,其中单位剂量含有预定量的组合物,所述组合物包含例如抗体或其抗原结合部分,具有或不具有一种或多种其他试剂。对于其他实施方案,这种单位剂量以一次性使用的预充式注射用注射器供应。在其他实施方案中,单位剂量中包含的组合物可以包含盐水、蔗糖或类似物;缓冲液,如磷酸盐等;和/或配制在稳定和有效的pH范围内。或者,在一些实施方案中,组合物可以作为冻干粉末提供,其可以在加入合适的液体(例如无菌水或盐溶液)后重建。在某些优选的实施方案中,组合物包含一种或多种抑制蛋白质聚集的物质,包括但不限于蔗糖和精氨酸。一种或多种容器上或与容器相关联的任何标签指示封装的组合物用于治疗选择的肿瘤疾病病况。
本发明还提供了用于产生融合蛋白以及任选地一种或多种抗癌剂的单剂量或多剂量施用单元的试剂盒。该试剂盒包括容器以及在容器上或与容器相关联的标签或包装插页。合适的容器包括例如瓶,小瓶,注射器等。容器可以由多种材料形成,例如玻璃或塑料,并且包含药学有效量的所公开的缀合或非缀合形式的抗体。在其他优选实施例中,一种或多种容器包括无菌存取口(例如容器可以是静脉内溶液袋或具有可被皮下注射针头刺穿的塞子的小瓶)。这样的试剂盒通常在合适的容器中包含抗体的药学上可接受的制剂,并且任选地在相同或不同的容器中包含一种或多种抗癌剂。试剂盒还可以含有其他药学上可接受的制剂,用于诊断或组合治疗。例如,除了本发明的抗体或其抗原结合部分之外,这样的试剂盒可以含有任何一种或多种抗癌剂,例如化学治疗剂或放射治疗剂;抗血管生成剂;抗转移剂;靶向抗癌剂;细胞毒性剂;和/或其他抗癌剂。
更具体地说,试剂盒可以具有含有所公开的抗体或其抗原结合部分的单个容器,其含有或不含另外的组分,或者它们可以具有用于每种所需试剂的不同容器。在提供用于缀合的组合治疗剂的情况下,可以按摩尔当量组合或一种组分多于另一种的方式预混合单一溶液。或者,试剂盒的抗体和任何任选的抗癌剂可以在施用于患者之前分开保存在不同的容器中。试剂盒还可以包含用于容纳无菌药学上可接受的缓冲液或其他稀释剂例如抑菌注射用水(BWFI)、磷酸盐缓冲盐水(PBS)、林格氏溶液和葡萄糖溶液的第二/第三容器装置。
当试剂盒的组分以一种或多种液体溶液提供时,液体溶液优选为水溶液,特别优选无菌水溶液或盐水溶液。然而,试剂盒的组分可以作为干粉提供。当试剂或组分以干粉形式提供时,可以通过添加合适的溶剂来重构粉末。可以设想溶剂也可以提供于另一个容器中。
如上简要所述,所述试剂盒还可含有向患者施用抗体或其抗原结合部分和任何任选组分的工具,例如一种或多种针,I.V.袋或注射器,或者甚至滴眼器、移液管或其他类似装置,通过其可以将制剂注射或引入动物体内或将其施用于身体的患病区域。本发明的试剂盒通常还包括用于容纳小瓶或类似物的装置以及用于商业销售的其他紧密封闭的部件,例如注射或吹塑塑料容器,其中放置并且保持所需的小瓶和其他装置。
序列表概述
本申请附带有包含许多氨基酸序列的序列表。下表A提供了所包含的序列的概述。
如本文中公开的一种示例性融合蛋白,称为WT1122-U14T1.G15-1.uIgG1(简写为WT1122)。
表A
实施例
通过参考以下实施例将更容易地理解本文一般地描述的本发明,这些实施例是以举例说明的方式提供的,并且不旨在限制本发明。这些实施例并不旨在表示下面的实验是全部或仅进行的实验。
实施例1
抗原、基准抗体和细胞系的制备
1.1抗原的制备
带有His标签的人PD-L1胞外结构域(ECD)抗原购自Sino Biological(目录号10084-H08H)。带有His标签的食蟹猴(cyno)PD-L1 ECD抗原购自Sino Biological(目录号90251-C08H)。人TGFβ1、TGFβ2和TGFβ3抗原购自R&D Systems(目录号7754-BH,7754-BH/CF;目录号302-B2,302-B2/CF;目录号8420-B3,8420-B3/CF)。
1.2表达PD-L1的细胞系的建立
表达人PD-L1的细胞系(W315-CHO-K1.hPro1.C11)、表达小鼠PD-L1的细胞系(W315-293F.mPro1.C1)和表达食蟹猴PD-L1的细胞系(W315-293F.cynoPro1.2A2)如下生成。简言之,使用Lipofectamine 2000(ThermoFisher-11668027)将CHO-K1或293F细胞用含有编码全长人PD-L1或食蟹猴PD-L1或小鼠PD-L1的基因的表达载体转染。将细胞在含有合适的选择压力的培养基中培养。通过有限稀释获得稳定的细胞系。
1.3基准抗体(BMK)的产生
融合有TGFβRII ECD的抗PD-L1 BMK抗体称为WT112-BMK2-IgG1,基于MerckPatent GmbH的专利US9676863B2中M7824的序列构建。用Expi293表达试剂盒(ThermoFisher-A14524)将含有重链基因的质粒和含有轻链基因的质粒共转染至Expi293细胞。将细胞培养几天,并收集上清液用于蛋白质纯化。
实施例2
生成融合有TGFβRII ECD的抗PD-L1抗体
WT1122-U14T1.G15-1.uIgG1是融合有TGFβRII ECD的抗PD-L1单克隆抗体。抗PD-L1抗体的序列来自PCT/CN2020/110494(通过引用全文并入本文)中的克隆W3152-r11.135.5-zAb17-m6。Fc的C末端通过接头连接至TGFβRII ECD的序列,该序列与WT112-BMK2-IgG1(SEQ ID NO:9)中的相同。Fc和TGFβRII ECD之间的接头是(G4S)4。下表1中列出了WT1122-U14T1.G15-1.uIgG1(在本文中简称为“WT1122”)的CDR序列。
表1
实施例3
WT1122的体外表征
3.1人TGF-β结合ELISA
通过ELISA测定抗体对人TGF-β1、TGF-β2和TGF-β3的结合。将板在4℃分别用人TGF-β1、TGF-β2或TGF-β3包被过夜。封闭和洗涤后,将各种浓度的测试抗体添加至板中,并在室温孵育1小时。然后洗涤板,并与HRP标记的山羊抗人IgG抗体(Bethyl)一起孵育1小时。洗涤后,加入TMB底物,并用2M HCl终止显色反应。使用酶标仪(SpectraMax M5e)读取450nm和540nm的吸光度。
抗体与板上包被的人TGF-β1,TGF-β2和TGF-β3的结合曲线如图1A所示。WT1122显示出与WT112-BMK2-IgG1类似的亲和力。它们与固定的TGF-β1(EC50=0.5nM)和TGF-β3(EC50=0.8nM)牢固结合,但不与固定的TGF-β2结合。
还通过固定有测试抗体的ELISA来测定抗体与人TGF-β2的结合。封闭和洗涤后,将各种浓度的TGF-β2加入板,并在室温孵育1小时。然后洗涤板,并与生物素化的TGF-β2检测抗体(R&D,DY240)一起孵育1小时,然后与链霉亲和素-HRP孵育1小时。洗涤后,加入TMB底物,并用2M HCl终止显色反应。使用酶标仪(SpectraMax M5e)读取450nm和540nm的吸光度。
抗体对可溶性人TGF-β2的结合曲线如图1B所示。固定化的WT1122和WT112-BMK2-IgG1能够以可比的EC50与可溶性TGF-β2结合,EC50分别为0.07nM和0.05nM。
3.2人PD-L1结合FACS
将各种浓度的测试抗体与表达人PD-L1的W315-CHO-K1.hPro1.C11在4℃孵育1小时。洗涤后,将细胞与PE标记的山羊抗人IgG-Fc抗体(Jackson Immuno Research)一起孵育。最后,通过流式细胞仪测量细胞的MFI,并通过FlowJo进行分析。
与人PD-L1转染细胞的结合曲线如图2A所示。WT1122和WT112-BMK2-IgG1与细胞表面人PD-L1牢固结合,EC50分别为0.7nM和1.21nM。
3.3交叉物种结合FACS
通过FACS确定测试抗体与食蟹猴或小鼠PD-L1的结合。将各种浓度的测试抗体与表达猕猴PD-L1的W315-293F.cynoPro1.2A2细胞或表达小鼠PD-L1的W315-293F.mPro1.C1细胞在4℃孵育1小时,然后用PE标记的山羊抗人IgG-Fc抗体(Jackson Immuno Research)检测抗体对细胞表面的结合。通过流式细胞仪测量细胞的MFI,并通过FlowJo进行分析。
图2B显示了与食蟹猴PD-L1转染细胞的结合,图2C显示了与小鼠PD-L1转染细胞的结合。WT1122和WT112-BMK2-IgG1能够与细胞表面的食蟹猴和小鼠PD-L1牢固结合。WT1122和WT112-BMK2-IgG1与食蟹猴PD-L1结合的EC50分别为1.08nM和1.59nM,与小鼠PD-L1结合的EC50分别为1.2nM和1.5nM。
3.4与人PD-L1和人TGF-β1的同时结合
通过ELISA测定测试抗体与人TGF-β1和人PD-L1的同时结合。用人TGF-β1包被板在4℃过夜。封闭和洗涤后,将各种浓度的测试抗体添加至板中,并在室温孵育1小时。然后洗涤板,并与生物素化的人PD-L1 ECD蛋白然后是链霉亲和素-HRP(Invitrogen)一起孵育1小时。洗涤后,加入TMB底物,并用2M HCl终止显色反应。使用酶标仪(SpectraMax M5e)读取450nm和540nm的吸光度。
类似地,还通过用人PD-L1包被板来测试同时的双重靶结合。在与各种浓度的测试抗体然后是TGF-β1抗原孵育后,在板中加入生物素化的人TGF-β1检测抗体(R&D,目录号840117)然后是链霉亲和素-HRP(Invitrogen)。最后,加入TMB底物,并用2M HCl终止显色反应。使用酶标仪(SpectraMax M5e)读取450nm和540nm的吸光度。
图3A和图3B所示的结果表明,当固定TGF-β1时,WT1122和WT112-BMK2-IgG1同时结合PD-L1和TGF-β1,EC50分别为0.29和0.17nM(图3A);当固定人PD-L1时,EC50分别为0.01nM和0.02nM(图3B)。
3.5通过竞争FACS测定的PD-1/PD-L1阻断
将各种浓度的测试抗体、阳性和阴性对照抗体与mFc标记的人PD-1混合,然后在4℃与表达人PD-L1的转染细胞孵育1小时。通过PE标记的抗小鼠IgG Fc抗体(Abcam)检测人PD-1与人PD-L1表达细胞的结合。通过流式细胞仪测量细胞的MFI,并通过FlowJo进行分析。
如图4所示,WT1122和WT112-BMK2-IgG1阻断PD-1与细胞表面PD-L1的结合,IC50分别为0.04nM和0.32nM。
3.6报告基因测定(RGA)
通过RGA测定测试了TGF-β1信号传导的阻断。RGA细胞系是通过稳定表达全长人激活素受体II B以及稳定整合的SBE荧光素酶报告基因而制得的。为了测定测试抗体的TGF-β1信号传导阻断活性,将人TGF-β1和各种浓度的抗体预先混合,并加入RGA细胞中,并在37℃、5%CO2下孵育过夜。孵育后,加入重构的荧光素酶底物(Promega,目录号E6130),并通过微板分光光度计测量荧光素酶强度。
通过RGA测定法测试了PD-1/PD-L1信号传导的阻滞。PD-1RGA细胞系是通过在Jurkat E6-1细胞中稳定表达PD-1的全长以及NFAT荧光素酶报道基因而制备的。将PD-1RGA细胞与表达人PD-L1的人工APC(表达人PD-L1和OKT3 sc-Fv的CHO-K1细胞)在各种浓度的测试抗体存在下于37℃、5%CO2孵育4-6小时。温育后,加入重构的荧光素酶底物,并通过微板分光光度计测量荧光素酶强度。
如图5A所示,WT1122显示出与WT112-BMK2相当的TGF-β1阻断,IC50为1.2nM,WT112-BMK2的IC50为0.7nM。如图5B所示,在RGA测定中,WT1122和WT112-BMK2-IgG1显示出较强的hPD-1/PD-L1信号阻断活性。WT1122和WT112-BMK2-IgG1的IC50分别为0.31nM和0.59nM。
3.7同种异体混合淋巴细胞反应(allo-MLR)
使用Ficoll-Paque PLUS(Stem Cell)梯度离心从健康供体中新鲜分离人外周血单核细胞(PBMC)。根据制造商的说明,使用CD14 MicroBeads(MiltenyiBiotec)分离单核细胞。将细胞在含有GM-CSF(Amoytop Biotech)和IL-4(R&D)的培养基中培养5至7天,以产生树突细胞(DC)。根据制造商的方案,使用人CD4+T细胞富集试剂盒(Stem Cell)分离人CD4+T细胞。将纯化的CD4+T细胞与同种异体未成熟DC(iDC)在存在测试抗体、阳性和阴性对照抗体的情况下在96孔板中共培养。将板在37℃、5%CO2下孵育。分别在第3天和第5天收获上清液用于IL-2和IFN-γ测试。
使用匹配的抗体对通过ELISA测量人IL-2和IFN-γ释放。重组人IL-2(R&D)和IFN-γ(PeproTech)分别用作标准品。分别在板上预涂对人IL-2(R&D)或IFN-γ(Pierce)特异性的捕获抗体。封闭后,将50μL标准品或样品吸移到每个孔中,并在环境温度孵育2小时。除去未结合的物质后,将对相应细胞因子具有特异性的缀合有生物素的检测抗体添加到孔中,并孵育一小时。然后将HRP标记的链霉亲和素添加至孔中,在室温孵育30分钟。通过加入50μL TMB底物显色,然后用50μL 2N HCl停止。使用微孔板分光光度计在450nm和540nm处读取吸光度。
图6A-6B中所示的结果表明,WT1122和WT112-BMK2-IgG1能够以剂量依赖性方式增强人CD4+T细胞同种异体MLR测定中的IL-2产生(图6A)和IFNγ产生(图6B)。
3.8血清稳定性
将WT1122在5%CO2培养箱中于37℃在新鲜分离的人血清(血清含量>95%)中培养。在指示的时间点,从培养箱中取出等分的血清处理样品,并在液氮中速冻,然后保存在-20℃直至准备测试。在稳定性测试之前立即将样品快速融化。同时结合ELISA、人TGF-β1结合ELISA和人PD-L1结合FACS的程序如上文所描述的。
如图7所示,这些WT1122样品显示出与靶标的正常结合,表明该抗体在人血清中稳定至少14天。
3.9抗体蛋白加速稳定性研究
3.9.1样品处理和加速稳定性研究
将WT1122通过透析袋(Spectrum-888-10987,MWCO 3.5kDa)透析到PBS缓冲液中,然后稀释至2ug/ml。通过分别在4℃、25℃和40℃孵育测试抗体1天、4天和7天,以及在-80℃冻融3个循环来进行加速稳定性研究(表2)。在每种测试条件下孵育后,立即对样品肉眼检查以仔细检测是否存在任何颗粒。所有样品均显示为无颗粒的澄清溶液。通过SDS-PAGE、分析性SEC-HPLC、DSF和DLS测定法来分析每个处理样品的抗体稳定性。表2中显示的结果表明WT1122在加速稳定性研究中是稳定的。
3.9.2通过DSF的热稳定性
使用实时荧光定量PCR(QuantStudio 7Flex,Thermo Fisher Scientific)进行DSF分析。简要地说,将19μL抗体溶液与1μL 62.5×SYPRO Orange溶液(Invitrogen)混合,然后添加到96孔板(Biosystems)中。以0.9℃/min的速率将板从26℃加热至95℃,并收集所得的荧光数据。计算相对于不同温度的荧光变化的负导数,并且将最大值定义为熔融温度。数据收集和Tm计算由操作软件(QuantStudioTM Real-Time PCR Software v1.3)自动进行。PBS缓冲液中WT1122的Tm约为65.6℃(表2)。
3.9.3通过DLS的分子半径测量
使用DynaPro Plate Reader III动态光散射(DLS)仪器(Wyatt DynaproTM)研究了分子半径测量。每个蛋白质样品进行了五次采集,每次采集时间为5s。每个孔在1536板(Aurora微孔板)中包含7.5μL溶液。对于每次测量,测定扩散系数。半径由操作软件(DYNAMICS 7.8.1.3)自动计算。表2中的结果表明,经过不同处理后的样品的半径范围为13.6nm至14.9nm,这与从-80℃刚融化的样品(T0的半径为13.7nm)相当。
表2.PBS中的加速稳定性结果
T0:冻融一次(从-80℃)。
3X:样品比T0多冻融3次。
3.10对PD-L1的完全动力学结合亲和力(通过SPR)
使用Biacore 8K通过SPR分析检测WT1122与人、小鼠和食蟹猴PD-L1的结合亲和力。在固定有抗人IgG Fc抗体的CM5传感器芯片(GE)上捕获抗体。将不同浓度的人或食蟹猴PD-L1以30μL/min的流速注入传感器芯片,持续180s的缔合阶段,然后解离3600s。将不同浓度的小鼠PD-L1以30μL/min的流速注入传感器芯片,持续120s的缔合阶段,然后解离1200s。每个结合循环后,芯片通过10mM甘氨酸(pH 1.5)再生。
从测试传感图中减去空白表面和缓冲液通道的传感图。对于WT1122与小鼠PD-L1的结合,在拟合过程中使用了0-300s的曲线。使用Langmiur分析通过1:1模型拟合实验数据。将40kDa的分子量用于计算人、小鼠和食蟹猴PD-L1的摩尔浓度。如表3所示,WT1122对人和食蟹猴PD-L1具有相似的亲和力。
表3.WT1122对人、食蟹猴和小鼠PD-L1的结合亲和力
3.11对TGFβ的完全动力学结合亲和力(通过SPR)
使用Biacore8K通过SPR测定法检测对TGFβ的抗体结合亲和力。将每种抗体固定在CM5传感器芯片(GE)上。将不同浓度的人TGFβ1和TGFβ3以50uL/min的流速注入传感器芯片,持续240s的缔合阶段,然后解离1200s。将不同浓度的人TGFβ2以50uL/min的流速注入传感器芯片,持续240s的缔合阶段,然后解离300s。每个结合循环后,芯片通过10mM甘氨酸(pH1.5)再生。
从测试传感图中减去空白表面和缓冲液通道的传感图。使用Langmiur分析通过1:1模型拟合实验数据。使用分子量22kDa、24kDa和22kDa分别计算分析物TGFβ1、TGFβ2和TGFβ3的摩尔浓度。结果列于表4。
表4.通过SPR测定的WT1122对TGFβ的结合亲和力。
3.12对FcRn的完全动力学结合亲和力(通过SPR)
使用Biacore 8K检测对人FcRn(ARCO,FCM-H5286)的抗体结合亲和力。将每种抗体固定在CM5传感器芯片(GE)上。将不同浓度的人FcRn以30uL/min的流速注入传感器芯片上,持续60s的缔合阶段,然后解离90s。然后在每个结合循环后,用10mM甘氨酸(pH 1.5)再生芯片。从测试传感图中减去空白表面和缓冲液通道的传感图。实验数据通过稳态亲和力模型拟合。将45KDa的分子量用于计算分析物FcRn的摩尔浓度。运行缓冲液是PBST,pH 6.0。
WT1122和WT112-BMK2-IgG1对FcRn的亲和力相似(表5)。
表5.通过SPR测定的对FcRn的亲和力
实施例4
体内抗肿瘤功效研究
4.1HCC827 PBMC模型中的体内抗肿瘤功效研究
在HCC827模型中对NCG雌性小鼠进行了WT1122抗肿瘤功效研究。研究中使用了13-14周龄的雌性NCG小鼠(南京银河生物制药有限公司)。HCC827细胞以单层培养的形式在37℃空气中5%CO2的气氛中,在补充有10%胎牛血清、100U/mL青霉素和100μg/mL链霉素的RPMI 1640培养基中进行体外维持。常规每周两次将肿瘤细胞传代培养两次,用0.25%胰蛋白酶-EDTA处理。收获在指数生长期生长的细胞,并计数肿瘤接种量。
对于治疗模型,每只小鼠的右前侧皮下均接种了HCC827肿瘤细胞(5.0×106细胞,在200μL PBS中含有50%的基质凝胶)。当平均肿瘤体积达到约173mm3时,将动物随机分为5组,每组包含7只小鼠。小鼠静脉注射人PBMC(5.0×106,Hemocare,批号19057819)。PBMC植入后1-2h,在第0天、第3天、第7天和第10天通过腹膜内注射对动物进行药物处理,共进行4次注射。4组(G2-G5)分别注射20mg/kg的WT112-BMK2-IgG1或0.2mg/kg、2mg/kg和20mg/kg的WT1122。对照组(G1)注射了媒介物-PBS。第一次注射的日期被认为是第0天。对于所有肿瘤研究,称重小鼠并使用测径器每周两次测量肿瘤生长。
本研究中与动物处理、护理和治疗有关的所有程序均按照上海SIPPR-BK实验动物有限公司的机构动物护理和使用委员会(IACUC)批准的指南,并遵循实验室动物护理评估和鉴定协会(AAALAC)的指导进行。用公式(1/2(长×宽2))计算肿瘤体积。结果用均值和标准误差(平均值±SEM)表示。数据通过Graphpad Prism 6.0使用双向ANOVA Tukey多重比较检验进行,P<0.05被认为具有统计学显著的。
如图8A所示,实验期间所有小鼠均正常,没有明显的体重减轻,表明抗体没有毒性。如图8B所示,在第一次给药后的第16天,媒介物组的平均肿瘤体积为798mm3,这表明HCC827模型已经很好地建立。与媒介物组相比,WT1122显示出有力的抗肿瘤作用并显著抑制了肿瘤的生长。每组第16天的TGI对于WT112-BMK2-IgG1(20mg/kg)为55.91%,对于0.2mg/kg、2mg/kg和20mg/kg的WT1122分别为55.42%、50.72%和77.13%。WT1122在高剂量时显示出比BMK2更好的抗肿瘤活性(p<0.05),在低剂量和中剂量时则显示出可比的抗肿瘤活性(p>0.05)。
4.2 WT1122以30mg/kg在食蟹猴中的体内药代动力学研究
将两只成年食蟹猴(一只雄性+一只雌性)通过静脉内注射施用30mg/Kg WT1122。每天进行体重、食物消耗和临床的观察。在不同时间点采集心电图(ECG)、血液和血清样品。将血液收集到装有EDTA-K2的试管中进行血液学检查,并将2.0mL血液收集到无添加剂的试管中进行血清化学测定。进行标准临床化学和血液学分析。为了进行PK和免疫学分析,收集了约1.2mL血液,在3500rpm和4℃离心15分钟收集了约0.5mL血清,并在约-70℃或更低的温度冷冻保存。进行每日临床观察并记录。所有与动物处理、护理和治疗有关的程序均按照广州中医药大学科技园公司的机构动物护理和使用委员会(IACUC)批准的指南遵循实验室动物护理评估与认证协会(AAALAC)的指导进行。血清中WT1122的浓度采用生物分析ELISA方法进行测定。使用Phoenix WinNonlin软件(8.1版,Pharsight,Mountain View,CA)对血清浓度进行非区室性药代动力学分析。应用线性/对数梯形法则获得PK参数,数据用均值±SD表示。
动物对单次静脉注射WT1122的剂量30mg/kg耐受良好,未观察到明显的副作用,包括心电图、日常临床观察、体重和主要血液学参数(ALT,AST,WBC,RBC,PLT,QTc等)。如表6和图9A所示,终末半衰期为92.1h,AUC0-inf为34993h*μg/mL,清除率为20.9ml/天/kg。
表5.单次静脉内注射30mg/kg后WT1122的PK谱
本领域技术人员可以认识和理解本专利描述,在不脱离其本质或基本特征的情况下,本发明可以以其他具体形式来实施。由于本发明的前述描述仅公开了其示例性实施方案,其他变化应该被理解为在本发明的范围内。因此,本发明不限于在此详细描述的特定实施方案。相反,应当参考所附权利要求来指示本发明的范围和内容。
参考文献
[1]Alsaab HO,Sau S,AlzhraniR,等人PD-1 and PD-L1 Checkpoint SignalingInhibition for Cancer Immunotherapy:Mechanism,Combinations,and ClinicalOutcome.Frontiers in Pharmacology 2017;8:561.
[2]Francisco LM,Sage PT,Sharpe AH.The PD-1 pathway in tolerance andautoimmunity.Immunological Reviews 2010;236:219–42.
[3]Gong,Jun,Chehrazi-Raffle,Alexander等人Development of PD-1and PD-L1inhibitors as a form of cancer immunotherapy:a comprehensive review ofregistration trials and future considerations.Journal for Immunotherapy ofCancer 2018;6:8.
[4]Justin M.David等人A novel bifunctional anti-PD-L1/TGF-β Trapfusion protein(M7824)efficiently reverts mesenchymalization of human lungcancer cells.Oncoimmunology.2017;6(10):e1349589.
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Claims (29)
1.一种融合蛋白,其包含特异性结合PD-L1的抗体或其抗原结合部分融合于能够结合TGFβ的人转化生长因子β受体(TGFβR)或其部分,其中所述抗体或其抗原结合部分包含:
重链CDR1(HCDR1),其包含SEQ ID NO:1或与SEQ ID NO:1相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
HCDR2,其包含SEQ ID NO:2或与SEQ ID NO:2相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
HCDR3,其包含SEQ ID NO:3或与SEQ ID NO:3相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
轻链CDR1(LCDR1),其包含SEQ ID NO:4或与SEQ ID NO:4相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;
LCDR2,其包含SEQ ID NO:5或与SEQ ID NO:5相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列;和
LCDR3,其包含SEQ ID NO:6或与SEQ ID NO:6相差不超过2个氨基酸的氨基酸添加、缺失和/或取代的氨基酸序列。
2.权利要求1的融合蛋白,其中所述人TGFβR选自TGFβRII和TGFβRIII,优选为TGFβRII。
3.前述权利要求中任一项的融合蛋白,其中所述能够结合TGFβ的人TGFβR或其部分包含:
(A)与野生型人TGFβRII的氨基酸序列至少85%、至少90%、或至少95%相同的氨基酸序列;
(B)与野生型人TGFβRII胞外结构域的氨基酸序列至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)野生型人TGFβRII的部分,其保留与TGFβ的结合能力的至少75%、至少80%、至少85%、至少90%、或至少95%。
4.前述权利要求中任一项的融合蛋白,其中所述TGFβR或其部分包含或组成为野生型人TGFβRII的胞外结构域,例如包含或组成为SEQ ID NO:9的氨基酸序列。
5.前述权利要求中任一项的融合蛋白,其中所述抗体或其抗原结合部分包含重链可变区(VH)和轻链可变区(VL),其中所述VH包含:
(A)如SEQ ID NO:7所示的氨基酸序列;
(B)与SEQ ID NO:7至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)与SEQ ID NO:7相比具有一个或多个(例如1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失、和/或取代的氨基酸序列;和/或所述VL包含:
(A)如SEQ ID NO:8所示的氨基酸序列;
(B)与SEQ ID NO:8至少85%、至少90%、或至少95%相同的氨基酸序列;或
(C)与SEQ ID NO:8相比具有一个或多个(例如1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失、和/或取代的氨基酸序列。
6.前述权利要求中任一项的融合蛋白,其中所述抗体或其抗原结合部分是全抗体、ScFv、Fab、F(ab’)2、或Fv片段,例如是全抗体。
7.前述权利要求中任一项的融合蛋白,其中所述抗体或其抗原结合部分在重链中包含VH区可操作地连接于Fc区。
8.权利要求7的融合蛋白,其中所述抗体或其抗原结合部分是IgG1同种型。
9.权利要求7或8的融合蛋白,其中抗体或其抗原结合部分的Fc区可操作地连接于人TGFβR或其部分的N末端,任选地经由接头。
10.权利要求9的融合蛋白,其中所述接头是肽接头。
11.权利要求10的融合蛋白,其中所述接头包含(G4S)n且n=2-4。
12.前述权利要求中任一项的融合蛋白,其中所述抗体或其抗原结合部分是人源化的抗体或全人抗体。
13.前述权利要求中任一项的融合蛋白,其中所述融合蛋白的重链和轻链分别包含SEQID NO:10和11。
14.一种分离的核酸分子,其包含编码如权利要求1-13中任一项限定的融合蛋白的抗体或其抗原结合部分、和/或人TGFβR或其部分的核酸序列。
15.包含权利要求14的核酸分子的载体。
16.包含权利要求14的核酸分子或权利要求15的载体的宿主细胞。
17.一种药物组合物,其包含权利要求1-13中任一项的融合蛋白以及药学可接受的载体。
18.一种产生如权利要求1-13中任一项限定的融合蛋白的方法,包括以下步骤:
-在包含编码所述融合蛋白的核酸序列的宿主细胞中表达所述融合蛋白;和
-从该宿主细胞分离所述融合蛋白。
19.一种调控受试者中免疫应答的方法,包括对所述受试者施用权利要求1-13中任一项的融合蛋白或权利要求17的药物组合物。
20.一种抑制受试者中与PD-1/PD-L1有关的肿瘤细胞生长的方法,包括对所述受试者施用有效量的权利要求1-13中任一项的融合蛋白或权利要求17的药物组合物。
21.一种预防或治疗受试者中与PD-1/PD-L1有关的癌症的方法,包括对所述受试者施用有效量的权利要求1-13中任一项的融合蛋白或权利要求17的药物组合物。
22.权利要求21的方法,其中所述癌症选自结肠癌、淋巴瘤、肺癌、肝癌、宫颈癌、乳腺癌、卵巢癌、胰腺癌、黑素瘤、胶质母细胞瘤、前列腺癌、食道癌和胃癌。
23.权利要求21或22的方法,其中所述癌症为肺癌,例如NSCLC。
24.权利要求19-23中任一项的方法,其中所述融合蛋白或药物组合物与化疗剂、放疗和/或用于癌症免疫治疗的其他药剂组合施用。
25.权利要求1-13中任一项限定的融合蛋白用于预防或治疗受试者中与PD-1/PD-L1有关的癌症的用途。
26.权利要求1-13中任一项限定的融合蛋白在制备用于调控受试者中的免疫应答或抑制与PD-1/PD-L1有关的肿瘤细胞生长的药物中的用途。
27.权利要求1-13中任一项限定的融合蛋白在制备用于治疗或预防与PD-1/PD-L1有关的癌症的药物中的用途。
28.权利要求27的用途,其中所述癌症选自结肠癌、淋巴瘤、肺癌、肝癌、宫颈癌、乳腺癌、卵巢癌、胰腺癌、黑素瘤、胶质母细胞瘤、前列腺癌、食道癌和胃癌。
29.一种用于治疗或诊断癌症的试剂盒,其包含在容器中的权利要求1-13中任一项限定的融合蛋白。
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