CN112279918A - Cd73抗体及其用途 - Google Patents
Cd73抗体及其用途 Download PDFInfo
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- CN112279918A CN112279918A CN202011018748.6A CN202011018748A CN112279918A CN 112279918 A CN112279918 A CN 112279918A CN 202011018748 A CN202011018748 A CN 202011018748A CN 112279918 A CN112279918 A CN 112279918A
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Abstract
本发明公开了一种分离的抗体或抗原结合片段及其用途,其中所述抗体或抗原结合片段对人CD73蛋白具有特异性,并与选自人CD73蛋白C端一半部分的一个或多个氨基酸残基结合,所述一个或多个氨基酸残基选自Y345、D399、E400、R401和R480。本发明还公开了一种组合物,所述组合物包含所述分离的抗体或抗原结合片段和药学上可接受的载体;以及一种分离的细胞,所述分离的细胞包含编码所述分离的抗体或抗原结合片段的一种或多种多核苷酸。
Description
背景技术
CD73,分化簇73,也称为5'-核苷酸酶(5'-NT)或胞外-5'-核苷酸酶,是一种将AMP转化为腺苷的酶。CD73催化细胞外腺苷的形成,其有助于免疫抑制性的肿瘤环境。CD73 在基质细胞和多种类型的肿瘤细胞以及Treg、和髓源性抑制细胞(MDSC)中过表达。
临床前证据显示,CD73的抑制阻止了腺苷介导的淋巴细胞的抑制,增加了CD8+效应细胞的活性,并减少了MDSC和Treg。有一些CD73抗体正在被开发为潜在的抗癌药物,但没有一个被批准在临床使用。
发明内容
本发明提供了CD73抗体,无论是单独存在还是存在于细胞上,其对人CD73蛋白具有高结合的亲和力,并且具有抑制CD73酶活的强效活性。此外,这些抗体的结合可诱导CD73的肿瘤细胞内化,导致细胞表面上的CD73活性进一步降低。同样令人惊讶的是,这些抗体的单价单位例如Fab片段,其具有的效力与全部抗体相当。然而已知的CD73抗体,例如来自Medimmune的MEDI-9447,则不具有这样的特征。同样地,与需要细胞表面高密度表达CD73以显示其抑制作用的MEDI-9447和11F11不同,本发明的抗体在细胞表面表达的不同水平都可达到完全的CD73抑制。本发明公开的抗体的这些令人惊讶和出乎意料的性质被认为至少部分归因于CD73蛋白上独特的结合位点。与结合CD73蛋白的N末端结构域的MEDI-9447和11F11不同,本发明公开的抗体结合其C末端结构域,尤其是结合氨基酸残基Y345、D399、E400、R401和R480。本发明公开的抗体的这些性质使其成为用于治疗和诊断用途的优秀候选者。
因此,本发明的一个实施例提供了一种分离的抗体或其片段,其对人CD73蛋白具有特异性,并与选自人CD73蛋白C端部分的一个或多个氨基酸残基结合。根据本领域公知常识,人CD73蛋白的C端部分包含从如SEQ ID NO:61所示的第337位残基开始的238个氨基酸残基。
在一些实施例中,抗体或其片段与人CD73蛋白的一个或多个C端结构域结合。在一些实施例中,抗体或其片段与选自由人CD73蛋白的Y345、D399、E400、R401和R480 组成的组中的至少一个氨基酸残基结合。在一些实施例中,抗体或其片段与至少两个氨基酸残基结合。
本发明的一个实施例提供了一种CD73抗体或其片段,其包含如SEQ ID NO:1所示的VH CDR1、如SEQ ID NO:1所示的VH CDR2、如SEQ ID NO:3所示的VH CDR3、如SEQ ID NO:4所示的VL CDR1、如SEQ ID NO:5所示的VL CDR2和如SEQ ID NO:6所示的VL CDR3。在一些实施例中,抗体或其片段可进一步包含重链恒定区、轻链恒定区、Fc区或其组合。在一些实施例中,轻链恒定区是κ链或λ链恒定区。在一些实施例中,抗体或其片段是IgG、IgM、IgA、IgE或IgD的其中一种同种型,或更具体为 IgG1、IgG2、IgG3或IgG4。
在一些实施例中,抗体或其片段是嵌合抗体、人源化抗体或全人源抗体。在一个实施例中,抗体或其片段是人源化抗体。
在一些实施例中,全人源或人源化抗体或其片段具有重链可变区,所述重链可变区包含选自下述组的一个或多个根据Kabat编号的氨基酸残基及其组合,所述组由:(a)第30位的Thr,(b)第44位的Lys,(c)第48位的Met,(d)第67位的Ile和(e)第71 位的Arg组成。在一些实施例中,全人源或人源化抗体或其片段具有轻链可变区,所述轻链可变区包含选自下述组的一个或多个根据Kabat编号的氨基酸残基及其组合,所述组由:(a)第5位的Ser,(b)第46位的Pro,(c)第47位的Trp,(d)第49位的Ser, (e)第70位的Ser和(f)第71位的Tyr组成。
因此,实例CD73抗体或其片段包括具有重链可变区的那些抗体或其片段,所述重链可变区包含选自由SEQ ID NO:7和9~13组成的组所示的氨基酸序列,或其序列与选自由SEQ ID NO:7和9~13组成的组所示的氨基酸序列至少有90%同一性的肽。在一些实施例中,重链可变区包含如SEQ ID NO:7或9所示的氨基酸序列。在一些实施例中,抗体或其片段包含轻链可变区,所述轻链可变区包含选自由SEQ ID NO:8、15~20和 22~24组成的组所示的氨基酸序列,或其序列与选自由SEQ ID NO:8、15~20和22~24 组成的组所示的氨基酸序列至少有90%同一性的肽。在一些实施例中,轻链可变区包含如SEQ ID NO:8所示的氨基酸序列。
如实验性实施例7所示,CDR区域可以容纳某些氨基酸的添加、缺失或取代,其能够保留甚至改善CD73抗体的特性。因此,在一些实施例中提供了一种分离的抗体或其片段,其中所述抗体或其片段对人CD73蛋白具有特异性,并且包含:(a)如SEQ ID NO: 1或SEQ IDNO:1的变体所示的VH CDR1,所述SEQ ID NO:1的变体在SEQ ID NO: 1序列的第1、2或3位有单一位点的取代、缺失或插入;(b)如SEQ ID NO:2或SEQ ID NO:2的变体所示的VH CDR2,所述SEQ ID NO:2的变体在SEQ ID NO:2序列的第6、7或8位有单一位点的取代、缺失或插入;(c)如SEQ ID NO:3或SEQ ID NO:3的变体所示的VH CDR3,所述SEQ ID NO:3的变体在SEQID NO:3的第7或8位有单一位点的取代、缺失或插入;(d)如SEQ ID NO:4或SEQ ID NO:4的变体所示的 VL CDR1,所述SEQ ID NO:4的变体在SEQ ID NO:4的第3或4位有单一位点的取代、缺失或插入;(e)如SEQ ID NO:5所示的VL CDR2,和(f)如SEQ ID NO:6或 SEQ ID NO:6的变体所示的VL CDR3,所述SEQ ID NO:6的变体在SEQ ID NO:6的第1、2、3或4位有单一位点的取代、缺失或插入。
在一些实施例中提供了一种分离的抗体或其片段,其中所述抗体或其片段对人CD73 蛋白具有特异性,并且包含:(a)如SEQ ID NO:1或SEQ ID NO:1的变体所示的VHCDR1,所述SEQ ID NO:1的变体在SEQ ID NO:1序列的第1、2或3位有单一位点的取代;(b)如SEQ ID NO:2或SEQ ID NO:2的变体所示的VH CDR2,所述SEQ ID NO:2的变体在SEQ ID NO:2序列的第6、7或8位有单一位点的取代;(c)如SEQ ID NO:3或SEQ ID NO:3的变体所示的VHCDR3,所述SEQ ID NO:3的变体在SEQ ID NO:3的第7或8位有单一位点的取代;(d)如SEQ IDNO:4或SEQ ID NO:4的变体所示的VL CDR1,所述SEQ ID NO:4的变体在SEQ ID NO:4的第3或4位有单一位点的取代;(e)如SEQ ID NO:5所示的VL CDR2,和(f)如SEQ ID NO:6或SEQID NO:6的变体所示的VL CDR3,所述SEQ ID NO:6的变体在SEQ ID NO:6的第 1、2、3或4位有单一位点的取代。
在一些实施例中,SEQ ID NO:1的变体选自由SEQ ID NO:26~29组成的组。在一些实施例中,SEQ ID NO:2的变体选自由SEQ ID NO:30~36组成的组。在一些实施例中,SEQID NO:3的变体选自由SEQ ID NO:37~41组成的组。在一些实施例中,SEQ ID NO:4的变体选自由SEQ ID NO:42~45组成的组。在一些实施例中,SEQ ID NO: 6的变体选自由SEQ IDNO:46~56组成的组。
在一些实施例中,还提供了一种组合物,其包含本发明的抗体或其片段和药学上可接受的载体。此外还提供了一种分离的细胞,其包含编码本发明的抗体或其片段的一种或多种多核苷酸。
在另一个实施例中,本发明提供了一种治疗有需要的患者中癌症的方法,其包括向所述患者施用本发明的抗体或其片段。在一些实施例中,所述癌症选自由膀胱癌、乳腺癌、结直肠癌、子宫内膜癌、食管癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、胰腺癌、前列腺癌和甲状腺癌组成的组。在一些实施例中,所述癌症是实体瘤。
在一些实施例中,所述方法还包括向患者施用第二种癌症治疗剂。在一些实施例中,第二种癌症治疗剂是免疫检查点抑制剂。在一些实施例中,所述抑制剂抑制程序性细胞死亡蛋白1(PD-1)、程序性死亡配体1(PD-L1)、细胞毒性T淋巴细胞相关蛋白4(CTLA- 4)、淋巴细胞活化蛋白3(LAG-3)或其组合的表达或活性。在一些实施例中,所述抑制剂是抗PD-1或抗PD-L1抗体。在一些实施例中,所述抑制剂选自由派姆单抗、纳武单抗、J43、RMP1-14、阿特朱单抗、伊匹单抗及其组合组成的组。
在一个实施例中,提供了治疗有需要的患者中癌症的方法,其包括:(a)用本发明的抗体或其片段在体外处理T细胞;和(b)将处理后的T细胞施用于患者体内。在一些实施例中,该方法还包括在步骤(a)之前从个体分离出T细胞。
在一些实施例中,所述T细胞是从患者体内分离出来。在一些实施例中,所述T细胞是从不同于患者的供体个体中分离出来。在一些实施例中,所述T细胞是肿瘤浸润性 T淋巴细胞、CD4+ T细胞、CD8+ T细胞或其组合。
在另一个实施例中,还提供了一种检测样品中CD73表达的方法,其包括将样品与本发明的抗体或其片段接触,使得所述抗体或其片段结合CD73,并检测反映样品中CD73 的表达量的结合。在一个实施例中,还提供了一种鉴定适合用抗CD73疗法治疗的癌症患者的方法,其包括从癌症患者分离出细胞,并用本发明的抗体或其片段检测CD73蛋白质的存在。
附图说明
图1显示了101-Mu抗体与重组人CD73蛋白的结合。
图2显示了101-Mu抗体与人卵巢癌细胞表面上的重组人CD73蛋白的结合。
图3显示了101-Mu抗体与重组CD73蛋白的结合动力学。
图4显示101-Mu抗体抑制了CD73的酶活。
图5显示101-Mu抗体抑制了细胞表面的CD73的酶活。
图6显示如IFN-γ的产生所示,101-Mu逆转了AMP介导的CD4+ T细胞抑制。
图7显示了人源化抗体的结合动力学。
图8显示了人源化抗体与细胞表面CD73蛋白结合。
图9显示人源化抗体抑制了CD73蛋白的酶活。
图10显示人源化抗体抑制细胞表面CD73蛋白的酶活。
图11显示如IFN-γ的产生所示,人源化抗体逆转了AMP介导的对CD4+ T细胞的抑制作用。
图12显示了Hu101-28与可溶性的和细胞表面的CD73的有效结合。
图13显示了Hu101-28与CD73的结合有效地阻断了CD73的酶活。
图14显示了Hu101-28非竞争性地抑制CD73的活性。
图15显示Hu101-28与CD73的结合诱导了CD73的内化。
图16显示Hu101-28逆转了AMP介导的T细胞应答抑制。
图17显示Hu101-28逆转了CD73+肿瘤细胞介导的T细胞应答抑制。
图18显示在A375肿瘤异种移植模型中Hu101-28抑制了体内CD73酶的染色图。
图19显示了在肿瘤异种移植模型中Hu101-28表现出单一的疗效。
图20显示了Hu101-28与抗PD-L1抗体在抑制肿瘤生长中的协同作用。
图21显示了Hu101-28对食蟹猴CD73活性的结合和抑制。
图22显示了Hu101-28结合CD73时不与MEDI-9447发生竞争。
图23列出了与Hu101-28相互作用的CD73的氨基酸残基。
图24显示了Hu101-28和MEDI-9447的表位。
图25显示了与MEDI-9447相比,Hu101-28的优越活性。
图26显示了Hu101-28在抑制具有不同CD73表达水平的细胞上的CD73方面是有效的。
具体实施方式
定义
应当注意的是,术语“一种”实体是指一种或多种该实体,例如“一种抗体”应当被理解为一种或多种抗体,因此,术语“一种”(或“一个”)、“一种或多种”和“至少一种”可以在本文中互换使用。
在本发明中,术语“多肽”旨在涵盖单数的“多肽”以及复数的“多肽”,并且是指由通过酰胺键(也称为肽键)线性连接的单体(氨基酸)组成的分子。术语“多肽”是指两个或更多个氨基酸的任何单条链或多条链,并且不涉及产物的特定长度。因此,“多肽”的定义中包括肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于指两个或多个氨基酸链的任何其他术语,并且术语“多肽”可以用来代替上述任何一个术语,或者与上述任何一个术语交替使用。术语“多肽”也旨在指多肽表达后修饰的产物,包括但不限于糖基化、乙酰化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割或非天然发生的氨基酸修饰。多肽可以源自天然生物来源或通过重组技术产生,但其不必从指定的核酸序列翻译所得。它可能以包括化学合成的任何方式产生。
本发明中关于细胞、核酸例如DNA或RNA所使用的术语“分离的”,是指分别与存在于大分子的天然来源中的其它DNA或RNA所分离的分子。本发明使用的术语“分离的”还指当通过重组DNA技术生产时基本上不含细胞材料、病毒材料或培养基,或化学合成时的化学前体或其他化学品的核酸或肽。此外,“分离的核酸”意在包括不以天然状态存在的核酸片段,并且不会以天然状态存在。术语“分离的”在本发明中也用于指从其他细胞蛋白质或组织分离的细胞或多肽。分离的多肽意在包括纯化的和重组的多肽。
在本发明中,术语“重组”涉及多肽或多核苷酸,意指非天然存在的多肽或多核苷酸的形式,其非限制性实施例可以通过组合产生通常并不存在的多核苷酸或多肽。
“同源性”或“同一性”或“相似性”是指两个肽之间或两个核酸分子之间的序列相似性。可以通过比较每个序列中可以比对的位置来确定同源性。当被比较的序列中的位置被相同的碱基或氨基酸占据时,则分子在该位置是同源的。序列之间的同源程度是由序列共有的匹配或同源位置的数目组成的一个函数。术语“不相关的”或“非同源的”序列表示与本发明公开的序列之一有小于40%的同一性,但优选小于25%的同一性。
多核苷酸或多核苷酸区域(或多肽或多肽区域)与另一序列有具有一定百分比(例如,60%、65%、70%、75%、80%、85%、90%、95%、98%或者99%)的“序列同一性”是指当序列比对时,所比较的两个序列中该百分比的碱基(或氨基酸)相同。该比对和同源性百分比或序列同一性可以使用本领域已知的软件程序,比如Ausubelet al.eds. (2007)在Current Protocols in Molecular Biology中所述的软件程序来确定。优选使用默认参数进行比对。其中一种比对程序是使用默认参数的BLAST。特别地,程序是BLASTN 和BLASTP,两者使用下列默认参数:Geneticcode=standard;filter=none;strand=both; cutoff=60;expect=10;Matrix=BLOSUM62;Descriptions=50sequences;sortby=HIGHSCORE;Databases=non-redundant;GenBank+EMBL+DDBJ+PDB+GenBankCDStranslations+SwissProtein+SPupdate+PIR。生物学上等同的多核苷酸是具有上述指定百分比的同源性并编码具有相同或相似生物学活性的多肽的多核苷酸。
术语“等价的核酸或多核苷酸”是指具有与核酸或其互补序列的核苷酸序列具有一定程度的同源性或序列同一性的核苷酸序列的核酸。双链核酸的同源物意指包括具有与其或其互补序列具有一定同源性的核苷酸序列的核酸。一方面,核酸的同源物能够与核酸或其互补序列杂交。同样地,“等价的多肽”是指与参考多肽的氨基酸序列具有一定同源性或序列同一性的多肽。在某些方面,序列同一性为至少约70%、75%、80%、85%、 90%、95%、98%或99%。在某些方面,与参考的多肽或多核苷酸相比,等价的多肽或多核苷酸具有1、2、3、4或5个添加、缺失、取代及其组合。在某些方面,等价的序列保留参考序列的活性(例如表位结合)或结构(例如盐桥)。
杂交反应可以在不同的“严谨性”条件下进行。通常在约40℃条件下,在约10×SSC或相同等离子强度/温度的溶液中进行低严谨的杂交反应。通常在约50℃条件下,在约6 ×SSC中进行中度严谨的杂交反应,通常在约60℃条件下,在约1×SSC中进行高度严谨的杂交反应。杂交反应也可以在本领域技术人员熟知的“生理条件”下进行。生理条件的非限制性实施例指在细胞中通常存在的温度、离子强度、pH和Mg2+浓度。
多核苷酸由四个核苷酸碱基的特定序列组成:腺嘌呤(A)、胞嘧啶(C)、鸟嘌呤(G)、胸腺嘧啶(T)、和当多核苷酸是RNA时胸腺嘧啶置换为尿嘧啶(U)。因此,术语“多核苷酸序列”是多核苷酸分子的字母表示。该字母表示可以被输入到具有中央处理单元的计算机中的数据库中,并用于生物信息学应用,例如用于功能基因组学和同源性搜索。术语“多态性”是指多种形式的基因或其部分的共存,具有至少两种不同形式(即两种不同的核苷酸序列)的基因的一部分被称为“基因的多态性区域”。多态性区域可以是单核苷酸,在不同的等位基因中其具有不同的同一性。
术语“多核苷酸”和“寡核苷酸”可互换使用,是指无论是脱氧核糖核苷酸还是核糖核苷酸或其类似物的任何长度的核苷酸的聚合形式。多核苷酸可以具有任何三维结构并且可以执行已知或未知的任何功能。以下是非限制性的多核苷酸的实施例:基因或基因片段(例如探针、引物、EST或SAGE标签)、外显子、内含子、信使RNA(mRNA)、转运RNA、核糖体RNA、核糖酶、cDNA、dsRNA、siRNA、miRNA、重组多核苷酸、分支的多核苷酸、质粒、载体、任何序列的分离的DNA、任何序列的分离的RNA、核酸探针和引物。多核苷酸可以包含修饰的核苷酸,例如甲基化的核苷酸和核苷酸类似物。如果存在该修饰,则对核苷酸的结构修饰可以在组装多核苷酸之前或之后进行。核苷酸的序列可以被非核苷酸组分中断。聚合后可以进一步修饰多核苷酸,例如通过与标记组分缀合。这个术语也指双链和单链分子。除另有说明或要求外,本公开的任何多核苷酸的实施例包括双链形式和已知或预测构成双链形式的两种可互补单链形式中的每一种。
术语“编码”应用于多核苷酸时,是指被称为“编码”多肽的多核苷酸,如果在其天然状态或当通过本领域技术人员公知的方法操作时,其可以被转录和/或翻译以产生多肽和/或其片段的mRNA。反义链是这种核酸的互补序列,其编码序列可以从中推导出来。
在本发明中,“抗体”或“抗原结合多肽”是指特异性识别和结合抗原的多肽或多肽复合物。抗体可以是完整的抗体及其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有具有与抗原结合的生物学活性的免疫球蛋白分子的至少一部分的任何蛋白质或肽。该种实施例包括但不限于重链或轻链或其配体结合部分的互补决定区(CDR)、重链或轻链可变区、重链或轻链恒定区、框架(FR)区或其任何部分、或结合蛋白的至少一部分。
在本发明中,术语“抗体片段”或“抗原结合片段”是抗体的一部分,例如F(ab’)2、F(ab)2、Fab'、Fab、Fv、scFv等。不管其结构如何,抗体片段与被完整抗体识别的同一抗原结合。术语“抗体片段”包括适体、镜像异构体和双价抗体。术语“抗体片段”还包括通过与特定抗原结合形成复合物而起抗体作用的任何合成或基因工程蛋白质。
“单链可变片段”或“scFv”是指免疫球蛋白的重链(VH)和轻链(VL)的可变区的融合蛋白。在一些方面,这些区域与10个至约25个氨基酸的短接头肽连接。接头可以富含甘氨酸以增加柔韧性,以及富含丝氨酸或苏氨酸以增加溶解性,并且可以连接VH 的N端和VL的C端,反之亦然。尽管该蛋白质被除去了恒定区和引入了接头,但其保留了原始免疫球蛋白的特异性。ScFv分子是本领域中已知的,例如在美国专利5,892,019 中有相关描述。
术语“抗体”包括可以在生物化学上区分的各种广泛种类的多肽。本领域技术人员将会理解,重链的类别包括gamma、mu、alpha、delta或epsilon(γ、μ、α、δ、ε),其中还有一些亚类(例如γ1-γ4)。该链的性质决定了抗体的“种类”分别为IgG、IgM、IgA、 IgG或IgE。免疫球蛋白亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgG5等,已被充分表征并且已知其赋予的功能特异性。鉴于本公开的内容,本领域普通技术人员容易辨别这些种类和同种型中的每一种的修饰形式,因此都在本发明公开的保护范围内。所有的免疫球蛋白种类都显然在本发明公开的保护范围内,后面的讨论通常针对免疫球蛋白分子的IgG种类。关于IgG,标准的免疫球蛋白分子包含分子量约23,000道尔顿的两条相同的轻链多肽和分子量约为53,000-70,000的两条相同的重链多肽。这四条链典型地通过二硫键以“Y”构型连接,其中轻链从“Y”的口开始并延续通过可变区包围重链。
本发明公开的抗体、抗原结合多肽、变体或衍生物包括但不限于多克隆、单克隆、多特异性、全人源、人源化、灵长类化或嵌合抗体、单链抗体、表位结合片段例如Fab、Fab'和F(ab')2、Fd、Fvs、单链Fvs(scFv)、单链抗体,二硫键连接的Fvs(sdFv),包含VK 或VH结构域的片段,由Fab表达文库产生的片段和抗独特型(抗Id)抗体(包括例如本发明公开的LIGHT抗体的抗Id抗体)。本发明公开的免疫球蛋白或抗体分子可以是免疫球蛋白的任何类型(例如IgG、IgE、IgM、IgD、IgA和IgY)或种类(例如,IgG1、 IgG2、IgG3、IgG4、IgA1和IgA2)或者亚类。
轻链可以分为kappa或lambda(κ、λ)。每个重链可以与κ或λ轻链结合。一般来说,当由杂交瘤、B细胞或基因工程宿主细胞生产免疫球蛋白时,其轻链和重链通过共价键结合,两条重链的“尾巴”部分通过共价二硫键或非共价键结合。在重链中,氨基酸序列从Y构型的叉状末端的N末端延伸至每条链底部的C末端。
轻链和重链都分成结构和功能同源性的区域。术语“恒定的”和“可变的”根据功能使用。就这点而言,应理解,轻链(Vκ)和重链(VH)链部分的可变区决定了抗原识别和特异性。相反地,轻链(CK)和重链(CH1、CH2或CH3)的恒定区赋予重要的生物学性质,如分泌、经胎盘移动、Fc受体结合、补体结合等。按照惯例,恒定区的编号随着它们远离抗体的抗原结合位点或氨基末端而增加。N端部分是可变区,C端部分是恒定区;CH3和CK结构域实际上分别包含重链和轻链的羧基端。
如上所述,可变区使得抗体能够选择性识别和特异性结合抗原上的表位。也就是说,抗体的VK结构域和VH结构域或互补决定区(CDR)的子集结合形成了限定三维抗原结合位点的可变区。该抗体四级结构形成存在于Y的每个臂末端的抗原结合位点。更具体地说,抗原结合位点由VH和VK链中各自的三个CDR(即CDR-H1、CDR-H2、CDR- H3、CDR-L1、CDR-L2和CDR-L3)限定。在某些情况下,例如某些来源于骆驼科动物的免疫球蛋白分子或基于骆驼科动物免疫球蛋白改造的免疫球蛋白分子,完整的免疫球蛋白分子可以仅由重链组成,没有轻链。例如参见Hamers-Casterman et al.,Nature 363: 446-448(1993)。
在天然存在的抗体中,假设抗体在含水环境中呈现其三维构型时,存在于每个抗原结合域中的六个“互补决定区”或“CDR”是特异性地定位以形成抗原结合结构域的短的、非连续的氨基酸序列。抗原结合结构域中被称为“构架”区域的剩余其它氨基酸显示出较小的分子间可变性。构架区大部分采用β-折叠构象,CDR形成与之连接的环状结构,或在某些情况下形成β折叠结构的一部分。因此,框架区通过形成支架从而通过链间非共价相互作用使CDR定位在正确的方位上。由定位的CDR形成的抗原结合域界定了与免疫反应性抗原上的表位互补的表面,该互补表面促进抗体和其同源表位的非共价结合。对于任何给定的重链或轻链可变区,本领域普通技术人员都可以容易地鉴定出包含CDR 和框架区的氨基酸,因为其已经被精确定义(参见“Sequences of Proteins of Immunological Interest,”Kabat,E.,et al.,U.S.Department of Health and Human Services,(1983)以及Chothiaand Lesk,J.MoI.Biol.,196:901-917(1987))。
在本领域中使用和/或接受的术语有两个或多个定义的情况下,除非明确地对立指出,否则本文使用的术语的定义包括其所有的含义。一个具体的例子是使用“互补决定区” (“CDR”)一词来描述在重链和轻链多肽的可变区内发现的非连续的抗原结合位点。这一特定区域在Kabat et al.,U.S.Dept.of Health and Human Services,"Sequences ofProteins of Immunological Interest"(1983)和Chothia等在J.Mol.Biol.196:901-917(1987)有相关描述,其通过本发明引用其全部内容并入本文。
根据Kabat和Chothia定义的CDR包括相互比较时的氨基酸残基的重叠或子集。尽管如此,应用任一定义来指代抗体或其变体的CDR都在本发明所定义和使用的术语的范围内。包含以上引用的每个参考文献所定义的CDR的适量的氨基酸残基在下表中被列出进行比较。包含特定CDR的确切残基编号将根据CDR的序列和大小而变化。本领域技术人员可以常规地根据抗体的可变区氨基酸序列确定出哪些残基包含特定的CDR。
Kabat | Chothia | |
CDR-H1 | 31-35 | 26-32 |
CDR-H2 | 50-65 | 52-58 |
CDR-H3 | 95-102 | 95-102 |
CDR-L1 | 24-34 | 26-32 |
CDR-L2 | 50-56 | 50-52 |
CDR-L3 | 89-97 | 91-96 |
Kabat等人还定义了适用于任何抗体的可变区序列的编号系统。本领域普通技术人员可以毫无疑义地将该“Kabat编号”系统应用到任何可变区序列,而不依赖于序列本身以外的任何实验数据。本发明所使用的“Kabat编号”是指由Kabat et al.,U.S.Dept.ofHealth and Human Services在“Sequence of Proteins of Immunological Interest”(1983)中提出的编号系统。
除上述表格之外,Kabat编号系统如下述方式描述CDR区:CDR-H1在大约第31个氨基酸(即第一个半胱氨酸残基之后的大约9个残基)开始,包括大约5-7个氨基酸,并在下一个色氨酸残基处结束。CDR-H2在CDR-H1结束后的第15个残基处开始,包括大约16-19个氨基酸残基,并在下一个精氨酸或赖氨酸残基处结束。CDR-H3从CDR-H2结束后的大约第33个氨基酸残基开始;包括3-25个氨基酸;并以序列W-G-X-G结束,其中X指任何氨基酸。CDR-L1大约从第24个残基开始(即在半胱氨酸残基之后);包括约10-17个残基;并在下一个色氨酸残基处结束。CDR-L2从CDR-L1结束后的大约第16 个残基开始,包括大约7个残基。CDR-L3在CDR-L2结束后的大约第33个残基(即在半胱氨酸残基之后)开始;包括大约7-11个残基并且以序列F或W-G-X-G结束,其中 X指任何氨基酸。
本发明公开的抗体可以来源于任何动物,包括鸟类和哺乳动物。较佳地,抗体是人源、鼠源、驴源、兔源、山羊源、豚鼠源、骆驼源、美洲驼源、马源或鸡源抗体。在另一实施例中,可变区可以是软骨鱼纲(condricthoid)来源(例如来自鲨鱼)。
在本发明中,术语“重链恒定区”包括来源于免疫球蛋白重链的氨基酸序列。包含重链恒定区的多肽包括CH1结构域、铰链(例如上、中和/或下铰链区)结构域、CH2结构域、CH3结构域或变体或片段中的至少一种。例如,本发明公开的抗原结合多肽可以包括含有CH1结构域的多肽链;包含CH1结构域以及至少一部分铰链区以及CH2结构域的多肽链;包含CH1结构域和CH3结构域的多肽链;包含CH1结构域、至少一部分铰链区以及CH3结构域的多肽链,或包含CH1结构域、至少一部分铰链区以及CH2结构域和CH3结构域的多肽链。在另一实施例中,本发明公开的多肽包括包含CH3结构域的多肽链。此外,本发明中使用的抗体可能缺少至少一部分CH2结构域(例如全部或部分CH2结构域)。如上所述,本领域普通技术人员应当理解,重链恒定区可以被修饰从而使得它们天然存在的免疫球蛋白分子的氨基酸序列发生变化。
在本发明中,抗体的重链恒定区可以来源于不同的免疫球蛋白分子。例如,多肽的重链恒定区可以包括源自IgG1分子的CH1结构域和源自IgG3分子的铰链区。在另一实施例中,重链恒定区可以包括部分源自IgG1分子和部分源自IgG3分子的铰链区。在另一实施例中,部分重链可以包括部分源自IgG1分子和部分源自IgG4分子的嵌合铰链区。
在本发明中,术语“轻链恒定区”包括来自抗体轻链的氨基酸序列。较佳地,轻链恒定区包含恒定κ结构域或恒定λ结构域中的至少一个。
“轻链-重链对”是指可通过轻链的CL结构域和重链的CH1结构域之间的二硫键形成二聚体的轻链和重链的集合。
如上所述,各种免疫球蛋白种类的恒定区的亚基结构和三维构型是众所周知的。在本发明中,术语“VH结构域”包括免疫球蛋白重链的氨基末端可变结构域,术语“CH1 结构域”包括免疫球蛋白重链的第一个(大部分氨基末端)恒定区。CH1结构域与VH结构域相邻,并且是免疫球蛋白重链分子铰链区的氨基端。
在本发明中,术语“CH2结构域”包括使用常规编号方案时,从抗体的约第244个残基延伸至第360个残基的部分重链分子(第244至360个残基,Kabat编号系统;第 231-340个残基,EU编号系统;参见Kabat et al.,U.S.Dept.of Health and Human Services,“Sequences of Proteins of Immunological Interest”(1983))。CH2结构域是独特的,因为该结构域不与其它结构域紧密配对,而是在完整的天然IgG分子的两个CH2结构域之间插入两个N-连接的分支碳水化合物链。还充分记载了CH3结构域从CH2结构域开始延伸到IgG分子的C-末端,大约包含108个残基。
在本发明中,术语“铰链区”包括连接CH1结构域和CH2结构域的部分重链分子。所述铰链区包含约25个残基并且是柔韧的,从而使得两个N端抗原结合区能够独立移动。铰链区可以被细分为三个不同的结构域:上、中和下铰链结构域(Rouxetal., J.Immunol161:4083(1998))。
在本发明中,术语“二硫键”包括两个硫原子之间形成的共价键。半胱氨酸包含可以与第二个硫醇基团形成二硫键或桥接的硫醇基团。在大多数天然存在的IgG分子中,CH1和CK区通过二硫键连接,两条重链通过两个二硫键在Kabat编号系统中对应的位置239 和242(位置226或229,EU编号系统)处相连接。
在本发明中,术语“嵌合抗体”被认为是指其免疫反应性区域或位点从第一个物种中获得或衍生,而其恒定区(在本发明中可以是完整的、部分的或修饰过的)来源于第二个物种的任何抗体。在某些实施例中,靶结合区或位点来自非人源(例如小鼠或灵长类动物),而恒定区是人源。
在本发明中,“人源化百分比”是通过测定人源化结构域与种系结构域之间的框架氨基酸差异(即非CDR区的差异)的数目,从氨基酸的总数中减去该数目,然后除以氨基酸总数乘以100计算而来。
“特异性结合”或“对……具有特异性”通常是指抗体通过其抗原结合结构域与表位结合,并且该结合需要抗原结合结构域和表位之间具有互补性。根据这个定义,当抗体通过其抗原结合结构域与该表位结合时,比它与随机的、不相关的表位结合更容易,其被称为“特异性结合”该表位。术语“特异性”在本发明中用于限定某种抗体与某个表位结合的相对亲和力。例如,可以认为抗体“A”比抗体“B”对特定表位具有更高的特异性,或者可以认为抗体“A”以比结合相关表位“D”更高的特异性结合表位“C”。
在本发明中,术语“治疗”是指治疗性治疗和预防性或防治性措施,其目的是预防或减缓(减少)不期望发生的生理改变或紊乱,例如癌症的进程。有益的或期望的临床结果包括但不限于以下无论是可检测还是不可检测的结果,包括症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善或缓和以及减轻(无论是部分还是全部)。“治疗”还意指与不接受治疗时预期的生存期限相比延长生存期限。需要治疗的包括那些已经患有病症或紊乱的人,以及那些容易患有病症或紊乱的人,或者那些需要预防该病症或紊乱的人。
“受试者”或“个体”或“动物”或“患者”或“哺乳动物”通常指需要诊断、预后或治疗的任何受试者,特别是哺乳动物受试者。哺乳动物受试者包括人类、家养动物、农场动物和动物园、运动或宠物动物如狗、猫、豚鼠、兔子、大鼠、小鼠、马、牛、奶牛等。
在本发明中,诸如“需要治疗的患者”或“需要治疗的受试者”等短语包括从施用本发明公开的抗体或组合物用于检测、诊断过程和/或治疗中受益的受试者,例如哺乳动物受试者。
CD73抗体
本发明提供了对人CD73蛋白具有高亲和力和抑制活性的CD73抗体。抗体可以与游离的CD73和细胞表面的CD73有效地结合。一旦与细胞表面的CD73蛋白结合,该结合可以引发内化,导致细胞表面CD73蛋白的表达量减少,从而使得细胞外腺苷和免疫抑制性肿瘤环境的减少。此外,由于这些抗体不与AMP底物竞争性地结合CD73的活性位点,而是变构地或通过其他非竞争性机制起作用,因此这些抗体不会干扰CD73与这些内源性AMP底物的结合,从而限制了这些抗体潜在的不利影响。
另外,如实验性实施例中所证实的,这些抗体表现出用已知的CD73抗体,例如来自Medimmune的MEDI-9447未观察到的一些独特性质。如实施例12所示,尽管MEDI- 9447和11F11与CD73蛋白的N末端结构域结合,但本发明的抗体(例如Y345、D399、 E400、R401和R480)的靶向氨基酸位于C末端结构域。
CD73酶由两个相同的70kD的亚基形成的二聚体组成,所述亚基通过糖基磷脂酰肌醇连接并与质膜外表面结合。人CD73的二聚体晶体结构显示了酶的开放和闭合形式之间广泛的构象转换,这对酶的正常功能是必需的。二聚化界面由C末端结构域形成。当 C末端结构域参与其他的结合时,预期二聚化和/或构象转换将被阻断,从而导致CD73 活性的抑制。相反,通过N末端结构域与抗体进行结合可能不会产生这种效果。
因此,可以预见的是,当目前公开的抗体结合CD73蛋白的C末端结构域时,它们将阻断蛋白的二聚化并有效地抑制其活性。因此,目前公开的抗体远优于先前已知的与 N末端结构域结合的CD73抗体。
因此,根据本发明的一个实施例提供的一种分离的抗体或其片段,其对人CD73蛋白具有特异性,并与选自人CD73蛋白C末端部分的一个或多个氨基酸残基结合。根据本领域公知常识,人CD73蛋白的C末端部分包含从第337位残基开始的238个氨基酸残基,如下表中的SEQ ID NO:61所示。
表A CD73序列:
在一些实施例中,抗体或其片段与人CD73蛋白的一个或多个C端结构域结合。在一些实施例中,抗体或其片段与选自由人CD73蛋白的Y345、D399、E400、R401和R480 组成的组中的至少一个氨基酸残基结合。在一些实施例中,抗体或其片段至少与两个氨基酸残基结合。
在一些实施例中,抗体或其片段至少与Y345和D399结合。在一些实施例中,抗体或其片段至少与Y345和E400结合。在一些实施例中,抗体或其片段至少与Y345和 R401结合。在一些实施例中,抗体或其片段至少与Y345和R480结合。在一些实施例中,抗体或其片段至少与D399和E400结合。在一些实施例中,抗体或其片段至少与 D399和R401结合。在一些实施例中,抗体或其片段至少与D399和R480结合。在一些实施例中,抗体或其片段至少与E400和R401结合。在一些实施例中,抗体或其片段至少与E400和R480结合。在一些实施例中,抗体或其片段至少与R401和R480结合。
在一些实施例中,抗体或其片段至少与Y345、D399和E400结合。在一些实施例中,抗体或其片段至少与Y345、D399和R401结合。在一些实施例中,抗体或其片段至少与 Y345、D399和R480结合。在一些实施例中,抗体或其片段至少与Y345、E400和R401 结合。在一些实施例中,抗体或其片段至少结合Y345、E400和R480结合。在一些实施例中,抗体或其片段至少与Y345、R401和R480结合。在一些实施例中,抗体或其片段至少与D399、E400和R401结合。在一些实施例中,抗体或其片段至少与D399、E400 和R480结合。在一些实施例中,抗体或其片段至少结合E400、R401和R480结合。
在一些实施例中,抗体或其片段至少与Y345、D399、E400和R401结合。在一些实施例中,抗体或其片段至少与Y345、D399、E400和R480结合。在一些实施例中,抗体或其片段至少与Y345、D399、R401和R480结合。在一些实施例中,抗体或其片段至少与Y345、E400、R401和R480结合。在一些实施例中,抗体或其片段至少与D399、E400、 R401和R480结合。在一些实施例中,抗体或其片段与Y345、D399、E400、R401和R480 中的每一个结合。
根据本发明的一个实施例提供的抗体,其包含具有如SEQ ID NO:1~6中定义的CDR 区的重链可变区和轻链可变区。
表1 CDR区的序列
名称 | 序列 | SEQ ID NO: |
VH CDR1 | <u>SGY</u>YWN | 1 |
VH CDR2 | YINYG<u>GSN</u>GYNPSLKS | 2 |
VH CDR3 | DYDAYY<u>EA</u>LDD | 3 |
VL CDR1 | RA<u>SS</u>RVNYMH | 4 |
VL CDR2 | ATSNLAS | 5 |
VL CDR3 | <u>QQWSS</u>NPPT | 6 |
如实验性实施例所证明的,含有这些CDR区的抗体,无论是小鼠的、人源化的还是嵌合的抗体,都具有有效的CD73结合活性和抑制活性。进一步的计算机模拟显示,可以修饰CDR内的某些残基以保留或改善抗体的性质。此类残基被认为是“热点残基”,在表1中用加下划线来表示。在一些实施例中,本发明的CD73抗体包含表1中列出的VH 和VL的CDR,具有一个、两个或三个进一步的修饰。这种修饰可以是氨基酸的添加、缺失或取代。
在一些实施例中,所述修饰是在不超过一个来自每个CDR的热点残基位置处的取代。在一些实施例中,所述修饰是在一个、两个或三个此类热点残基位置处的取代。在一个实施例中,所述修饰是在热点残基位置之一的取代。在一些实施例中,这样的取代是保守取代。
“保守性氨基酸取代”是指其中氨基酸残基被具有相似侧链的氨基酸残基置换。本领域已经定义了具有相似侧链的氨基酸家族,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(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)、非极性侧链(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、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,优选将免疫球蛋白多肽中的非必需氨基酸残基置换为来自同一侧链家族的另一种氨基酸残基。在另一个实施例中,一串氨基酸可以用同一个侧链家族成员中顺序和/或组成不同而结构相似的一串氨基酸进行置换。
下表中提供了保守的氨基酸取代的非限制性实施例,其中0或更高的类似得分表明了两个氨基酸之间的保守的可取代性。
表2 氨基酸相似性矩阵
表3 保守的氨基酸取代
在实施例7中的SEQ ID NO:26~56提供了经过合适取代的CDR的具体实施例。因此,在一些实施例中,本发明的抗体包括如SEQ ID NO:1或26~29中任一所示的VH CDR1。在一些实施例中,本发明的抗体包括如SEQ ID NO:2或30~36中任一所示的VH CDR2。在一些实施例中,本发明的抗体包括如SEQ ID NO:1或37~41中任一所示的VH CDR3。在一些实施例中,本发明的抗体包括如SEQ ID NO:4或42~45中任一所示的VL CDR1。在一些实施例中,本发明的抗体包括如SEQ ID NO:5所示的VL CDR2。在一些实施例中,本发明的抗体包括如SEQ ID NO:6或46~56中任一所示的VL CDR3。
在一些实施例中,抗体或其片段包含不多于一个、不多于两个或不多于三个的上述取代。在一些实施例中,抗体或其片段包含如SEQ ID NO:1或SEQ ID NO:26~29中任一所示的VH CDR1、如SEQ ID NO:2所示的VH CDR2、如SEQ ID NO:3所示的VH CDR3、如SEQ IDNO:4所示的VL CDR1、如SEQ ID NO:5所示的VL CDR2和如SEQ ID NO:6所示的VL CDR3。
在一些实施例中,抗体或其片段包含如SEQ ID NO:1所示的VH CDR1、如SEQ IDNO:2或SEQ ID NO:30~36中任一所示的VH CDR2、如SEQ ID NO:3所示的VH CDR3、如SEQ IDNO:4所示的VL CDR1、如SEQ ID NO:5所示的VL CDR2和如SEQ ID NO:6所示的VL CDR3。
在一些实施例中,抗体或其片段包含如SEQ ID NO:1所示的VH CDR1、如SEQ IDNO:2所示的VH CDR2、如SEQ ID NO:3或SEQ ID NO:37~41中任一所示的VH CDR3、如SEQ IDNO:4所示的VL CDR1、如SEQ ID NO:5所示的VL CDR2和如SEQ ID NO:6所示的VL CDR3。
在一些实施例中,抗体或其片段包含如SEQ ID NO:1所示的VH CDR1、如SEQ IDNO:2所示的VH CDR2、如SEQ ID NO:3所示的VH CDR3、如SEQ ID NO:4或SEQ ID NO:42~45中任一所示的VL CDR1、如SEQ ID NO:5所示的VL CDR2和如SEQ ID NO:6所示的VL CDR3。
在一些实施例中,抗体或其片段包含如SEQ ID NO:1所示的VH CDR1、如SEQ IDNO:2所示的VH CDR2、如SEQ ID NO:3所示的VH CDR3、如SEQ ID NO:4所示的VL CDR1、如SEQID NO:5所示的VL CDR2和如SEQ ID NO:6或SEQ ID NO: 46~56中任一所示的VL CDR3。
在SEQ ID NO:7和9~13中提供了VH的非限制性实例,其中SEQ ID NO:10是小鼠VH,并且SEQ ID NO:7、9和11~13是人源化VH。此外,在人源化VH中,SEQ ID NO:7、9和12~13包括相对于小鼠序列的一个或多个回复突变。同样地,在SEQ ID NO: 8、15~20和22~24中提供了VL(VK)的非限制性实例。SEQ ID NO:15是小鼠序列, SEQ ID NO:16和22是如实施例中所示的最原始衍生出的人源化序列。SEQ ID NO:8、 17~20和22~24是具有回复突变的人源化VL。
回复突变被证明有助于保留CD73抗体的某些特征。因此,在一些实施例中,本发明的CD73抗体,特别是人或人源化抗体,包含一个或多个回复突变。在一些实施例中, VH回复突变(即包含在指定位置处的氨基酸)是选自(a)第30位的Thr,(b)第44位的Lys,(c)第48位的Met,(d)第67位的Ile,和(e)第71位的Arg中的一个或多个根据Kabat编号的氨基酸残基及其组合。在一些实施例中,VL回复突变选自(a)第5位的Ser,(b)第46位的Pro,(c)第47位的Trp,(d)第49位的Ser,(e)第70位的Ser,和(f)第71位的Tyr中的一个或多个根据Kabat编号的氨基酸残基及其组合。
在一些实施例中,本发明的CD73抗体包含如SEQ ID NO:7或9~13中任一所示的VH,如SEQ ID NO:8或15~20和22~24中任一所示的VL,或它们各自的生物学等价物。VH或VL的生物学等价物是包含指定氨基酸的序列,同时总体上具有80%、85%、 90%、95%、98%或99%的序列同一性。因此,SEQ ID NO:7的生物学等价物可以是总体上与SEQ ID NO:7具有80%、85%、90%、95%、98%或99%的序列同一性但保留了CDR(SEQ ID NO:1~6或它们的变体)的VH,并且任选地保留了一个或多个或所有的回复突变。
在一个实施例中,VH具有如SEQ ID NO:7所示的氨基酸序列,并且VL具有如 SEQID NO:8所示的氨基酸序列。在一个实施例中,VH具有如SEQ ID NO:9所示的氨基酸序列,并且VL具有如SEQ ID NO:8所示的氨基酸序列。
本领域普通技术人员还应当理解,本发明所公开的抗体是可以被修饰的,修饰后其氨基酸序列不同于衍生出该抗体的天然存在的结合多肽的氨基酸序列。例如,衍生自同一指定蛋白质的多肽或氨基酸序列可以是与起始序列相似的,例如具有一定的百分比同一性,例如它可以与起始序列的百分比同一性是60%、70%、75%、80%、85%、90%、95%、98%或99%。
在某些实施例中,抗体包含氨基酸序列或一个或多个通常不与抗体结合的基团。下面更详细地描述了示例性修饰。例如,本发明公开的抗体可以包含有柔性的接头序列,或者可以被修饰以添加功能性部分(例如PEG、药物、毒素或标签)。
本发明公开的抗体、变体或衍生物包括被修饰的衍生物,即通过任何类型的分子与抗体的共价连接进行修饰,其中共价连接不会阻止抗体与表位结合。包括但不限制以下实例,抗体可以通过例如糖基化、乙酰化、聚乙二醇化、磷酸化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割、与细胞配体或其他蛋白质连接等进行修饰。众多化学修饰中的任一种修饰可以通过现有技术进行,包括但不限于特定的化学裂解、乙酰化、甲酰化、衣霉素的代谢合成等。此外,抗体可以含有一个或多个非经典的氨基酸。
在一些实施例中,抗体可以缀合到治疗剂、药物前体、肽、蛋白质、酶、病毒、脂类、生物反应调节剂、药剂或PEG。
抗体可以与治疗剂缀合或融合,所述治疗剂可包括可检测标记如放射性标记、免疫调节剂、激素、酶、寡核苷酸、光敏治疗剂或诊断剂、可以是药物或毒素的细胞毒性剂、超声增强剂、非放射性标记物及其组合,和本领域已知的其它此类试剂。
抗体可以通过将其偶联至化学发光化合物而可被检测地标记。然后通过检测在化学反应过程中出现的发光,来确定化学发光标记的抗原结合多肽的存在。特别有用的化学发光标记化合物的实例是鲁米诺、异鲁米诺、芳香吖啶酯(theromatic acridiniumester)、咪唑、吖啶盐和草酸酯。
抗体还可以使用荧光发射金属元素例如152Eu或其它镧系元素来可检测地标记。这些金属元素可以使用如二乙基三胺五乙酸(DTPA)或乙二胺四乙酸(EDTA)这样的金属螯合基团连接到抗体上。用于将各种基团缀合至抗体的技术是众所周知的,参见例如 Arnon etal.,“Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”,inMonoclonal Antibodies And Cancer Therapy、Reisfeld et al.(eds.),pp.243-56(AlanR.Liss, Inc.(1985)、Hellstrom et al.,“Antibodies For Drug Delivery”,inControlled Drug Delivery(2nd Ed.)、Robinson et al.,(eds.),Marcel Dekker,Inc.,pp.623-53(1987)、Thorpe,“Antibody Carriers Of Cytotoxic Agents In CancerTherapy:A Review”,in Monoclonal Antibodies'84: Biological And ClinicalApplications、Pinchera et al.(eds.),pp.475-506(1985)、“Analysis, Results,AndFuture Prospective Of The Therapeutic Use Of Radiolabeled Antibody In CancerTherapy”,in Monoclonal Antibodies For Cancer Detection And Therapy、Baldwin etal.(eds.), Academic Press pp.303-16(1985)和Thorpe et al.,“The Preparation AndCytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol.Rev.(52:119-58(1982))。
编码抗体的多核苷酸和制备抗体的方法
本发明还公开了编码本发明所述抗体、变体及其衍生物的分离的多核苷酸或核酸分子。多核苷酸的实施例包括SEQ ID NO:57~60。本发明公开的多核苷酸可以编码在同一多核苷酸分子上或在不同的多核苷酸分子上的抗原结合多肽、变体或衍生物的整个重链和轻链可变区。此外,本发明公开的多核苷酸可以编码在相同的多核苷酸分子上或在不同的多核苷酸分子上的抗原结合多肽、变体或衍生物的部分重链和轻链可变区。
制备抗体的方法是本领域公知的,并且在本发明中描述。在某些实施例中,本发明公开的抗原结合多肽的可变区和恒定区都是全人源的。可以使用本领域中公开的技术和本发明所述的技术制备全人源抗体。例如,针对特定抗原的全人源抗体可以通过将抗原施用于转基因动物中来制备,所述转基因动物已经被改良过以响应抗原攻击而产生此类抗体,但其内源基因座已被禁用。可用于制备这种抗体的示例性技术参见美国专利 6,150,584、6,458,592、6,420,140,其全部内容通过引用并入本文。
在某些实施例中,制备的抗体不会在待治疗的动物、例如人类中引起有害的免疫应答。在一个实施例中,本发明公开的抗原结合多肽、变体或衍生物使用本领域公认技术修饰以降低其免疫原性。例如,抗体可以被人源化、灵长类化、去免疫化或者可以制备嵌合抗体。这些类型的抗体来源于非人抗体,通常是鼠类或灵长类抗体,其保留或基本保留亲本抗体的抗原结合特性,但在人体中免疫原性较低。其可以通过多种方法来实现,包括(a)将整个非人源的可变区移植到人源的恒定区以产生嵌合抗体;(b)将一个或多个非人类互补决定区(CDR)的至少一部分移植到人源的框架和恒定区中,保留或不保留关键的框架残基;或(c)移植整个非人源的可变区,但通过用类人源的部分置换表面残基从而“隐藏”它们。此类方法参见Morrison et al.,Proc.Natl.Acad.Sci.USA 57:6851- 6855(1984)、Morrisonet al.,Adv.Immunol.44:65-92(1988)、Verhoeyen et al.,Science 239:1534-1536(1988)、Padlan,Molec.Immun.25:489-498(1991)、Padlan,Molec.Immun. 31:169-217(1994)和专利号为5,585,089、5,693,761、5,693,762和6,190,370的美国专利,其全部内容通过引用并入本文。
去免疫化也可用于降低抗体的免疫原性。在本发明中,术语“去免疫化”包括改变抗体以修饰T细胞表位(参见例如国际申请公开号:WO/9852976A1和WO/0034317A2)。例如,分析来自起始抗体的可变重链和可变轻链的序列,并建立来自每个V区的人T细胞表位“图谱”,其显示表位相对于互补决定区(CDRs)和序列内其它关键残基的位置。分析来自T细胞表位图的单个T细胞表位,以鉴定具有较低风险改变最终抗体活性的可选择的氨基酸取代。设计包含氨基酸取代组合的一系列可选的可变重链和可变轻链序列,随后将这些序列掺入到一系列结合多肽中。典型地,产生12至24种抗体的变体,并检测其结合能力和/或功能。然后将包含修饰过的可变区和人类恒定区的完整重链和轻链的基因克隆到表达载体中,随后将质粒转入细胞系以产生完整的抗体。然后利用合适的生物化学和生物学实验中比较抗体,鉴定出最佳的变体。
本发明公开的抗原结合多肽的结合特异性可以通过体外实验,例如免疫共沉淀、放射免疫实验(RIA)或酶联免疫吸附实验(ELISA)来检测。
可选地,描述的用于生产单链单元的技术(美国专利号4,694,778、Bird,Science242:423-442(1988)、Huston et al.,Proc.Natl.Acad.Sci.USA 55:5879-5883(1988)和Ward et al.,Nature 334:544-554(1989))可适用于生产本发明公开的单链单元。通过经由氨基酸桥接Fv区的重链和轻链片段形成单链单元,产生单链融合肽。也可以使用在大肠杆菌中组装功能性Fv片段的技术(Skerra et al.,Science 242:1038-1041(1988))。
可用于生产单链Fv(scFv)和抗体的技术的实例如美国专利4,946,778和5,258,498,以及Huston et al.,Methods in Enzymology 203:46-88(1991)、Shu et al.,Proc.Natl.Sci.USA 90:1995-1999(1993)和Skerra et al.,Science 240:1038-1040(1988)中所述。对于包括在人体内使用抗体和体外检测实验的某些用途,可以优选使用嵌合抗体、人源化抗体或全人源抗体。嵌合抗体是抗体的不同部分源自不同动物物种的一类分子,例如具有鼠源单克隆抗体的可变区和人源免疫球蛋白恒定区的抗体。生产嵌合抗体的方法是本领域已知的,参见Morrison,Science 229:1202(1985)、Oi et al.,BioTechniques 4:214(1986)、Gillies et al., J.Immunol.Methods 125:191-202(1989)和美国专利5,807,715、4,816,567和4,816397,其全部内容通过引用并入本文。
人源化抗体是能够结合目标抗原的非人源抗体衍生的抗体分子,所述目标抗原具有非人源的一个或多个互补决定区(CDR)和来自人免疫球蛋白分子的框架区。通常人框架区中的框架残基将被来自CDR供体抗体的相应残基取代,以改变、优选能够改善抗原的结合。这些框架取代可以通过本领域公知的方法鉴定,例如通过模拟CDR和框架残基的相互作用,以鉴定对抗原结合起重要作用的框架残基,和通过序列对比以鉴定特定位置上异常的框架残基。(参考Queen et al.,美国专利号5,585,089、Riechmann et al.,Nature 332:323(1988),其全部内容通过引用并入本文)。可以使用本领域公知的多种技术使抗体人源化,例如CDR移植(EP 239,400、PCT公布文本WO 91/09967、美国专利号5,225,539、 5,530,101和5,585,089),镶饰或重塑(EP 592,106、EP 519,596、Padlan,Molecular Immunology28(4/5):489-498(1991)、Studnicka et al.,Protein Engineering 7(6):805-814(1994)、Roguska. et al.,Proc.Natl.Sci.USA 91:969-973(1994)),以及链替换(U.S.Pat.No.5,565,332),其全部内容通过引用并入本文。
对于治疗人类患者来说,全人源抗体是特别理想的。全人源抗体可以通过本领域已知的多种方法制备,包括使用来自人免疫球蛋白序列的抗体文库进行的噬菌体展示方法。也可参考美国专利4,444,887和4,716,111,以及PCT公布文本WO 98/46645、WO 98/50433、 WO 98/24893、WO 98/16654、WO 96/34096、WO 96/33735和WO 91/10741,每个专利其全部内容通过引用并入本文。
还可以用转基因小鼠来生产人源抗体,所述小鼠不能表达功能性内源性免疫球蛋白但能表达人类免疫球蛋白基因。例如,人重链和轻链免疫球蛋白基因复合物可以随机引入或通过同源重组引入到小鼠胚胎干细胞。或者,除了人重链和轻链基因之外,还可以将人的可变区、恒定区和多样性区域引入小鼠胚胎干细胞中。小鼠重链和轻链的免疫球蛋白基因可以通过同源重组分别或同时通过引入人免疫球蛋白基因座而丧失功能。特别地,JH区域的纯合缺失可以防止内源抗体的产生。将修饰过的胚胎干细胞扩增并显微注射进囊胚中以产生嵌合小鼠。然后培育嵌合小鼠以产生表达人源抗体的纯合后代。用选择出的抗原例如全部或部分期望的多肽靶点以常规方式免疫转基因小鼠。可以使用常规杂交瘤技术从免疫的转基因小鼠获得靶向抗原的单克隆抗体。转基因小鼠携带的人免疫球蛋白转基因在B细胞分化过程中重排,随后发生类别转换和体细胞突变。因此,使用这种技术可以产生可用于治疗的IgG、IgA、IgM和IgE抗体。关于这种生产全人源抗体的技术相关综述,可以参见Lonberg and Huszar Int.Rev.Immunol.73:65-93(1995)。关于生产全人源抗体和人单克隆抗体的该技术的详细讨论和生产这种抗体的步骤,本发明全部参见PCT公布文本WO 98/24893、WO 96/34096、WO 96/33735,以及美国专利5,413,923、 5,625,126、5,633,425、5,569,825、5,661,016、5,545,806、5,814,318和5,939,598,其全部内容通过引用并入本文。此外,诸如Abgenix(Freemont,Calif.)和GenPharm(San Jose, Calif.)之类的公司,可以使用上述类似技术提供针对所选抗原的全人源抗体。
也可以使用被称为“引导选择”的技术来生产识别选择性表位的全人源抗体。在该方法中使用选择的非人单克隆抗体、例如小鼠抗体来引导识别相同表位的全人源抗体的筛选。(参见Jespers et al.,Bio/Technology 72:899-903(1988)以及美国专利5,565,332,其全部内容通过引用并入本文)。
在另一个实施例中,使用常规方法(例如使用能够特异性结合编码鼠抗体重链和轻链的基因的寡核苷酸探针),可以容易地分离编码所需单克隆抗体的DNA并对其进行测序。分离的和亚克隆的杂交瘤细胞作为此类DNA的优选来源。一旦分离出来,DNA可以被置于表达载体中,然后被转染到不另外产生免疫球蛋白的原核或真核宿主细胞如大肠杆菌细胞、猿猴COS细胞、中国仓鼠卵巢(CHO)细胞或骨髓瘤细胞中。更特别地,分离的DNA(如本文所述可以是合成的)可用于克隆用于制备抗体的恒定区和可变区的序列,如本发明引用的Newman et al和公布于1995年1月25日的美国专利5,658,570中所述,其全部内容通过引用并入本文。基本上,这需要从所选细胞中提取RNA并转化成 cDNA,然后使用Ig特异性引物通过PCR技术进行扩增。适于此目的的合适的引物在美国专利5,658,570中也有所提及。如下面将更详细地讨论的,可以相对大批量培养表达所需抗体的转化细胞以提供免疫球蛋白的临床和商业需求。
此外,使用常规重组DNA技术可将本发明的抗原结合多肽的一个或多个CDR插入框架区,例如插入到人类框架区以构建人源化非全人源抗体。框架区可以是天然存在的或共有的框架区,并且优选人类框架区(参见Chothia et al.,J.Mol.Biol.278:457-479(1998),其列出一系列人类框架区)。优选地,用框架区和CDR组合产生的多核苷酸编码与所需多肽(例如LIGHT)的至少一个表位特异性结合的抗体。优选地,在框架区内进行一个或多个氨基酸取代,并且优选能够提高抗体与其抗原结合的氨基酸取代。另外,可用此法进行参与到链间二硫键形成的一个或多个可变区中半胱氨酸残基的取代或缺失,从而产生缺少一个或多个链间二硫键的抗体分子。本领域技术范围内的对多核苷酸进行的其他改变也涵盖于本发明中。
此外,还开发了用于生产“嵌合抗体”的技术(Morrison et al.,Proc.Natl.Acad.Sci. USA:851-855(1984)、Neuberger et al.,Nature 372:604-608(1984)、Takeda et al.,Nature 314:452-454(1985)),其通过剪接来自鼠抗分子、具有合适抗原特异性的基因,以及可以使用的来自具有合适生物学活性的人抗分子的基因。在本发明中,嵌合抗体是其不同部分来源于不同动物物种的分子,例如那些含有源自鼠单克隆抗体的可变区和人免疫球蛋白恒定区的嵌合抗体。
此外,在Newman,Biotechnology 10:1455-1460(1992)中公开了另一种生产重组抗体的高效方法。具体而言,该技术能产生含有猴可变区和人恒定区序列的灵长类抗体,该参考文献的全部内容通过引用并入本文。此外,该技术也在共同转让的美国专利 5,658,570、5,693,780和5,756,096中有所提及,上述每种专利的全部内容通过引用并入本文。
或者,可以使用本领域技术人员公知的技术选择和培养生产抗体的细胞系。这些技术在各种实验室手册和主要出版物中均有描述。在这方面,下文描述的适合本发明使用的技术参考在Current Protocols in Immunology,Coligan et al.,Eds.,GreenPublishing Associates and Wiley-Interscience,John Wiley and Sons,New York(1991)有所提及,其全部内容包括补充内容通过引用并入全文。
此外,可以使用本领域技术人员已知的标准技术在编码本发明所述抗体的核苷酸序列中引入突变,包括但不限于导致氨基酸取代的定点突变和PCR介导的突变。优选地,变体(包括衍生物)编码相对于参考的重链可变区CDR-H1、CDR-H2、CDR-H3和轻链可变区CDR-L1、CDR-L2或CDR-L3来说少于50个氨基酸的取代、少于40个氨基酸的取代、少于30个氨基酸的取代、少于25个氨基酸的取代、少于20个氨基酸的取代、少于15个氨基酸的取代、少于10个氨基酸的取代、小于5个氨基酸的取代、小于4个氨基酸的取代、小于3个氨基酸的取代或小于2个氨基酸的取代。或者可以沿着全部或部分编码序列时随机引入突变,例如通过饱和突变,以及可以筛选所得突变体的生物活性以鉴定保留活性的突变体。
治疗方法
在本发明中,本发明的抗体、变体或衍生物可用于某些治疗和诊断方法中。
本发明将进一步描述基于抗体的疗法,其包括将本发明所述的抗体施用于患者例如动物、哺乳动物和人体内,从而治疗本文所述的一种或多种紊乱或病症。本发明的治疗性化合物包括但不限于本发明所述抗体(包括本发明所述的变体和衍生物)和编码本发明所述抗体(包括本发明所述的变体和衍生物)的核酸或多核苷酸。
本发明的抗体也可以用于治疗或抑制癌症。如上所述,CD73可以在肿瘤细胞中过表达。肿瘤衍生的CD73可以作为胞外酶产生细胞外腺苷,其经由腺苷受体信号传导来限制抗肿瘤T细胞的免疫,从而促进肿瘤生长。在小鼠肿瘤模型中使用小分子抑制剂或靶向CD73的单克隆抗体的结果表明,靶向CD73疗法是有效控制肿瘤生长的重要的替代性和现实性方法。特别地是,它通过增强适应性免疫应答机制来辅助基于T细胞的治疗,这可能会增加肿瘤浸润T淋巴细胞的功能,并导致癌症患者的生存率提高。
因此,在一些实施例中,提供了用于治疗有需要的患者的癌症的方法。在一个实施例中,所述方法需要向患者施用有效量的本发明公开的抗体。在一些实施例中,患者中的至少一种癌细胞(例如基质细胞)过度表达CD73。
癌症的非限制性实例包括膀胱癌、乳腺癌、结直肠癌,子宫内膜癌、食管癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、胰腺癌、前列腺癌和甲状腺癌。
本发明还提供了细胞疗法,并且更具体地说是嵌合抗原受体(CAR)T细胞疗法。可以使用合适的T细胞,其与本发明的CD73抗体接触(或者可选地进行工程改造以表达本发明的CD73抗体)。经过这样的接触或工程改造后,可以将T细胞引入需要治疗的癌症患者中。癌症患者可能具有本发明公开的任何类型的癌症。T细胞可以是例如肿瘤浸润T淋巴细胞、CD4+ T细胞、CD8+ T细胞或其组合,但不限于此。
在一些实施例中,T细胞是从癌症患者他或她自身体内分离出来。在一些实施例中, T细胞由供体或细胞库提供。当T细胞是从癌症患者中分离出来时,可以将不希望的免疫反应降至最低。
可以用本发明所述抗体或变体或其衍生物来治疗、预防、诊断和/或预测的、与细胞存活增加相关的其他疾病或病症,包括但不限于恶性肿瘤和/或相关疾病的进程或转移,所述疾病例如白血病{包括急性白血病[例如急性淋巴细胞性白血病、急性骨髓性白血病(包括成髓细胞性、早幼粒细胞性、粒单核细胞性、单核细胞性和红白血病)]和慢性白血病[例如慢性髓细胞性(粒细胞性)白血病和慢性淋巴细胞性白血病]}、真性红细胞增多症、淋巴瘤(例如霍奇金淋巴瘤和非霍奇金淋巴瘤)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链病,以及实体瘤,包括但不限于肉瘤和癌症如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑色素瘤、成神经细胞瘤和成视网膜细胞瘤。
对于任何特定患者的具体剂量和治疗方案将取决于多种因素,包括所使用的特定抗体及其变体或衍生物、患者的年龄和体重、一般健康状况、性别和饮食,以及给药时间、排泄频率、药物组合,以及所治疗的特定疾病的严重程度。医疗护理人员对这些因素的判断在本领域普通技术人员的范围内。所述剂量还将取决于待治疗的个体患者、给药途径、制剂类型、所用化合物的特性、疾病的严重程度以及期望的效果。所用剂量可以通过本领域熟知的药理学和药代动力学原理确定。
抗体及其变体的施用方法包括但不限于真皮内、肌肉内、腹腔内、静脉内、皮下、鼻内、硬膜外和口服注射。抗原结合多肽或组合物可以通过任何方便的途径施用,例如通过输注或推注,通过上皮或皮肤粘膜衬里(例如口腔粘膜、直肠和肠粘膜等)吸收,并且可以与其他生物活性剂共同施用。因此,含有本发明的抗原结合多肽的药物组合物可以口服给药、直肠给药、肠胃外给药、脑池给药、阴道内给药、腹腔内给药、局部给药(如通过粉末、软膏、滴剂或透皮贴剂)、口腔给药或通过口服或鼻腔喷雾。
本发明使用的术语“肠胃外”是指包括静脉内、肌肉内、腹腔内、胸骨内、皮下和关节内注射和输注的施用方式。
施用方式可以是全身施用或局部施用。此外,可能需要通过任何合适的途径将本发明的抗体引入中枢神经系统,包括脑室内和鞘内注射;脑室内注射可以通过脑室内导管连接到如贮液囊,例如Ommaya贮液囊来辅助注射。也可以通过肺部给药,例如通过使用吸入器或喷雾器,以及使用雾化剂的制剂。
可能需要将本发明的抗原结合多肽或组合物局部施用于需要治疗的区域;可以通过但不限于以下方式实现:手术期间局部输注、局部应用例如与手术后伤口敷料联合使用、通过注射、通过导管、借助栓剂或借助植入物来实现,所述植入物是多孔的、无孔的或凝胶状的材料,包括膜例如硅橡胶膜(sialastic membrane),或纤维。优选地,当施用本发明的蛋白质(包括抗体)时,必须注意使用不吸收蛋白质的材料。
在另一个实施例中,抗原结合多肽或组合物可以递送到囊泡,特别是脂质体中(参见Langer,1990,Science 249:1527-1533、Treat et al.,in Liposomes in the Therapyof Infectious Disease and Cancer,Lopez-Berestein and Fidler(eds.),Liss,NewYork,pp.353-365(1989)、 Lopez-Berestein,同上,pp.317-327;参见同上)
在其他实施例中,还可以在控释系统中递送抗原结合多肽或组合物。在一个实施例中,可以施用泵(参见Sefton,1987,CRC Crit.Ref.Biomed.Eng.14:201、Buchwald etal., 1980,Surgery 88:507、Saudek et al.,1989,N.Engl.J.Med.321:574)。在另一个实施例中,可以使用聚合物材料(参见Medical Applications of Controlled Release,Langer and Wise (eds.),CRC Pres.,Boca Raton,Fla.(1974)、Controlled DrugBioavailability,Drug Product Design and Performance,Smolen and Ball(eds.),Wiley,New York(1984)、Ranger and Peppas, J.,1983,Macromol.Sci.Rev.Macromol.Chem.23:61、另见Levy et al.,1985,Science 228:190、 During et al.,1989,Ann.Neurol.25:351、Howard et al.,1989,J.Neurosurg.71:105)。在另一个实施方案中,还可以将控释系统放置在治疗靶位,即大脑的附近,因此仅需要全身剂量的一部分剂量(参见例如Goodson,in Medical Applications of Controlled Release,supra, vol.2,pp.115-138(1984))。其他控释系统在Langer的综述(1990,Science 249:1527-1533) 中进行了讨论。
在一具体实施例中,本发明组合物包含编码蛋白质的核酸或多核苷酸,核酸可以体内施用以促进其编码的蛋白质的表达,通过将其构建为合适的核酸表达载体的一部分并施用,因此其变为胞内部分,例如通过使用逆转录病毒载体(参见美国专利4,980,286),或通过直接注射,或通过使用微粒轰击(例如基因枪;Biolistic,Dupont),或用脂质或细胞表面受体或转染试剂包被,或者通过与已知进入细胞核的同源异型盒类肽连接施用(参见例如Joliot et al.,1991,Proc.Natl.Acad.Sci.USA 88:1864-1868)等等。可选地,核酸可以通过同源重组在引入细胞内并整合至宿主细胞DNA中用于表达。
可以通过标准的临床技术,来确定本发明抗体治疗、抑制和预防炎症、免疫或恶性疾病、紊乱或病症的有效剂量。此外,可以任选地采用体外实验来帮助确定最佳剂量范围。制剂使用的准确剂量也取决于给药途径和疾病、紊乱或病症的严重程度,且应根据医师的判断和每个患者的情况来决定。有效剂量可以从体外或动物模型测试系统得到的剂量反应曲线推测出来。
作为一般建议,本发明的抗原结合多肽施用于患者的剂量通常为0.1mg至100mg/每 kg患者体重,0.1mg至20mg/每kg病人的体重,或1mg到10mg/每kg病人的体重。通常地,由于对外源多肽的免疫应答,人抗体在人体内的半衰期比其他物种的抗体长。因此,较低剂量的人抗体和较少的给药频率通常是可行的。此外,可以通过例如脂质化等修饰来增强抗体摄取和组织穿透能力(例如进入脑内),从而减少本发明抗体的施用的剂量和频率。
通常在进行体外测试用于治疗感染性或恶性疾病、紊乱或病症的方法,包括施用本发明所述抗体、变体或衍生物,然后在可接受的动物模型中体内测试期望的治疗性或预防性活性,最后施用于人体。合适的动物模型包括转基因动物是本领域普通技术人员所公知的。例如,用于证明本发明所述抗原结合多肽的治疗用途的体外测定包括抗原结合多肽对细胞系或患者组织样品的影响。抗原结合多肽对细胞系和/或组织样品的作用可以利用本领域技术人员已知的技术来确定,例如本发明其他部分公开的技术。根据本发明的内容,可用于确定是否施用特异性抗原结合多肽的体外测定实验包括体外细胞培养实验,其中患者组织样品在培养物中培养,并暴露于或以其他方式施用化合物,并观察这种化合物对组织样品的影响。
各种递送系统是已知的,并且可用于施用本发明抗体或编码本发明抗体的多核苷酸时,例如包封于脂质体、微粒、微胶囊、能够表达所述化合物的重组细胞、受体介导的内吞作用(参见例如Wu and Wu,1987,J.Biol.Chem.262:4429-4432)、作为逆转录病毒或其它载体的一部分的核酸的构建等。
在另一个实施例中,本发明公开的组合物与抗肿瘤剂、抗病毒剂、抗菌剂或抗生素剂或抗真菌剂组合施用。本领域任何已知的这些药剂可以在本发明公开的组合物中施用。
在另一个实施例中,本发明的组合物与化疗剂组合施用。可与本发明组合物一起施用的化疗剂包括但不限于抗生素衍生物(例如阿霉素、博来霉素、柔红霉素和放线菌素D)、抗雌激素药(如他莫昔芬)、抗代谢物(如氟尿嘧啶、5-FU、甲氨蝶呤、氟尿苷、干扰素α-2b、谷氨酸、光神霉素,巯基嘌呤和6-硫基鸟嘌呤)、细胞毒性剂(如卡莫司汀、 BCNU、洛莫司汀、CCNU、阿糖胞苷、环磷酰胺、雌莫司汀、羟基脲、甲基苄肼、丝裂霉素、白消安、顺铂和硫酸长春新碱)、激素(如甲羟孕酮、雌莫司汀磷酸钠、炔雌醇、雌二醇、醋酸甲地孕酮、甲睾酮、己烯雌酚二磷酸、氯烯雌醚和睾内酯)、氮芥衍生物(例美法仑、苯丁酸氮芥、二氯甲基二乙铵(氮芥)和噻替哌)、类固醇及其组合(如倍他米松磷酸钠),以及其它化合物(如达卡巴嗪、天冬酰胺酶、米托坦、硫酸长春新碱、硫酸长春碱和依托泊苷)。
在另一个实施例中,本发明的组合物与细胞因子组合施用。可与本发明组合物一起施用的细胞因子包括但不限于IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、抗CD40、CD40L和TNF-α。
在另外的实施例中,本发明的组合物与其他治疗的或预防的方法例如放射疗法组合施用。
组合疗法
本发明还提供了组合疗法,包括一种或多种本发明的CD73抗体连同第二抗癌剂(化治剂)一起使用。化疗剂可以通过其作用机制归类为例如以下分组:
-抗代谢物/抗癌剂,如嘧啶类似物氟尿苷、卡培他滨和阿糖胞苷;
-嘌呤类似物、叶酸拮抗剂和相关抑制剂;
-DNA损伤剂如放线菌素、安吖啶、白消安、卡铂、苯丁酸氮芥、顺铂、环磷酰胺放线菌素D、柔红霉素、阿霉素、表阿霉素、异环磷酰胺、美法仑、氮芥、丝裂霉素、米托蒽醌、亚硝基脲、甲基苄肼、紫杉醇、泰索帝、替尼泊苷、依托泊苷和三乙基硫代磷酰胺;
-抗生素如放线菌素D、柔红霉素、阿霉素、伊达比星、蒽环类抗生素、米托蒽醌、博来霉素、光神霉素(光辉霉素)和丝裂霉素等;
-酶类如L-天冬酰胺酶,其系统地代谢L-天冬酰胺并且去除不具有合成其自身天冬酰胺能力的细胞;
-抗血小板药物;
-抗增殖/抗有丝分裂的烷化剂如氮芥环磷酰胺及其类似物(美法仑、苯丁酸氮芥、六甲基三聚氰胺和噻替派)、烷基亚硝基脲(卡莫司汀)及其类似物、链脲佐菌素和三氮烯(达卡巴嗪);
-抗增殖/抗有丝分裂抗代谢物,如叶酸类似物(甲氨蝶呤);
-铂配位络合物(顺铂、奥沙利铂和卡铂)、甲基苄肼、羟基脲、米托坦和氨鲁米特;
-激素、激素类似物(雌激素、他莫昔芬、戈舍瑞林、比卡鲁胺和尼鲁米特)和芳香酶抑制剂(来曲唑和阿那曲唑);
-抗凝血剂,如肝素、合成肝素盐和其他凝血酶抑制剂;
-纤维蛋白溶解剂,如组织纤溶酶原激活剂、链激酶、尿激酶、阿司匹林、双嘧达莫、噻氯匹定和氯吡格雷;
-抗迁移剂;
-抗分泌剂(布雷韦丁);
-免疫抑制剂:他克莫司、西罗莫司、硫唑嘌呤和霉酚酸酯;
-化合物(TNP-470、染料木黄酮)和生长因子抑制剂(血管内皮生长因子抑制剂和成纤维细胞生长因子抑制剂);
-血管紧张素受体抑制剂,一氧化氮供体;
-反义寡核苷酸;
-抗体,如曲妥珠单抗和利妥昔单抗;
-细胞周期抑制剂和分化诱导剂,如维甲酸;
-抑制剂、拓扑异构酶抑制剂(阿霉素、柔红霉素、放线菌素D、西尼平苷(eniposid)、表阿霉素、依托泊苷、依达比星、伊立替康、米托蒽醌、拓扑替康和伊立替康)和皮质类固醇(可的松、地塞米松、氢化可的松、甲基强的松龙、泼尼松和泼尼松龙);
-生长因子信号转导激酶抑制剂;
-功能障碍诱导剂;
-毒素如霍乱毒素,蓖麻毒蛋白,假单胞菌外毒素,百日咳博德特氏菌腺苷酸环化酶毒素,白喉毒素和半胱天冬酶激活剂;
-和染色质。
化疗剂的其他实例还包括:
-烷基磺酸盐,如白消安、胺丙磺酯和哌泊舒凡;
-氮丙啶类,如苯并多巴、卡波醌、偏脲多巴、脲多巴;
-埃米鲁胺(emylerumines)和二甲氨基三聚氰胺(memylamelamines),包括α-烯丙基苯乙胺、三烯丙基胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三甲基三聚氰胺;
-乙酰类,特别是泡番枝辛和泡番枝辛酮;
-喜树碱,包括合成的类似物拓扑替康;
-苔藓抑素;
-愈创木素(callystatin);
-CC-1065,包括阿多来新、卡折来新和比折来新的合成类似物;
-隐藻菌素,特别是隐藻菌素1和隐藻菌素8;
-多拉司他汀;
-多卡霉素,包括合成类似物KW-2189和CBI-TMI;
-软珊瑚醇(eleutherobin);
-潘克拉他汀(pancratistatin);
-萨科迪克汀(sarcodictyin);
-海绵抑制素;
-氮芥,例如苯丁酸氮芥、氯萘嗪、环磷酰胺、雌莫司汀、异环磷酰胺、二氯甲基二乙铵、盐酸氧氮芥、美法仑、新恩比兴、苯芥胆甾醇、泼尼莫司汀、曲磷胺和尿嘧啶氮芥;
-亚硝基脲,如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和拉尼莫司汀;
-抗生素,如烯二炔抗生素(如卡里奇霉素,特别是卡里奇霉素γII和卡里奇霉素φI1)、达因霉素(dynemicin)包括达因霉素A、双磷酸盐如氯膦酸盐、埃斯波霉素、新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团、阿克拉霉素、放线菌素,安曲霉素、重氮丝氨酸、博来霉素、卡诺霉素、卡拉霉素、卡立霉素、嗜癌素、色霉素、放线菌素D、柔红霉素、地托比星、6-重氮-5-氧-L-正亮氨酸、阿霉素(包括吗啉代-阿霉素,氰基吗啉基-阿霉素,2-吡咯啉-阿霉素和脱氧阿霉素)、表柔比星、依索比星、伊达比星、马塞罗霉素、丝裂霉素如丝裂霉素C、麦考酚酸、诺卡霉素、橄榄霉素、培洛霉素、甲基丝裂霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链脲霉素、杀结核菌素、乌苯美司、净司他丁和佐柔比星;
-抗代谢物,如甲氨蝶呤和5-氟尿嘧啶(5-FU);
-叶酸类似物,例如去氨蝶呤、甲氨蝶呤、蝶罗呤和三甲曲沙;
-嘌呤类似物,如氟达拉滨、6-巯基嘌呤、硫唑嘌呤胺和硫鸟嘌呤;
-嘧啶类似物,如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨和氟尿苷;
-雄激素,如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷和睾内酯;
-抗肾上腺药物,如氨鲁米特、米托坦和曲洛司坦;
-叶酸补充体,如亚叶酸;
-单端孢菌毒素,特别是T-2毒素、疣孢霉素A(verracurin)、杆孢菌素A和蛇形菌素(anguidine);
-铂类似物,如顺铂和卡铂;
-醋葡醛内酯、醛磷酰胺糖苷、氨基乙酰丙酸、恩尿嘧啶、安吖啶、黑斯特拉布奇(hestrabucil)、比生群、依达曲沙、地福法胺(defofamine)、地美可辛、地亚醌、艾尔芬辛(elformthine)、依利醋铵、埃博霉素、乙环氧啶、硝酸镓、羟基脲、香菇多糖、亚叶酸、氯尼达明、美登木素生物碱如美登素和安丝菌素、米托胍腙、米托蒽醌;莫哌达醇、硝氨丙吖啶、喷司他丁、蛋氨氮芥、吡柔比星、洛索蒽醌、氟嘧啶、亚叶酸、鬼臼酸、2- 乙基酰肼、甲基苄肼、多糖-K(PSK)、雷佐生、根霉素、西佐糖、螺环锗、细交链孢菌酮酸、三乙撑亚胺苯醌、2,2′,2″-三尖杉酯胺(2,2',2”-tricUorotriemylamine)、氨基甲酸乙酯、长春地辛、达卡巴嗪、甘露醇氮芥、二溴甘露醇、卫矛醇、哌血生、咖胞嘧啶 (gacytosine)、阿拉伯糖苷(“Ara-C”)、环磷酰胺、噻替派、苯丁酸氮芥、吉西他滨6-硫鸟嘌呤、巯基嘌呤、甲氨蝶呤、长春碱、铂、依托泊苷(VP-16)、异环磷酰胺、米托蒽醌、长春新碱、长春瑞滨盐酸米托蒽醌、替尼泊苷;依达曲沙、柔红霉素、氨喋呤、塞罗达(xeoloda)、伊班膦酸钠、CPT-11、拓扑异构酶抑制剂RFS 2000、二氟甲基鸟氨酸(DFMO)、类视色素如视黄酸、卡培他滨、FOLFIRI (氟尿嘧啶、亚叶酸和伊立替康);
-药学上可接受的盐类、酸以及上述任一种的衍生物。
定义的“化疗剂”还包括抗激素药,如抗雌激素药和选择性雌激素受体调节剂(SERMs)、芳香酶抑制剂、抗雄激素药和上述任何一种药学上可接受的盐类、酸或衍生物,其用于调节或抑制激素对肿瘤的作用。
抗雄性激素的实例包括氟他胺、尼鲁米特、比卡鲁胺、亮脯利特和戈舍瑞林。
化疗剂的实例还包括抗血管生成剂,包括但不限于维甲酸及其衍生物、2-甲氧基雌二醇、血管抑素内皮抑素苏拉明、角鲨胺、金属蛋白酶-1的组织抑制剂、金属蛋白酶-2的组织抑制剂、纤溶酶原激活物抑制剂-1、纤溶酶原激活剂抑制剂-2、软骨衍生抑制剂、紫杉醇(nab-紫杉醇)、血小板因子4、硫酸鱼精蛋白(鲱精蛋白)、硫酸化几丁质衍生物(由皇后蟹壳制备)、硫酸化多糖肽聚糖复合物 (sp-pg)、星形孢菌素、基质代谢调节剂包括脯氨酸类似物[1-氮杂环丁烷-2-羧酸(LACA)]、顺式羟脯氨酸、d,I-3,4-脱氢脯氨酸、硫代脯氨酸、α,α’-联吡啶、β-氨基丙腈富马酸盐、4- 丙基-5-(4-吡啶基)-2(3h)-恶唑酮、甲氨喋呤、米托蒽醌、肝素、干扰素、2-巨球蛋白血清、鸡金属蛋白酶-3抑制剂(ChIMP-3)、糜蛋白酶素、β-1-环糊精十四硫酸盐、埃泼尼霉素(eponemycin)、烟曲霉素、硫代苹果酸金钠、d-青霉胺、β-1-抗胶原酶血清、α-2- 抗纤维蛋白溶酶、比生群、氯苯扎利二钠、n-2-羧基苯基-4-氯金酸二钠或“CCA”、沙利度胺、血管生成抑制类固醇、羧基氨基咪唑和金属蛋白酶抑制剂如BB-94。其它抗血管生成剂包括抗体,优选靶向这些血管生成生长因子的单克隆抗体:β-FGF、α-FGF、FGF-5、 VEGF异构体、VEGF-C、HGF/SF和Ang-1/Ang-2。
化疗剂的实例还包括抗纤维化药物,包括但不限于诸如β-氨基丙腈(BAPN)的化合物,以及在美国专利4,965,288(Palfreyman,et al.)所公开的化合物,涉及赖氨酰氧化酶抑制剂及其在治疗与胶原异常沉积有关的疾病和病症中的用途,和美国专利4,997,854(Kagan et al.)所公开的能够抑制LOX治疗各种病理性纤维化状态的化合物,其全部内容通过引用并入本文。其他代表性的抑制剂包括美国专利4,943,593(Palfreyman et al.)所公开的涉及诸如2-异丁基-3-氟-、氯-或溴-烯丙基胺的化合物,涉及2-(1-萘氧基甲基)-3-氟烯丙基胺的美国专利5,021,456(Palfreyman et al.)、5,059,714(Palfreyman etal.)、 5,120,764(Mccarthy et al.)、5,182,297(Palfreyman et al.)、和5,252,608(Palfreyman et al.),以及美国公开文本2004/0248871(Farjanel et al.),其全部内容通过引用并入本文。
代表性的抗纤维化剂还包括与赖氨酰氧化酶的活性位点的羰基反应的伯胺,更具体地说,是与羰基结合后产生通过共振稳定的产物的伯胺,例如以下伯胺:烯丙醇胺(emylenemamine)、肼、苯肼及其衍生物、氨基脲和脲衍生物、氨基腈如BAPN或2-硝基乙胺、不饱和或饱和的卤代胺如2-溴-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺和对卤代苄胺和硒高半胱氨酸内酯。
其他抗纤维化剂是能够穿透或不穿透细胞的铜螯合剂。代表性的化合物包括间接抑制剂,其能够阻断源自赖氨酰氧化酶对赖氨酰和羟赖氨酰残基的氧化脱氨基的醛衍生物。实例包括硫代胺,特别是D-青霉胺及其类似物比如2-氨基-5-巯基-5-甲基己酸、D-2-氨基 -3-甲基-3-((2-乙酰氨基乙基)二硫代)丁酸、p-2-氨基-3-甲基-3-((2-氨基乙基)二硫代) 丁酸、4-((p-1-二甲基-2-氨基-2-羧乙基)二硫代)丁烷磺酸钠,2-乙酰氨基乙基-2-乙酰氨基乙硫醇磺酸盐和4-巯基丁磺酸钠三水合物。
化疗剂的实例还包括免疫治疗剂,包括但不限于适用于治疗患者的治疗性抗体。治疗性抗体的一些实例包括辛妥珠单抗(simtuzumab)、阿巴伏单抗(abagovomab)、阿德卡妥姆单抗(adecatumumab)、阿富妥珠单抗(afutuzumab)、阿仑单抗(alemtuzumab)、阿妥莫单抗(altumomab)、阿马妥昔单抗(amatuximab)、阿纳妥姆单抗(anatumomab)、阿西莫单抗(arcitumomab)、巴维妥昔单抗(bavituximab)、贝妥莫单抗(bectumomab)、贝伐单抗(bevacizumab)、比伐单抗(bivatuzumab)、布莱纳妥姆单抗(blinatumomab)、布伦妥昔单抗(brentuximab)、坎妥珠单抗(cantuzumab)、卡妥马索单抗(catumaxomab)、西妥昔单抗(cetuximab)、西妥珠单抗(citatuzumab)、西妥木单抗(cixutumumab)、克里瓦妥珠单抗(clivatuzumab)、克那妥姆单抗(conatumumab)、达拉妥姆单抗(daratumumab)、乔奇妥单抗(drozitumab)、杜利戈妥单抗(duligotumab)、杜西吉妥单抗(dusigitumab)、地莫单抗(detumomab)、达塞妥珠单抗(dacetuzumab)、达洛妥珠单抗(dalotuzumab)、埃克洛莫昔单抗(ecromeximab)、埃洛妥珠单抗(elotuzumab)、恩西妥昔单抗(ensituximab)、厄妥马索单抗(ertumaxomab)、伊他拉昔珠单抗(etaracizumab)、法勒妥珠单抗 (farletuzumab)、菲可拉妥珠单抗(ficlatuzumab)、菲吉妥姆单抗(figitumumab)、弗兰沃妥单抗(flanvotumab)、富妥昔单抗(futuximab)、加尼妥单抗(ganitumab)、吉妥珠单抗(gemtuzumab)、吉伦妥昔单抗(girentuximab)、格兰巴妥姆单抗(glembatumumab)、替伊莫单抗(ibritumomab)、伊戈伏单抗(igovomab)、伊姆加妥珠单抗(imgatuzumab)、英达妥昔单抗(indatuximab)、伊诺妥珠单抗(inotuzumab)、因替妥姆单抗(intetumumab)、伊匹单抗(ipilimumab)、伊拉妥姆单抗(iratumumab)、拉贝妥珠单抗(labetuzumab)、来沙木单抗(lexatumumab)、林妥珠单抗(lintuzumab)、洛沃妥珠单抗(lorvotuzumab)、卢卡妥姆单抗(lucatumumab)、玛帕妥姆单抗(mapatumumab)、玛妥珠单抗(matuzumab)、米拉妥珠单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥姆单抗(mitumomab)、莫斜妥姆单抗(moxetumomab)、纳那妥单抗(narnatumab)、纳妥姆单抗(naptumomab)、内吉妥姆单抗(necitumumab)、尼莫妥珠单抗(nimotuzumab)、诺费妥单抗(nofetumomab)、奥卡妥珠单抗(ocaratuzumab)、奥法木单抗(ofatumumab)、奥拉妥珠单抗(olaratumab)、奥那妥珠单抗(onartuzumab)、奥泼妥珠单抗(oportuzumab)、奥戈伏单抗(oregovomab)、帕尼单抗(panitumumab)、帕萨妥珠单抗(parsatuzumab)、帕崔妥单抗(patritumab)、彭妥姆单抗(pemtumomab)、帕妥珠单抗(pertuzumab)、平妥姆单抗(pintumomab)、普拖木单抗(pritumumab)、拉蔻妥姆单抗(racotumomab)、拉吉妥姆单抗(radretumab)、里洛妥姆单抗(rilotumumab)、利妥昔单抗(rituximab)、洛巴妥姆单抗(robatumumab)、沙妥莫单抗(satumomab)、思布妥珠单抗(sibrotuzumab)、思妥昔单抗(siltuximab)、索力图单抗(solitomab)、塔卡妥珠单抗(tacatuzumab)、塔普利妥珠单抗(taplitumomab)、特纳妥姆单抗(tenatumomab)、特普洛妥姆单抗(teprotumumab)、提咖妥珠单抗(tigatuzumab)、拖西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、图库图珠单抗(tucotuzumab)、尤不理妥昔单抗(ublituximab)、维尔妥珠单抗(veltuzumab)、沃思妥珠单抗(vorsetuzumab)、伏妥莫单抗(votumumab)、扎鲁妥姆单抗(zalutumumab)、CC49和3F8。利妥昔单抗可用于治疗惰性B细胞癌,包括边缘区淋巴瘤、WM、CLL和小淋巴细胞性淋巴瘤。利妥昔单抗和化疗药物的组合是特别有效的。
代表性治疗性抗体可以进一步被标记或与放射性同位素颗粒例如铟-111、钇-90或碘 -131组合。
在一个实施例中,另外的治疗剂是氮芥烷基化剂。氮芥烷化剂的非限制性实例包括苯丁酸氮芥。
在一个实施例中,本文所述化合物和组合物可以与一种或多种其它治疗剂一起使用或组合。所述一种或多种治疗剂包括但不限于Abl抑制剂、活化的CDC激酶(ACK)、腺苷A2B受体(A2B)、凋亡信号调节激酶(ASK)、Auroa激酶、布鲁顿氏酪氨酸激酶 (BTK)、BET-溴结构域(BRD)如BRD4、c-Kit、c-Met、CDK激活激酶(CAK)、钙调蛋白依赖性蛋白激酶(CaMK)、细胞周期蛋白依赖性激酶(CDK)、酪蛋白激酶(CK)、盘状结构域受体(DDR)、表皮生长因子受体(EGFR)、粘着斑激酶(FAK)、Flt-3、FYN、糖原合酶激酶(GSK)、HCK、组蛋白脱乙酰酶(HDAC)、IKK如IKKβε、异柠檬酸脱氢酶(IDH)如IDH1、Janus激酶(JAK)、KDR、淋巴细胞特异性蛋白酪氨酸激酶(LCK)、赖氨酰氧化酶蛋白质、赖氨酰氧化酶样蛋白(LOXL)、LYN、基质金属蛋白酶(MMP)、 MEK、有丝分裂原激活蛋白激酶(MAPK)、NEK9、NPM-ALK、p38激酶、血小板衍生生长因子(PDGF)、磷酸化酶激酶(PK)、polo样激酶(PLK)、磷脂酰肌醇3-激酶(PI3K)、蛋白激酶(PK)如蛋白激酶A、B和/或C、PYK、脾酪氨酸激酶(SYK)、丝氨酸/苏氨酸激酶TPL2、丝氨酸/苏氨酸激酶STK、信号转导和转录(STAT)、SRC、丝氨酸/苏氨酸蛋白激酶(TBK)如TBK1、TIE、酪氨酸激酶(TK)、血管内皮生长因子受体(VEGFR) 或以上任何组合。
ASK抑制剂包括ASK1抑制剂。ASK1抑制剂的实例包括但不限于在WO 2011/008709(Gilead Sciences)和WO 2013/112741(Gilead Sciences)中所述的抑制剂。
BTK抑制剂的实例包括但不限于依鲁替尼、HM71224、ONO-4059和CC-292。
DDR抑制剂包括DDR1和/或DDR2的抑制剂。DDR抑制剂的实例包括但不限于在 WO2014/047624(Gilead Sciences)、US 2009/0142345(武田药品)、US 2011/0287011(Oncomed制药)、WO 2013/027802(中外制药)和WO 2013/034933(帝国创新)中公开的那些抑制剂。
HDAC抑制剂的实例包括但不限于普拉西诺司他(pracinostat)和帕诺比诺司他(panobinostat)。
JAK抑制剂抑制JAK1、JAK2和/或JAK3。JAK抑制剂的实例包括但不限于:菲格替尼(filgotinib)、鲁索替尼、费德拉替尼(fedratinib)、托法替尼、巴瑞替尼、来他替尼、帕瑞替尼(pacritinib)、XL019、AZD1480、INCB039110、LY2784544、BMS911543和NS018。
LOXL抑制剂包括LOXL1、LOXL2、LOXL3、LOXL4和/或LOXL5的抑制剂。LOXL 抑制剂的实例包括但不限于WO 2009/017833(Arresto Biosciences)中所述的抗体。
LOXL2抑制剂的实例包括但不限于WO 2009/017833(Arresto Biosciences)、WO2009/035791(Arresto Biosciences)和WO 2011/097513(Gilead Biologics)中所述的抗体。
MMP抑制剂包括MMP1-10的抑制剂。MMP9抑制剂的实例包括但不限于马立马司他(BB-2516)、西马司他(cipemastat,Ro 32-3555)和WO 2012/027721(Gilead Biologics)中所述的抑制剂。
PI3K抑制剂包括PI3Kγ、PI3Kδ、PI3Kβ、PI3Kα和/或pan-PI3K抑制剂。PI3K抑制剂的实例包括但不限于渥曼青霉素、BKM120、CH5132799、XL756和GDC-0980。
PI3Kγ抑制剂的实例包括但不限于ZSTK474、AS252424、LY294002和TG100115。
PI3Kδ抑制剂的实例包括但不限于PI3K II、TGR-1202、AMG-319、GSK2269557、 X-339、X-414、RP5090、KAR4141、XL499、OXY111A、IPI-145、IPI-443,以及在WO 2005/113556(ICOS)、WO 2013/052699(Gilead Calistoga)、WO 2013/116562(Gilead Calistoga)、WO2014/100765(Gilead Calistoga)、WO 2014/100767(Gilead Calistoga)和 WO 2014/201409(Gilead Sciences)中所述的化合物。
PI3Kβ抑制剂的实例包括但不限于GSK2636771、BAY10824391和TGX221。
PI3Kα抑制剂的实例包括但不限于布帕里斯泊(buparlisib)、BAY 80-6946、BYL719、PX-866、RG7604、MLN1117、WX-037、AEZA-129和PA799。
pan-PI3K抑制剂的实例包括但不限于LY294002、BEZ235、XL147(SAR245408)和GDC-0941。
SYK抑制剂的实例包括但不限于塔玛替尼(tamatinib,R406)、福斯塔玛替尼(fostamatinib,R788)、PRT062607、BAY-61-3606、NVP-QAB205AA、R112、R343以及美国专利8,450,321(Gilead Connecticut)所述的抑制剂。
TKI可以靶向表皮生长因子受体(EGFR)以及成纤维细胞生长因子(FGF)受体、血小板衍生生长因子(PDGF)受体和血管内皮生长因子(VEGF)受体。靶向EGFR的 TKI的实例包括但不限于吉非替尼和厄洛替尼。舒尼替尼是靶向FGF、PDGF和VEGF受体的TKI的非限制性实例。
与免疫检查点抑制剂的组合使用
在一些实施例中,本发明的CD73抗体可以与免疫检查点抑制剂一起使用。免疫检查点是免疫系统中的一类分子,其可以是一种上调信号(共刺激分子)或是一种下调信号。许多癌症通过抑制T细胞信号来保护自己免受免疫系统的攻击。免疫检查点抑制剂可以帮助阻止这种保护机制。免疫检查点抑制剂可以靶向以下检查点分子中的任何一个或多个:PD-1、PD-L1、CTLA-4、LAG-3(也称为CD223)、CD28、CD122、4-1BB(也称为CD137)或BTLA(也称为CD272)。
程序性T细胞死亡1(PD-1)是在T细胞表面发现的跨膜蛋白,当其与肿瘤细胞上的程序性T细胞死亡配体1(PD-L1)结合时,会抑制T细胞的活性和降低T细胞介导的细胞毒性。因此,PD-1和PD-L1是免疫下调或免疫检查点“切断开关”。PD-1抑制剂的实例包括但不限于纳武单抗(nivolumab,Opdivo,BMS-936558)、派姆单抗(Keytruda)、皮德里珠单抗(pidilizumab)、AMP-224、MEDI0680(AMP-514)、PDR001、MPDL3280A、 MEDI4736、BMS-936559和MSB0010718C。
程序性死亡配体1(PD-L1)也被称为分化簇274(CD274)或B7同源体1(B7-H1),其是人类中由CD274基因编码的蛋白质。PD-L1抑制剂的非限制性实例包括阿特朱单抗(Tecentriq)、德瓦鲁单抗(Durvalmab,MEDI4736)、阿维鲁单抗(Avelumab, MSB0010718C)、MPDL3280A、BMS935559(MDX-1105)和AMP-224。
CTLA-4是下调免疫系统的蛋白受体。CTLA-4抑制剂的非限制性实例包括伊匹单抗(Yervoy,也称为BMS-734016、MDX-010、MDX-101)和替里米姆单抗[tremelimumab,曾被称为替契利姆单抗(ticilimumab)、CP-675、206]。
淋巴细胞激活基因3(LAG-3)是位于细胞表面的一类免疫检查点受体,其通过作用于Treg或直接作用于CD8+T细胞,从而抑制免疫应答。LAG-3抑制剂包括但不限于 LAG525和BMS-986016。
CD28几乎于所有的人CD4+T细胞上和大约一半的CD8+T细胞上组成性表达,其能够促进T细胞扩增。其非限制性实例包括TGN1412。
CD122能够提高CD8+效应T细胞的增殖。其非限制性实例包括NKTR-214。
4-1BB(也称为CD137)参与T细胞增殖。CD137介导的信号传导也被证实能够保护T细胞,特别是使CD8+T细胞免于激活诱导的细胞死亡。CD137抑制剂的实例包括 PF-05082566、Urelumab(BMS-663513)和脂质运载蛋白。
对于任何上述组合治疗,CD73抗体可以与另一种抗癌剂同时或分开施用。当单独施用时,可以在施用另一种抗癌剂之前或之后施用CD73抗体。
诊断方法
在某些肿瘤样品中观察到CD73的过表达,并且具有CD73过表达的细胞的患者可能对使用本发明的CD73抗体的治疗有反应。因此,本发明的抗体也可以用于诊断和预后。
优选包含细胞的样品可以从患者体内获得,该患者可以是癌症患者或希望诊断的患者。细胞是肿瘤组织或肿瘤块、血液样本、尿液样本或来自患者的任何样本的细胞。在选择性地对样品进行预处理之后,可以在允许抗体与可能存在于样品中的CD73蛋白相互作用的条件下,将样品与本发明的抗体一起孵育。可以使用诸如ELISA的方法,利用CD73 抗体来检测样品中CD73蛋白的存在。
样品中CD73蛋白的存在(任意的含量或浓度)可以用于诊断癌症,其可以作为患者适用抗体治疗的指示,或作为患者已经(或没有)对癌症治疗作出反应的指示。对于预后方法,可以在开始癌症治疗时在特定阶段进行一次、两次或更多次地检测,以指示治疗的进展。
组合物
本发明还提供了药物组合物。这样的组合物包含有效剂量的抗体和可接受的载体。在一些实施例中,组合物还包含第二种抗癌制剂(如一种免疫检查点抑制剂)。
在一个具体实施例中,术语“药学上可接受的”是指由联邦或州政府的监管机构批准的或在美国药典或其他公认的药典中列出的用于动物,特别是用于人类的药物。此外,“药学上可接受的载体”通常将是任何类型的无毒固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。
术语“载体”是指施用于治疗的稀释剂、佐剂、赋形剂或载体。此类药物载体可以是无菌液体,如水和油,包括石油、动植物或合成来源的油,如花生油、大豆油、矿物油、芝麻油等。当药物组合物静脉内给药时,水是优选的载体。盐水溶液和葡萄糖水溶液和甘油溶液也可用作液体载体,特别是用于注射溶液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如有需要,组合物还可以含有少量的润湿剂或乳化剂,或pH缓冲剂如乙酸盐、柠檬酸盐或磷酸盐。抗菌剂如苯甲醇或对羟基苯甲酸甲酯、抗氧化剂如抗坏血酸或亚硫酸氢钠、螯合剂如乙二胺四乙酸,以及调节张力的试剂如氯化钠或右旋葡萄糖在本发明中也是可以预见的。这些组合物可以采取溶液剂、悬液、乳剂、片剂、丸剂、胶囊剂、散剂、缓释制剂等形式。该组合物可以用传统的粘合剂和载体如甘油三酯配制成栓剂。口服制剂可以包括标准载体,例如药物等级的甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。合适的药物载体的实例在E.W.Martin的Remington's PharmaceuticalSciences中有所描述,在此通过引用并入本发明。此类组合物将含有临床有效剂量的抗原结合多肽,优选以纯化后的形式,连同合适数量的载体,以提供适合于患者的给药形式。该制剂应该适用于给药模式。亲本制剂可以封装在安瓿瓶、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
在一个实施例中,根据常规步骤将组合物配制成适合静脉内注射于人体的药物组合物。具有代表性地是,用于静脉内给药的组合物是在无菌等渗水性缓冲液中的溶液。必要时,组合物还可包含增溶剂和局部麻醉剂如利多卡因,从而缓解注射部位的疼痛。一般而言,有效成分以单位剂量形式单独供给或混在一起供给,如以干燥的冻干粉末或无水浓缩物的形式装在可指示活性剂份量的密封容器如安瓿瓶或小袋中。在通过输注施用组合物的情况下,可以用含有无菌药用级水或盐水的输液瓶来分装组合物。在通过注射施用组合物的情况下,可以使用注射用的无菌水或盐水的安瓿瓶,使得可以在施用之前混合有效成分。
本发明的化合物可以配制成中性的或盐的形式。药学上可接受的盐包括衍生自如盐酸、磷酸、乙酸、草酸、酒石酸等的与阴离子形成的盐,以及衍生自如钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的与阳离子形成的盐。
实施例1.鼠抗体101-Mu的克隆
本实施例描述了使用杂交瘤技术制备抗人CD73小鼠单克隆抗体的方法。使用表达CD73的重组CHOK1细胞系(CD73-CHOK1)制备人CD73蛋白。为生产抗人CD73的小鼠单克隆抗体,首先用1.5×107个CD73-CHOK1细胞对6-8周的雌性BALB/c小鼠进行免疫。首次免疫后的第14天和第33天,用1.5×107个CD73-CHOK1细胞对免疫后的小鼠进行再次免疫。为选出能够产生与CD73蛋白结合的抗体的小鼠,用ELISA法对免疫后的小鼠血清进行检测。简言之,用1μg/ml的人CD73蛋白PBS溶液包被微孔板, 100μl/孔,室温(RT)过夜,然后用100μl/孔的5%BSA封闭。将来自免疫小鼠的血浆稀释液加入到每个孔中,室温孵育1~2小时。用PBS/Tween洗涤微孔板,然后加入缀合了辣根过氧化物酶(HRP)的抗小鼠IgG抗体,室温孵育1小时。洗板后,在微孔板中加入ABTS底物并用分光光度计在OD405nm的条件下分析数值。在免疫后第54天,用 50μg的人CD73-Fc蛋白对有足够效价的抗CD73IgG的小鼠进行加强免疫。所得小鼠用于融合。用ELISA实验检测杂交瘤上清液中的抗CD73IgG。8个不同的杂交瘤克隆被鉴定出来,其中101-Mu被选出用于进一步分析。101-MU的VH序列在表6中显示为SEQ ID NO:10,VL序列在表7和SEQ ID NO:15显示。相应的DNA序列在表10中显示为SEQ ID NO:57和58。
实施例2. 101-Mu对CD73的结合
本实施例检测了小鼠抗CD73单克隆抗体(mAb)101-Mu与重组人CD73蛋白(1ug /ml@100ul)的ELISA结合的剂量响应,所述重组人CD73蛋白可以是单独存在或存在于细胞表面。
用1μg/ml的重组人CD73蛋白(Novoprotein)PBS溶液室温下包被微孔板2小时。包被抗原后,用含有1%BSA的PBS/0.05%吐温(PBST)在室温封闭微孔板1小时。用 PBST洗涤各孔后,将不同浓度的抗CD73抗体加入到孔中并在室温下孵育1小时。为了检测结合的抗体,加入缀合了HRP的抗小鼠Fc的第二抗体(Jackson Immuno Research),然后加入荧光底物(Roche)。在所有孵育的步骤之间,微孔板的孔均用PBST洗涤三次。在TECANSpectrafluor读板器中检测荧光。
用人抗CD73,即mAb1作为阳性对照。根据US2016/0194407中公开的序列生产mAb1。比较的结果在图中呈现,其显示101-Mu的EC50为0.08nM,mAb1的EC50为 0.03nM。
图2显示使用了内源表达人CD73于细胞表面的人卵巢癌细胞系(SK-OV-3细胞) 的结合测定的结果。与指定抗体进行孵育后,用不同浓度的IgG对照、小鼠抗CD73(101- Mu)抗体和参考抗体(mAb1)对细胞在4℃染色30分钟。然后,用PBS洗涤细胞三次,再与APC标记的抗小鼠Fc特异性抗体(Invitrogen)在4℃孵育30分钟。使用FACSCanto (Becton-Dickinson)检测所述结合。与图1类似,该图显示101-Mu具有与mAb1等效的对CD73的结合亲和力(对于101-Mu,EC50为0.54nM;对于mAb1,EC50为0.30 nM)。
图3绘制了重组人CD73与101-Mu和mAb1的结合动力学(重组人CD73被设定为具有连续浓度(100、50、25、12.5、6.25、3.125nM)的分析物)。抗体对抗原的结合动力学采用人抗体捕获方法并使用Biacore T200系统进行检测。根据制造商的说明书,将抗小鼠Fc IgG固定在CM5传感器芯片上。注射被测抗体,并通过固定化的抗人Fc IgG 进行捕获。然后分别注射一系列浓度的抗原,并分别记录每种浓度抗原分析物的结合谱。通过注射pH为1.5的10mM甘氨酸-HCl,持续30秒来再生该检测系统。运行缓冲液是 HBS-EP+(10mM HEPES,pH 7.4,150mM NaCl,3mM EDTA和0.05%P20)。测定温度为25℃,结合和解离时间分别为180和600秒。使用Biacore T200评估软件1.0,根据 1:1结合模型拟合Biacore的数据以计算结合(ka)和解离(kd)速率常数以及平衡常数 (KD)。除了图3之外,下表列出了一些汇总数据。
样品 | ka(1/Ms) | kd(1/s) | KD(M) |
101-Mu | 8.13E+04 | 3.42E-05 | 4.21E-10 |
mAb1 | 2.08E+05 | 2.73E-05 | 1.31E-10 |
实施例3. 101-Mu对CD73酶活性的抑制
本实施例检测了101-Mu抗体抑制CD73酶活性的能力。
在不同剂量的抗CD73或同种型对照抗体存在的情况下,将重组人CD73蛋白(0.3ug/ml)在96孔平底微量培养板中孵育。将平板在37℃孵育15分钟,然后加入ATP(100 uM)和AMP(100uM)至每孔中,37℃孵育30分钟。将含荧光素酶的CellTiter-Glo (Promega)加入到平板的孔中,并通过光度计(Molecular Device)检测光发射的抑制。
已知过量的AMP能够阻断ATP依赖性的萤光素酶活性。添加能够催化AMP产生腺苷和无机磷酸盐的CD73可以恢复萤光素酶活性和光发射。因此,阻断CD73酶活性的抗体可以减少光发射。酶活性的百分比按照如下所述进行评估:残余CD73的活性计算为:(CD73+Ab+ATP+AMP)-(ATP+AMP)/(CD73+ATP+AMP)-(ATP+AMP)*100。结果绘制在图4中,其显示与阴性对照IgG不同的是,101-Mu剂量依赖性地抑制了CD73的酶活性(IC50=3.89nM)。
在不同剂量的CD73抗体或同种型对照抗体存在的情况下,将表达CD73的SK-OV- 3细胞以1×105个细胞/孔接种到96孔板中。将平板在37℃孵育15分钟后,将AMP(100 uM)加入到每个孔中并在37℃孵育1小时。将上清液收集到新的96孔板中,加入ATP 至终浓度为100μM。将CellTiter-Glo试剂(Promega)以1:1加入,并通过测量光发射的光度计(Molecular Device)测定细胞中CD73的酶活性。酶活性的百分比按照如下所述进行评估:残余CD73活性计算为:(SK-OV-3细胞+Ab+ATP+AMP)-(ATP+AMP)/(SK- OV-3细胞+ATP+AMP)-(ATP+AMP)*100。结果绘制在图5中,其显示与阴性对照IgG不同的是,101-Mu剂量依赖性地抑制了CD73的酶活性(IC50=4.62nM)。
实施例4. 101-Mu对AMP介导的CD4+ T细胞抑制的逆转
本实施例检测了抗体逆转AMP介导的CD4+ T细胞抑制的能力。
人CD4+ T细胞通过使用人CD4微珠(Miltenyi Biotech)利用阳性选择从PBMC中纯化出来。在AMP(500μM)存在或不存在的情况下,用预先包被的抗CD3抗体(2 μg/ml)和可溶性抗CD28抗体(1μg/ml)刺激分离的CD4+ T细胞。将CD73抗体和对照IgG的一系列稀释液加入到每个孔中并培养72小时,并利用ELISA分析上清液中的 IFN-γ。如图6所示,101-Mu剂量依赖性地增加了CD4+细胞中IFN-γ的产生,而对照则无相关影响。
实施例5. 101-Mu的人源化
以上实施例显示了101-Mu抗体是CD73酶活性的有效抑制剂,并且可以完全逆转腺苷对T细胞活化的免疫抑制作用。因此,选择该抗体作为人源化的基础。
使用101-Mu可变区基因来创建人源化MAb。将101-MU的Rhe VH和VK与可用的人Ig基因序列数据库进行比较,以鉴定总体最佳匹配的人种系Ig基因序列。对于轻链来说,最接近的人类匹配序列是A10/Jk4(设计1)和L6/Jk4(设计2)基因,对于重链来说,最接近的人类匹配序列是VH4-B/JH6基因。然后设计人源化可变区序列,其中将 101-MU轻链的CDR1(SEQID NO.4)、2(SEQ ID NO.5)和3(SEQ ID NO.6)移植到匹配的轻链基因的框架序列上,并且将101-MU VH的CDR1(SEQ ID NO.1)、2(SEQ ID NO.2)和3(SEQ ID NO.3)序列移植到匹配的VH基因的框架序列上。
然后建立3D模型,以确定是否存在任何将小鼠氨基酸取代为人氨基酸的框架位置会影响结合和/或CDR构象。下表列出了鉴定的有用的回复突变以及包含此类突变的肽序列(下划线)。
表3 VH回复突变和具有回复突变的VH序列:
表4 VK回复突变和具有回复突变的VK序列(设计1):
表5 VK回复突变和具有回复突变的VK序列(设计1):
表6 人源化VH和具有回复突变的人源化VH:
粗体:CDR区域;下划线:回复突变
表7 人源化VK和具有回复突变的人源化VK(设计1):
表8 人源化VK和具有回复突变的人源化VK(设计2):
粗体:CDR区域;下划线:回复突变
人源化VH和VK基因是通过合成产生的,然后分别克隆到含有人γ1和人κ恒定结构域的载体中。人VH和人VK的配对产生了许多如下表所列出的人源化抗体。
表9 人源化抗体
表10显示编码101-MU和Hu101-28抗体的VH和VL区的几个示例性核苷酸序列。
表10 核苷酸序列
实施例6.人源化抗体的检测
本实施例检测了人源化抗体的结合亲和力和抑制活性。检测程序与实施例1-4中所述的那些类似,结果显示在图7-11中。
采用人抗体捕获方法并使用Biacore T200系统对于结合试验进行检测。根据制造商的说明,将抗人Fc IgG固定在CM5传感器芯片上。注射被测抗体,并提供固定化的抗人FcIgG进行捕获。然后分别注射一系列浓度的抗原,并分别记录每种浓度抗原分析物的结合谱。通过注射pH为1.5的10mM甘氨酸-HCl,持续30秒来再生该检测系统。运行缓冲液是HBS-EP+(10mM HEPES,pH 7.4,150mM NaCl,3mM EDTA和0.05%P20)。测定温度为25℃,结合和解离时间分别为180和600秒。使用Biacore T200评估软件1.0,根据1:1结合模型拟合Biacore的数据,以计算结合(ka)和解离(kd)速率常数以及平衡常数(KD)。
在所有检测的抗体中,Hu101-25和Hu101-28显示出最高的结合亲和力(参见图7和下表),并被用于接下来的分析。
样品 | ka(1/Ms) | kd(1/s) | KD(M) |
Hu101-25 | 7.37E+04 | 5.51E-05 | 7.47E-10 |
Hu101-28 | 5.89E+05 | 3.47E-05 | 5.90E-10 |
使用不同浓度的IgG对照、嵌合的抗CD73(101-Mu-Chimeric或101-Chi)和人源化抗CD73抗体(Hu101-25和Hu101-28)对内源表达人CD73于细胞表面的人卵巢癌细胞系(SK-OV-3细胞)在℃染色30分钟。然后,用PBS洗涤细胞三次,接着在4℃下与 APC标记的抗人Fc特异性抗体(Invitrogen)孵育30分钟。使用FACSCanto(Becton- Dickinson)检测该结合,结果显示在图8中。(另见下表)。
101-嵌合体 | EC50=1.35nM |
Hu101-25 | EC50=2.38nM |
Hu101-28 | EC50=1.35nM |
在不同剂量的抗CD73抗体或同种型对照抗体存在的情况下,将重组人CD73蛋白(0.3ug/ml)在96孔平底微量板中进行孵育。将平板在37℃孵育15分钟。然后每孔加入ATP(100μM)和AMP(100μM),并在37℃继续孵育30分钟。将含荧光素酶的 CellTiter-Glo(Promega)加入到孔中,并通过光度计(Molecular Device)检测光发射的抑制。已知过量的AMP能够阻断ATP依赖性的萤光素酶的活性。添加催化AMP产生腺苷和无机磷酸盐的CD73可以恢复萤光素酶活性和光发射。因此,阻断CD73酶活性的抗体将减少光发射。酶活性的百分比按照如下所述进行评估:残余CD73的活性为: (CD73+Ab+ATP+AMP)-(ATP+AMP)/(CD73+ATP+AMP)-(ATP+AMP)*100。
图9显示了所有三种被测抗体都显示出强烈的抑制活性(另见下表)。
IC50(nM) | 最大抑制率(%) | |
101-嵌合体 | 4.25 | 98% |
Hu101-25 | 4.72 | 99% |
Hu101-28 | 9.35 | 98% |
图10显示了人源化抗体对CD73酶活性的抑制的检测结果。在不同剂量的抗CD73抗体或同种型对照抗体存在的情况下,将表达CD73的SK-OV-3细胞以1×105个细胞/孔接种到96孔板中。将孔板在37℃孵育15分钟,然后每孔加入AMP(100μM),于37℃孵育1小时。收集上清至新的96孔板,加入ATP使其终浓度为100μM。以1:1加入 CellTiter-Glo试剂(Promega),并通过测量光发射光度计(Molecular Device)测定细胞性的CD73酶活性。酶活性的百分比按照如下所述进行评估:残余CD73的活性为:(SK- OV-3细胞+Ab+ATP+AMP)-(ATP+AMP)/(SK-OV-3细胞+ATP+AMP)-(ATP+AMP)*100。结果显示在图10及下表中,其证明了这些抗体的有效抑制作用。
为了检测抗体对AMP介导的CD4+ T细胞抑制进行逆转的能力,使用人类CD4微珠(Miltenyi Biotech)通过阳性选择从PBMC中纯化出人类CD4+ T细胞。在AMP(500 μM)存在或不存在的情况下,用预先包被的抗CD3抗体(2μg/ml)和可溶性抗CD28抗体(1μg/ml)刺激分离的CD4+ T细胞。在每个孔中加入一系列抗CD73抗体和对照IgG 的稀释液并培养72小时,通过ELISA分析上清液中的IFN-γ。如图11所示,所有三种被测抗体剂量依赖性地逆转了AMP介导的CD4+ T细胞抑制。
实施例7.人源化抗体的进一步变化和优化的计算机模拟
预期CDR区或框架区内的某些氨基酸残基可被改变以进一步改善或保留抗体的活性和/或稳定性。针对其结构、构象和功能特性,使用计算工具(VectorNTI,可从www.ebi.ac.uk/tools/msa/clustalo/获得)对变体进行检测,并且那些(在CDR区域内)显示有潜力的变体在下表中列出。
表11.适合包含在人源化抗体中的VH和VL CDR及其变体:
名称 | 序列 | SEQ ID NO: |
VH CDR1 | <u>SGY</u>YWN | 1 |
Variant | <u>T</u>GYYWN | 26 |
Variant | <u>C</u>GYYWN | 27 |
Variant | S<u>A</u>YYWN | 28 |
Variant | S<u>P</u>YYWN | 29 |
名称 | 序列 | SEQ ID NO: |
VH CDR2 | YINYG<u>GSN</u>GY NPSLKS | 2 |
Variant | YINYG<u>A</u>SNGY NPSLKS | 30 |
Variant | YINYG<u>P</u>SNGY NPSLKS | 31 |
Variant | YINYGG<u>T</u>NGY NPSLKS | 32 |
Variant | YINYGG<u>C</u>NGY NPSLKS | 33 |
Variant | YINYGGS<u>D</u>GY NPSLKS | 34 |
Variant | YINYGGS<u>E</u>GY NPSLKS | 35 |
Variant | YINYGGS<u>Q</u>GY NPSLKS | 36 |
名称 | 序列 | SEQ ID NO: |
VH CDR3 | DYDAYY<u>EA</u>LD D | 3 |
Variant | DYDAYY<u>DA</u>LD D | 37 |
Variant | DYDAYY<u>Q</u>ALD D | 38 |
Variant | DYDAYY<u>N</u>ALD D | 39 |
Variant | DYDAYYE<u>G</u>LD D | 40 |
Variant | DYDAYYE<u>C</u>LD D | 41 |
名称 | 序列 | SEQ ID NO: |
VL CDR1 | RA<u>SS</u>RVNYM H | 4 |
Variant | RA<u>T</u>SRVNYM H | 42 |
Variant | RA<u>C</u>SRVNYM H | 43 |
Variant | RAS<u>T</u>RVNYM H | 44 |
Variant | RAS<u>C</u>RVNYM H | 45 |
名称 | 序列 | SEQ ID NO: |
VL CDR3 | <u>QQWSS</u>NPPT | 6 |
Variant | <u>N</u>QWSSNPPT | 46 |
Variant | <u>D</u>QWSSNPPT | 47 |
Variant | <u>E</u>QWSSNPPT | 48 |
Variant | Q<u>N</u>WSSNPPT | 49 |
Variant | Q<u>D</u>WSSNPPT | 50 |
Variant | Q<u>E</u>WSSNPPT | 51 |
Variant | QQ<u>Y</u>SSNPPT | 52 |
Variant | QQW<u>T</u>SNPPT | 53 |
Variant | QQW<u>C</u>SNPPT | 54 |
Variant | QQWS<u>T</u>NPPT | 55 |
Variant | QQWS<u>C</u>NPPT | 56 |
下划线:热点突变残基及其替代物
实施例8.Hu101-28是一种双重机制的抗CD73抗体
本实例显示了Hu101-28具有双重的作用机制。它不仅以非竞争性的方式阻断了CD73的酶活性,而且诱导了细胞表面CD73的内化。
用可溶性的和细胞表面的CD73检测CD73蛋白的结合,结果显示在图12中。在左图中,100μl含有重组人CD73(2μg/ml)的溶液用于ELISA结合测定,图表显示Hu101- 28。在右图中,用不同浓度的Hu101-28对人卵巢癌细胞系(SK-OV-3)进行染色,并通过流式细胞技术分析表面的结合。如图所示,该测试中EC50分别为88.7pM和0.67nM,其强调了抗体的高亲和力。
接着,Hu101-28阻断CD73活性的能力。将重组人CD73(0.3μg/ml)与Hu101-28 孵育15分钟。然后再加入ATP(100μM)和AMP(100μM)进行孵育30分钟。加入 CellTiter-Glo(Promega)并通过光度计检测光发射的抑制。如图13所示,在左图中,溶液中IC50为2.84nM。对于在细胞发现中的CD73,将SK-OV-3或MDA-MB-231细胞 (1×105个细胞)与Hu101-28孵育15分钟,然后依次加入AMP(100μM)和ATP(100 μM),继续孵育1小时。加入CellTiter-Glo(Promega)并通过光度计检测光发射的抑制。如图13所示,在右图中,SK-OV-3和MDA-MB-231的IC50分别为2.52nM和8.21nM。
进一步的实验显示,Hu101-28不与AMP底物竞争性地结合活性位点,但是变构地或通过其他非竞争性的机制起作用,该机制在避免与多种内源性AMP底物竞争的需要方面是更优选的。如图14所示,增加AMP底物的浓度并不能阻止Hu101-28对水解的抑制,表明Hu101-28充当了非竞争性抑制剂的作用。相比之下,ADP的抑制活性可以通过增加底物的浓度使其超过与活性位点结合的ADP来克服。
在图15中显示出了令人惊讶和意外的发现。Hu101-28结合后CD73的内化通过流式细胞技术检测细胞表面的CD73水平或在缀合了毒素的第二抗体的存在下使用Hu309 结合后检测MDA-MB-231细胞的活力被证实。与不改变细胞表面CD73水平的IgG相比,Hu101-28在6小时内(左图)导致细胞表面CD73的水平降低了一半以上,甚至导致更显著的细胞杀伤力(右图)。
因此,上述实验证实了Hu101-28具有双重的作用机制(MoA):以非竞争性的方式阻断CD73的酶活性并诱导细胞表面CD73的内化。
实施例9.Hu101-28完全逆转了AMP或肿瘤细胞介导的CD4+和CD8+ T细胞应答的抑制
本实施例显示Hu101-28完全逆转了AMP和肿瘤细胞介导的CD4+和CD8+ T细胞应答的抑制。
用CFSE标记人类CD4+或CD8+ T细胞,并在AMP存在或不存在的情况下用抗 CD3/CD28抗体进行刺激。将Hu101-28加入到培养物中培养72小时。通过ELISA分析培养上清液中IFN-g的产生。在图16的左图中,Hu101-28剂量依赖性地增加了CD4+细胞中IFN-γ的产生。同样,如右图所示,Hu101-28剂量依赖性地增加了CD8+细胞中IFN- γ的产生。
为了检测Hu101-28对肿瘤细胞介导的T细胞应答的抑制的影响,用丝裂霉素C处理表达CD73的SK-OV-3细胞,并在抗CD3/CD28抗体存在的情况下与纯化的CD4+或 CD8+ T细胞共培养。将Hu101-28加入到培养物中培养72小时,通过ELISA分析上清液中IFN-γ的产生。如图17的左图所示,Hu101-28剂量依赖性地增加CD4+细胞中IFN- γ的产生。同样,如右图所示,Hu101-28剂量依赖性地增加了CD8+细胞中IFN-γ的产生。
实施例10.Hu101-28抑制肿瘤生长
本实施例证明Hu101-28在对肿瘤衍生的CD73活性的抑制方面是有效的,通过单一的或组合的治疗导致抑制肿瘤的生长。
体内CD73的酶活性通过在A375异种移植肿瘤模型中进行酶组织化学来检测,染色结果如图18中所示。棕色表示有活性的CD73的存在,而棕色的缺乏表明CD73酶的活性被抗体抑制。收集用Hu101-28或IgG对照处理的A375异种移植模型的肿瘤,结果显示与IgG对照组相比,Hu101-28的处理显著降低了肿瘤切片中CD73的活性。
在肿瘤异种移植模型中还评估了Hu101-28的单一治疗功效。将A375黑素瘤细胞和人PBMC移植到NSG免疫缺陷小鼠中。在移植当天,通过腹膜内注射给荷瘤小鼠施用不同剂量的Hu101-28或IgG对照,并每隔一天注射一次。如图19所示,Hu101-28剂量依赖性地并可持续地抑制肿瘤的生长。
评估Hu101-28和抗PD-L1抗体的组合效应。将HCC827细胞移植入NSG小鼠中。当肿瘤体积达到100-150mm3时,通过尾静脉注射将新鲜分离的人类PBMC施用于荷瘤小鼠,随后从PBMC移植起每隔一天以指定的剂量用IgG对照、单独的PD-L1抗体、单独的Hu101-28以及PD-L1抗体加上Hu101-28进行处理。图20显示Hu101-28与抗PD- L1抗体之间的协同效应。
实施例11.Hu101-28与Cyno CD73交叉反应
本实施例显示人源化抗体Hu101-28与食蟹猴CD73交叉反应,并在探索性临床前研究中发挥可接受的PK和安全性概况。
图21显示Hu101-28对食蟹猴CD73活性的结合和抑制作用。通过体外生物化学测定,Hu101-28在结合和抑制食蟹猴CD73活性方面具有与结合和抑制人CD73相比相当的效力,而Hu101-28不与啮齿动物CD73结合。这个结果支持了将食蟹猴用于非临床研究模型以评估Hu101-28的毒性、PK和TK。
实施例12.Hu101-28与CD73的C端结构域结合
本实施例显示人源化的抗体之一Hu101-28与CD73蛋白的C端结构域结合,该C端结构域不同于已知的与N-末端结构域结合的抗CD-73抗体。
通过竞争性ELISA评估CD73抗体的表位结合。将CD73ECD蛋白和Hu101-28进行预孵育,然后加入生物素化的MEDI-9447(Medimmune),并用链霉亲和素-HRP抗体进行检测。结果显示加入生物素化的R9447不与Hu101-28的结合竞争,表明两种抗体都置于非重叠的表位结合中(图22)。作为对照,添加生物素化的MEDI-9447可以竞争其自身的结合。
为了鉴定Hu101-28的表位,制备了单个氨基酸突变的CD73变体的克隆文库。通过高通量流式细胞技术确定Hu101-28Fab与文库中每个变体的结合,一式两份。对于每种CD73变体,将平均结合值作为图中CD73表达(由对照反应性表示)的函数进行作图,并从图中鉴定出关键性残基。CD73Fab结合的关键残基(以红色标出)被鉴定为那些突变对于检测Fab的结合是阴性,但是对于对照MAb是阳性的残基。针对筛选中确定的关键残基列出了其平均结合反应性(和范围),并且在图23中显示。Hu309与CD73的C 端的Y345、D399、E400、R401和R480的表位结合(在图24中显示,左上图),而MEDI- 9447与其N端结合(参见图24中的对比)。
据认为,与已知抗体相比,Hu101-28的独特结合特性产生了其优越的CD73抑制特性。这在图25中有所证明。图中上面的对比显示Hu101-28表现出对CD73活性的完全抑制,没有“钩状效应”,而MEDI-9447在高剂量下表现出显著的“钩状效应”。在下面的比较组中,Hu101-28Fab在用完全IgG的CD73活性抑制中表现出相当的效力,而 MEDI-9447Fab不能抑制可溶性的CD73。
这表明CD73的抑制需要结合完整MEDI-9447抗体上的两个结合位点,而Hu101-28进行单价结合就足够了。据推测,MEDI-9447与两种不同的CD73二聚体结合以发挥其抑制活性,而Hu101-28没有这样的要求。为了检验这一假设,用具有不同CD73表达水平的细胞检测了Hu101-28的抑制作用。如图26所示,Hu101-28能够完全抑制表达不同水平的CD73的细胞表面上的CD73的活性,包括CD73分子可能彼此远离的具有低表达CD73的那些细胞。
本发明的范围并不受所述旨在作为各个方面的单个说明的具体实施例的限制,并且在功能上等同的任何组合物或方法均在本发明的保护范围内。对本领域的技术人员来说显而易见的是,在不脱离本发明的精神或范围的情况下,可以对本发明的方法和组合物进行各种修改和变化。因此,落入本发明所附的权利要求及其等同物范围内的修改和变化均属于本发明保护范围。
本发明中提及的所有出版物和专利申请通过引用结合于此,其程度相同于每个单独的出版物或专利申请被具体地和单独地指示通过引用结合于此。
SEQUENCE LISTING
<110> 天境生物科技(上海)有限公司
<120> CD73抗体及其用途
<130> P20135563WPD
<150> PCT/CN2017/072445
<151> 2017-01-24
<160> 61
<170> PatentIn version 3.5
<210> 1
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Ser Gly Tyr Tyr Trp Asn
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<212> PRT
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Tyr Ile Asn Tyr Gly Gly Ser Asn Gly Tyr Asn Pro Ser Leu Lys Ser
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Asp Tyr Asp Ala Tyr Tyr Glu Ala Leu Asp Asp
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Arg Ala Ser Ser Arg Val Asn Tyr Met His
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Ala Thr Ser Asn Leu Ala Ser
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Gln Gln Trp Ser Ser Asn Pro Pro Thr
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Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Gly
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Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Lys Leu Glu Trp
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Met Gly
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Glu Ile Val Leu Ser Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
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His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Pro Trp Ile Ser
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Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
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Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
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Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
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Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly
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Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
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Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
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Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly
50
<210> 15
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<400> 15
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Ser
35 40 45
Ala Thr
50
<210> 16
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Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
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Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys
35 40 45
Ala Thr
50
<210> 17
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<400> 17
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys
35 40 45
Ala Thr
50
<210> 18
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<212> PRT
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Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Ser
35 40 45
Ala Thr
50
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Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
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Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
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His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Pro Trp Ile Ser
35 40 45
Ala Thr
50
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Glu Ile Val Leu Ser Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
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Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
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His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Pro Trp Ile Ser
35 40 45
Ala Thr
50
<210> 21
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Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
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Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser
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Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala
50
<210> 22
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Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr
50
<210> 23
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Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr
50
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Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
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His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Ser
35 40 45
Ala Thr
50
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Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala
50
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Thr Gly Tyr Tyr Trp Asn
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Cys Gly Tyr Tyr Trp Asn
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Ser Ala Tyr Tyr Trp Asn
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Ser Pro Tyr Tyr Trp Asn
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Tyr Ile Asn Tyr Gly Ala Ser Asn Gly Tyr Asn Pro Ser Leu Lys Ser
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Tyr Ile Asn Tyr Gly Pro Ser Asn Gly Tyr Asn Pro Ser Leu Lys Ser
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Tyr Ile Asn Tyr Gly Gly Thr Asn Gly Tyr Asn Pro Ser Leu Lys Ser
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<223> 合成的
<400> 33
Tyr Ile Asn Tyr Gly Gly Cys Asn Gly Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 34
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 34
Tyr Ile Asn Tyr Gly Gly Ser Asp Gly Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 35
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 35
Tyr Ile Asn Tyr Gly Gly Ser Glu Gly Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 36
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 36
Tyr Ile Asn Tyr Gly Gly Ser Gln Gly Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 37
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 37
Asp Tyr Asp Ala Tyr Tyr Asp Ala Leu Asp Asp
1 5 10
<210> 38
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 38
Asp Tyr Asp Ala Tyr Tyr Gln Ala Leu Asp Asp
1 5 10
<210> 39
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 39
Asp Tyr Asp Ala Tyr Tyr Asn Ala Leu Asp Asp
1 5 10
<210> 40
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 40
Asp Tyr Asp Ala Tyr Tyr Glu Gly Leu Asp Asp
1 5 10
<210> 41
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 41
Asp Tyr Asp Ala Tyr Tyr Glu Cys Leu Asp Asp
1 5 10
<210> 42
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 42
Arg Ala Thr Ser Arg Val Asn Tyr Met His
1 5 10
<210> 43
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 43
Arg Ala Cys Ser Arg Val Asn Tyr Met His
1 5 10
<210> 44
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 44
Arg Ala Ser Thr Arg Val Asn Tyr Met His
1 5 10
<210> 45
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 45
Arg Ala Ser Cys Arg Val Asn Tyr Met His
1 5 10
<210> 46
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 46
Asn Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 47
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 47
Asp Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 48
Glu Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 49
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 49
Gln Asn Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 50
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 50
Gln Asp Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 51
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 51
Gln Glu Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 52
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 52
Gln Gln Tyr Ser Ser Asn Pro Pro Thr
1 5
<210> 53
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 53
Gln Gln Trp Thr Ser Asn Pro Pro Thr
1 5
<210> 54
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 54
Gln Gln Trp Cys Ser Asn Pro Pro Thr
1 5
<210> 55
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 55
Gln Gln Trp Ser Thr Asn Pro Pro Thr
1 5
<210> 56
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 56
Gln Gln Trp Ser Cys Asn Pro Pro Thr
1 5
<210> 57
<211> 360
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 57
Gly Ala Thr Gly Thr Ala Cys Ala Gly Cys Thr Thr Cys Ala Gly Gly
1 5 10 15
Ala Gly Thr Cys Ala Gly Gly Ala Cys Cys Thr Gly Gly Cys Cys Thr
20 25 30
Cys Gly Thr Gly Ala Ala Ala Cys Cys Thr Thr Cys Thr Cys Ala Gly
35 40 45
Thr Cys Thr Cys Thr Gly Thr Cys Thr Cys Thr Cys Ala Cys Cys Thr
50 55 60
Gly Cys Thr Cys Thr Gly Thr Cys Ala Cys Thr Gly Gly Cys Thr Ala
65 70 75 80
Cys Thr Cys Cys Ala Thr Cys Ala Cys Cys Ala Gly Thr Gly Gly Thr
85 90 95
Thr Ala Thr Thr Ala Cys Thr Gly Gly Ala Ala Cys Thr Gly Gly Ala
100 105 110
Thr Cys Cys Gly Gly Cys Ala Gly Thr Thr Thr Cys Cys Ala Gly Gly
115 120 125
Ala Ala Ala Cys Ala Ala Ala Cys Thr Gly Gly Ala Ala Thr Gly Gly
130 135 140
Ala Thr Gly Gly Gly Cys Thr Ala Cys Ala Thr Ala Ala Ala Cys Thr
145 150 155 160
Ala Cys Gly Gly Cys Gly Gly Thr Ala Gly Cys Ala Ala Thr Gly Gly
165 170 175
Cys Thr Ala Cys Ala Ala Cys Cys Cys Ala Thr Cys Thr Cys Thr Cys
180 185 190
Ala Ala Ala Ala Gly Thr Cys Gly Gly Ala Thr Cys Thr Cys Cys Ala
195 200 205
Thr Cys Ala Cys Thr Cys Gly Gly Gly Ala Cys Ala Cys Ala Thr Cys
210 215 220
Thr Ala Ala Gly Ala Ala Cys Cys Ala Gly Thr Thr Thr Thr Thr Cys
225 230 235 240
Cys Thr Gly Ala Ala Gly Cys Thr Gly Ala Ala Thr Thr Cys Thr Gly
245 250 255
Thr Gly Ala Cys Thr Ala Cys Thr Gly Ala Gly Gly Ala Cys Ala Cys
260 265 270
Ala Gly Cys Thr Ala Cys Ala Thr Ala Thr Thr Ala Cys Thr Gly Thr
275 280 285
Gly Cys Ala Ala Gly Ala Gly Ala Cys Thr Ala Thr Gly Ala Thr Gly
290 295 300
Gly Thr Thr Ala Cys Thr Ala Cys Gly Ala Ala Gly Cys Thr Cys Thr
305 310 315 320
Gly Gly Ala Cys Gly Ala Cys Thr Gly Gly Gly Gly Thr Cys Ala Ala
325 330 335
Gly Gly Ala Ala Cys Cys Thr Cys Ala Gly Thr Cys Ala Cys Cys Gly
340 345 350
Thr Cys Thr Cys Cys Thr Cys Ala
355 360
<210> 58
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 58
Cys Ala Ala Ala Thr Thr Gly Thr Thr Cys Thr Cys Thr Cys Cys Cys
1 5 10 15
Ala Gly Thr Cys Thr Cys Cys Ala Gly Cys Ala Ala Thr Cys Cys Thr
20 25 30
Gly Thr Cys Thr Gly Cys Ala Thr Cys Thr Cys Cys Ala Gly Gly Gly
35 40 45
Gly Ala Gly Ala Ala Gly Gly Thr Cys Ala Cys Ala Ala Thr Gly Ala
50 55 60
Cys Thr Thr Gly Cys Ala Gly Gly Gly Cys Cys Ala Gly Cys Thr Cys
65 70 75 80
Ala Cys Gly Thr Gly Thr Ala Ala Ala Thr Thr Ala Cys Ala Thr Gly
85 90 95
Cys Ala Cys Thr Gly Gly Thr Ala Cys Cys Ala Gly Cys Ala Gly Ala
100 105 110
Ala Gly Cys Cys Ala Gly Gly Ala Thr Cys Cys Thr Cys Cys Cys Cys
115 120 125
Cys Ala Ala Ala Cys Cys Cys Thr Gly Gly Ala Thr Thr Thr Cys Thr
130 135 140
Gly Cys Cys Ala Cys Ala Thr Cys Cys Ala Ala Cys Cys Thr Gly Gly
145 150 155 160
Cys Thr Thr Cys Thr Gly Gly Ala Gly Thr Cys Cys Cys Thr Gly Cys
165 170 175
Thr Cys Gly Cys Thr Thr Cys Ala Gly Thr Gly Gly Cys Ala Gly Thr
180 185 190
Gly Gly Gly Thr Cys Thr Gly Gly Gly Ala Cys Cys Thr Cys Thr Thr
195 200 205
Ala Cys Thr Cys Thr Cys Thr Cys Ala Cys Ala Ala Thr Thr Ala Gly
210 215 220
Cys Ala Gly Ala Gly Thr Ala Gly Ala Gly Ala Cys Thr Gly Ala Ala
225 230 235 240
Gly Ala Thr Gly Cys Thr Gly Cys Cys Ala Cys Thr Thr Ala Thr Thr
245 250 255
Ala Cys Thr Gly Cys Cys Ala Gly Cys Ala Gly Thr Gly Gly Ala Gly
260 265 270
Thr Ala Gly Thr Ala Ala Cys Cys Cys Ala Cys Cys Cys Ala Cys Gly
275 280 285
Thr Thr Cys Gly Gly Ala Gly Gly Gly Gly Gly Gly Ala Cys Cys Ala
290 295 300
Ala Gly Cys Thr Gly Gly Ala Ala Ala Thr Ala Ala Ala Ala
305 310 315
<210> 59
<211> 360
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 59
Gly Ala Gly Gly Thr Ala Cys Ala Gly Cys Thr Thr Cys Ala Gly Gly
1 5 10 15
Ala Gly Thr Cys Ala Gly Gly Ala Cys Cys Thr Gly Gly Cys Cys Thr
20 25 30
Cys Gly Thr Gly Ala Ala Ala Cys Cys Thr Thr Cys Thr Gly Ala Gly
35 40 45
Ala Cys Thr Cys Thr Gly Thr Cys Thr Cys Thr Cys Ala Cys Cys Thr
50 55 60
Gly Cys Gly Cys Thr Gly Thr Cys Thr Cys Thr Gly Gly Cys Thr Ala
65 70 75 80
Cys Thr Cys Cys Ala Thr Cys Ala Cys Cys Ala Gly Thr Gly Gly Thr
85 90 95
Thr Ala Thr Thr Ala Cys Thr Gly Gly Ala Ala Cys Thr Gly Gly Ala
100 105 110
Thr Cys Cys Gly Gly Cys Ala Gly Cys Cys Thr Cys Cys Ala Gly Gly
115 120 125
Ala Ala Ala Gly Ala Ala Gly Cys Thr Gly Gly Ala Ala Thr Gly Gly
130 135 140
Ala Thr Gly Gly Gly Cys Thr Ala Cys Ala Thr Cys Ala Ala Cys Thr
145 150 155 160
Ala Cys Gly Gly Cys Gly Gly Thr Ala Gly Cys Ala Ala Thr Gly Gly
165 170 175
Cys Thr Ala Cys Ala Ala Cys Cys Cys Ala Thr Cys Thr Cys Thr Cys
180 185 190
Ala Ala Ala Ala Gly Thr Cys Gly Gly Ala Thr Cys Ala Cys Cys Ala
195 200 205
Thr Cys Thr Cys Thr Ala Gly Gly Gly Ala Cys Ala Cys Ala Thr Cys
210 215 220
Thr Ala Ala Gly Ala Ala Cys Cys Ala Gly Thr Thr Thr Thr Cys Cys
225 230 235 240
Cys Thr Gly Ala Ala Gly Cys Thr Gly Ala Gly Thr Thr Cys Thr Gly
245 250 255
Thr Gly Ala Cys Thr Gly Cys Thr Gly Cys Cys Gly Ala Cys Ala Cys
260 265 270
Ala Gly Cys Thr Gly Thr Gly Thr Ala Thr Thr Ala Cys Thr Gly Thr
275 280 285
Gly Cys Ala Ala Gly Ala Gly Ala Cys Thr Ala Thr Gly Ala Thr Gly
290 295 300
Cys Thr Thr Ala Cys Thr Ala Cys Gly Ala Ala Gly Cys Thr Cys Thr
305 310 315 320
Gly Gly Ala Cys Gly Ala Cys Thr Gly Gly Gly Gly Thr Cys Ala Ala
325 330 335
Gly Gly Ala Ala Cys Cys Ala Cys Ala Gly Thr Cys Ala Cys Cys Gly
340 345 350
Thr Cys Thr Cys Cys Thr Cys Ala
355 360
<210> 60
<211> 318
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 60
Gly Ala Ala Ala Thr Thr Gly Thr Thr Cys Thr Cys Thr Cys Cys Cys
1 5 10 15
Ala Gly Thr Cys Thr Cys Cys Ala Gly Cys Ala Ala Cys Cys Cys Thr
20 25 30
Gly Thr Cys Thr Cys Thr Gly Thr Cys Thr Cys Cys Ala Gly Gly Gly
35 40 45
Gly Ala Gly Ala Gly Gly Gly Cys Cys Ala Cys Ala Cys Thr Gly Thr
50 55 60
Cys Thr Thr Gly Cys Ala Gly Gly Gly Cys Cys Ala Gly Cys Thr Cys
65 70 75 80
Ala Cys Gly Thr Gly Thr Ala Ala Ala Thr Thr Ala Cys Ala Thr Gly
85 90 95
Cys Ala Cys Thr Gly Gly Thr Ala Cys Cys Ala Gly Cys Ala Gly Ala
100 105 110
Ala Gly Cys Cys Ala Gly Gly Ala Cys Ala Gly Thr Cys Cys Cys Cys
115 120 125
Cys Ala Gly Ala Cys Cys Cys Thr Gly Gly Ala Thr Thr Thr Cys Thr
130 135 140
Gly Cys Cys Ala Cys Ala Thr Cys Cys Ala Ala Cys Cys Thr Gly Gly
145 150 155 160
Cys Thr Thr Cys Thr Gly Gly Ala Gly Thr Cys Cys Cys Thr Gly Cys
165 170 175
Thr Cys Gly Cys Thr Thr Cys Ala Gly Thr Gly Gly Cys Ala Gly Thr
180 185 190
Gly Gly Gly Thr Cys Thr Gly Gly Gly Ala Cys Cys Thr Cys Thr Thr
195 200 205
Ala Cys Ala Cys Thr Cys Thr Cys Ala Cys Ala Ala Thr Thr Ala Gly
210 215 220
Cys Ala Gly Cys Cys Thr Gly Gly Ala Gly Cys Cys Ala Gly Ala Ala
225 230 235 240
Gly Ala Thr Thr Thr Cys Gly Cys Cys Gly Thr Gly Thr Ala Thr Thr
245 250 255
Ala Cys Thr Gly Cys Cys Ala Gly Cys Ala Gly Thr Gly Gly Ala Gly
260 265 270
Thr Ala Gly Thr Ala Ala Cys Cys Cys Ala Cys Cys Cys Ala Cys Gly
275 280 285
Thr Thr Cys Gly Gly Ala Gly Gly Gly Gly Gly Gly Ala Cys Cys Ala
290 295 300
Ala Gly Gly Thr Gly Gly Ala Ala Ala Thr Cys Ala Ala Ala
305 310 315
<210> 61
<211> 574
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 61
Met Cys Pro Arg Ala Ala Arg Ala Pro Ala Thr Leu Leu Leu Ala Leu
1 5 10 15
Gly Ala Val Leu Trp Pro Ala Ala Gly Ala Trp Glu Leu Thr Ile Leu
20 25 30
His Thr Asn Asp Val His Ser Arg Leu Glu Gln Thr Ser Glu Asp Ser
35 40 45
Ser Lys Cys Val Asn Ala Ser Arg Cys Met Gly Gly Val Ala Arg Leu
50 55 60
Phe Thr Lys Val Gln Gln Ile Arg Arg Ala Glu Pro Asn Val Leu Leu
65 70 75 80
Leu Asp Ala Gly Asp Gln Tyr Gln Gly Thr Ile Trp Phe Thr Val Tyr
85 90 95
Lys Gly Ala Glu Val Ala His Phe Met Asn Ala Leu Arg Tyr Asp Ala
100 105 110
Met Ala Leu Gly Asn His Glu Phe Asp Asn Gly Val Glu Gly Leu Ile
115 120 125
Glu Pro Leu Leu Lys Glu Ala Lys Phe Pro Ile Leu Ser Ala Asn Ile
130 135 140
Lys Ala Lys Gly Pro Leu Ala Ser Gln Ile Ser Gly Leu Tyr Leu Pro
145 150 155 160
Tyr Lys Val Leu Pro Val Gly Asp Glu Val Val Gly Ile Val Gly Tyr
165 170 175
Thr Ser Lys Glu Thr Pro Phe Leu Ser Asn Pro Gly Thr Asn Leu Val
180 185 190
Phe Glu Asp Glu Ile Thr Ala Leu Gln Pro Glu Val Asp Lys Leu Lys
195 200 205
Thr Leu Asn Val Asn Lys Ile Ile Ala Leu Gly His Ser Gly Phe Glu
210 215 220
Met Asp Lys Leu Ile Ala Gln Lys Val Arg Gly Val Asp Val Val Val
225 230 235 240
Gly Gly His Ser Asn Thr Phe Leu Tyr Thr Gly Asn Pro Pro Ser Lys
245 250 255
Glu Val Pro Ala Gly Lys Tyr Pro Phe Ile Val Thr Ser Asp Asp Gly
260 265 270
Arg Lys Val Pro Val Val Gln Ala Tyr Ala Phe Gly Lys Tyr Leu Gly
275 280 285
Tyr Leu Lys Ile Glu Phe Asp Glu Arg Gly Asn Val Ile Ser Ser His
290 295 300
Gly Asn Pro Ile Leu Leu Asn Ser Ser Ile Pro Glu Asp Pro Ser Ile
305 310 315 320
Lys Ala Asp Ile Asn Lys Trp Arg Ile Lys Leu Asp Asn Tyr Ser Thr
325 330 335
Gln Glu Leu Gly Lys Thr Ile Val Tyr Leu Asp Gly Ser Ser Gln Ser
340 345 350
Cys Arg Phe Arg Glu Cys Asn Met Gly Asn Leu Ile Cys Asp Ala Met
355 360 365
Ile Asn Asn Asn Leu Arg His Thr Asp Glu Met Phe Trp Asn His Val
370 375 380
Ser Met Cys Ile Leu Asn Gly Gly Gly Ile Arg Ser Pro Ile Asp Glu
385 390 395 400
Arg Asn Asn Gly Thr Ile Thr Trp Glu Asn Leu Ala Ala Val Leu Pro
405 410 415
Phe Gly Gly Thr Phe Asp Leu Val Gln Leu Lys Gly Ser Thr Leu Lys
420 425 430
Lys Ala Phe Glu His Ser Val His Arg Tyr Gly Gln Ser Thr Gly Glu
435 440 445
Phe Leu Gln Val Gly Gly Ile His Val Val Tyr Asp Leu Ser Arg Lys
450 455 460
Pro Gly Asp Arg Val Val Lys Leu Asp Val Leu Cys Thr Lys Cys Arg
465 470 475 480
Val Pro Ser Tyr Asp Pro Leu Lys Met Asp Glu Val Tyr Lys Val Ile
485 490 495
Leu Pro Asn Phe Leu Ala Asn Gly Gly Asp Gly Phe Gln Met Ile Lys
500 505 510
Asp Glu Leu Leu Arg His Asp Ser Gly Asp Gln Asp Ile Asn Val Val
515 520 525
Ser Thr Tyr Ile Ser Lys Met Lys Val Ile Tyr Pro Ala Val Glu Gly
530 535 540
Arg Ile Lys Phe Ser Thr Gly Ser His Cys His Gly Ser Phe Ser Leu
545 550 555 560
Ile Phe Leu Ser Leu Trp Ala Val Ile Phe Val Leu Tyr Gln
565 570
Claims (28)
1.一种分离的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段对人CD73蛋白具有特异性,并与选自人CD73蛋白C端一半部分的一个或多个氨基酸残基结合,所述一个或多个氨基酸残基选自Y345、D399、E400、R401和R480。
2.如权利要求1所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段与至少两个氨基酸残基结合。
3.如权利要求1所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段与Y345、D399、E400、R401和R480中的每一个结合。
4.一种分离的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段对人CD73蛋白具有特异性,并且包含:
(a)如SEQ ID NO:1或SEQ ID NO:1的变体所示的VH CDR1,所述SEQ ID NO:1的变体选自由SEQ ID NO:26~29组成的组;
(b)如SEQ ID NO:2或SEQ ID NO:2的变体所示的VH CDR2,所述SEQ ID NO:2的变体选自由SEQ ID NO:30~36组成的组;
(c)如SEQ ID NO:3或SEQ ID NO:3的变体所示的VH CDR3,所述SEQ ID NO:3的变体选自由SEQ ID NO:37~41组成的组;
(d)如SEQ ID NO:4或SEQ ID NO:4的变体所示的VL CDR1,所述SEQ ID NO:4的变体选自由SEQ ID NO:42~45组成的组;
(e)如SEQ ID NO:5所示的VL CDR2,和
(f)如SEQ ID NO:6或SEQ ID NO:6的变体所示的VL CDR3,所述SEQ ID NO:6的变体选自由SEQ ID NO:46-56组成的组。
5.如权利要求4所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段进一步包含重链恒定区、轻链恒定区、Fc区或其组合。
6.如权利要求5所述的抗体或抗原结合片段,其特征在于,所述轻链恒定区是κ或λ链恒定区。
7.如权利要求1所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段是IgG、IgM、IgA、IgE或IgD的其中一种同种型。
8.如权利要求7所述的抗体或抗原结合片段,其特征在于,所述同种型是IgG1、IgG2、IgG3或IgG4。
9.如权利要求1所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段是嵌合抗体或人源化抗体。
10.如权利要求1所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段仅包含一对结合人CD73蛋白的VH和VL。
11.如权利要求1~10任一项所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段为双特异性抗体。
12.一种组合物,其特征在于,所述组合物包含如权利要求1~11任一项所述的抗体或抗原结合片段和药学上可接受的载体。
13.一种分离的细胞,其特征在于,所述细胞包含编码如权利要求1~11任一项所述的抗体或抗原结合片段的一种或多种多核苷酸。
14.如权利要求1~11任一项所述的抗体或抗原结合片段在制备用于治疗癌症的药物中的用途。
15.如权利要求14所述的用途,其特征在于,所述癌症选自由膀胱癌、乳腺癌、结直肠癌、子宫内膜癌、食管癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、胰腺癌、前列腺癌和甲状腺癌组成的组。
16.如权利要求14所述的用途,其特征在于,所述癌症是实体瘤。
17.如权利要求14所述的用途,其特征在于,所述方法进一步包括向所述患者施用第二种癌症治疗剂。
18.如权利要求17所述的用途,其特征在于,所述第二种癌症治疗剂是免疫检查点抑制剂。
19.如权利要求18所述的用途,其特征在于,所述抑制剂抑制程序性细胞死亡蛋白1(PD-1)、程序性死亡配体1(PD-L1)、细胞毒性T淋巴细胞相关蛋白4(CTLA-4)、淋巴细胞活化蛋白3(LAG-3)或其组合的表达或活性。
20.如权利要求19所述的用途,其特征在于,所述抑制剂是抗PD-1或抗PD-L1抗体。
21.如权利要求20所述的用途,其特征在于,所述抑制剂选自由派姆单抗、纳武单抗、J43、RMP1-14、阿特朱单抗、伊匹单抗及其组合组成的组。
22.如权利要求14所述的用途,其特征在于,所述治疗包括:
(a)用如权利要求1~11任一项所述的抗体或抗原结合片段在体外处理T细胞;和
(b)将处理后的T细胞施用于患者体内。
23.如权利要求22所述的用途,其特征在于,所述方法在步骤(a)之前进一步包括从所述个体分离出所述T细胞。
24.如权利要求23所述的用途,其特征在于,所述T细胞从所述患者体内分离出来。
25.如权利要求23所述的用途,其特征在于,所述T细胞从不同于所述患者的供体个体中分离出来。
26.如权利要求22~25任一项所述的用途,其特征在于,所述T细胞是肿瘤浸润性T淋巴细胞、CD4+T细胞、CD8+T细胞或其组合。
27.一种检测样品中CD73表达的方法,其特征在于,所述方法包括使样品与权利要求1~11任一项所述的抗体或抗原结合片段接触,使得所述抗体或抗原结合片段结合CD73,并检测反映样品中CD73的表达量的所述结合,所述方法为非诊断方法。
28.一种鉴定适合用抗CD73疗法治疗的癌症患者的方法,其特征在于,所述方法包括从癌症患者体内分离出细胞,并用如权利要求1~11任一项所述的抗体或抗原结合片段检测CD73蛋白质的存在,所述方法为非诊断方法。
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CNPCT/CN2017/072445 | 2017-01-24 | ||
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US (2) | US10584169B2 (zh) |
EP (2) | EP4050030A1 (zh) |
JP (1) | JP7206193B2 (zh) |
KR (3) | KR20200108915A (zh) |
CN (2) | CN109476755B (zh) |
AU (2) | AU2018213549B2 (zh) |
BR (1) | BR112019012040A2 (zh) |
CA (1) | CA3045376C (zh) |
CL (1) | CL2019001756A1 (zh) |
CO (1) | CO2019006657A2 (zh) |
DK (1) | DK3383916T3 (zh) |
EA (1) | EA201991099A1 (zh) |
ES (1) | ES2908662T3 (zh) |
HR (1) | HRP20220629T1 (zh) |
HU (1) | HUE058975T2 (zh) |
IL (2) | IL267942B (zh) |
LT (1) | LT3383916T (zh) |
MX (1) | MX2019008758A (zh) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112552406A (zh) * | 2021-02-24 | 2021-03-26 | 吴江近岸蛋白质科技有限公司 | 抗人cd73抗体 |
CN112574313A (zh) * | 2021-02-25 | 2021-03-30 | 吴江近岸蛋白质科技有限公司 | 抗cd73抗体及其用途 |
WO2022179039A1 (zh) * | 2021-02-24 | 2022-09-01 | 苏州近岸蛋白质科技股份有限公司 | 抗人cd73抗体及其应用 |
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Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3037380A1 (en) | 2016-10-11 | 2018-04-19 | Agenus Inc. | Anti-lag-3 antibodies and methods of use thereof |
AU2019227607C1 (en) | 2018-02-27 | 2023-07-20 | Incyte Corporation | Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors |
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EP3981790A4 (en) * | 2019-06-06 | 2023-10-11 | Jacobio Pharmaceuticals Co., Ltd. | CD73-SPECIFIC BINDING MOLECULE AND USE OF THE BINDING MOLECULE |
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US20230357425A1 (en) * | 2019-08-21 | 2023-11-09 | Harbour Biomed (Shanghai) Co., Ltd | Anti-cd73 antibody and application thereof |
MX2022002682A (es) | 2019-09-06 | 2022-04-07 | Servier Lab | Anticuerpos anti-cd73. |
KR20220100929A (ko) * | 2019-11-15 | 2022-07-18 | 젠자임 코포레이션 | 이중파라토프성 cd73 항체 |
WO2021138467A1 (en) * | 2020-01-03 | 2021-07-08 | Incyte Corporation | Anti-cd73 antibodies and uses thereof |
JP2023509442A (ja) | 2020-01-03 | 2023-03-08 | インサイト・コーポレイション | Cd73阻害剤とa2a/a2bアデノシン受容体阻害剤の併用療法 |
WO2021163064A2 (en) * | 2020-02-14 | 2021-08-19 | Jounce Therapeutics, Inc. | Antibodies and fusion proteins that bind to ccr8 and uses thereof |
AU2021253830A1 (en) * | 2020-04-09 | 2022-12-08 | Aprilbio Co., Ltd. | Monoclonal antibodies and antigen binding fragments thereof for suppressing CD73 immune checkpoint and uses thereof |
JP2023522365A (ja) * | 2020-04-22 | 2023-05-30 | アケソ・バイオファーマ・インコーポレイテッド | 抗cd73抗体とその利用 |
WO2021259199A1 (zh) | 2020-06-22 | 2021-12-30 | 信达生物制药(苏州)有限公司 | 抗cd73抗体及其用途 |
EP4196500A2 (en) | 2020-08-13 | 2023-06-21 | Innate Pharma | Cancer treatment methods using anti-cd73 antibodies |
CN114380915B (zh) * | 2020-10-19 | 2024-03-22 | 中山康方生物医药有限公司 | 抗cd73的抗体及其用途 |
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US20220233529A1 (en) | 2020-12-29 | 2022-07-28 | Incyte Corporation | Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies |
KR20230127292A (ko) * | 2020-12-30 | 2023-08-31 | 아이-맵 바이오파마 컴파니 리미티드 | 항-cd73 항체의 제제 |
CA3209479A1 (en) | 2021-02-03 | 2022-08-11 | Mozart Therapeutics, Inc. | Binding agents and methods of using the same |
WO2023076876A1 (en) | 2021-10-26 | 2023-05-04 | Mozart Therapeutics, Inc. | Modulation of immune responses to viral vectors |
TW202400242A (zh) * | 2022-03-14 | 2024-01-01 | 大陸商上海華奧泰生物藥業股份有限公司 | 抗體藥物偶聯物及其應用 |
WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
WO2024040195A1 (en) | 2022-08-17 | 2024-02-22 | Capstan Therapeutics, Inc. | Conditioning for in vivo immune cell engineering |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101809035A (zh) * | 2007-09-10 | 2010-08-18 | 安美基公司 | 能结合胸腺基质淋巴细胞生成素的抗原结合蛋白 |
WO2016081748A2 (en) * | 2014-11-21 | 2016-05-26 | Bristol-Myers Squibb Company | Antibodies against cd73 and uses thereof |
Family Cites Families (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4444887A (en) | 1979-12-10 | 1984-04-24 | Sloan-Kettering Institute | Process for making human antibody producing B-lymphocytes |
US4716111A (en) | 1982-08-11 | 1987-12-29 | Trustees Of Boston University | Process for producing human antibodies |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4694778A (en) | 1984-05-04 | 1987-09-22 | Anicon, Inc. | Chemical vapor deposition wafer boat |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
US4980286A (en) | 1985-07-05 | 1990-12-25 | Whitehead Institute For Biomedical Research | In vivo introduction and expression of foreign genetic material in epithelial cells |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US5892019A (en) | 1987-07-15 | 1999-04-06 | The United States Of America, As Represented By The Department Of Health And Human Services | Production of a single-gene-encoded immunoglobulin |
US4943593A (en) | 1988-02-25 | 1990-07-24 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US5021456A (en) | 1988-02-25 | 1991-06-04 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US5059714A (en) | 1988-02-25 | 1991-10-22 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US4965288A (en) | 1988-02-25 | 1990-10-23 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US5252608A (en) | 1988-02-25 | 1993-10-12 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US5182297A (en) | 1988-02-25 | 1993-01-26 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US5120764A (en) | 1988-11-01 | 1992-06-09 | Merrell Dow Pharmaceuticals Inc. | Inhibitors of lysyl oxidase |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5413923A (en) | 1989-07-25 | 1995-05-09 | Cell Genesys, Inc. | Homologous recombination for universal donor cells and chimeric mammalian hosts |
US4997854A (en) | 1989-08-25 | 1991-03-05 | Trustees Of Boston University | Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in-situ using adjacently positioned diamine analogue substrates |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
SG48759A1 (en) | 1990-01-12 | 2002-07-23 | Abgenix Inc | Generation of xenogenic antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
EP0546073B1 (en) | 1990-08-29 | 1997-09-10 | GenPharm International, Inc. | production and use of transgenic non-human animals capable of producing heterologous antibodies |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
DE69233482T2 (de) | 1991-05-17 | 2006-01-12 | Merck & Co., Inc. | Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen |
IE922437A1 (en) | 1991-07-25 | 1993-01-27 | Idec Pharma Corp | Recombinant antibodies for human therapy |
US5756096A (en) | 1991-07-25 | 1998-05-26 | Idec Pharmaceuticals Corporation | Recombinant antibodies for human therapy |
US5565332A (en) | 1991-09-23 | 1996-10-15 | Medical Research Council | Production of chimeric antibodies - a combinatorial approach |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US6130364A (en) | 1995-03-29 | 2000-10-10 | Abgenix, Inc. | Production of antibodies using Cre-mediated site-specific recombination |
EP1978033A3 (en) | 1995-04-27 | 2008-12-24 | Amgen Fremont Inc. | Human antibodies derived from immunized xenomice |
CA2219486A1 (en) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
US6420140B1 (en) | 1996-10-11 | 2002-07-16 | Abgenix, Inc. | Production of multimeric protein by cell fusion method |
ES2301183T3 (es) | 1996-12-03 | 2008-06-16 | Amgen Fremont Inc. | Anticuerpo completamente humano que se une al receptor del egfr. |
RU2224766C2 (ru) | 1997-04-14 | 2004-02-27 | Микромет Аг | Способ получения рецепторов для человеческих антигенов и их применение |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
EP0983303B1 (en) | 1997-05-21 | 2006-03-08 | Biovation Limited | Method for the production of non-immunogenic proteins |
WO1999004705A1 (en) | 1997-07-25 | 1999-02-04 | Tsui Ban C H | Devices, systems and methods for determining proper placement of epidural catheters |
WO2000034317A2 (en) | 1998-12-08 | 2000-06-15 | Biovation Limited | Method for reducing immunogenicity of proteins |
MXPA01011279A (es) | 1999-05-07 | 2002-07-02 | Genentech Inc | Tratamiento de enfermedades autoinmunes con antagonistas que se unene a los marcadores de superficie, de celulas b. |
FR2828206B1 (fr) | 2001-08-03 | 2004-09-24 | Centre Nat Rech Scient | Utilisation d'inhibiteurs des lysyl oxydases pour la culture cellulaire et le genie tissulaire |
CN101031569B (zh) | 2004-05-13 | 2011-06-22 | 艾科斯有限公司 | 作为人磷脂酰肌醇3-激酶δ抑制剂的喹唑啉酮 |
US20090142345A1 (en) | 2005-03-15 | 2009-06-04 | Takeda Pharmaceutical Company Limited | Prophylactic/therapeutic agent for cancer |
JP5382692B2 (ja) * | 2006-07-10 | 2014-01-08 | 学校法人藤田学園 | 抗体の分類法、抗原の同定法、抗体又は抗体セットの取得法、抗体パネルの作成法、並びに抗体又は抗体セット及びその用途 |
ES2402334T3 (es) | 2007-08-02 | 2013-04-30 | Gilead Biologics, Inc | Procedimientos y composiciones para el tratamiento y el diagnóstico de la fibrosis |
WO2010019702A2 (en) | 2008-08-12 | 2010-02-18 | Oncomed Pharmaceuticals, Inc. | Ddr1-binding agents and methods of use thereof |
US8450321B2 (en) | 2008-12-08 | 2013-05-28 | Gilead Connecticut, Inc. | 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor |
TWI491606B (zh) | 2009-07-13 | 2015-07-11 | Gilead Sciences Inc | 調節細胞凋亡信號之激酶的抑制劑 |
SG183174A1 (en) | 2010-02-04 | 2012-09-27 | Gilead Biologics Inc | Antibodies that bind to lysyl oxidase-like 2 (loxl2) and methods of use therefor |
JP5878538B2 (ja) | 2010-08-27 | 2016-03-08 | ギリアド バイオロジクス, インク.Gilead Biologics, Inc. | マトリクスメタロプロティナーゼ9に対する抗体 |
EP2749572A4 (en) | 2011-08-23 | 2015-04-01 | Chugai Pharmaceutical Co Ltd | NEW ANTI-DDR1 ANTIBODY WITH ANTITUMORACTIVITY |
GB201115529D0 (en) | 2011-09-08 | 2011-10-26 | Imp Innovations Ltd | Antibodies, uses and methods |
US20140235643A1 (en) | 2011-10-04 | 2014-08-21 | Gilead Calistoga Llc | Novel quinoxaline inhibitors of pi3k |
UY34573A (es) | 2012-01-27 | 2013-06-28 | Gilead Sciences Inc | Inhibidor de la quinasa que regula la señal de la apoptosis |
WO2013116562A1 (en) | 2012-02-03 | 2013-08-08 | Gilead Calistoga Llc | Compositions and methods of treating a disease with (s)-4 amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile |
WO2014047624A1 (en) | 2012-09-24 | 2014-03-27 | Gilead Sciences, Inc. | Anti-ddr1 antibodies |
NZ708864A (en) | 2012-12-21 | 2016-09-30 | Gilead Calistoga Llc | Substituted pyrimidine aminoalkyl-quinazolones as phosphatidylinositol 3-kinase inhibitors |
US9029384B2 (en) | 2012-12-21 | 2015-05-12 | Gilead Calistoga, LLC. | Phosphatidylinositol 3-kinase inhibitors |
CN104211814A (zh) * | 2013-05-29 | 2014-12-17 | 三星电子株式会社 | 用于消耗靶膜蛋白的组合物 |
WO2014201409A1 (en) | 2013-06-14 | 2014-12-18 | Gilead Sciences, Inc. | Phosphatidylinositol 3-kinase inhibitors |
WO2016131950A1 (en) * | 2015-02-20 | 2016-08-25 | Innate Pharma | Cd73 blockade |
EP3204417B1 (en) * | 2014-10-10 | 2020-07-22 | Innate Pharma | Cd73 blockade |
SI3218406T1 (sl) * | 2014-11-10 | 2021-08-31 | Medimmune Limited | Vezavne molekule specifične za CD73 in njihove uporabe |
WO2016075176A1 (en) | 2014-11-11 | 2016-05-19 | Medimmune Limited | Therapeutic combinations comprising anti-cd73 antibodies and a2a receptor inhibitor and uses thereof |
SI3221346T1 (sl) * | 2014-11-21 | 2020-11-30 | Bristol-Myers Squibb Company | Protitelesa vsebujoča modificirana težko konstantna območja |
KR20180134837A (ko) | 2015-12-09 | 2018-12-19 | 코버스 파마슈티칼스, 인크. | 인간화된 항-cd73 항체 |
CN110785187B (zh) | 2017-06-22 | 2024-04-05 | 诺华股份有限公司 | 针对cd73的抗体分子及其用途 |
BR112020017382A2 (pt) | 2018-03-09 | 2021-01-26 | Agenus Inc. | anticorpos anti-cd73 e métodos de uso dos mesmos |
-
2018
- 2018-01-23 PT PT187331533T patent/PT3383916T/pt unknown
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101809035A (zh) * | 2007-09-10 | 2010-08-18 | 安美基公司 | 能结合胸腺基质淋巴细胞生成素的抗原结合蛋白 |
WO2016081748A2 (en) * | 2014-11-21 | 2016-05-26 | Bristol-Myers Squibb Company | Antibodies against cd73 and uses thereof |
TW201625693A (zh) * | 2014-11-21 | 2016-07-16 | 必治妥美雅史谷比公司 | 抗cd73抗體及其用途 |
Non-Patent Citations (4)
Title |
---|
ANTONIOLI L等: "Anti-CD73 in cancer immunotherapy: awakening new opportunities", 《TRENDS CANCER》 * |
TERP MG等: "Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells", 《JOURNAL OF IMMUNOLOGY》 * |
李晓波: "5’-核苷酸酶的研究进展", 《国外医学(生理、病理科学与临床分册)》 * |
陈景等: "CD73在肿瘤免疫治疗中的研究进展", 《癌症进展》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112552406A (zh) * | 2021-02-24 | 2021-03-26 | 吴江近岸蛋白质科技有限公司 | 抗人cd73抗体 |
WO2022179039A1 (zh) * | 2021-02-24 | 2022-09-01 | 苏州近岸蛋白质科技股份有限公司 | 抗人cd73抗体及其应用 |
CN112574313A (zh) * | 2021-02-25 | 2021-03-30 | 吴江近岸蛋白质科技有限公司 | 抗cd73抗体及其用途 |
WO2022247826A1 (zh) * | 2021-05-28 | 2022-12-01 | 和铂医药(上海)有限责任公司 | 靶向pd-l1和cd73的特异性结合蛋白 |
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