CN113166242A - 用于癌症的组合疗法 - Google Patents
用于癌症的组合疗法 Download PDFInfo
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- CN113166242A CN113166242A CN201980071763.6A CN201980071763A CN113166242A CN 113166242 A CN113166242 A CN 113166242A CN 201980071763 A CN201980071763 A CN 201980071763A CN 113166242 A CN113166242 A CN 113166242A
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Abstract
本公开提供了向有需要的受试者,例如癌症患者施用特异性地结合至人B7‑H4的抗体及其抗原结合片段与诸如抗PD‑1抗体的PD‑1/PD‑L1拮抗剂组合的方法。
Description
技术领域
本公开涉及施用特异性地结合至人B7-H4的抗体与诸如派姆单抗的PD-1/PD-L1拮抗剂组合来治疗诸如癌症的疾病的方法。提供了有利的剂量方案。
1.背景技术
B7-H4(也称为B7x、B7-S1和VTCN1)是与其他B7家族成员(包括PD-L1)具有同源性的免疫调控分子。它是由IgV和IgC胞外结构域组成的I型跨膜蛋白。尽管健康组织中B7-H4的表达在蛋白质水平上相对有限,但B7-H4在几种实体瘤(诸如乳腺、卵巢和子宫内膜的妇科癌)中表达。B7-H4在肿瘤中的表达往往与不良预后相关。B7-H4的受体是未知的,但据信所述受体在T细胞上表达。据信B7-H4直接抑制T细胞活性。
鉴于B7-H4的表达和功能,正在开发特异性地结合至B7-H4的抗体用于涉及B7-H4活性的调节的疗法,例如用于治疗癌症。
PD-1是由活化的T细胞和B细胞表达的关键免疫检查点受体并介导免疫抑制。PD-1是CD28受体家族的成员,该受体家族包括CD28、CTLA-4、ICOS、PD-1和BTLA。已经鉴别了PD-1的两种细胞表面糖蛋白配体,程序性死亡配体1(PD-L1)和程序性死亡配体2(PD-L2),它们在抗原呈递细胞以及许多人癌症上表达并且已显示出与PD-1结合时会下调T细胞活化和细胞因子分泌。对PD-1/PD-L1相互作用的抑制,例如通过抗PD-1或抗PD-L1抗体的抑制,介导了有效的抗肿瘤活性。
因此,需要有效的给药方案来施用与B7-H4结合的抗体和PD-1/PD-L1相互作用的抑制剂。
2.发明内容
本文提供使用治疗有效的剂量方案施用抗B7-H4抗体和其抗原结合片段与PD-1/PD-L1拮抗剂组合的方法。抗B7-H4抗体及其抗原结合片段可以是20502抗体或其抗原结合片段;或包含20502抗体的重链和轻链可变区CDR的抗体或抗原结合片段;或包含20502抗体的重链和轻链可变区的抗体或抗原结合片段,包括上述任一者的无岩藻糖基化形式。PD-1/PD-L1拮抗剂可以是抗PD-1抗体,诸如派姆单抗,或包含派姆单抗的重链和轻链可变区CDR的抗体或抗原结合片段;或包含派姆单抗的重链和轻链可变区的抗体或抗原结合片段。
在某些方面,一种治疗人受试者的实体瘤的方法包括向所述受试者施用(a)约0.1至约20mg/kg的抗体或其抗原结合片段,所述抗体或其抗原结合片段特异性地结合至人B7-H4并且包含20502抗体的重链可变区(VH)互补决定区(CDR)1、VH CDR2、VH CDR3和轻链可变区(VL)CDR1、VL CDR2和VL CDR3序列;和(b)约200mg的派姆单抗。在某些实施方案中,(a)和(b)同时或顺序施用。
在某些方面,一种治疗人受试者的实体瘤的方法包括向所述受试者施用(a)药物组合物,所述药物组合物包含(i)抗体或其抗原结合片段,其中所述抗体或其抗原结合片段特异性地结合至人B7-H4并且包含20502抗体的重链可变区(VH)互补决定区(CDR)1、VHCDR2、VH CDR3和轻链可变区(VL)CDR1、VL CDR2和VL CDR3序列;和(ii)药学上可接受的赋形剂,其中所述组合物中至少95%的所述抗体或其抗原结合片段无岩藻糖基化,并且其中施用约0.1至约20mg/kg的所述抗体或其抗原结合片段;和(b)包含派姆单抗的药物组合物,其中施用约200mg的派姆单抗。在某些实施方案中,(a)和(b)同时或顺序施用。
在某些方面,所述抗体或其抗原结合片段的CDR是Kabat定义的CDR、Chothia定义的CDR或AbM定义的CDR。在某些方面,所述VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2和CDR3序列分别包含SEQ ID NO:5-10中所示的氨基酸序列。
在某些方面,向所述受试者施用约20mg/kg或20mg/kg的抗B7-H4抗体或其抗原结合片段。在某些方面,向所述受试者施用约10mg/kg或10mg/kg的抗B7-H4抗体或其抗原结合片段。在某些方面,向所述受试者施用约3mg/kg或3mg/kg的抗B7-H4抗体或其抗原结合片段。在某些方面,向所述受试者施用约1mg/kg或1mg/kg的抗B7-H4抗体或其抗原结合片段。在某些方面,向所述受试者施用约0.3mg/kg或0.3mg/kg的抗B7-H4抗体或其抗原结合片段。在某些方面,向所述受试者施用约0.1mg/kg或0.1mg/kg的抗B7-H4抗体或其抗原结合片段。
在某些方面,约每三周施用一次所述抗B7-H4抗体或其抗原结合片段和/或派姆单抗。
在某些方面,静脉内施用所述抗B7-H4抗体或其抗原结合片段和/或派姆单抗。
在某些方面,在施用之前已经使用免疫组织化学(IHC)在所述实体瘤中检测到B7-H4。
在某些方面,所述抗B7-H4抗体或其抗原结合片段包含VH和/或VL,所述VH包含SEQID NO:11中列出的氨基酸序列,所述VL包含SEQ ID NO:12中列出的氨基酸序列。在某些方面,所述抗B7-H4抗体或抗原结合片段包含重链恒定区和/或轻链恒定区。在某些方面,所述重链恒定区是人免疫球蛋白IgG1重链恒定区,和/或所述轻链恒定区是人免疫球蛋白IgGκ轻链恒定区。在某些方面,所述抗体或其抗原结合片段包含重链恒定区和/或轻链恒定区,所述重链恒定区包含SEQ ID NO:25中列出的氨基酸序列,所述轻链恒定区包含SEQ ID NO:23中列出的氨基酸序列。在某些方面,所述抗B7-H4抗体或其抗原结合片段包含重链和/或轻链,所述重链包含SEQ ID NO:21中列出的氨基酸序列,所述轻链包含SEQ ID NO:22中列出的氨基酸序列。
在某些方面,所述抗体或其抗原结合片段是人抗体或其抗原结合片段。
在某些方面,所述抗B7-H4抗体或其抗原结合片段无岩藻糖基化。
在某些方面,所述抗体或其抗原结合片段是全长抗体。在某些方面,所述抗体或其抗原结合片段是抗原结合片段。在某些方面,所述抗原结合片段包含或是Fab、Fab'、F(ab’)2、单链Fv(scFv)、二硫键连接的Fv、V-NAR结构域、IgNar、胞内抗体、IgGΔCH2、微型抗体、F(ab’)3、四价抗体、三价抗体、二价抗体、单结构域抗体、DVD-Ig、Fcab、mAb2、(scFv)2或scFv-Fc。
在某些方面,岩藻糖基化在所述包含抗B7-H4抗体的组合物中不可检测到。
在某些方面,所述实体瘤表达B7-H4。
在某些方面,所述实体瘤是不可切除的、局部晚期的或转移性的。
在某些方面,所述实体瘤选自由以下组成的组:乳腺癌、导管癌、子宫内膜癌、卵巢癌、尿路上皮癌、非小细胞肺癌、胰腺癌、甲状腺癌、肾癌和膀胱癌。在某些方面,所述实体瘤是乳腺癌、卵巢癌、子宫内膜癌或尿路上皮癌。在某些方面,所述乳腺癌是晚期乳腺癌。在某些方面,所述乳腺癌是HER2阴性乳腺癌。在某些方面,所述乳腺癌是三阴性乳腺癌。在某些方面,所述乳腺癌是激素受体(HR)阳性乳腺癌。在某些方面,所述非小细胞肺癌是鳞状细胞癌。在某些方面,所述受试者未接受过使用PD-1/PD-L1拮抗剂的先前疗法。
在某些方面,所述方法还包括监测所述肿瘤中的免疫细胞的数量。在某些方面,所述方法还包括监测所述肿瘤中的自然杀伤(NK)细胞、CD4+细胞和/或CD8+细胞的数量。在某些方面,所述方法还包括监测所述受试者的细胞因子水平。在某些方面,所述方法还包括监测所述受试者的IL-2、IL-6、IL-10、TNF和/或干扰素γ(IFNγ)水平。
在某些方面,所述抗B7-H4抗体或其抗原结合片段和所述抗PD-1抗体或其抗原结合片段的施用产生协同效应。
在某些方面,一种治疗人受试者中的实体瘤的方法包括向所述受试者施用(i)约20mg/kg的抗B7-H4抗体,所述抗体特异性地结合至人B7-H4并且包含具有SEQ ID NO:11的氨基酸序列的VH和具有SEQ ID NO:12的氨基酸序列的VL;和(ii)约200mg的抗PD-1抗体,所述抗体包含具有SEQ ID NO:32的氨基酸序列的VH和具有SEQ ID NO:33的氨基酸序列的VL,其中所述抗B7-H4抗体和所述抗PD-1抗体约每三周静脉内施用一次。
在某些方面,一种治疗人受试者的实体瘤的方法包括向所述受试者施用(a)药物组合物,所述药物组合物包含(i)抗B7-H4抗体,所述抗体特异性地结合至人B7-H4并且包含具有SEQ ID NO:11的氨基酸序列的VH和具有SEQ ID NO:12的氨基酸序列的VL,和(ii)药学上可接受的赋形剂,其中所述组合物中至少95%的所述抗B7-H4抗体无岩藻糖基化,并且其中施用约20mg/kg的所述抗体;和(b)药物组合物,所述药物组合物包含抗PD-1抗体或其抗原结合片段,所述抗体或其抗原结合片段包含具有SEQ ID NO:32的氨基酸序列的VH和具有SEQ ID NO:33的氨基酸序列的VL;和药学上可接受的赋形剂,其中施用约200mg的所述抗体或其抗原结合片段,其中所述抗B7-H4抗体和所述抗PD-1抗体约每三周静脉内施用一次。
在某些方面,所述抗B7-H4抗体包含重链和轻链,所述重链包含SEQ ID NO:21中列出的氨基酸序列,所述轻链包含SEQ ID NO:22中列出的氨基酸序列。在某些方面,所述抗PD-1抗体包含重链和轻链,所述重链包含SEQ ID NO:30中列出的氨基酸序列,所述轻链包含SEQ ID NO:31中列出的氨基酸序列。
在某些方面,实体瘤是乳腺癌或卵巢癌,任选地其中所述乳腺癌是三阴性乳腺癌。
3.附图说明
图1A、1B和1C示出了抗B7-H4抗体组合抗PD-1抗体的体内抗肿瘤功效。(参见实施例4。)
图2示出了抗B7-H4抗体的剂量依赖性抗肿瘤活性。(参见实施例4。)
图3示出,抗B7-H4抗体与抗PD1抗体以协同方式组合,即使在抗B7-H4抗体的施用剂量作为单一疗法并非有效时。(参见实施例4。)
4.具体实施方式
本文提供施用特异性地结合至B7-H4(例如,人B7-H4)的抗体(例如,单克隆抗体)和其抗原结合片段与PD-1/PD-L1拮抗剂(例如,派姆单抗)组合的方法。抗B7-H4抗体及其抗原结合片段可与PD-1/PD-L1拮抗剂(例如,派姆单抗)组合施用,例如,以治疗受试者的实体瘤。在具体实施方案中,约20mg/kg、约10mg/kg、约3mg/kg、约1mg/kg、约0.3mg/kg或约0.1mg/kg的所述抗体或其抗原结合片段与约200mg的派姆单抗组合施用于所述受试者,例如,其中约每三周施用一次。
4.1术语
如本文所用,术语“B7-H4”是指哺乳动物B7-H4多肽,包括但不限于天然B7-H4多肽和B7-H4多肽的同工型。“B7-H4”涵盖全长、未加工的B7-H4多肽以及由细胞内加工产生的B7-H4多肽的形式。如本文所用,术语“人B7-H4”是指包含SEQ ID NO:1的氨基酸序列的多肽。“B7-H4多核苷酸”、“B7-H4核苷酸”或“B7-H4核酸”是指编码B7-H4的多核苷酸。
术语“抗体”意指通过位于免疫球蛋白分子的可变区内的至少一个抗原识别位点识别并特异性地结合至靶标(诸如蛋白、多肽、肽、碳水化合物、多核苷酸、脂质或前述的组合)的免疫球蛋白分子。如本文所用,术语“抗体”涵盖完整的多克隆抗体、完整的单克隆抗体、嵌合抗体、人源化抗体、人抗体、包含抗体的融合蛋白以及任何其他经修饰的免疫球蛋白分子,只要所述抗体表现出所需的生物活性即可。抗体可以是以下五种主要类别的免疫球蛋白中的任一种:IgA、IgD、IgE、IgG和IgM或其亚类(同种型)(例如IgG1、IgG2、IgG3、IgG4、IgA1以及IgA2),基于它们的重链恒定结构域的特性分别被称为α、δ、ε、γ和μ。不同种类的免疫球蛋白具有不同且众所周知的亚基结构和三维构型。抗体可以是裸的或与其他分子(诸如毒素、放射性同位素等)缀合。
术语“抗体片段”是指完整抗体的一部分。“抗原结合片段”、“抗原结合结构域”或“抗原结合区”是指完整抗体的与抗原结合的一部分。抗原结合片段可含有完整抗体的抗原识别位点(例如,足以特异性地结合抗原的互补决定区(CDR))。抗体的抗原结合片段的实例包括但不限于Fab、Fab’、F(ab’)2和Fv片段、线性抗体和单链抗体。抗体的抗原结合片段可源自任何动物物种,诸如啮齿动物(例如,小鼠、大鼠或仓鼠)和人,或者可人工产生。
术语“抗B7-H4抗体”、“B7-H4抗体”和“结合至B7-H4的抗体”是指能够以足够的亲和力特异性地结合B7-H4,以使得抗体在靶向B7-H4中可用作诊断剂和/或治疗剂的抗体。如本文所用,术语“特异性地结合”、“免疫特异性地结合”、“免疫特异性地识别”和“特异性地识别”在抗体或其抗原结合片段的背景下是类似术语。这些术语表明,抗体或其抗原结合片段经由其抗原结合结构域结合至表位,并且结合需要在抗原结合结构域与表位之间具有一定的互补性。因此,“特异性地结合”至人B7-H4(SEQ ID NO:1)的抗体也可结合至来自其他物种的B7-H4(例如,食蟹猴、小鼠和/或大鼠B7-H4)和/或由其他人等位基因产生的B7-H4蛋白,但与不相关的非B7-H4蛋白(例如,其他B7蛋白家族成员,如PD-L1)结合的程度小于所述抗体与B7-H4的结合的约10%,如例如通过放射免疫测定(RIA)所测量。在一个具体实施方案中,本文提供了特异性地结合至人、食蟹猴、小鼠和大鼠B7-H4的抗体或其抗原结合片段。
“单克隆”抗体或其抗原结合片段是指参与单个抗原决定簇或表位的高度特异性结合的同质性抗体或抗原结合片段群体。这与通常包括针对不同抗原决定簇的不同抗体的多克隆抗体形成对照。术语“单克隆抗体”或其抗原结合片段涵盖完整和全长单克隆抗体以及抗体片段(诸如Fab、Fab'、F(ab')2、Fv)、单链(scFv)突变体、包含抗体部分的融合蛋白和包含抗原识别位点的任何其他经修饰的免疫球蛋白分子。此外,“单克隆”抗体或其抗原结合片段是指以任何数量的方式制备的此类抗体及其抗原结合片段,所述方式包括但不限于杂交瘤、噬菌体选择、重组表达和转基因动物。
如本文所用,术语“可变区”或“可变结构域”可互换使用并且在本领域中是常见的。可变区通常是指抗体的一部分,一般而言是轻链或重链的一部分,通常是成熟重链中的约氨基末端110至120个氨基酸或110至125个氨基酸和成熟轻链中的约90至115个氨基酸,其在抗体之间的序列方面不同并且用于特定抗体对其特定抗原的结合和特异性。序列的变异性集中在称为互补决定区(CDR)的那些区域中,而可变结构域中保守性更高的区域被称为框架区(FR)。不希望受任何特定机制或理论的束缚,据信轻链和重链的CDR主要负责抗体与抗原的相互作用和特异性。在某些实施方案中,可变区是人可变区。在某些实施方案中,可变区包含啮齿动物或鼠类CDR和人框架区(FR)。在特定实施方案中,可变区是灵长类动物(例如,非人灵长类动物)可变区。在某些实施方案中,可变区包含啮齿动物或鼠类CDR和灵长类动物(例如,非人灵长类动物)框架区(FR)。
术语“VL”和“VL结构域”可互换使用来指抗体的轻链可变区。
术语“VH”和“VH结构域”可互换使用来指抗体的重链可变区。
术语“Kabat编号”和类似术语在本领域中是公认的,并且是指对抗体或其抗原结合片段的重链和轻链可变区中的氨基酸残基进行编号的系统。在某些方面,可根据Kabat编号系统来确定CDR(参见例如,Kabat EA和Wu TT(1971)Ann NY Acad Sci 190:382-391以及Kabat EA等人,(1991)Sequences of Proteins of Immunological Interest,第五版,美国卫生和公共服务部,NIH出版号91-3242)。使用Kabat编号系统,抗体重链分子内的CDR通常存在于氨基酸位置31至35(其任选地可在35之后包含一个或两个另外氨基酸(在Kabat编号方案中称为35A和35B))(CDR1)、氨基酸位置50至65(CDR2)和氨基酸位置95至102(CDR3)。使用Kabat编号系统,抗体轻链分子内的CDR通常存在于氨基酸位置24至34(CDR1)、氨基酸位置50至56(CDR2)和氨基酸位置89至97(CDR3)。在一个具体实施方案中,已经根据Kabat编号方案确定了本文所述的抗体的CDR。
相反,Chothia是指结构环的位置(Chothia和Lesk,J.Mol.Biol.196:901-917(1987))。当使用Kabat编号惯例编号时,Chothia CDR-H1环的末端根据环的长度在H32与H34之间变化(这是由于Kabat编号方案将插入物放置于H35A和H35B处;如果35A和35B均不存在,则环结束于32处;如果仅35A存在,则环结束于33处;如果35A和35B均存在,则环结束于34处)。AbM高变区代表Kabat CDR与Chothia结构环之间的折衷,并且通过OxfordMolecular的AbM抗体建模软件来使用。
如本文所用,术语“恒定区”和“恒定结构域”是可互换的,并且在本领域中具有它们的共同含义。恒定区是不直接参与抗体与抗原的结合、但可表现出多种效应子功能,如与Fc受体的相互作用的抗体部分,例如轻链和/或重链的羧基末端部分。相对于免疫球蛋白可变结构域,免疫球蛋白分子的恒定区通常具有更保守的氨基酸序列。在某些方面,抗体或抗原结合片段包含足以用于抗体依赖性细胞介导的细胞毒性(ADCC)的恒定区或其部分。
如本文所用,基于恒定结构域的氨基酸序列,术语“重链”在关于抗体使用时可指任何不同的类型,例如,α(α)、δ(δ)、ε(ε)、γ(γ)和μ(μ),分别产生IgA、IgD、IgE、IgG和IgM类别的抗体,包括IgG的亚类,例如IgG1、IgG2、IgG3和IgG4。重链氨基酸序列是本领域众所周知的。在具体实施方案中,重链是人重链。
如本文所用,基于恒定结构域的氨基酸序列,术语“轻链”在关于抗体使用时可指任何不同的类型,例如κ(κ)或λ(λ)。轻链氨基酸序列是本领域众所周知的。在具体实施方案中,轻链是人轻链。
术语“嵌合”抗体或其抗原结合片段是指其中氨基酸序列源自两种或更多种物种的抗体或其抗原结合片段。通常,轻链和重链的可变区对应于源自一种哺乳动物物种(例如小鼠、大鼠、兔等)的抗体或其抗原结合片段的具有所需特异性、亲和力和能力可变区,而恒定区与源自另一物种(通常为人)的抗体或其抗原结合片段中的序列同源,以避免在所述物种中引发免疫应答。
术语“人源化抗体”或其抗原结合片段是指作为含有最少非人(例如,鼠类)序列的特异性免疫球蛋白链、嵌合免疫球蛋白或其片段的非人(例如,鼠类)抗体或其抗原结合片段形式。通常,人源化抗体或其抗原结合片段是其中来自互补决定区(CDR)的残基被来自非人物种(例如,小鼠、大鼠、兔、仓鼠)的CDR的具有所需特异性、亲和力和能力的残基置换的人免疫球蛋白(“CDR移植”)(Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature 332:323-327(1988);Verhoeyen等人,Science 239:1534-1536(1988))。在一些情况下,人免疫球蛋白的某些Fv框架区(FR)残基被来自非人物种的抗体或片段中的具有所需特异性、亲和力和能力的对应残基置换。人源化抗体或其抗原结合片段可通过取代Fv框架区中和/或非人CDR残基内的另外残基来进一步修饰,以改善和优化抗体或其抗原结合片段的特异性、亲和力和/或能力。一般来说,人源化抗体或其抗原结合片段将包含可变结构域,所述可变结构域含有所有或基本上所有对应于非人免疫球蛋白的CDR区,而所有或基本上所有FR区是人免疫球蛋白共有序列的那些。人源化抗体或其抗原结合片段还可包含免疫球蛋白恒定区或结构域(Fc)的至少一部分,通常是人免疫球蛋白的至少一部分。用于产生人源化抗体的方法的实例描述于美国专利5,225,539;Roguska等人,Proc.Natl.Acad.Sci.,USA,91(3):969-973(1994);和Roguska等人,Protein Eng.9(10):895-904(1996)中。在一些实施方案中,“人源化抗体”是表面重构的抗体。
术语“人”抗体或其抗原结合片段是指具有源自人免疫球蛋白基因座的氨基酸序列的抗体或其抗原结合片段,其中使用本领域中已知的任何技术来制备这种抗体或其抗原结合片段。人抗体或其抗原结合片段的此定义包括完整或全长抗体及其片段。
“无岩藻糖基化”抗体或其抗原结合片段或“缺乏岩藻糖”的抗体或其抗原结合片段是指在其恒定区糖基化中缺乏岩藻糖的IgG1或IgG3同种型抗体或其抗原结合片段。人IgG1或IgG3的糖基化发生在Asn297处,因为核心岩藻糖基化的双触角复合物寡糖糖基化终止于至多2个Gal残基。在一些实施方案中,无岩藻糖基化抗体在Asn297处缺乏岩藻糖。取决于末端Gal残基的量,将这些结构命名为G0、Gl(a 1,6或a 1,3)或G2聚糖残基。参见例如,Raju,T.S.,BioProcess Int.1:44-53(2003)。抗体Fc的CHO型糖基化描述于例如Routier,F.FL,Glycoconjugate J.14:201-207(1997)中。
测量岩藻糖的方法包括本领域中已知的任何方法。出于本文的目的,通过WO2015/017600的实施例1中描述的方法来检测岩藻糖,所述专利以引用的方式整体并入本文。简言之,通过从抗体中释放聚糖(例如,通过酶促释放)、用邻氨基苯甲酸(2-AA)标记所述聚糖、然后纯化所述标记的聚糖来进行聚糖分析。使用具有荧光检测的正相HPLC来分离聚糖,并测量抗体中每种聚糖的相对含量。可通过质谱法将聚糖明确地鉴定为缺乏或包括岩藻糖。在一些实施方案中,岩藻糖在包含多种无岩藻糖基化抗体或其抗原结合片段的组合物中不可检测到。在一些实施方案中,无岩藻糖基化抗体或其抗原结合片段对FcγRIIIA具有增强的亲和力。在一些实施方案中,无岩藻糖基化抗体或其抗原结合片段对FcγRIIIA(V158)具有增强的亲和力。在一些实施方案中,无岩藻糖基化抗体或其抗原结合片段对FcγRIIIA(F158)具有增强的亲和力。
“结合亲和力”通常是指分子(例如,抗体或其抗原结合片段)的单一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。除非另有说明,否则如本文中所用,“结合亲和力”是指内在结合亲和力,其反映结合对的成员(例如,抗体或其抗原结合片段与抗原)之间的1:1相互作用。分子X对其配偶体Y的亲和力可通常由解离常数(KD)表示。亲和力可以本领域中已知的多种方式来测量和/或表示,包括但不限于平衡解离常数(KD)和平衡缔合常数(KA)。KD是根据koff/kon的商计算的,而KA是根据kon/koff的商计算的。kon是指例如抗体或其抗原结合片段与抗原的缔合速率常数,并且koff是指例如抗体或其抗原结合片段与抗原的解离。kon和koff可通过本领域普通技术人员已知的技术,如或KinExA来确定。
如本文所用,“表位”是本领域中的术语,并且是指抗体或其抗原结合片段可与其特异性地结合的抗原的局部区域。表位可以是例如多肽的连续氨基酸(线性或连续表位),或者表位可例如来自一种或多种多肽的两个或更多个非连续区域(构象性、非线性、不连续或非连续的表位)。在某些实施方案中,抗体或其抗原结合片段所特异性地结合的表位可通过例如NMR光谱法、X射线衍射晶体学研究、ELISA测定、结合质谱法的氢/氘交换(例如,液相色谱电喷雾质谱法)、基于阵列的寡肽扫描测定和/或诱变作图(例如,定点诱变作图)来确定。对于X射线晶体学,可使用本领域中任何已知的方法来完成结晶(例如,GiegéR等人,(1994)Acta Crystallogr D Biol Crystallogr 50(Pt 4):339-350;McPherson A(1990)Eur J Biochem 189:1-23;Chayen NE(1997)Structure 5:1269-1274;McPherson A(1976)J Biol Chem 251:6300-6303)。抗体/其抗原结合片段:抗原晶体可使用众所周知的X射线衍射技术进行研究,并且可使用计算机软件如X-PLOR(Yale University,1992,由Molecular Simulations,Inc.分售;参见例如,Meth Enzymol(1985)第114和115卷,Wyckoff HW等人编辑;U.S.2004/0014194)和BUSTER(Bricogne G(1993)Acta CrystallogrD Biol Crystallogr 49(Pt 1):37-60;Bricogne G(1997)Meth Enzymol 276A:361-423,Carter CW编辑;Roversi P等人,(2000)Acta Crystallogr D Biol Crystallogr 56(Pt10):1316-1323)进行改善。诱变作图研究可使用本领域技术人员已知的任何方法来完成。关于诱变技术的描述,包括丙氨酸扫描诱变技术,参见例如Champe M等人,(1995)J BiolChem 270:1388-1394和Cunningham BC&Wells JA(1989)Science 244:1081-1085。
术语“程序性细胞死亡蛋白1”和“PD-1”是指属于CD28家族的免疫抑制性受体。PD-1主要在体内于先前活化的T细胞上表达并与两个配体PD-L1和PD-L2结合。如本文所用的术语“PD-1”包括人PD-1(hPD-1)、hPD-1的天然存在的变体和同工型以及hPD-1的物种同源物。
术语“程序性细胞死亡1配体1”和“PD-L1”是指PD-1的两种细胞表面糖蛋白配体之一(另一者是PD-L2),所述两种细胞表面糖蛋白配体在与PD-1结合后下调T细胞活化和细胞因子分泌。如本文所用的术语“PD-L1”包括人PD-L1(hPD-L1)、hPD-1的天然存在的变体和同工型以及hPD-L1的物种同源物。
术语“PD-1/PD-L1拮抗剂”是指破坏PD-1/PD-L1信号传导途径的部分。在一些实施方案中,拮抗剂通过与PD-1和/或PD-L1结合而抑制PD-1/PD-L1信号传导途径。在一些实施方案中,PD-1/PD-L1拮抗剂也结合PD-L2。在一些实施方案中,PD-1/PD-L1拮抗剂阻断PD-1与PD-L1和任选地与PD-L2的结合。非限制性示例性PD-1/PD-L1拮抗剂包括PD-1拮抗剂,如结合至PD-1的抗体,例如纳武利尤单抗(OPDIVO)和派姆单抗(KEYTRUDA);PD-L1拮抗剂,如结合至PD-L1的抗体(例如,阿特珠单抗(TECENTRIQ)、德瓦鲁单抗和阿维鲁单抗);融合蛋白,如AMP-224;以及肽,如AUR-012。
“经分离”的多肽、抗体、多核苷酸、载体、细胞或组合物为处于自然界中不存在的形式中的多肽、抗体、多核苷酸、载体、细胞或组合物。分离的多肽、抗体、多核苷酸、载体、细胞或组合物包括已经被纯化至不再呈它们在自然界被发现的形式的程度的那些。在一些实施方案中,经分离的抗体、多核苷酸、载体、细胞或组合物是基本上纯的。如本文所用,“基本上纯的”是指至少50%纯的(即,不含污染物)、至少90%纯的、至少95%纯的、至少98%纯的或至少99%纯的材料。
术语“多肽”、“肽”和“蛋白质”在本文中可互换使用来指任何长度的氨基酸聚合物。所述聚合物可以是线性或支化的,它可包含经修饰的氨基酸,并且它可被非氨基酸间断。所述术语还涵盖已经天然地或通过干预修饰的氨基酸聚合物;例如二硫键形成、糖基化、脂化、乙酰化、磷酸化或任何其他操纵或修饰,诸如与标记组分缀合。还包括在定义内的是例如,含有氨基酸(包括例如,非天然氨基酸等)的一种或多种类似物以及本领域中已知的其他修饰的多肽。应了解,因为本发明的多肽是基于抗体,所以在某些实施方案中,所述多肽可作为单链或缔合的链而存在。
如本文所用,术语“宿主细胞”可以是任何类型的细胞,例如原代细胞、培养中的细胞或来自细胞系的细胞。在具体实施方案中,术语“宿主细胞”是指用核酸分子转染的细胞和这种细胞的子代或潜在子代。这种细胞的子代可与用核酸分子转染的亲本细胞不相同,例如这归因于可发生在传代或核酸分子整合至宿主细胞基因组中的过程中的突变或环境影响。
术语“药物制剂”是指这样的制剂,其形式为允许活性成分的生物活性有效,并且不包含对将向其施用所述制剂的受试者有不可接受的毒性的其他组分。所述制剂可以是无菌的。
如本文所用,术语“施用(administer)”、“施用(administering)”、“施用(administration)”等是指可用于实现将药物,例如抗B7-H4抗体或其抗原结合片段递送至所需的生物作用部位的方法(例如,静脉内施用)。可与本文所述的剂和方法一起使用的施用技术在例如Goodman和Gilman,The Pharmacological Basis of Therapeutics,现行版,Pergamon;和Remington’s,Pharmaceutical Sciences,现行版,Mack Publishing Co.,Easton,Pa中找到。
如本文所用,术语“受试者”和“患者”可互换使用。受试者可以是动物。在一些实施方案中,受试者是哺乳动物,如非人动物(例如,牛、猪、马、猫、狗、大鼠、小鼠、猴或其他灵长类动物等)。在一些实施方案中,受试者是食蟹猴。在一些实施方案中,受试者是人。
术语“治疗有效量”是指可有效治疗受试者的疾病或病症的药物,例如抗B7-H4抗体或其抗原结合片段的量。在癌症的情况下,药物的治疗有效量可减少癌细胞的数量;减小肿瘤尺寸或负担;在一定程度上抑制癌细胞浸润至周围器官中;在一定程度上抑制肿瘤转移;在一定程度上抑制肿瘤生长;在一定程度上缓解与癌症相关的一种或多种症状;和/或产生有利的应答,如无进展生存(PFS)、无疾病生存(DFS)、总体生存(OS)、完全应答(CR)、部分应答(PR)增加,或者在一些情况下,稳定疾病(SD)、进行性疾病(PD)减少、进展时间(TTP)减少或它们的任何组合。在所述药物可防止生长和/或杀死现有的癌细胞的程度上,它可为细胞抑制的和/或细胞毒性的。
诸如“治疗”、“治疗”、“治疗”、“减轻”和“减轻”的术语是指能够治愈、减缓、减轻病理性疾患或病症的症状和/或阻止其进展的治疗措施。因此,需要治疗的那些包括已经诊断患有或疑似患有所述病症的那些。在某些实施方案中,如果患者显示出一种或多种以下情况,则受试者的癌症被成功地根据本发明的方法“治疗”:癌细胞的数量减少或完全不存在;肿瘤尺寸减小;抑制或未出现癌细胞浸润至周围器官中,包括例如癌症扩散到软组织和骨中;抑制或未出现肿瘤转移;抑制或未出现肿瘤生长;与特定癌症相关的一种或多种症状减轻;发病率和死亡率降低;生活品质改善;致瘤性、致瘤性频率或肿瘤的致瘤能力降低;肿瘤中癌症干细胞的数量或频率降低;致瘤性细胞分化成非致瘤性状态;无进展生存(PFS)、无疾病生存(DFS)、总体生存(OS)、完全应答(CR)、部分应答(PR)增加,稳定疾病(SD),进行性疾病(PD)减少,进展时间(TTP)减少或它们的任何组合。
术语“癌症”和“癌性的”是指或描述哺乳动物中的生理疾患,其中细胞群体以不受调控的细胞生长为特征。癌症的实例包括但不限于妇科癌症(例如,乳腺癌(包括三阴性乳腺癌、激素受体(HR)阳性乳腺癌、导管癌、卵巢癌和子宫内膜癌))、非小细胞肺癌、胰腺癌、甲状腺癌、肾癌(例如,肾细胞癌)和膀胱癌(例如,尿路上皮细胞癌)。癌症可以是“表达B7-H4的癌症”或“B7-H4表达癌症”或“B7-H4阳性癌症”。此类术语是指包含表达B7-H4的细胞的癌症。癌症可以是表达B7-H4的实体瘤。癌症可以是原发性肿瘤,或者可以是晚期或转移性癌症。
“难治性”癌症是即使向癌症患者施用了抗肿瘤治疗(如化学疗法),仍会进展的癌症。
“复发性”癌症是对初始疗法产生应答后在初始部位或远处再生长的癌症。
如本文所证明,抗B7-H4抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的施用可以提供“协同作用”或是“协同的”,即当活性成分一起使用时的效果大于单独使用活性成分所产生的效果总和。当活性成分是:(1)共同配制,并以组合的单位剂量制剂形式同时施用或递送;(2)作为单独的制剂依次地、交替地或并行地递送;或(3)通过一些其他方案时,可以获得协同作用。在交替疗法中递送的情况下,当化合物按顺序地施用或递送(例如通过分开的注射器进行不同的注射)时,可以获得协同作用。
如本公开和权利要求书中所使用,除非上下文另外明确指明,否则单数形式“一个/种(a/an)”和“所述(the)”包括复数形式。
应当理解,当在本文用语言“包含”来描述实施方案时,还提供了就“由……组成”和/或“主要由……组成”而言所描述的其他类似实施方案。在本公开中,“包含(comprises)”、“包含(comprising)”、“含有(containing)”和“具有(having)”等可具有美国专利法赋予它们的含义,并且可意指“包括(includes)”、“包括(including)”等;“基本上由……组成(consisting essentially of”)”或“基本上由……组成(consistsessentially)”同样具有美国专利法赋予的含义,并且所述术语是开放式的,从而允许超出所叙述的存在,只要所叙述的基本或新颖特征不被超过叙述的存在改变,但是排除现有技术实施方案。
除非明确固定或从上下文显而易见,否则如本文所使用的,术语“或”被理解为包括在内。本文在诸如“A和/或B”的短语中使用的术语“和/或”意图包括“A和B”、“A或B”、“A”以及“B”。同样,如在诸如“A、B和/或C”的短语中所使用的术语“和/或”意图涵盖以下实施方案中的每一个:A、B和C;A、B或C;A或C;A或B;B或C;A和C;A和B;B和C;A(单独);B(单独);以及C(单独)。
如本文所用,术语“约”和“大约”在用于修饰数值或数字范围时表示所述值或范围之上5%至10%和之下5%至10%的偏差仍在所叙述值或范围的预期含义范围内。
本文提供的任何组合物或方法可与本文提供的任何其他组合物和方法中的一者或多者组合。
4.2治疗癌症的方法
在一方面,本文提供了用于治疗人受试者的癌症的方法,所述方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或其本文所述的药物组合物,与(ii)本文所述的PD-1/PD-L1抑制剂或其本文所述的药物组合物组合,并且其中(i)和(ii)同时或依次施用。对于“同时”施用,在一些实施方案中,(i)和(ii)中的剂在同一天作为单独的制剂施用,一个在另一个之后施用;或在其他实施方案中,将(i)和(ii)中的剂在施用前混合在一起,因此作为混合物施用。例如,在一些实施方案中,可以将(i)和(ii)中的剂包装并存储在同一小瓶中(即,固定剂量制剂),或者替代地,可以将包含每种单独剂的小瓶在即将施用之前混合在一起。对于“依次”施用,(i)和(ii)中的剂在不同天作为单独的制剂施用。在各种实施方案中,剂可以通过多种途径在体内施用,包括但不限于静脉内途径。
抗B7-H4抗体或其抗原结合片段与PD-1/PD-L1抑制剂的组合可以是协同的。
在一方面,PD-1抑制剂是派姆单抗。下表列出了派姆单抗的重链和轻链序列。在重链和轻链序列的背景下,CDR序列以粗体显示,并且可变区序列带下划线。
派姆单抗序列
在一方面,PD-1抑制剂是包含派姆单抗的重链和轻链可变区CDR的抗体或抗原结合片段;或包含派姆单抗的重链和轻链可变区的抗体或抗原结合片段。
在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约0.005至约20mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。
在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约0.1mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约0.3mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约1mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约3mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约10mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约20mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以例如约每三周一次的频率同时或依次施用。
在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约0.1mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约0.3mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约1mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约3mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约10mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以每三周一次的频率同时或依次施用。在一方面,一种治疗人受试者的癌症的方法包括向有需要的受试者施用(i)本文所述的抗B7-H4抗体或其抗原结合片段或本文所述的其药物组合物,其中施用约20mg/kg的所述抗B7-H4抗体或其抗原结合片段,和(ii)本文所述的派姆单抗或其药物组合物,其中施用约200mg的派姆单抗,并且其中(i)和(ii)以每三周一次的频率同时或依次施用。
在本文提供的方法的某些实施方案中,静脉内施用所述抗B7-H4抗体或其抗原结合片段或所述包含抗B7-H4抗体或其抗原结合片段的药物组合物。在本文提供的方法的某些实施方案中,静脉内施用派姆单抗或其药物组合物。
在某些实施方案中,本文提供了用于治疗选自由以下组成的组的癌症的方法:乳腺癌(例如,晚期乳腺癌、三阴性乳腺癌、激素受体(HR)阳性乳腺癌或导管癌)、子宫内膜癌、卵巢癌、尿路上皮癌、非小细胞肺癌(例如,鳞状细胞癌)、头颈部鳞状细胞癌(HNSCC)、霍奇金淋巴瘤(例如,经典霍奇金淋巴瘤)、黑素瘤、胰腺癌、甲状腺癌、肾癌(例如,肾细胞癌)、膀胱癌(例如,尿路上皮癌)、胃癌、子宫颈癌和高度微卫星不稳定性癌。在某一实施方案中,本文提供了治疗晚期乳腺癌(包括三阴性乳腺癌、激素受体(HR)阳性)、卵巢癌、子宫内膜癌或尿路上皮癌的方法。在某一实施方案中,本文提供了治疗乳腺癌的方法。在某一实施方案中,所述乳腺癌是三阴性乳腺癌。在某一实施方案中,本文提供了治疗激素受体(HR)阳性乳腺癌的方法。在某一实施方案中,本文提供了治疗卵巢癌的方法。在某一实施方案中,本文提供了治疗子宫内膜癌的方法。在某一实施方案中,本文提供了治疗尿路上皮癌的方法。在某一实施方案中,本文提供了治疗胃肠道癌的方法。在某一实施方案中,本文提供了治疗妇科癌症的方法。在某一实施方案中,本文提供了治疗头颈癌的方法。在某一实施方案中,本文提供了治疗泌尿生殖系统癌症的方法。在某一实施方案中,本文提供了,受试者未接受过使用PD-1/PD-L1拮抗剂的先前疗法。在某些实施方案中,此类方法包括向有需要的患者(例如,人患者)施用本文提供的抗B7-H4抗体或其抗原结合片段,或本文提供的包含抗B7-H4抗体或其抗原结合片段的药物组合物,与本文提供的PD-1/PD-L1抑制剂或其药物组合物组合。
在一些实施方案中,所述癌症是表达B7-H4的癌症。在某些实施方案中,所述癌症是表达B7-H4的实体瘤。在某些实施方案中,已经在获自受试者的生物样品中检测到B7-H4(例如,使用免疫组织化学(IHC))。
生物样品可以是从受试者、细胞系、组织或潜在表达B7-H4的其他细胞来源获得的任何生物样品。用于从人获得组织活检和体液的方法在本领域中是众所周知的。生物样品包括外周血单核细胞。生物样品也可以是血液样品,其中循环肿瘤细胞(或“CTC”)可表达B7-H4并被检测到。
B7-H4蛋白的表达水平的测定意图包括直接(例如,通过测定或估计绝对蛋白质水平)或相对(例如,通过与第二生物样品中的蛋白质水平进行比较)定性地或定量地测量或估计第一生物样品中B7-H4蛋白的水平。可测量或估计所述第一生物样品中的B7-H4多肽表达水平并且与标准B7-H4蛋白质水平进行比较,所述标准从未患病的第二生物样品确定或通过对来自未患病的样品群体的水平进行平均化来确定。正如本领域中将了解的,一旦已知“标准”B7-H4多肽水平,它就可重复地用作比较的标准。
在另一个实施方案中,将本文所述的抗B7-H4抗体或其抗原结合片段或药物组合物施用至被诊断为患有癌症的患者(例如,人患者),以增加所述患者体内的T细胞、CD4+T细胞或CD8+T细胞的增殖。在这样的实施方案中,本文所述的PD-1/PD-L1拮抗剂,例如派姆单抗,施用于患者以阻断PD-1与PD-L1和PD-L2的结合并活化T细胞。在另一个实施方案中,将抗B7-H4抗体或其抗原结合片段或药物组合物施用至被诊断为患有癌症的患者(例如,人患者),以增加所述患者体内的干扰素-γ(IFNγ)产生。在这样的实施方案中,本文所述的PD-1/PD-L1拮抗剂,例如派姆单抗,施用于患者以阻断PD-1与PD-L1和PD-L2的结合并活化T细胞。在另一个实施方案中,将抗B7-H4抗体或其抗原结合片段或药物组合物施用至被诊断为患有癌症的患者(例如,人患者),以阻断所述患者体内的B7-H4针对T细胞的抑制活性。在这样的实施方案中,本文所述的PD-1/PD-L1拮抗剂,例如派姆单抗,施用于患者以阻断PD-1与PD-L1和PD-L2的结合并活化T细胞。在另一个实施方案中,将抗B7-H4抗体或其抗原结合片段或药物组合物施用至被诊断为患有癌症的患者(例如,人患者),以消减所述患者体内的表达B7-H4的癌细胞。在这样的实施方案中,本文所述的PD-1/PD-L1拮抗剂,例如派姆单抗,施用于患者以阻断PD-1与PD-L1和PD-L2的结合并活化T细胞。
在一些实施方案中,本发明涉及一种本文提供的抗B7-H4抗体或其抗原结合片段或药物组合物,用于与PD-1/PD-L1拮抗剂诸如派姆单抗或其药物组合物组合作为药物,其中所述药物用于施用约0.1mg/kg至约20mg/kg(例如,约0.1mg/kg、约0.3mg/kg、约1mg/kg、约3mg/kg、约10mg/kg或约20mg/kg)的所述抗体或其抗原结合片段,以及约200mg的派姆单抗。在这样的实施方案中,抗体或其抗原结合片段和派姆单抗可以被共同配制或分开配制以同时或依次施用。在一些方面,本发明涉及一种本文提供的抗B7-H4抗体或其抗原结合片段或药物组合物,用于与PD-1/PD-L1拮抗剂诸如派姆单抗或其药物组合物组合用于治疗癌症的方法中,其中施用约0.1mg/kg至约20mg/kg(例如,约0.1mg/kg、约0.3mg/kg、约1mg/kg、约3mg/kg、约10mg/kg或约20mg/kg)的所述抗体或其抗原结合片段,并且施用约200mg的派姆单抗,其中施用是依次的或同时的。在一些方面,本发明涉及一种本文提供的抗B7-H4抗体或其抗原结合片段或药物组合物,用于与PD-1/PD-L1拮抗剂诸如派姆单抗组合用于治疗受试者癌症的方法中,所述方法包括向受试者施用约0.1mg/kg至约20mg/kg(例如,约0.1mg/kg、约0.3mg/kg、约1mg/kg、约3mg/kg、约10mg/kg或约20mg/kg)的本文提供的抗体或其抗原结合片段或药物组合物,以及施用约200mg的本文提供的派姆单抗或其药物组合物,其中施用是依次的或同时的。
在一些实施方案中,本发明涉及一种本文提供的抗B7-H4抗体或其抗原结合片段或药物组合物,用于与PD-1/PD-L1拮抗剂诸如派姆单抗或其药物组合物组合作为药物,其中所述药物用于施用0.1mg/kg至20mg/kg(例如,0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、10mg/kg或20mg/kg)的所述抗体或其抗原结合片段,以及200mg的派姆单抗。在这样的实施方案中,抗体或其抗原结合片段和派姆单抗可以被共同配制或分开配制以同时或依次施用。在一些方面,本发明涉及一种本文提供的抗B7-H4抗体或其抗原结合片段或药物组合物,用于与PD-1/PD-L1拮抗剂诸如派姆单抗或其药物组合物组合用于治疗癌症的方法中,其中施用0.1mg/kg至20mg/kg(例如,0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、10mg/kg或20mg/kg)的所述抗体或其抗原结合片段,并且施用200mg的派姆单抗,其中施用是依次的或同时的。在一些方面,本发明涉及一种本文提供的抗B7-H4抗体或其抗原结合片段或药物组合物,用于与PD-1/PD-L1拮抗剂诸如派姆单抗组合用于治疗受试者癌症的方法中,所述方法包括向受试者施用0.1mg/kg至20mg/kg(例如,0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、10mg/kg或20mg/kg)的本文提供的抗体或其抗原结合片段或药物组合物,以及施用200mg的本文提供的派姆单抗或其药物组合物,其中施用是依次的或同时的。
在某些方面,人PD-1的氨基酸是:
MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL(SEQ IDNO:40)。
在某些方面,人PD-L1的氨基酸序列是:
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET(SEQ IDNO:41)。
4.3 B7-H4抗体及其抗原结合片段
本文提供了治疗人受试者的癌症的方法,所述方法包括向所述受试者施用特异性地结合至B7-H4(例如,人B7-H4)的抗体(例如,单克隆抗体,诸如嵌合、人源化或人抗体)及其抗原结合片段,与PD-1/PD-L1拮抗剂(诸如派姆单抗)组合。可用于本文提供的方法中的示例性B7-H4抗体及其抗原结合片段是本领域中已知的。人、食蟹猴、鼠类和大鼠B7-H4的氨基酸序列是本领域中已知的,并且也在本文中提供,分别由SEQ ID NO:1-4表示。
人B7-H4:
MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKASLCVSSFFAISWALLPLSPYLMLK(SEQ ID NO:1)
食蟹猴B7-H4:
MASLGQILFWSIISIIFILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVIGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKASLCVSSFLAISWALLPLAPYLMLK(SEQ ID NO:2)
鼠类B7-H4
MASLGQIIFWSIINIIIILAGAIALIIGFGISGKHFITVTTFTSAGNIGEDGTLSCTFEPDIKLNGIVIQWLKEGIKGLVHEFKEGKDDLSQQHEMFRGRTAVFADQVVVGNASLRLKNVQLTDAGTYTCYIRTSKGKGNANLEYKTGAFSMPEINVDYNASSESLRCEAPRWFPQPTVAWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTDSEVKRRSQLQLLNSGPSPCVFSSAFVAGWALLSLSCCLMLR(SEQ ID NO:3)
大鼠B7-H4
MASLGQIIFWSIINVIIILAGAIVLIIGFGISGKHFITVTTFTSAGNIGEDGTLSCTFEPDIKLNGIVIQWLKEGIKGLVHEFKEGKDDLSQQHEMFRGRTAVFADQVVVGNASLRLKNVQLTDAGTYTCYIHTSKGKGNANLEYKTGAFSMPEINVDYNASSESLRCEAPRWFPQPTVAWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTDSEVKRRSQLELLNSGPSPCVSSVSAAGWALLSLSCCLMLR(SEQ ID NO:4)
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4。在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人和食蟹猴B7-H4。在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人、鼠类和大鼠B7-H4。在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人、食蟹猴、鼠类和大鼠B7-H4。
B7-H4含有IgC胞外结构域(SEQ ID NO:1的氨基酸153-241)和IgV胞外结构域(SEQID NO:1的氨基酸35-146)。在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4的IgV结构域。因此,本文提供了施用抗体或其抗原结合片段的方法,所述抗体或其抗原结合片段包含特异性地结合至由SEQ ID NO:1的氨基酸35-146组成的多肽。
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含如表1和表2中列出的20502抗体的六个CDR。“20502”是指本文所述的20502抗体。
表1.VH CDR氨基酸序列1
1表1中的VH CDR是根据Kabat确定的。
表2.VL CDR氨基酸序列2
2表2中的VL CDR是根据Kabat确定的。
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表3中列出的20502抗体的VH。
表3:可变重链(VH)氨基酸序列
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表4中列出的20502抗体的VL。
表4:可变轻链(VL)氨基酸序列
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表3和表4中列出的20502抗体的VH和VL。
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表5中列出的20502抗体的VH框架区。
表5.VH FR氨基酸序列3
3表5中描述的VH框架区是基于CDR的Kabat编号系统的边界确定的。因此,VH CDR由Kabat确定,并且框架区是可变区中围绕CDR的氨基酸残基,呈形式FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表6中列出的20502抗体的VL框架区。
表6.VL FR氨基酸序列4
4表6中描述的VL框架区是基于CDR的Kabat编号系统的边界确定的。因此,VL CDR由Kabat确定,并且框架区是可变区中围绕CDR的氨基酸残基,呈形式FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表5和表6中列出的20502抗体的四个VH框架区和四个VL框架区。
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表7中列出的20502抗体的重链序列。
表7:全长重链氨基酸序列
在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段特异性地结合至人B7-H4,并且包含表8中列出的20502抗体的轻链序列。
表8:全长轻链氨基酸序列
在某些实施方案中,用于本文所述的方法中的抗体或抗原结合片段特异性地结合至人B7-H4,并且包含表7和表8中列出的20502抗体的重链序列和轻链序列。
在某些方面,用于本文所述的方法中的抗体或其抗原结合片段通过其单独的VL结构域、或其单独的VH结构域、或其单独的3个VL CDR或其单独的3个VH CDR进行描述。参见例如,Rader C等人,(1998)PNAS 95:8910-8915,所述文献以引用的方式整体并入本文,其描述通过以下方式来进行小鼠抗αvβ3抗体的人源化:鉴定分别来自人轻链或重链文库的互补轻链或重链,从而产生亲和力与原始抗体的亲和力一样高或高于原始抗体的亲和力的人源化抗体变体。还参见Clackson T等人,(1991)Nature 352:624-628,所述文献以引用的方式整体并入本文,描述了通过以下方式产生特异性地结合特异性抗原的抗体的方法:使用特异性VL结构域(或VH结构域)并筛选文库中的互补VH结构域或(VL结构域)。通过ELISA,所述筛选产生了针对特异性VH结构域的14个新的配偶体和针对特异性VL结构域的13个新的配偶体,所述配偶体是强结合剂,如通过ELISA所确定。还参见Kim SJ和Hong HJ,(2007)JMicrobiol 45:572-577,所述文献以引用的方式整体并入本文,描述了通过以下方式产生特异性地结合特异性抗原的抗体的方法:使用特异性VH结构域并筛选文库(例如,人VL文库)中的互补VL结构域;所选择的VL结构域进而可用于指导其他互补(例如人)VH结构域的选择。
在某些方面,可根据Chothia编号方案来确定抗体或其抗原结合片段的CDR,Chothia编号方案是指免疫球蛋白结构环的位置(参见例如,Chothia C和Lesk AM,(1987),J Mol Biol 196:901-917;Al-Lazikani B等人,(1997)J Mol Biol 273:927-948;ChothiaC等人,(1992)J Mol Biol 227:799-817;Tramontano A等人,(1990)J Mol Biol 215(1):175-82;以及美国专利号7,709,226)。通常,当使用Kabat编号惯例时,Chothia CDR-H1环存在于重链氨基酸26至32、33或34处,Chothia CDR-H2环存在于重链氨基酸52至56处,并且Chothia CDR-H3环存在于重链氨基酸95至102,而Chothia CDR-L1环存在于轻链氨基酸24至34处,Chothia CDR-L2环存在于轻链氨基酸50至56处,并且Chothia CDR-L3环存在于轻链氨基酸89至97处。当使用Kabat编号惯例编号时,Chothia CDR-H1环的末端根据环的长度在H32与H34之间变化(这是由于Kabat编号方案将插入物放置于H35A和H35B处;如果35A和35B均不存在,则环结束于32处;如果仅35A存在,则环结束于33处;如果35A和35B均存在,则环结束于34处)。
在某些方面,本文提供了施用抗体及其抗原结合片段的方法,所述抗体及其抗原结合片段特异性地结合至B7-H4(例如,人B7-H4)并且包含表3和表4中列出的20502抗体的Chothia VH和VL CDR。在某些实施方案中,本文提供了施用抗体或其抗原结合片段的方法,所述抗体或其抗原结合片段特异性地结合至B7-H4(例如,人B7-H4)并且包含一个或多个CDR,其中Chothia和Kabat CDR具有相同的氨基酸序列。在某些实施方案中,本文提供了施用抗体及其抗原结合片段的方法,所述抗体及其抗原结合片段特异性地结合至B7-H4(例如,人B7-H4)并且包含Kabat CDR和Chothia CDR的组合。
在某些方面,可根据如Lefranc M-P,(1999)The Immunologist 7:132-136和Lefranc M-P等人,(1999)Nucleic Acids Res 27:209-212中所述的IMGT编号系统来确定抗体或其抗原结合片段的CDR。根据IMGT编号方案,VH-CDR1位于位置26至35处,VH-CDR2位于位置51至57处,VH-CDR3位于位置93至102处,VL-CDR1位于位置27至32处,VL-CDR2位于位置50至52处,并且VL-CDR3位于位置89至97处。在一个特定实施方案中,本文提供了施用抗体及其抗原结合片段的方法,所述抗体及其抗原结合片段特异性地结合至B7-H4(例如,人B7-H4)并且包含表3和表4中列出的20502抗体的IMGT VH和VL CDR,例如,如Lefranc M-P(1999)同上和Lefranc M-P等人,(1999)同上中所描述。
在某些方面,可根据MacCallum RM等人,(1996)J Mol Biol 262:732-745来确定抗体或其抗原结合片段的CDR。还参见例如,Martin A.“Protein Sequence and StructureAnalysis of Antibody Variable Domains,”于Antibody Engineering,Kontermann和Dübel,编辑,第31章,第422-439页,Springer-Verlag,Berlin(2001)中。在一个特定实施方案中,本文提供了施用抗体或其抗原结合片段的方法,所述抗体或其抗原结合片段特异性地结合至B7-H4(例如,人B7-H4)并且包含如通过MacCallum RM等人中的方法确定的表3和表4中列出的20502抗体的VH和VL CDR。
在某些方面,可根据AbM编号方案来确定抗体或其抗原结合片段的CDR,AbM编号方案是指表示Kabat CDR与Chothia结构环之间的折衷的AbM高变区,并且由OxfordMolecular的AbM抗体建模软件(Oxford Molecular Group,Inc.)使用。在一个特定实施方案中,本文提供了施用抗体或其抗原结合片段的方法,所述抗体或其抗原结合片段特异性地结合至B7-H4(例如,人B7-H4)并且包含如通过AbM编号方案确定的表3和表4中列出的20502抗体的VH和VL CDR。
在具体方面,本文提供了施用抗体的方法,所述抗体包含重链和轻链。
关于轻链,在一个具体实施方案中,本文描述的抗体的轻链是κ轻链。人κ轻链的恒定区可包含以下氨基酸序列:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:23)。
人κ轻链的恒定区可由以下核苷酸序列编码:
CGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(SEQ ID NO:24)。
在一个特定实施方案中,用于本文所述的方法中的免疫特异性地结合至B7-H4多肽(例如,人B7-H4)的抗体包含轻链,其中VL结构域的氨基酸序列包含表4中列出的序列,并且其中所述轻链的恒定区包含人κ轻链恒定区的氨基酸序列。
在一个特定实施方案中,用于本文所述的方法中的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体包含重链,其中VH结构域的氨基酸序列包含表3中列出的氨基酸序列,并且其中所述重链的恒定区包含人γ(γ)重链恒定区的氨基酸序列。
人IgG1重链的恒定区可包含以下氨基酸序列:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:25)。
人IgG1重链的恒定区可由以下核苷酸序列编码:
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA。(SEQ ID NO:26)
在一个具体实施方案中,用于本文所述的方法中的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体包含VH结构域和VL结构域,所述VH结构域和VL结构域包含本文所述的任何VH和VL结构域的氨基酸序列,并且其中恒定区包含IgG(例如,人IgG)免疫球蛋白分子的恒定区的氨基酸序列。在另一个具体实施方案中,用于本文所述的方法中的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体包含VH结构域和VL结构域,所述VH结构域和VL结构域包含本文所述的任何VH和VL结构域的氨基酸序列,并且其中恒定区包含IgG1(例如人IgG1)免疫球蛋白分子的恒定区的氨基酸序列。
据报告,岩藻糖含量降低的抗体对Fc受体,例如像FcγRIIIA的亲和力增加。因此,在某些实施方案中,用于本文所述的方法中的抗体或其抗原结合片段具有降低的岩藻糖含量或缺乏岩藻糖(即“无岩藻糖基化”)。此类抗体或其抗原结合片段可使用本领域技术人员已知的技术来产生。例如,它们可在缺乏或缺少岩藻糖基化能力的细胞中表达。在一个具体实例中,具有α1,6-岩藻糖基转移酶基因(FUT8)的两个等位基因敲除的细胞系可用于产生岩藻糖含量降低的抗体或其抗原结合片段。系统(Lonza)是可用于产生岩藻糖含量降低的抗体及其抗原结合片段的这种系统的实例。或者,可通过例如以下方式来产生岩藻糖含量降低或无岩藻糖含量的抗体或其抗原结合片段:(i)在防止或减少岩藻糖基化的条件下培养细胞;(ii)翻译后除去岩藻糖(例如,用岩藻糖苷酶);(iii)例如在重组表达非糖基化糖蛋白之后,翻译后添加所需的碳水化合物;或(iv)纯化糖蛋白以选择未岩藻糖基化的抗体或其抗原结合片段。关于用于产生无岩藻糖含量或岩藻糖含量降低的抗体的方法,参见例如,Longmore GD和Schachter H(1982)Carbohydr Res 100:365-92以及Imai-Nishiya H等人,(2007)BMC Biotechnol.7:84。
在一些实施方案中,与具有相同氨基酸序列的岩藻糖基化B7-H4抗体或其抗原结合片段相比,无岩藻糖基化B7-H4抗体或其抗原结合片段在体外具有增强的ADCC活性。在一些实施方案中,与使用岩藻糖基化B7-H4抗体情况下的特异性裂解相比,无岩藻糖基化B7-H4抗体或其抗原结合片段引起高至少10、至少15、至少20、至少25、至少30、至少35、至少40、至少45、至少50、至少60、至少65、至少70或至少75个百分点的特异性裂解。可如本文实施例2中所述确定特异性裂解。
在一些实施方案中,与具有相同氨基酸序列的岩藻糖基化B7-H4抗体或其抗原结合片段相比,B7-H4抗体或其抗原结合片段对FcγRIIIA具有增强的亲和力。在一些实施方案中,与岩藻糖基化B7-H4抗体或其抗原结合片段相比,无岩藻糖基化B7-H4抗体或其抗原结合片段以高至少2倍、至少3倍、至少4倍、至少5倍、至少7倍、至少10倍、至少12倍、至少15倍、至少17倍或至少20倍的亲和力结合至FcγRIIIA。在一些实施方案中,使用表面等离振子共振来测定对FcγRIIIA的亲和力。在一些实施方案中,FcγRIIIA选自FcγRIIIA(V158)和FcγRIIIA(F158)。在一些实施方案中,FcγRIIIA是FcγRIIIA(V158)。
在一些实施方案中,可通过包括高效液相色谱法(HPLC)、毛细管电泳或MALDI-TOF质谱法的方法来确定岩藻糖的存在。
在具体实施方案中,抗体或其抗原结合片段(i)包含20502的CDR序列、20502的VH和VL序列或20502的重链和轻链序列,并且(ii)无岩藻糖基化。
在具体实施方案中,组合物包含抗体或其抗原结合片段,所述抗体或其抗原结合片段(i)包含20502的CDR序列、20502的VH和VL序列或20502的重链和轻链序列,并且(ii)无岩藻糖基化,例如,其中所述组合物中至少95%的所述抗体无岩藻糖基化,或其中岩藻糖基化在所述组合物中不可检测到。
工程化的糖型可适用于多种目的,包括但不限于增强或减小效应功能。用于产生本文所述的抗体或其抗原结合片段中的工程化的糖型的方法包括但不限于例如以下中公开的那些:P等人,(1999)Nat Biotechnol 17:176-180;Davies J等人,(2001)Biotechnol Bioeng 74:288-294;Shields RL等人,(2002)J Biol Chem 277:26733-26740;Shinkawa T等人,(2003)J Biol Chem 278:3466-3473;Niwa R等人,(2004)ClinCancer Res 1:6248-6255;Presta LG等人,(2002)Biochem Soc Trans 30:487-490;KandaY等人,(2007)Glycobiology 17:104-118;美国专利号6,602,684;6,946,292;和7,214,775;美国专利公布号US 2007/0248600;2007/0178551;2008/0060092;和2006/0253928;国际公布号WO 00/61739;WO 01/292246;WO 02/311140;和WO 02/30954;PotillegentTM技术(Biowa,Inc.Princeton,N.J.);以及糖基化工程化技术(Glycartbiotechnology AG,Zurich,Switzerland)。还参见例如,Ferrara C等人,(2006)Biotechnol Bioeng 93:851-861;国际公布号WO 07/039818;WO 12/130831;WO 99/054342;WO 03/011878;以及WO 04/065540。
在某些实施方案中,可将本文所述的任何恒定区突变或修饰引入具有两个重链恒定区的本文所述的抗体或其抗原结合片段的一个或两个重链恒定区中。
在另一个特定实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段包含重链和轻链,其中(i)所述重链包含VH结构域,所述VH结构域包含表1中列出的20502抗体的VH CDR1、VL CDR2和VL CDR3氨基酸序列(分别是SEQ IDNO:5、6和7);(ii)所述轻链包含VL结构域,所述VL结构域包含表2中列出的20502抗体的VLCDR1、VH CDR2和VH CDR3氨基酸序列(分别是SEQ ID NO:8、9和10);(iii)所述重链还包含恒定重链结构域,所述恒定重链结构域包含人IgG1重链的恒定结构域的氨基酸序列;并且(iv)所述轻链还包含恒定轻链结构域,所述恒定轻链结构域包含人κ轻链的恒定结构域的氨基酸序列。
在另一个特定实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段包含重链和轻链,其中(i)所述重链包含VH结构域,所述VH结构域包含表3中列出的20502抗体的VH结构域的氨基酸序列(SEQ ID NO:11);(ii)所述轻链包含VL结构域,所述VL结构域包含表4中列出的20502抗体的VL结构域的氨基酸序列(SEQID NO:12);(iii)所述重链还包含恒定重链结构域,所述恒定重链结构域包含人IgG1重链的恒定结构域的氨基酸序列;并且(iv)所述轻链还包含恒定轻链结构域,所述恒定轻链结构域包含人κ轻链的恒定结构域的氨基酸序列。
在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段表现出T细胞检查点阻断活性。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段增加T细胞中的干扰素-γ(IFNγ)产生。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段增加T细胞增殖。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段增加CD4+T细胞增殖。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段增加CD8+T细胞增殖。
在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段表现出抗体依赖性细胞毒性(ADCC)活性。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段在具有至少300,000个细胞表面B7-H4分子的细胞系(例如,SK-BR-3细胞)上表现出抗体依赖性细胞毒性(ADCC)活性。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段在具有至少100,000个细胞表面B7-H4分子的细胞系(例如,HCC1569细胞)上表现出抗体依赖性细胞毒性(ADCC)活性。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段在具有至少50,000个细胞表面B7-H4分子的细胞系(例如,ZR-75-1细胞)上表现出抗体依赖性细胞毒性(ADCC)活性。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段在具有至少30,000个细胞表面B7-H4分子的细胞系(例如,MDA-MB-468细胞)上表现出抗体依赖性细胞毒性(ADCC)活性。在具体实施方案中,本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体或其抗原结合片段在具有至少15,000个细胞表面B7-H4分子的细胞系(例如,HCC1964细胞)上表现出抗体依赖性细胞毒性(ADCC)活性。
在一个具体方面,如本文所述的免疫特异性地结合至B7-H4(例如,人B7-H4)的抗原结合片段选自由以下组成的组:Fab、Fab’、F(ab’)2和scFv,其中所述Fab、Fab’、F(ab’)2或scFv包含如本文所述的抗B7-H4抗体或其抗原结合片段的重链可变区序列和轻链可变区序列。Fab、Fab’、F(ab’)2或scFv可通过本领域技术人员已知的任何技术来产生。在某些实施方案中,Fab、Fab’、F(ab’)2或scFv还包含延长体内抗体半衰期的部分。所述部分也被称为“延长半衰期的部分”。可使用本领域技术人员已知的用于在体内延长Fab、Fab’、F(ab’)2或scFv的半衰期的任何部分。例如,延长半衰期的部分可包括Fc区、聚合物、白蛋白或白蛋白结合蛋白或化合物。所述聚合物可包括天然或合成的、任选取代的直链或支链的聚亚烷基、聚亚烯基、聚氧化烯、多糖、聚乙二醇、聚丙二醇、聚乙烯醇、甲氧基聚乙二醇、乳糖、直链淀粉、葡聚糖、糖原或它们的衍生物。取代基可包括一个或多个羟基、甲基或甲氧基。在某些实施方案中,可通过添加一个或多个用于连接延长半衰期的部分的C-末端氨基酸来修饰Fab、Fab’、F(ab’)2或scFv。在某些实施方案中,延长半衰期的部分是聚乙二醇或人血清白蛋白。在某些实施方案中,Fab、Fab’、F(ab’)2或scFv融合至Fc区。
4.4药物组合物
本文提供了施用组合物的方法,所述组合物包含生理上可接受的载体、赋形剂或稳定剂中的具有所需纯度的抗B7-H4抗体或其抗原结合片段(Remington’sPharmaceutical Sciences(1990)Mack Publishing Co.,Easton,PA)。可接受的载体、赋形剂或稳定剂在所用剂量和浓度下对接受者无毒。(参见例如Gennaro,Remington:TheScience and Practice of Pharmacy with Facts and Comparisons:Drugfacts Plus,第20版(2003);Ansel等人,Pharmaceutical Dosage Forms and Drug Delivery Systems,第7版,Lippencott Williams and Wilkins(2004);Kibbe等人,Handbook ofPharmaceutical Excipients,第3版,Pharmaceutical Press(2000))。有待用于体内施用的组合物可以是无菌的。这易于通过,例如无菌过滤膜过滤来实现。
在一些实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或其抗原结合片段和药学上可接受的载体。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少80%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少85%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少90%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少95%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少96%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少97%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少98%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,例如,其中所述组合物中至少99%的所述抗体无岩藻糖基化。在具体实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含无岩藻糖基化抗B7-H4抗体或抗原结合片段,其中岩藻糖在所述组合物中不可检测到。
在一些实施方案中,提供了施用药物组合物的方法,其中所述药物组合物包含(i)特异性地结合至人B7-H4的分离的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含(a)分别SEQ ID NO:5-10重链可变区(VH)互补决定区(CDR)1、VH CDR2、VH CDR3和轻链可变区(VL)CDR1、CDR2和CDR3序列,(b)包含SEQ ID NO:11的氨基酸序列的可变重链区和包含SEQ ID NO:12的氨基酸序列的可变轻链区,或(c)包含SEQ ID NO:21的氨基酸序列的重链和包含SEQ ID NO:22的氨基酸序列的轻链;和(ii)药学上可接受的赋形剂。
本文还提供了施用药物组合物的方法,其中所述药物组合物包含(i)抗体或其抗原结合片段,所述抗体或其抗原结合片段特异性地结合至人B7-H4并且包含分别为SEQ IDNO:5-10的重链可变区(VH)互补决定区(CDR)1、VH CDR2、VH CDR3和轻链可变区(VL)CDR1、CDR2和CDR3序列,和(ii)药学上可接受的赋形剂,其中所述组合物中至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的所述抗体或其抗原结合片段无岩藻糖基化。在一个实施方案中,(i)所述抗体或其抗原结合片段包含含有SEQ IDNO:11的氨基酸序列的可变重链区和含有SEQ ID NO:12的氨基酸序列的可变轻链区,或(ii)所述抗体包含含有SEQ ID NO:21的氨基酸序列的重链和含有SEQ ID NO:22的氨基酸序列的轻链。
本文还提供除包含抗B7-H4抗体或其抗原结合片段的药物组合物之外还施用另外的药物组合物的方法。在这样的实施方案中,另外的药物组合物包含PD-1/PD-L1拮抗剂,诸如派姆单抗。在这样的实施方案中,包含派姆单抗的另外的药物组合物以用于重构的单剂量小瓶中的50mg冻干粉末形式提供,或以单剂量小瓶中的100mg/4ml(25mg/ml)的溶液形式提供。在这样的实施方案中,提供一定量的另外的药物组合物以在给定的施用中向患者递送200mg派姆单抗。所述另外的药物组合物可以与包含抗B7-H4抗体或其抗原结合片段的药物组合物同时或依次施用。
4.5抗体产生和多核苷酸
免疫特异性地结合至B7-H4(例如,人B7-H4)的抗体及其抗原结合片段可通过本领域已知的用于合成抗体及其抗原结合片段的任何方法,例如通过化学合成或通过重组表达技术来产生。除非另有说明,否则本文描述的方法采用分子生物学、微生物学、遗传分析、重组DNA、有机化学、生物化学、PCR、寡核苷酸合成和修饰、核酸杂交以及本领域技术范围内的相关领域中的常规技术。这些技术例如在本文引用的参考文献中进行了描述,并且在文献中进行了充分说明。参见例如,Sambrook J等人,(2001)Molecular Cloning:A LaboratoryManual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Ausubel FM等人,Current Protocols in Molecular Biology,John Wiley&Sons(1987and annualupdates);Current Protocols in Immunology,John Wiley&Sons(1987and annualupdates)Gait(编辑)(1984)Oligonucleotide Synthesis:A Practical Approach,IRLPress;Eckstein(编辑)(1991)Oligonucleotides and Analogues:A PracticalApproach,IRL Press;Birren B等人,(编辑)(1999)Genome Analysis:A LaboratoryManual,Cold Spring Harbor Laboratory Press。
在某些方面,本文提供了施用抗B7-H4抗体或其抗原结合片段或包含此类抗体或片段的药物组合物的方法,其中所述抗体或片段通过在宿主细胞中重组表达包含核苷酸序列的多核苷酸来产生。
在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表9中所示的核苷酸序列(即SEQ ID NO:27)的多核苷酸编码的重链可变区。在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表9中所示的核苷酸序列(即SEQ ID NO:27)的多核苷酸编码的重链可变区和编码人γ(γ)重链恒定区的核苷酸序列。在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表9中所示的核苷酸序列(即SEQ ID NO:27)的多核苷酸编码的重链可变区和由包含SEQ IDNO:26的核苷酸序列的多核苷酸编码的重链恒定结构域。
表9:编码重链可变区的多核苷酸序列
在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表10中所示的核苷酸序列(即SEQ ID NO:28)的多核苷酸编码的轻链可变区。在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表10中所示的核苷酸序列(即SEQ ID NO:28)的多核苷酸编码的轻链可变区和编码人λ轻链恒定区的核苷酸序列。在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表10中所示的核苷酸序列(即SEQ ID NO:28)的多核苷酸编码的轻链可变区和由包含SEQ IDNO:24的核苷酸序列的多核苷酸编码的轻链恒定结构域。
表10:编码轻链可变区的多核苷酸序列
在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含由包含表9中所示的编码可变重链的核苷酸序列(即SEQ ID NO:27)的多核苷酸编码的可变重链和由包含表10中所示的编码可变轻链的核苷酸序列(即SEQ ID NO:28)的多核苷酸编码的可变轻链。
在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含(i)由包含表9中所示的编码可变重链的核苷酸序列(即SEQ ID NO:27)的多核苷酸编码的重链和编码人γ(γ)重链恒定区的核苷酸序列,以及(ii)由包含表10中所示的编码可变轻链的核苷酸序列(即SEQ ID NO:28)的多核苷酸编码的轻链和编码人λ轻链恒定区的核苷酸序列。
在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段包含(i)由包含表9中所示的编码可变重链的核苷酸序列(即SEQ ID NO:27)的多核苷酸编码的重链和SEQ ID NO:26的编码重链恒定结构域的核苷酸序列,以及(ii)由包含表10中所示的编码可变轻链的核苷酸序列(即SEQ ID NO:28)的多核苷酸编码的轻链和SEQ ID NO:24的编码轻链恒定结构域的核苷酸序列。
在某些方面,根据本文提供的方法施用的抗B7-H4抗体或抗原结合片段由编码抗B7-H4抗体或其抗原结合片段或其结构域的经优化的多核苷酸编码,所述优化例如,通过密码子/RNA优化、用异源信号序列置换以及消除mRNA不稳定元件。通过引入密码子变化(例如,由于遗传密码的简并性而编码相同氨基酸的密码子变化)和/或消除mRNA中的抑制区域来产生用于重组表达的编码抗B7-H4抗体或其抗原结合片段或其结构域(例如,重链、轻链、VH结构域或VL结构域)的优化的核酸的方法因此可通过采用例如在美国专利号5,965,726;6,174,666;6,291,664;6,414,132;以及6,794,498中描述的优化方法来进行。
多核苷酸可以例如呈RNA形式或DNA形式。DNA包括cDNA、基因组DNA和合成DNA。DNA可以是双链或单链。如果是单链,则DNA可以是编码链或非编码(反义)链。在某些实施方案中,多核苷酸是缺少一个或多个内含子的cDNA或DNA。在某些实施方案中,多核苷酸是非天然存在的多核苷酸。在某些实施方案中,多核苷酸是重组产生的。在某些实施方案中,多核苷酸是分离的。在某些实施方案中,多核苷酸是基本上纯的。在某些实施方案中,多核苷酸是从天然组分中纯化的。
在某些方面,载体(例如,表达载体)包含编码抗B7-H4抗体及其抗原结合片段或其结构域的核苷酸序列,以在宿主细胞中、优选在哺乳动物细胞中重组表达。在某些方面,细胞(例如宿主细胞)包含用于重组表达本文所述的抗B7-H4抗体或其抗原结合片段(例如,人或人源化抗体或其抗原结合片段)的此类载体。因此,用于产生本文所述的抗体或其抗原结合片段的方法可包括在宿主细胞中表达这种抗体或其抗原结合片段。
可通过常规技术将表达载体转移至细胞(例如宿主细胞),并且然后可通过常规技术培养所得细胞以产生本文所述的抗体或其抗原结合片段(例如,包含20502的六个CDR、VH、VL、VH和VL、重链、轻链或重链和轻链的抗体或抗原结合片段)或其结构域(例如,20502的VH、VL、VH和VL、重链或轻链)。
在一些实施方案中,在缺乏功能性α-1,6-岩藻糖基转移酶基因(FUT8)基因的宿主细胞中产生根据本文提供的方法施用的抗B7-H4抗体或其抗原结合片段(例如,包含20502的CDR的抗体或其抗原结合片段)。在一些实施方案中,宿主细胞是CHO细胞。
在具体实施方案中,根据本文提供的方法施用的抗体或其抗原结合片段是分离或纯化的。通常,分离的抗体或其抗原结合片段是基本上不含与分离的抗体或其抗原结合片段具有不同抗原特异性的其他抗体或其抗原结合片段的抗体或其抗原结合片段。例如,在一个特定的实施方案中,本文所述的抗体或其抗原结合片段的制剂基本上不含细胞材料和/或化学前体。
通过说明而不是通过限制的方式提供以下实施例。
5.实施例
本部分中的实施例是以说明方式提供而不是以限制方式提供。
5.1实施例1:评估多种适应症中B7-H4表达的普遍性
B7-H4小鼠单克隆抗体A57.1(ATCC目录号PTA-5180)用于检测档案样品、整个切片的混合物和肿瘤微阵列上B7-H4的存在。用第一抗体处理样品,并使用附接至DAB的聚合物检测系统(Ventana Medical Systems)进行检测。
从各种癌症患者(包括浸润性导管癌、三阴性乳腺癌、卵巢癌、非小细胞肺癌和子宫内膜癌)收获的肿瘤组织内的细胞膜和细胞溶质中容易地检测到B7-H4。此外,在表11中列出的适应症中表达频率也较高。
表11:肿瘤中的B7-H4检测
B7-H4在其他癌症中表达,诸如乳腺癌、肾癌(例如,肾细胞癌)、膀胱癌(例如,尿路上皮细胞癌)、胰腺癌和甲状腺癌。参见例如,Zhu,J.,等人,Asian Pacific J.CancerPrev.14:3011-3015(2011);Krambeck A,等人,PNAS 103:10391-10396(2006);Fan,M.等人,Int.J.Clin.Exp.Pathol.7:6768-6775(2014);Xu,H.,等人,Oncology Letters 11:1841-1846(2016);以及Liu,W.,等人,Oncology Letters 8:2527-2534(2014)。
5.2实施例2:无岩藻糖基化和岩藻糖基化20502抗体
与完全岩藻糖基化抗体相比,具有在聚糖部分中岩藻糖含量降低的Fc区的抗体可表现出更高的ADCC活性(Niwa R等人,Clinical Cancer Research 11(6):2327-36(2005))。B7-H4抗体在用于产生通常岩藻糖基化抗体的CHO-x细胞(Yamane-Ohnuki N,等人Biotechnology and Bioengineering 87(5):614-22(2004))中和在经工程化以产生无岩藻糖基化抗体的CHO细胞系(CHO-y细胞)中(同上)产生。
岩藻糖基化和无岩藻糖基化20502抗体通过表面等离子体共振(SPR)进行表征。简言之,将抗人Fab抗体固定在羧基衍生化的SPR芯片表面上,并将抗B7-H4抗体以5ug/ml捕获在所得的表面上持续30秒。然后将各种浓度(0nM、3.7nM、11.1nM、33.3nM、100nM和300nM)的B7-H4 IgV-huIgG1流过所述表面,并使其在缔合阶段期间结合至抗B7-H4抗体,随后在解离阶段期间进行缓冲液洗涤。
B7-H4 IgV-huIgG1:
MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:29)
使用1:1结合模型对数据进行拟合,并且岩藻糖基化和无岩藻糖基化20502显示与人B7-H4蛋白的相似结合。因此,糖基化对结合没有影响。
还通过表面等离子体共振(SPR)表征了岩藻糖基化20502(Ab-F)和无岩藻糖基化20502(Ab-A)的Fc区与FcγRIIIa(V158)的结合亲和力。简言之,使用胺偶联试剂盒将蛋白质A与100mM乙二胺在作为封闭试剂的100mM硼酸钠缓冲液(pH 8.0)中共价连接至葡聚糖芯片。Ab-A或Ab-F以2个密度捕获在单独的流动池中,并且蛋白质A衍生化流充当参考对照。将FcγRIIIA(V158)在HBS-P+运行缓冲液中稀释,并以6种浓度(0nM、1.37nM、12.3nM、37nM、111nM、333nM和1000nM)一式两份注入。使用Biacore T200评估软件1:1结合模型计算缔合常数、解离常数和对Ab-A结合的亲和力。使用Biacore T200评估软件稳态亲和模型确定Ab-A和Ab-F结合的亲和常数。无岩藻糖基化B7-H4抗体对Fcγ受体IIIA(V158)的亲和力是具有岩藻糖基化Fc(Ab-F)的相同抗体的140倍(表12)。
表12:Fcγ受体IIIa(FcγRIIIa)V158等位基因结合
ka(1/Ms) | kd(1/s) | K<sub>D</sub>(nM) | |
Ab-A | 6.46E+05 | 9.54E-10 | 15 |
Ab-F | N/A | N/A | 210 |
还表征了岩藻糖基化和无岩藻糖基化20502抗体的T细胞检查点阻断活性。在这些实验中,根据制造商的说明书,使用EasySepTM人T细胞富集试剂盒从PBMC中富集了原代人T细胞。将富集的T细胞以2x105个细胞/mL与抗CD3/抗CD28 Dynabeads以每细胞一个珠粒的比率在37℃下孵育。六天后,磁性除去珠粒,并且将T细胞洗涤并以1x106个细胞/mL与10U/mL IL-2一起在37℃下孵育。四天后,将T细胞洗涤并以1x106个细胞/mL与2x106个细胞/mL浓度的人工抗原呈递细胞(aAPC)在存在B7-H4抗体剂量滴定的情况下在37℃下孵育。将aAPC用丝裂霉素C在37℃下处理一小时,然后在添加至T细胞共培养物之前充分洗涤。在T细胞、aAPC和B7-H4抗体的共培养后72小时,将板离心,并收获上清液且通过ELISA评估IFNγ产生。将IFNγ产生相对于抗体浓度作图,并使用非线性回归曲线拟合(GraphPad Prism)计算EC50效力。
如通过IFNγ产生的增加所测量,B7-H4抗体显示有效的T细胞检查点阻断活性。此外,无岩藻糖基化抗体与岩藻糖基化抗体之间的效力没有明显差异(表13)。
表13:T细胞检查点阻断效力
在另外的实验中,还针对表达B7-H4的靶细胞系对岩藻糖基化和无岩藻糖基化20502抗体的ADCC活性进行了表征。具体地,在37℃下用200IU/mL IL-2将原代人PBMC细胞以1x106个细胞/mL进行细胞因子活化。第二天,将细胞洗涤并以40:1效应物:靶比率与用钙黄绿素-AM标记的SK-BR-3靶细胞一起孵育。在孵育4小时后,使用荧光计定量靶细胞裂解。Triton/X处理的样品充当最大裂解对照样品,而单独的培养基处理的样品充当本底裂解对照样品。特异性裂解百分比(%)计算如下:[1-((样品–培养基对照)/(最大裂解–培养基对照))]x100。将特异性裂解百分比(%)相对于抗体浓度作图,并使用非线性回归曲线拟合(GraphPad Prism)计算EC50效力。
B7-H4抗体对表达内源性B7-H4的乳腺细胞系SK-BR-3表现出有效的剂量依赖性ADCC活性。此外,与岩藻糖基化抗体相比,无岩藻糖基化抗体表现出显著更强效的ADCC活性(表14)。
表14:ADCC活性
5.3实施例3:ADCC活性与受体密度的相关性
通过FACS根据制造商的说明书在SK-BR-3、HCC1569、ZR-75-1、MDA-MB-48和HCC1964细胞表面上对B7-H4密度进行定量。具体地,将1x105个细胞与15ug/mL B7-H4抗体一起在冰上孵育25分钟。并行地,将一滴QuantumTM Simply Cellular(QSC)微球(用浓度递增的抗小鼠IgG捕获抗体预先包被)也与15ug/mL B7-H4抗体在冰上孵育25分钟。在孵育后,将细胞和QSC微球沉淀并洗涤,并在流式细胞仪上采集样品。使用FlowJo软件分析数据。计算平均荧光强度(MFI),并将其输入到电子表格中。将自动计算将每个珠粒的荧光通道值与其预先分配的抗体结合能力(ABC)值相关联的回归。一旦将标记细胞的MFI值也添加到模板中,就会分配ABC值。
评估了B7-H4抗体针对具有不同水平的B7-H4细胞表面密度的表达B7-H4的靶细胞系的ADCC活性。具体地,将1x104个SK-BR-3、HCC1569、ZR-75-1、MDA-MB-468或HCC1964靶细胞与剂量滴定的B7-H4抗体一起4℃下共孵育。25分钟后,将来自Promega的Jurkat-huCD16报告细胞的单次使用小瓶解冻,并将7.5x104个细胞添加至靶细胞/B7-H4抗体混合物并在37℃下孵育。24小时后,使样品达到至室温(RT)并与Bio-Glo缓冲液一起孵育。在EnVision多标记阅读器上定量底物和发光。将数据绘制为发光对比抗体浓度,并使用非线性回归曲线拟合(GraphPad Prism)计算EC50效力。
B7-H4抗体ADCC活性取决于B7-H4细胞表面密度:随着细胞表面分子的数量减少,最大ADCC活性的量也减少。此外,与岩藻糖基化抗体相比,无岩藻糖基化抗体表现出改善的ADCC活性,尤其是针对具有较低B7-H4细胞表面密度水平的靶细胞(图1)。
5.4实施例4:与抗PD-1抗体组合的体内抗肿瘤功效
方法:八周龄的雌性BALB/c小鼠购自Charles River Laboratories(Hollister,CA),并在研究开始前适应长达两周。将鼠乳腺癌细胞系4T1工程化以表达包含鼠B7-H4的细胞外结构域和鼠B7H3的跨膜结构域的嵌合蛋白。将肿瘤细胞以0.5x105个细胞/50μl/小鼠原位植入小鼠的乳腺脂肪垫中。在接种前,将细胞在补充有10%热灭活胎牛血清(FBS)的RPMI 1640培养基中培养不超过三代。将细胞在具有5%CO2的潮湿环境中在37℃下生长。达到80-85%汇合后,收获细胞并将其重悬于无血清的RPMI 1640中,在每只小鼠的腹侧注入乳腺脂肪垫中。
在细胞植入后每周两次监测小鼠的肿瘤生长。使用卡尺测量每个肿瘤的长度和宽度,并根据下式计算体积:肿瘤体积(mm3)=(宽度(mm)×长度(mm)2)/2。在治疗开始当天,测量所有肿瘤,排除异常值,并将小鼠随机分配至治疗组。对于抗B7-H4治疗,使用名为20502-msIgG2a-F的20502小鼠替代品,其包含与岩藻糖基化的小鼠IgG2a融合的20502可变区。作为对照,给小鼠施用msIgG2a(抗HEL)。从接种后第11天开始,每周两次通过静脉内(i.v.)注射施用四次20502-msIgG2a-F或msIgG2a。从接种后第11天开始,每周两次通过腹膜内(i.p.)注射施用抗PD-1(含有Fc沉默msIgG2a结构域的RMP1-14(Bio X细胞)的改良版)。继续每周至少两次测量肿瘤,直到肿瘤体积超过动物体重的10%或大约2000mm3为止。
结果:肿瘤大小的变化、平均肿瘤体积的变化和生存百分比分别显示在图1A、1B和1C中。与msIgG2a对照相比,用20502-msIgG2a-F或抗PD-1治疗显着降低了肿瘤生长(p<0.05)。与任一种单一疗法相比,共同施用20502-msIgG2a-F和抗PD-1显着增强了肿瘤生长抑制(p<0.05)。此外,组合疗法导致12只小鼠中的5只完全消退肿瘤。在研究的每一天使用计算的肿瘤体积的单向ANOVA分析对P值进行计算,并在各组之间进行多次比较。
在另外的实验中,在工程化的4T1模型中,低剂量1mg/kg和3mg/kg时,作为单一疗法的20502-msIgG2a-F表现出剂量依赖性的抗肿瘤活性(图2)。将0.3mg/kg、3mg/kg或30mg/kg剂量的20502-msIgG2a-F与抗PD-1抗体(5mg/kg)组合在工程化的4T1模型和类似工程化的B16(黑色素瘤)模型中在几乎所有20502-msIgG2a-F测试剂量下都产生协同的抗肿瘤活性(图3)。(PD-1抗体与前三剂20502-msIgG2a-F在同一天对4T1模型施用三次,并与第二剂和第四剂20502-msIgG2a-F于同一天对B16模型施用两次)。对于0.3mg/kg剂量,这种协同作用尤其出乎意料,因为以该剂量单独施用20502-msIgG2a-F没有对肿瘤体积产生明显影响(图2)。此外,在0.3mg/kg剂量的20502-msIgG2a-F与抗PD1组合时观察到的功效(生存百分率)令人惊讶地与在3mg/kg或30mg/kg剂量与抗PD1组合时观察到的功效相当、甚至更好。因此,这些结果表明,抗PD1与抗B7-H4抗体在后者作为单一疗法无功效的剂量下协同地组合,并且这不仅在功效方面具有优势,而且在安全性方面也具有优势。
5.5实施例5:非临床药代动力学
在小鼠、大鼠和食蟹猴中每周一次和/或重复静脉内(IV)施用后,评估无岩藻糖基化20502的药代动力学(PK)和毒物动力学(TK)。在所有研究中观察到的PK特征一致。在所有物种中,无岩藻糖基化20502表现出线性PK,以及随着剂量增加,暴露的剂量成比例增加(血清浓度-时间曲线下面积[AUC])。在第一个剂量和最后一个剂量之间每周4次施用20502后,每周暴露(AUC0-7天)增加大约2倍;然而,没有达到稳定状态。在血清无岩藻糖基化20502浓度-时间特征曲线中没有明显的性别差异。在食蟹猴中(跨2项不同的研究),从恢复动物估计的半衰期在大约8.8天至12天的范围内,剂量水平在1至100mg/kg的范围内。以40mg/kg单次静脉内输注施用后大鼠的估计半衰期是大约13.2天。动物中无岩藻糖基化20502的PK特征支持人中每3周一次(Q3W)剂量方案进行IV输注。
5.6实施例6:毒理学
在大鼠和食蟹猴中进行了无岩藻糖基化20502的毒理学研究。所述研究包括大鼠中的初步单剂量药代动力学(PK)/耐受性研究、食蟹猴中的初步重复剂量毒性研究以及大鼠和食蟹猴中的研究用新药物(IND)实现的良好实验室操作规范(GLP)重复剂量毒性研究以及使用人、大鼠和食蟹猴组织的GLP组织交叉反应性研究。
在大鼠中的单剂量初步耐受性研究中,动物接受高达40mg/kg的剂量作为30分钟静脉内(IV)输注。无岩藻糖基化20502对临床观察结果、体重、食物消耗、临床病理学(血清化学或血液学)评估、总体观察结果、器官重量或组织病理学评估没有影响。
在初步重复剂量毒理学研究中,食蟹猴每周接受4次高达100mg/kg的静脉内无糖基化20502的剂量作为30分钟静脉内输注。食蟹猴对所有剂量都耐受良好。在评估临床观察结果、体重、临床病理学、尸检、器官重量或组织病理学参数期间,没有与测试物品相关的计划外死亡率或归因于岩藻糖基化20502的施用的变化。
在重复剂量GLP毒理学研究中,无岩藻糖基化20502以1、10和100mg/kg/剂量的剂量水平静脉内施用至大鼠和食蟹猴,每周给药4次。在最终施用后的6周恢复期内评估了毒性的可逆性。评估参数包括眼科检查、临床观察结果、体温、体重、食物消耗、血液学、凝血、临床化学、尿液分析、器官重量、宏观和微观评估。在食蟹猴研究中,还对心电图(ECG)进行了评估,以评估潜在心脏毒性。
在进行GLP大鼠研究的评估期间,无岩藻糖基化20502通常耐受性良好,并且没有归因于无岩藻糖基化20502的毒性作用。Sprague Dawley大鼠中未观察到不良作用水平(NOAEL)被认为是100mg/kg/剂量。
在GLP食蟹猴研究中,无岩藻糖基化20502通常耐受性良好,并且在任何评估参数中均未观察到归因于无岩藻糖基化20502的不良事件(AE)。在研究过程中,在较高剂量组中在给药期结束时观察到较高的腹泻发生率。由于在中和高剂量以及在给药期后期发作的受影响动物的发病率较高,因此可能与无岩藻糖基化20502暴露有关。用无岩藻糖基化20502处理的动物(包括患有腹泻的动物)中的肠道无微观变化;因此,此发现被认为是非不利的,但可能与测试物品有关。在研究中存在一例死亡。在最后一次剂量后14天,在研究第35天发现中剂量恢复组中的一只动物死亡。临床观察结果、宏观和微观评估与肠扭转的诊断一致。食蟹猴偶尔会发生肠扭转,并且这被认为是这种动物的自发症状,而与测试物品无关。食蟹猴中的NOAEL被认为是100mg/kg/剂量。
除体内毒理学研究外,还进行了GLP顺应性组织交叉反应性研究,以比较无岩藻糖基化20502与来自大鼠、食蟹猴和人的一组36种组织的结合。结果表明,无岩藻糖基化20502的结合模式在3种物种中相似,并且限于乳腺上皮。
因此,在食蟹猴和大鼠中无岩藻糖基化20502耐受性良好。两种物种中的NOAEL被认为是100mg/kg/剂量,其是当以每周4次静脉内剂量给予时测试的最高剂量。
5.7实施例7:研究无岩藻糖基化的20502与派姆单抗组合的1a期剂量递增/安全性导入和1b期剂量扩展
为方便起见,在本实施例中将无岩藻糖基化的20502称为A-20502。
标题:在晚期实体瘤患者中抗B7-H4抗体与派姆单抗(抗PD1抗体)组合的1a/1b期研究
1a期目标和终点:
1b期目标和终点:
在某些实施方案中,用于注射的派姆单抗以无菌、不含防腐剂的白色至灰白色冻干粉末形式提供在单剂量小瓶中。每个小瓶可以重构并稀释用于静脉内输注。每2mL这种重构溶液包含50mg派姆单抗,并在L-组氨酸(3.1mg)、聚山梨酸酯80(0.4mg)和蔗糖(140mg)中配制。可包含盐酸/氢氧化钠以将pH值调节至5.5。通过添加2.3mL无菌注射用水(USP),将水沿小瓶的壁而不是直接在冻干粉末上注入来重构冻干粉末(所得浓度为25mg/mL)。缓慢旋转小瓶(不摇动),长达5分钟以清除气泡。
在其他实施方案中,派姆单抗可以单次使用小瓶中的100mg/4mL(25mg/mL)溶液进行注射。注射剂是无菌、不含防腐剂、透明至微乳白色、无色至微黄色的溶液,需要稀释以进行静脉内输注。每个小瓶在4mL溶液中包含100mg派姆单抗。每1mL溶液包含25mg派姆单抗,并在:L-组氨酸(1.55mg)、聚山梨酸酯80(0.2mg)、蔗糖(70mg)和注射用水(USP)中配制。
研究设计:这是一项1a/1b期开放标签、多中心研究,旨在评估A-20502与派姆单抗组合在晚期实体瘤中的给药、安全性、耐受性、药代动力学(PK)、药效学和初步功效。
这项研究包括对于A-20502与派姆单抗组合而言的1a期剂量递增/安全性导入部分(1a期剂量递增)和1b期剂量扩展部分(1b期剂量扩展)。
可以对档案肿瘤组织(如果没有档案组织,则用获得的新鲜活检组织)进行预先筛选,通过在中心实验室进行的免疫组织化学(IHC)来测试B7-H4(B7家族的跨膜蛋白,也称为B7S1、B7x或VTCN1)表达水平,用于1a期剂量探索和1b期剂量扩展的患者以及用于生物标志物分析。
在某些实施方案中,档案肿瘤组织和/或新鲜活检组织提供如下:
1a期剂量递增:
·提供档案肿瘤组织(如果没有档案组织,则用获得的新鲜活检组织)以进行患者的回顾性生物标志物分析。
1a期剂量探索:
·档案肿瘤组织通过在中心实验室进行的IHC测试来评估B7-H4表达水平以用于预筛选和用于生物标志物分析;如果没有档案组织,则将使用新鲜的活检组织进行此测试。
·在筛选和后处理期间将使用新鲜活检组织。
1b期剂量扩展:
·档案肿瘤组织通过在中心实验室进行的IHC测试来评估B7-H4表达水平以用于预筛选和用于生物标志物分析;如果没有档案组织,则使用新鲜的活检组织进行此测试。
·在筛选和后处理期间,对于一部分患者(例如,每30位患者队列中至少10位患者)将使用新鲜活检组织,用于扩展的药效学分析。
以下针对本提要的1a期剂量递增和1b期剂量扩展部分的每个研究阶段提供了另外的详细信息。
1a期安全性导入(A-20502与派姆单抗组合):至少3位患者将被招募参与最大耐受剂量(MTD)和/或推荐剂量(RD)的A-20502作为单一疗法组合200mg派姆单抗Q3W并评估剂量限制性毒性(DLT)。另外的患者总计多达10位患者可用RD的A-20520和派姆单抗治疗。如果需要,可根据下面描述的递减算法减少A-20502的剂量。提议的剂量水平为:
·1aC1:A-20502(RD)+派姆单抗200mg IV Q3W
·1aC2:A-20502(10mg/kg)+派姆单抗200mg IV Q3W
·1aC3:A-20502(3mg/kg)+派姆单抗200mg IV Q3W
缩写:IV=静脉内;Q3W=每3周一次;RD=建议剂量。
在一些实施方案中,RD为20mg/kg。在针对晚期实体瘤患者的1a/1b期单一疗法研究中,A-20502在高达20mg/kg的剂量下具有良好的耐受性,且无剂量限制性毒性。基于在1a/1b期单一疗法研究中对患者的药代动力学研究,在20mg/kg的RD下观察到的A-20502谷浓度预计对于B7-H4和FcγIIIa两者就亲和力而言将达到≥95%的受体饱和度。A-20502在≥0.3mg/kg的剂量下达到剂量成比例暴露,且半衰期为1至2周。在不同的肿瘤类型(乳腺、卵巢和子宫内膜)中,不论是否使用派姆单抗,20mg/kg时A-20502的血清浓度随时间推移均是相似的。
在组合研究中可使用其他剂量水平(例如0.1、0.3、1或20mg/kg),例如基于安全性、耐受性、客观应答、PK和药效学以及根据非临床数据推断的有效暴露量估算值。例如,可使用基于安全性数据的较低或中等剂量的A-20502。A-20502和派姆单抗的组合的DLT标准如下:
1a期剂量递增期间的DLT被定义为以下任何事件,无论归属如何(那些明显是由潜在疾病或外在原因引起的事件除外):
·在治疗的21天内发生任何3级或更高的非血液毒性(3级恶心、呕吐和腹泻除外)
·在治疗的前21天内发生3级恶心、呕吐、腹泻持续>72小时,尽管有最佳的支持性治疗
·在治疗的前21天内发生高热性中性粒细胞减少症和/或有绝对中性粒细胞计数(ANC)<1.0×109/L的记录感染、持续超过7天的4级中性粒细胞减少症、4级血小板减少症(<25.0×109/L)、或3级血小板减少症(<50.0–25.0×109/L)伴有出血
·天冬氨酸转氨酶/丙氨酸转氨酶(AST/ALT)>3×正常上限(ULN)和并发总胆红素>2×ULN,与癌症的肝脏受累无关
·任何4级实验值,不考虑临床后遗症
·根据研究者与申办者协议(Investigator and Sponsor agreement)不具有临床意义、72小时内未消解的其他3级实验值
A-20502和派姆单抗组合的具体DLT注意事项
·因为派姆单抗是已知的免疫检查点抑制剂,并且提议的A-20502作用机制之一是免疫检查点阻断,所以预计这种组合会发生免疫相关不良事件(irAE)。irAE被定义为病因不明的、与研究药物暴露相关的具有临床意义的AE,并且与免疫介导的机制一致。基于此背景,以下irAE的首次出现将不被视为DLT,因为它们有望通过免疫疗法治疗:
·3级燃瘤(tumor flare)(定义为处于已知或可疑肿瘤的部位处的局部疼痛、刺激或皮疹),
·3级皮疹
·在14天内消解至1级或以下的3级免疫相关不良事件(irAE)。
·短暂的(发作的6小时内消解)3级输注相关AE
在同一患者或不同患者中第二次发生这些事件(3级燃瘤除外)将被视为DLT。
DLT评估间隔在治疗的第一天开始输注后开始,并且持续21天。下表中概述的算法将适用于给药决策。响应于DLT,A-20502的剂量可以根据需要降低。A-20502与派姆单抗组合的MTD和/或RD将是≤1/3-6的患者发生DLT的剂量。
1a期中与派姆单抗组合时A-20502安全性导入的剂量递减决策的算法:
1b期组合扩展:
1b期可由通过IHC前瞻性地鉴定为具有B7-H4表达的队列组成。在某些实施方案中,有两个在以下选择的肿瘤类型中的A-20502组合派姆单抗的队列:
·队列1bC1:TNBC(A-20502与派姆单抗组合)
·队列1bC2:卵巢癌(A-20502与派姆单抗组合)
在另一个实施方案中,1b期组合有一个初始队列,并且诸如TNBC的其他队列可随后在1b期试验中招募:
·队列1bC1:卵巢癌(A-20502与派姆单抗组合)
在某些实施方案中,可添加多达3个另外的组合队列。
基于研究中新出现的可用临床和翻译数据,在试验期间可以开放将要用A-20502组合派姆单抗治疗的另外的肿瘤类型队列(例如,任何单个队列中的30位患者或更少)。
给药:在某些实施方案中,A-20502将在每个21天周期中的第1天,以60分钟(±5分钟)IV输注Q3W作为单一剂施用。A-20502的剂量将基于第1周期第1天(C1D1)的体重。第1个周期后,只要患者的体重相对于第1周期第1天已改变>10%,就将在每次输注回访时对A-20502剂量重新计算。
派姆单抗将以200mg的剂量通过30分钟(±5分钟)的IV输注在A-20502的IV输注完成后施用,在第1周期第1天开始并在每个21天周期的第1天重复Q3W。
A-20502与派姆单抗组合没有预先指定的最大剂量数。患者可以根据其研究指定的队列/剂量继续接受呈组合形式的两种药物,直到研究者评估疾病进展或患者符合任何其他协议规定的退出标准为止。如果患者停用两种药物中的一种,则患者可继续单独接受另一种药物。
如果益处/风险评估有利于研究治疗的继续施用(例如,如果患者继续经历如研究者评估的临床益处以及耐受的治疗),则根据Response Evaluation Criteria in SolidTumors 1.1版(RECIST v1.1),可对进行性疾病患者进行超出疾病进展的治疗。
研究持续时间:对个体患者的研究持续时间包括筛选(长达28天)、治疗和治疗结束(EOT)随访期,所述随访期包括最后一剂后的大约28(±7)天和100(±7)天时的回访。由于所有患者都有资格在疾病进展之前接受治疗,因此每位个体患者的实际治疗持续时间将根据其各自肿瘤类型的预计进展时间而有所不同。
此外,1b期剂量扩展中招募的患者将进行长达2年的生存期(LTFU,包括扫描和生存状态,Q12W)随访。
患者数量:此研究所计划的患者数量估计如下,但是此数量可以适当调整。
1a期可招募6至22位患者或10至22位患者,所述患者将在安全性导入中接受A-20502与派姆单抗的组合。将招募另外一个或两个评估A-20502与派姆单抗组合的队列,例如30位或更少的患者。
资格标准:
纳入标准:1a期纳入标准
招募进入1a期的患者的纳入标准如下:
1)经组织学确认的实体瘤,原发性中枢神经系统(CNS)肿瘤除外。
2)不可切除的、局部晚期的或转移性的疾病。
3)在任何研究特定的评估之前,能够理解并签署机构审查委员会/独立伦理委员会(IRB/IEC)批准的知情同意书(ICF)。
4)对已知为患者的疾患提供临床益处的现有疗法是难治或不耐受的。
5)根据RECIST v1.1,所有患者在基线时必须具有至少一个可测量的病变;除非已证实病变进展,否则不认为位于先前辐照区域或接受其他局部区域疗法的区域中的肿瘤部位是可测量的。
6)对于先前的抗癌疗法有足够的清洗期(即,从最后一次剂量起≥5个半衰期或4周,以较短者为准)。
7)是否有档案肿瘤组织并同意提供档案肿瘤用于回顾性生物标志物分析,或者如果没有档案组织,则患者必须在筛选期间进行新鲜肿瘤活检(对1a期剂量探索部分的患者要求进行活检)。
8)签署ICF时年龄≥18岁。
9)美国东部肿瘤协作组(ECOG)的体能状态评分为0或1。
10)研究者认为预期寿命为至少3个月。
11)愿意并能够遵守所有研究程序。
12)必须在第一剂研究药物之前至少2周完成先前的放疗。
13)必须在第一剂研究药物之前至少8周完成先前的放射性药物(例如锶、钐)。
14)必须在第一剂研究药物施用之前至少1周完成先前的需要全身麻醉的手术。必须在第一剂研究药物施用之前至少72小时完成需要局部/硬膜外麻醉的手术。患者必须从任何手术中康复。
15)筛选实验室值必须符合以下条件:
血液学
a.中性粒细胞≥1200个细胞/μL
b.血小板≥75×103/μL
c.血红蛋白(Hb)≥9.0g/dL
肾脏:
血清肌酐<1.5×ULN或肌酐清除率(CrCl)≥40mL/分钟(使用Cockcroft/Gault公式)
肝脏:
d.AST和ALT≤3×ULN(允许肝转移患者中AST和ALT<5×ULN)
e.胆红素<1.5×ULN(吉尔伯特综合症患者除外,这些患者必须总胆红素<3mg/dL)
16)第1周期第1天治疗前≤96小时血清β-人绒毛膜促性腺激素(β-hCG)妊娠试验阴性(仅限有生育能力的妇女)。
17)在性活跃的患者(有生育能力的妇女和男性)中,愿意使用2种有效的避孕方法,其中1种必须是物理屏障方法(避孕套、隔膜或宫颈/穹顶帽),直到最后一剂A-20502后的6个月。其他有效的避孕形式包括:
◆筛选前至少6个月进行永久绝育(子宫切除术和/或双侧卵巢切除术、或双侧输卵管结扎术或输精管切除术)
◆有生育能力的妇女,在研究前至少90天接受稳定的口服避孕疗法或宫内节育器或植入装置,或将放弃性行为作为生活方式
1b期的纳入标准如下:
18)1a期的所有纳入标准(例外:纳入标准#1)。
19)如通过附随的经过验证的中心实验室IHC测定所评估,档案或新鲜肿瘤样品中的B7-H4表达呈阳性。
20)允许其他恶性肿瘤的病史,前提是在过去2年内有过确定性治疗且无复发迹象(例外:允许在2年内有过确定性治疗的非黑素瘤皮肤癌、原位小叶癌和原位宫颈癌)。
1b期的另外的队列特定纳入标准
队列1bC1卵巢癌:
·经组织学或细胞学确认的对已知可提供临床益处的现有疗法而言难治的复发性上皮性卵巢癌、原发性腹膜癌或输卵管癌的诊断
·在至少两种先前治疗方案时或之后进行性疾病,包括至少一种含铂方案,或不能耐受另外的化学疗法
·之前未使用抗PD1或PD-L1定向药物进行治疗
队列1bC2 TNBC:
·经组织学或细胞学确认的转移性TNBC
·至少两个先前线的全身化学疗法,其中至少一个在转移性环境中施用
·之前未使用抗PD1或PD-L1定向药物进行治疗
资格标准:排除标准(1a期和1b期)
符合以下任一条件的患者可被排除在外:
1)必须在第一剂研究药物之前至少2周停止免疫抑制剂量的全身性药物,诸如类固醇或吸收的局部类固醇(剂量>10mg/天的泼尼松或每日等效剂量)。允许短期高剂量类固醇,持续低剂量(泼尼松<10mg/天),吸入、鼻内、眼内和关节内类固醇注射。
2)筛选时美国纽约心脏协会(NYHA)给出心脏功能下降>2级。
3)不受控制或严重的心脏病,诸如不稳定的心绞痛
4)筛选时,根据机构指南对心率校正的QT间隔(QTc)对于男性>450msec,或对于女性>470msec。
5)对之前生物试剂有抗药物抗体(ADA)、严重过敏、过敏性反应或其他输注相关的反应的病史。
6)对研究产品(IP)制剂的任何成分和/或对派姆单抗的已知超敏反应。
7)在第一剂研究药物前4周内的疫苗(例如人乳头瘤病毒[HPV]疫苗)。灭活的季节性流感疫苗可以在治疗之前和治疗期间无限制地给予患者。可允许含有活病毒的流感疫苗或其他临床上指定的用于传染病(即,气胸、水痘等)的疫苗接种,但必须与申办者的医学监察员(Sponsor’s Medical Monitor)讨论,并且在施用疫苗前后可能需要研究药物清洗期。
8)当前未消解的感染或有慢性、急性、具有临床意义的感染(病毒、细菌、真菌或其他)的病史,研究者认为其可能会将患者排除在暴露于生物试剂之外或可能对患者构成安全风险。
9)血清化学值异常的患者,研究者认为这些异常值具有临床意义。这包括表现出与其异常血清化学值有关的临床体征和症状的患者,以及血清化学值无症状但研究者认为具有临床意义的患者(例如,低钾血症或低钠血症)。
10)任何不受控制的医学疾患或精神病症,研究者认为其会对患者构成安全风险,或干扰研究的参与或对个别患者结果的解释。
11)怀孕或哺乳。
12)在过去2年中需要治疗的活跃的、已知的或可疑的自身免疫性疾病。患有I型糖尿病、仅需要激素替代的甲状腺功能减退、不需要全身治疗的皮肤病症(诸如白癜风、牛皮癣或脱发)或在没有外部触发的情况下预计不会复发的疾患的患者允许被招募。
13)人类免疫缺陷病毒(HIV)1或2测试呈阳性的已知病史或已知的获得性免疫缺陷综合症(AIDS)。
14)对乙型肝炎病毒表面抗原(HBsAg)测试阳性,或指示急性或慢性感染的可检测到的丙型肝炎病毒核糖核酸(HCV RNA)。
15)基于美国国家癌症研究所(NCI)不良事件通用术语标准(CTCAE),来自先前治疗>1级(2级脱发或周围神经病变除外)的持续不良反应。
16)有症状的间质性肺疾病或炎性肺炎。
17)未治疗的或活跃的CNS或软脑膜转移。如果已经对转移瘤进行治疗并且在第一剂研究药物之前至少2周,患者在神经学上恢复到基线或神经学稳定(与CNS治疗相关的残留体征或症状除外),则患者符合资格。
18)凝血病或出血素质的证据。允许患者接受稳定治疗剂量的抗凝剂。
19)在第一剂研究药物之前72小时内完成血液或血小板的输注。
20)任何不受控制的炎症性胃肠道(GI)疾病,包括克罗恩病和溃疡性结肠炎
测试和观察:安全性评估包括生命体征、体重、体格检查、ECOG评分、实验室测试(血液学、血清化学和尿液分析)、心电图(ECG)以及对不良事件(AE)和伴随药物的监测。
将收集档案肿瘤组织和提供档案肿瘤的同意书(或在筛选期间愿意进行新鲜肿瘤活检)用于生物标志物分析,以探索基线目标水平、肿瘤免疫表型与药效学应答之间的关系。
对于1a期剂量探索的所有患者和1b期剂量扩展的一部分患者(每30患者队列的多达15位患者)收集治疗前和治疗中的肿瘤组织,用于扩展的药效学分析。
功效评估可包括每6周进行一次的放射成像。将根据RECIST v1.1来评估应答。
统计方法
功效分析
ORR可以按每个剂量/队列在90%置信区间(CI)下的频率和百分比进行汇总。完全应答(CR)和部分应答(PR)患者的应答持续时间(DOR)可以按应答者数量、事件/删失的数量和百分比以及95%CI下中位DOR的Kaplan-Meier估计值进行汇总。经治疗患者的无进展生存期(PFS)可以按每个剂量/队列的PFS患者数量和百分比进行汇总。PFS也可使用95%CI下的Kaplan-Meier方法进行汇总。可以使用RECIST v1.1确定ORR、DOR和PFS。
药代动力学分析
可以将单个和平均值(±SD)血清A-20502浓度-时间数据按剂量水平/队列进行制表和绘图。适当和适用时,可将PK参数按剂量水平/队列进行制表和汇总。免疫原性对A-20502暴露的影响可以在数据允许的情况下按剂量水平/队列进行评估、制表和汇总。派姆单抗浓度-时间数据的单个和平均值(±SD)Cmax和C谷可按队列进行制表和绘图。如果数据可用,PK参数,诸如累积比和稳态的到达,可按剂量水平/队列进行制表和汇总。
免疫原性分析
基线ADA阳性受试者定义为在基线具有ADA阳性样品的受试者。ADA阳性受试者是指在治疗开始后相对于基线具有至少一个ADA阳性样品的受试者。可分别为A-20502和派姆单抗汇总基线ADA阳性受试者和治疗开始后ADA阳性受试者的频率分布。
药效学分析
对于选定的药效学生物标志物在治疗前和治疗中肿瘤与外周血样品之间的有意义的变化进行评估。
* * *
本发明的范围不受本文所述的具体实施方案限制。实际上,除所描述的那些以外,根据前述描述和附图,对发明的多种修改对于本领域技术人员来说将变得显而易见。此类修改意图属于所附权利要求的范围之内。
本文所引用的所有参考文献(例如,公布或专利或专利申请)均以引用的方式整体并入本文,并且出于所有目的,所述引用的程度就好像具体地且单独地出于所有的目的将每个单独的参考文献(例如,公布或专利或专利申请)以引用的方式整体并入。
其他实施方案在以下权利要求内。
序列表
<110> 戊瑞治疗有限公司(FIVE PRIME THERAPEUTICS, INC)
<120> 用于癌症的组合疗法
<130> 3986.018PC03
<150> US 62/854,494
<151> 2019-05-30
<150> US 62/802,091
<151> 2019-02-06
<150> US 62/745,464
<151> 2018-10-15
<160> 41
<170> PatentIn version 3.5
<210> 1
<211> 282
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser Ile Ile Ser Ile Ile
1 5 10 15
Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly Ile Ser
20 25 30
Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala Gly Asn Ile
35 40 45
Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu
50 55 60
Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val Leu Gly Leu Val
65 70 75 80
His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu Gln Asp Glu Met
85 90 95
Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Ile Val Gly Asn
100 105 110
Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr
115 120 125
Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu
130 135 140
Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Val Asn Val Asp Tyr Asn
145 150 155 160
Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln
165 170 175
Pro Thr Val Val Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser
180 185 190
Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met
195 200 205
Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser
210 215 220
Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val
225 230 235 240
Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn Ser
245 250 255
Lys Ala Ser Leu Cys Val Ser Ser Phe Phe Ala Ile Ser Trp Ala Leu
260 265 270
Leu Pro Leu Ser Pro Tyr Leu Met Leu Lys
275 280
<210> 2
<211> 282
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 食蟹猴B7-H4
<400> 2
Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser Ile Ile Ser Ile Ile
1 5 10 15
Phe Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly Ile Ser
20 25 30
Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala Gly Asn Ile
35 40 45
Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu
50 55 60
Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val Ile Gly Leu Val
65 70 75 80
His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu Gln Asp Glu Met
85 90 95
Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Ile Val Gly Asn
100 105 110
Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr
115 120 125
Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu
130 135 140
Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Val Asn Val Asp Tyr Asn
145 150 155 160
Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln
165 170 175
Pro Thr Val Val Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser
180 185 190
Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met
195 200 205
Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser
210 215 220
Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val
225 230 235 240
Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn Ser
245 250 255
Lys Ala Ser Leu Cys Val Ser Ser Phe Leu Ala Ile Ser Trp Ala Leu
260 265 270
Leu Pro Leu Ala Pro Tyr Leu Met Leu Lys
275 280
<210> 3
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 鼠类B7-H4
<400> 3
Met Ala Ser Leu Gly Gln Ile Ile Phe Trp Ser Ile Ile Asn Ile Ile
1 5 10 15
Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly Ile Ser
20 25 30
Gly Lys His Phe Ile Thr Val Thr Thr Phe Thr Ser Ala Gly Asn Ile
35 40 45
Gly Glu Asp Gly Thr Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu
50 55 60
Asn Gly Ile Val Ile Gln Trp Leu Lys Glu Gly Ile Lys Gly Leu Val
65 70 75 80
His Glu Phe Lys Glu Gly Lys Asp Asp Leu Ser Gln Gln His Glu Met
85 90 95
Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Val Val Gly Asn
100 105 110
Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr
115 120 125
Thr Cys Tyr Ile Arg Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu
130 135 140
Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Ile Asn Val Asp Tyr Asn
145 150 155 160
Ala Ser Ser Glu Ser Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln
165 170 175
Pro Thr Val Ala Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser
180 185 190
Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met
195 200 205
Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser
210 215 220
Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val
225 230 235 240
Thr Asp Ser Glu Val Lys Arg Arg Ser Gln Leu Gln Leu Leu Asn Ser
245 250 255
Gly Pro Ser Pro Cys Val Phe Ser Ser Ala Phe Val Ala Gly Trp Ala
260 265 270
Leu Leu Ser Leu Ser Cys Cys Leu Met Leu Arg
275 280
<210> 4
<211> 282
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 大鼠B7-H4
<400> 4
Met Ala Ser Leu Gly Gln Ile Ile Phe Trp Ser Ile Ile Asn Val Ile
1 5 10 15
Ile Ile Leu Ala Gly Ala Ile Val Leu Ile Ile Gly Phe Gly Ile Ser
20 25 30
Gly Lys His Phe Ile Thr Val Thr Thr Phe Thr Ser Ala Gly Asn Ile
35 40 45
Gly Glu Asp Gly Thr Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu
50 55 60
Asn Gly Ile Val Ile Gln Trp Leu Lys Glu Gly Ile Lys Gly Leu Val
65 70 75 80
His Glu Phe Lys Glu Gly Lys Asp Asp Leu Ser Gln Gln His Glu Met
85 90 95
Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Val Val Gly Asn
100 105 110
Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr
115 120 125
Thr Cys Tyr Ile His Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu
130 135 140
Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Ile Asn Val Asp Tyr Asn
145 150 155 160
Ala Ser Ser Glu Ser Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln
165 170 175
Pro Thr Val Ala Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser
180 185 190
Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met
195 200 205
Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser
210 215 220
Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val
225 230 235 240
Thr Asp Ser Glu Val Lys Arg Arg Ser Gln Leu Glu Leu Leu Asn Ser
245 250 255
Gly Pro Ser Pro Cys Val Ser Ser Val Ser Ala Ala Gly Trp Ala Leu
260 265 270
Leu Ser Leu Ser Cys Cys Leu Met Leu Arg
275 280
<210> 5
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH CDR1
<400> 5
Gly Ser Ile Lys Ser Gly Ser Tyr Tyr Trp Gly
1 5 10
<210> 6
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH CDR2
<400> 6
Asn Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Ser
1 5 10 15
<210> 7
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH CDR3
<400> 7
Ala Arg Glu Gly Ser Tyr Pro Asn Gln Phe Asp Pro
1 5 10
<210> 8
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL CDR1
<400> 8
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL CDR2
<400> 9
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL CDR3
<400> 10
Gln Gln Tyr His Ser Phe Pro Phe Thr
1 5
<210> 11
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH氨基酸
<400> 11
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Lys Ser Gly
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Asn Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Arg Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Ser Tyr Pro Asn Gln Phe Asp Pro Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 12
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL氨基酸
<400> 12
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr His Ser Phe Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH FR1
<400> 13
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
20 25
<210> 14
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH FR2
<400> 14
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 15
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH FR3
<400> 15
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
20 25 30
<210> 16
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH FR4
<400> 16
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 17
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL FR1
<400> 17
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 18
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL FR2
<400> 18
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 19
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL FR3
<400> 19
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 20
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL FR4
<400> 20
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 21
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 全长重链氨基酸
<400> 21
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Lys Ser Gly
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Asn Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Arg Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Ser Tyr Pro Asn Gln Phe Asp Pro Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 22
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 全长轻链氨基酸
<400> 22
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr His Ser Phe Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 23
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人κ轻链的恒定区
<400> 23
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 24
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 人κ轻链的恒定区
<400> 24
cggaccgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60
ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120
tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180
agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240
aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300
agcttcaaca ggggagagtg t 321
<210> 25
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人IgG1重链
<400> 25
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 26
<211> 990
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重链恒定结构域
<400> 26
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540
agcacgtacc gggtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960
cagaagagcc tctccctgtc tccgggtaaa 990
<210> 27
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码可变重链的核苷酸
<400> 27
cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcaaa agtggtagtt actactgggg ctggatccgc 120
cagcccccag ggaaggggct ggagtggatt gggaacatct attatagtgg gagcacctac 180
tacaacccgt ccctcagaag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240
tccctgaagc tgagttctgt gaccgccgca gacacggcgg tgtactactg cgccagagaa 300
ggatcttacc ccaatcagtt tgatccatgg ggacagggta cattggtcac cgtctcctca 360
<210> 28
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码可变轻链的核苷酸序列
<400> 28
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag taccactcct tccctttcac ttttggcgga 300
gggaccaagg ttgagatcaa a 321
<210> 29
<211> 385
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> B7-H4 IgV-huIgG1
<400> 29
Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser Ile Ile Ser Ile Ile
1 5 10 15
Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly Ile Ser
20 25 30
Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala Gly Asn Ile
35 40 45
Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu
50 55 60
Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val Leu Gly Leu Val
65 70 75 80
His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu Gln Asp Glu Met
85 90 95
Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Ile Val Gly Asn
100 105 110
Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr
115 120 125
Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu
130 135 140
Tyr Lys Thr Gly Ala Phe Ser Gly Ser Glu Pro Lys Ser Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Lys
385
<210> 30
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体重链
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 31
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体轻链
<400> 31
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
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 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 32
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VH氨基酸序列
<400> 32
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 33
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VL氨基酸序列
<400> 33
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
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 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 34
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VH-CDR1
<400> 34
Asn Tyr Tyr Met Tyr
1 5
<210> 35
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VH-CDR2
<400> 35
Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe Lys
1 5 10 15
Asn
<210> 36
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VH-CDR3
<400> 36
Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr
1 5 10
<210> 37
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VL-CDR1
<400> 37
Arg Ala Ser Lys Gly Val Ser Thr Ser Gly Tyr Ser Tyr Leu His
1 5 10 15
<210> 38
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VL-CDR2
<400> 38
Leu Ala Ser Tyr Leu Glu Ser
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗PD-1抗体VL-CDR3
<400> 39
Gln His Ser Arg Asp Leu Pro Leu Thr
1 5
<210> 40
<211> 288
<212> PRT
<213> 智人(Homo sapiens)
<400> 40
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp
20 25 30
Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys
180 185 190
Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro
195 200 205
Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly
210 215 220
Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro
225 230 235 240
Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly
245 250 255
Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg
260 265 270
Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu
275 280 285
<210> 41
<211> 290
<212> PRT
<213> 智人(Homo sapiens)
<400> 41
Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu
1 5 10 15
Asn Ala Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr
20 25 30
Gly Ser Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu
35 40 45
Asp Leu Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile
50 55 60
Ile Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser
65 70 75 80
Tyr Arg Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn
85 90 95
Ala Ala Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr
100 105 110
Arg Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val
115 120 125
Lys Val Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val
130 135 140
Asp Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr
145 150 155 160
Pro Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser
165 170 175
Gly Lys Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn
180 185 190
Val Thr Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr
195 200 205
Cys Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu
210 215 220
Val Ile Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His
225 230 235 240
Leu Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr
245 250 255
Phe Ile Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys
260 265 270
Gly Ile Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu
275 280 285
Glu Thr
290
Claims (53)
1.一种治疗人受试者的实体瘤的方法,所述方法包括向所述受试者施用(i)约0.1至约20mg/kg的抗B7-H4抗体或其抗原结合片段,所述抗体或其抗原结合片段特异性地结合至人B7-H4并且包含具有SEQ ID NO:5氨基酸序列的重链可变区(VH)互补决定区(CDR)1、具有SEQ ID NO:6氨基酸序列的VH CDR2、具有SEQ ID NO:7氨基酸序列的VH CDR3、具有SEQ IDNO:8氨基酸序列的轻链可变区(VL)CDR1、具有SEQ ID NO:9氨基酸序列的VL CDR2和具有SEQ ID NO:10氨基酸序列的VL CDR3;和(ii)约200mg的抗PD-1抗体或其抗原结合片段,所述抗体或其抗原结合片段包含具有SEQ ID NO:34氨基酸序列的VH CDR1、具有SEQ ID NO:35氨基酸序列的VH CDR2、具有SEQ ID NO:36氨基酸序列的VH CDR3、具有SEQ ID NO:37氨基酸序列的VL CDR1、具有SEQ ID NO:38氨基酸序列的VL CDR2和具有SEQ ID NO:39氨基酸序列的VL CDR3。
2.一种治疗人受试者中实体瘤的方法,所述方法包括向所述受试者施用
(a)药物组合物,所述药物组合物包含(i)抗B7-H4抗体或其抗原结合片段,其中所述抗B7-H4抗体或其抗原结合片段特异性地结合至人B7-H4并且包含具有SEQ ID NO:5氨基酸序列的VH CDR1、具有SEQ ID NO:6氨基酸序列的VH CDR2、具有SEQ ID NO:7氨基酸序列的VHCDR3、具有SEQ ID NO:8氨基酸序列的VL CDR1、具有SEQ ID NO:9氨基酸序列的VL CDR2和具有SEQ ID NO:10氨基酸序列的VL CDR3;和(ii)药学上可接受的赋形剂,
其中所述组合物中至少95%的所述抗B7-H4抗体或其抗原结合片段无岩藻糖基化,并且
其中施用约0.1至约20mg/kg的所述抗体或其抗原结合片段;和
(b)药物组合物,所述药物组合物包含抗PD-1抗体或其抗原结合片段,所述抗PD-1抗体或其抗原结合片段包含具有SEQ ID NO:34氨基酸序列的VH CDR1、具有SEQ ID NO:35氨基酸序列的VH CDR2、具有SEQ ID NO:36氨基酸序列的VH CDR3、具有SEQ ID NO:37氨基酸序列的VL CDR1、具有SEQ ID NO:38氨基酸序列的VL CDR2和具有SEQ ID NO:39氨基酸序列的VL CDR3;和药学上可接受的赋形剂,其中施用约200mg的所述抗体或抗原结合片段。
3.如权利要求1或2所述的方法,其中向所述受试者施用约20mg/kg的所述抗B7-H4抗体或其抗原结合片段。
4.如权利要求1或2所述的方法,其中向所述受试者施用约10mg/kg的所述抗B7-H4抗体或其抗原结合片段。
5.如权利要求1或2所述的方法,其中向所述受试者施用约3mg/kg的所述抗B7-H4抗体或其抗原结合片段。
6.如权利要求1或2所述的方法,其中向所述受试者施用约1mg/kg的所述抗B7-H4抗体或其抗原结合片段。
7.如权利要求1或2所述的方法,其中向所述受试者施用约0.3mg/kg的所述抗B7-H4抗体或其抗原结合片段。
8.如权利要求1或2所述的方法,其中向所述受试者施用约0.1mg/kg的所述抗B7-H4抗体或其抗原结合片段。
9.如权利要求1-8中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段和所述抗PD-1抗体或抗原结合片段同时施用。
10.如权利要求9所述的方法,其中所述抗B7-H4抗体或其抗原结合片段和所述抗PD-1抗体或抗原结合片段在同一天作为单独制剂施用。
11.如权利要求1-8中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段和所述抗PD-1抗体或其抗原结合片段依次施用。
12.如权利要求8所述的方法,其中在施用所述抗B7-H4抗体或其抗原结合片段之后,施用所述抗PD-1抗体或其抗原结合片段。
13.如权利要求1-12中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段约每三周施用一次。
14.如权利要求1-12中任一项所述的方法,其中所述抗PD-1抗体或其抗原结合片段约每三周施用一次。
15.如权利要求1-12中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段和所述抗PD-1抗体或其抗原结合片段各自约每三周施用一次。
16.如权利要求1-15中任一项所述的方法,其中静脉内施用所述抗B7-H4抗体或其抗原结合片段。
17.如权利要求1-16中任一项所述的方法,其中静脉内施用所述抗PD-1抗体或其抗原结合片段。
18.如权利要求1-17中任一项所述的方法,其中在施用之前已经使用免疫组织化学(IHC)在所述实体瘤中检测到B7-H4。
19.如权利要求1-18中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段包含VH和/或VL,所述VH包含SEQ ID NO:11中列出的氨基酸序列,所述VL包含SEQ ID NO:12中列出的氨基酸序列。
20.如权利要求1-19中任一项所述的方法,其中所述抗B7-H4抗体或抗原结合片段包含重链恒定区和/或轻链恒定区。
21.如权利要求20所述的方法,其中所述重链恒定区是人免疫球蛋白IgG1重链恒定区,和/或其中所述轻链恒定区是人免疫球蛋白IgGκ轻链恒定区。
22.如权利要求1-21中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段包含重链恒定区和/或轻链恒定区,所述重链恒定区包含SEQ ID NO:25中列出的氨基酸序列,所述轻链恒定区包含SEQ ID NO:23中列出的氨基酸序列。
23.如权利要求1-22中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段包含重链和/或轻链,所述重链包含SEQ ID NO:21中列出的氨基酸序列,所述轻链包含SEQ IDNO:22中列出的氨基酸序列。
24.如权利要求1-23中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段是人抗体或其抗原结合片段。
25.如权利要求1和3-24中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段无岩藻糖基化。
26.如权利要求1-25中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段是全长抗体。
27.如权利要求1-25中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段是抗原结合片段。
28.如权利要求27所述的方法,其中所述抗原结合片段包含Fab、Fab’、F(ab’)2、单链Fv(scFv)、二硫键连接的Fv、V-NAR结构域、IgNar、胞内抗体、IgGΔCH2、微型抗体、F(ab’)3、四价抗体、三价抗体、二价抗体、单结构域抗体、DVD-Ig、Fcab、mAb2、(scFv)2或scFv-Fc。
29.如权利要求2-29中任一项所述的方法,其中所述抗B7-H4抗体或其抗原结合片段的岩藻糖基化在所述组合物中不可检测到。
30.如权利要求1-29中任一项所述的方法,其中所述抗PD-1抗体或抗原结合片段包含VH和VL,所述VH包含SEQ ID NO:32的氨基酸序列,所述VL包含SEQ ID NO:33的氨基酸序列。
31.如权利要求1-30中任一项所述的方法,其中所述抗PD-1抗体或抗原结合片段是派姆单抗。
32.如权利要求31所述的方法,其中所述方法包括施用200mg的派姆单抗。
33.如权利要求1-32中任一项所述的方法,其中所述方法包括向所述受试者施用(i)3、10或20mg/kg的抗B7-H4抗体或其抗原结合片段,所述抗体或其抗原结合片段特异性地结合至人B7-H4并且包含具有SEQ ID NO:11中列出的氨基酸序列的VH和具有SEQ ID NO:12中列出的氨基酸序列的VL,其中所述抗B7-H4抗体或抗原结合片段是未检测到岩藻糖基化的;和(ii)200mg的派姆单抗;其中(i)和(ii)在同一天作为单独制剂静脉内施用。
34.如权利要求33所述的方法,其中所述抗B7-H4抗体包含重链和轻链,所述重链包含SEQ ID NO:21中列出的氨基酸序列,所述轻链包含SEQ ID NO:22中列出的氨基酸序列。
35.如权利要求1-34中任一项所述的方法,其中所述实体瘤表达B7-H4。
36.如权利要求1-35中任一项所述的方法,其中所述实体瘤是不可切除的、局部晚期的或转移性的。
37.如权利要求1-36中任一项所述的方法,其中所述实体瘤选自由以下组成的组:乳腺癌、导管癌、子宫内膜癌、卵巢癌、尿路上皮癌、非小细胞肺癌、胰腺癌、甲状腺癌、肾癌和膀胱癌。
38.如权利要求37所述的方法,其中所述实体瘤是乳腺癌或卵巢癌。
39.如权利要求38所述的方法,其中所述实体瘤是乳腺癌。
40.如权利要求39所述的方法,其中所述乳腺癌是晚期乳腺癌。
41.如权利要求38-40中任一项所述的方法,其中所述乳腺癌是三阴性乳腺癌。
42.如权利要求38-40中任一项所述的方法,其中所述乳腺癌是激素受体(HR)阳性乳腺癌。
43.如权利要求37所述的方法,其中所述非小细胞肺癌是鳞状细胞癌。
44.如权利要求1-43中任一项所述的方法,其中所述患者未接受过使用PD-1/PD-L1拮抗剂的先前疗法。
45.如权利要求1-44中任一项所述的方法,其中所述方法还包括监测所述肿瘤中的免疫细胞的数量。
46.如权利要求1-44中任一项所述的方法,其中所述方法还包括监测所述肿瘤中的自然杀伤(NK)细胞、CD4+细胞和/或CD8+细胞的数量。
47.如权利要求1-47中任一项所述的方法,其中方法还包括监测所述受试者中的细胞因子水平。
48.如权利要求1-47中任一项所述的方法,其中所述方法还包括监测所述受试者中的IL-2、IL-6、IL-10、TNF和/或干扰素γ(IFNγ)水平。
49.一种治疗人受试者的实体瘤的方法,所述方法包括向所述受试者施用(i)约20mg/kg的抗B7-H4抗体,所述抗体特异性地结合至人B7-H4并且包含具有SEQ ID NO:11的氨基酸序列的VH和具有SEQ ID NO:12的氨基酸序列的VL;和(ii)约200mg的抗PD-1抗体,所述抗体包含具有SEQ ID NO:32的氨基酸序列的VH和具有SEQ ID NO:33的氨基酸序列的VL,其中所述抗B7-H4抗体和所述抗PD-1抗体约每三周静脉内施用一次。
50.一种治疗人受试者的实体瘤的方法,所述方法包括向所述受试者施用
(a)药物组合物,所述药物组合物包含(i)抗B7-H4抗体,所述抗体特异性地结合至人B7-H4并且包含具有SEQ ID NO:11的氨基酸序列的VH和具有SEQ ID NO:12的氨基酸序列的VL,和(ii)药学上可接受的赋形剂,
其中所述组合物中至少95%的所述抗B7-H4抗体无岩藻糖基化,并且
其中施用约20mg/kg的所述抗体;和
(b)药物组合物,所述药物组合物包含抗PD-1抗体或其抗原结合片段,所述抗PD-1抗体或其抗原结合片段包含具有SEQ ID NO:32的氨基酸序列的VH和具有SEQ ID NO:33的氨基酸序列的VL,和药学上可接受的赋形剂,其中施用约200mg的所述抗体或抗原结合片段,
其中所述抗B7-H4抗体和所述抗PD-1抗体约每三周静脉内施用一次。
51.如权利要求49或50所述的方法,其中所述抗B7-H4抗体包含重链和轻链,所述重链包含SEQ ID NO:21中列出的氨基酸序列,所述轻链包含SEQ ID NO:22中列出的氨基酸序列。
52.如权利要求49-51中任一项所述的方法,其中所述抗PD-1抗体包含重链和轻链,所述重链包含SEQ ID NO:30中列出的氨基酸序列,所述轻链包含SEQ ID NO:31中列出的氨基酸序列。
53.如权利要求49-53中任一项所述的方法,其中所述实体瘤是乳腺癌或卵巢癌,任选地其中所述乳腺癌是三阴性乳腺癌。
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CA3091801A1 (en) | 2018-03-02 | 2019-09-06 | Five Prime Therapeutics, Inc. | B7-h4 antibodies and methods of use thereof |
CA3229113A1 (en) * | 2020-08-18 | 2022-02-24 | Abl Bio, Inc. | Anti-b7-h4/anti-4-1bb bispecific antibodies and use thereof |
BR112023013263A2 (pt) | 2021-01-04 | 2023-12-12 | Mersana Therapeutics Inc | Conjugados anticorpo-fármaco alvejados a b7h4 e métodos de uso dos mesmos |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US6174666B1 (en) | 1992-03-27 | 2001-01-16 | The United States Of America As Represented By The Department Of Health And Human Services | Method of eliminating inhibitory/instability regions from mRNA |
DK2180007T4 (da) | 1998-04-20 | 2017-11-27 | Roche Glycart Ag | Glycosyleringsteknik for antistoffer til forbedring af antistofafhængig cellecytotoxicitet |
PT1176195E (pt) | 1999-04-09 | 2013-07-18 | Kyowa Hakko Kirin Co Ltd | Processo para controlar a actividade de uma molécula funcional sob o ponto de vista imunológico |
AU7950400A (en) | 1999-10-19 | 2001-04-30 | Kyowa Hakko Kogyo Co. Ltd. | Process for producing polypeptide |
PT1522590E (pt) | 2000-06-28 | 2009-10-26 | Glycofi Inc | Métodos para a produção de glicoproteínas modificadas |
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US6946292B2 (en) | 2000-10-06 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Cells producing antibody compositions with increased antibody dependent cytotoxic activity |
EP3263702A1 (en) | 2000-10-06 | 2018-01-03 | Kyowa Hakko Kirin Co., Ltd. | Cells producing antibody compositions |
EP2298809A3 (en) | 2001-07-12 | 2012-02-15 | FOOTE, Jefferson | Super humanized antibodies |
MXPA04001072A (es) | 2001-08-03 | 2005-02-17 | Glycart Biotechnology Ag | Variantes de glicosilacion de anticuerpos que tienen citotoxicidad celulares dependiente de anticuerpos incrementada. |
JP4532118B2 (ja) | 2002-03-19 | 2010-08-25 | スティヒティング ディーンスト ランドバウクンディフ オンデルズーク | 植物体内のグリカンプロセシングの最適化 |
US20040014194A1 (en) | 2002-03-27 | 2004-01-22 | Schering Corporation | Beta-secretase crystals and methods for preparing and using the same |
EP2264151B1 (en) | 2003-01-22 | 2016-04-20 | Roche Glycart AG | Fusion constructs and use of same to produce antibodies with increased FC receptor binding affinity and effector function |
RU2007145509A (ru) | 2005-05-09 | 2009-06-20 | Гликарт Биотехнологи Аг (Ch) | Антигенсвязывающие молекулы, имеющие модифицированные fc-участки и измененное связывание с fc-рецепторами |
CA2637254A1 (en) | 2006-01-17 | 2007-07-26 | Biolex Therapeutics, Inc. | Compositions and methods for humanization and optimization of n-glycans in plants |
US7846724B2 (en) | 2006-04-11 | 2010-12-07 | Hoffmann-La Roche Inc. | Method for selecting CHO cell for production of glycosylated antibodies |
CL2008003526A1 (es) * | 2007-11-30 | 2010-01-11 | Medarex Inc | Conjugado de anticuerpo-molécula asociada que comprende un anticuerpo monoclonal humano anti b7-h4/08e/b7x/b7s1/bl-cam/b3/leu-14/lyb-8 humana; composición que lo comprende; método in vitro de inhibición de célula tumoral que expresa b7-h4/08e/b7x/b7s1/bl-cam/b3/leu-14/lyb-8; y uso para tratar cancer. |
EP3590965A1 (en) | 2011-03-29 | 2020-01-08 | Roche Glycart AG | Antibody fc variants |
US9562099B2 (en) * | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
NZ715201A (en) | 2013-08-01 | 2021-12-24 | Five Prime Therapeutics Inc | Afucosylated anti-fgfr2iiib antibodies |
CN113698488A (zh) * | 2014-09-12 | 2021-11-26 | 基因泰克公司 | 抗-b7-h4抗体及免疫缀合物 |
JP2019503349A (ja) * | 2015-12-17 | 2019-02-07 | ノバルティス アーゲー | Pd−1に対する抗体分子およびその使用 |
AU2017373944B2 (en) * | 2016-12-07 | 2022-02-03 | Agenus Inc. | Anti-CTLA-4 antibodies and methods of use thereof |
CN110300599A (zh) * | 2016-12-07 | 2019-10-01 | 艾吉纳斯公司 | 抗体和其使用方法 |
BR112020003533A2 (pt) * | 2017-08-25 | 2020-11-17 | Five Prime Therapeutics, Inc. | anticorpos b7-h4 e métodos de uso dos mesmos |
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