CN113474372B - 一种抗ceacam5的单克隆抗体及其制备方法和用途 - Google Patents
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Abstract
提供的是能特异性结合人癌胚抗原细胞粘附分子5(CEACAM5)的单克隆抗体及其抗原结合片段。还提供了所述抗体及其抗体结合片段的制备方法和用途。
Description
技术领域
本申请属于生物免疫技术领域,具体涉及能特异性结合人癌胚抗原细胞粘附分子5(CEACAM5)的单克隆抗体及其抗原结合片段。本申请还涉及所述抗体及其抗原结合片段的制备方法和用途。
背景技术
人癌胚抗原细胞粘附分子(CEACAM)基因家族早在上世纪60年代就被发现,包括位于19号染色体(q13.1-13.3之间)的35个基因/伪基因,在这其中有21个编码蛋白质。CEACAM属于免疫球蛋白超家族黏附分子,其结构域高度糖基化,通常包括1-2个免疫球蛋白可变区样结构域(N domain)和0-6个免疫球蛋白恒定区样结构域。CEACAM蛋白位于细胞膜外,其中CEACAM1、CEACAM3和CEACAM4通过疏水跨膜结构域与细胞膜连接;CEACAM5-8则通过糖基磷酰肌醇连接到细胞膜上。这些细胞外域通常作为细胞(例如上皮、内皮、树突状和白细胞)间的粘附分子。
CEACAM涉及多种细胞功能,以细胞间的黏附功能为基础,通过信号转导调节细胞生长和分化,并在胰岛素稳态、血管生成及免疫调节中发挥重要作用。CEACAM基因家族成员参与各种各样的病理生理作用,包括作为微生物病原体的受体。它们在致癌中起重要作用,特别是在癌症检测、进展和转移中。CEACAM5(简称为CEA,又称为CD66e)是具有约180kDa分子量的糖蛋白。CEACAM5含有经由糖基磷脂酰肌醇(GPI)锚与细胞膜连接的7个结构域。7个结构域包括单一N端Ig可变域和与Ig恒定域同源的6个结构域(A1-B1-A2-B2-A3-B3)。CEACAM5最初被认为是在胎儿组织中表达的蛋白质,现在已经在几种正常成年组织中被鉴定出来。CEACAM5的过量表达在许多类型的癌症中被观察到。例如,在结肠癌患者的血液中可以检测到CEACAM5。并且,进一步研究确定了它的过量表达与许多恶性肿瘤,通常是不良预后相关。在前列腺癌和结直肠癌中,CEACAM5的过度表达被证明可以作为肿瘤生物标志物。
此外,在多种恶性肿瘤,如乳房、胰腺、卵巢、结肠、肺和胃腺肿瘤中CEACAM5/CEACAM6亦被发现呈过度表达,并且与肿瘤的侵袭性和转移有关。在肝转移的起始过程中,CEACAM5与其受体CEAr结合,它们的相互作用导致促炎细胞因子的活化和产生,主要是IL-1、IL-6、IL-10和TNF-α。总之,这些细胞因子改变肝细胞和Kupffer细胞的微环境,以及它们与肝窦细胞的相互作用。这些相互作用不仅影响肿瘤细胞或其他肝细胞,似乎也促进了脑脊液中CSC和其他循环肿瘤细胞的活力。
基于此,除了已知的CEACAM5被用作肿瘤标记,测量癌症患者血液中升高的CEACAM5的免疫学测定法已在临床上用于癌症的预后和控制之外,更重要的是,CEACAM5已成为用于靶向治疗的潜在有用的肿瘤相关抗原。已经报道的使用CEACAM5靶向免疫治疗癌症主要有2种主要方法。一种方法使用抗CEACAM5抗体引发免疫细胞的溶解活性,特别是通过抗体依赖性细胞毒性(ADCC)或补体依赖性细胞毒性(CDC),以消除表达CEACAM5的肿瘤细胞;另一种方法是通过抗CEACAM5抗体或抗体片段与例如药物、毒素、放射性核苷酸、免疫调节剂或细胞因子等效应分子缀合,特异性靶向表达CEACAM5的肿瘤细胞,从而发挥效应分子的治疗作用。鉴于CEACAM5更多地过量表达于一些诸如结肠直肠癌、胰腺癌、肺癌、胃癌、肝细胞瘤、乳腺癌和甲状腺癌等实体肿瘤中,因此当前的研究集中在抗CEACAM5抗体的抗原识别能力。
总之,当前的研究表明,靶向CEACAM5的治疗方法将有助于抑制肿瘤的转移过程。特别地,对CEACAM5具有较强特异性的抗体,能够更好的避免抗体脱靶而造成的毒副作用。例如CEACAM1,CEACAM3广泛分布于人免疫系统及骨髓,例如中性粒细胞等,特异性的CEACAM5抗体,可降低药物可能存在的副作用,提高治疗窗口。
基于此,当前对亲和力更高,特异性更强的抗CEACAM抗体存在需求。
发明内容
在本申请中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、分子遗传学、核酸化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本申请,下面提供相关术语的定义和解释。
术语定义
本申请中的″抗体″一词包括任意可结合某特定抗原的免疫球蛋白、单克隆抗体、多克隆抗体、多特异性抗体或双特异性(双价)抗体。一个天然的完整抗体包含两条重链和两条轻链。每条重链由一可变区和第一、第二、第三恒定区组成;每条轻链由一可变区和一恒定区组成。哺乳动物的重链可分为α、δ、ε、γ和μ,哺乳动物的轻链可分为λ或κ。抗体呈″Y″型,Y型结构的颈部由两条重链的第二和第三恒定区组成,其通过二硫键结合。″Y″型结构的每条臂包括其中一条重链的可变区和第一恒定区,其与一条轻链的可变区和恒定区结合。轻链和重链的可变区决定抗原的结合。每条链的可变区均含有三个高变区,称互补决定区(CDR)。轻链(L)的CDR包含VLCDR1、VLCDR2、VLCDR3,重链(H)的CDR包含VHCDR1、VHCDR2、VHCDR3。本申请中公开的抗体和抗原结合片段的CDR边界可通过Kabat,Chothia或Al-Lazikani命名法命名或识别。(Al-Lazikani,B.,Chothia,C.,Lesk,A.M.,J.Mol.Biol.,273(4):927(1997);Chothia,C.等,J.Mol.Biol.,186(3):651-63(1985);Chothia,C.andLesk,A.M.,J.Mol.Biol.,196:901(1987);Chothia,C.等,Nature,342(6252):877-83(1989);Kabat,E.A.等,National Institutes of Health,Bethesda,Md.(1991))。其中,三个CDR由被称为框架区(FR)的侧面连续部分间隔开,框架区比CDR更加高度保守并形成一个支架支撑超变环。重链和轻链的恒定区与抗原结合无关,但具有多种效应功能。抗体依据重链恒定区的氨基酸序列可以分成几类。根据是否含有α、δ、ε、γ和μ重链,抗体可分别分为五个主要的分类或异构体:IgA、IgD、IgE、IgG和IgM。几个主要的抗体分类还可分为亚类,如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)等。
本申请中的″抗原结合片段″一词,指由含有一个或多个CDR的抗体部分或者任何其它结合抗原但不具有完整抗体结构的抗体片段所形成的一种抗体片段。抗原结合片段的例子包括,但不限于,如双功能抗体(diabody)、Fab、Fab′、F(ab′)2、Fv片段、二硫键稳定的Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv′)、二硫键稳定的双功能抗体(dsdiabody)、单链抗体分子(scFv)、scFv二聚体(双价的双功能抗体)、双价单链抗体(BsFv)、多特异性抗体、骆驼化单域抗体(camelized single domain antibody)、纳米抗体、域抗体和双价域抗体。抗原结合片段可以与母体抗体结合相同的抗原。在某些实施方式中,抗原结合片段可以含有来自某特定人抗体的一个或多个CDR,移接至来自一个或多个不同人抗体的框架区。
抗体的″Fab″片段是指由一条轻链(包括可变区和恒定区)和一条重链的可变区和部分恒定区经二硫键结合起来的那部分抗体分子。
″Fab’″片段是指包含了部分绞链区的Fab片段。
″F(ab′)2″指的是Fab的二聚体。
抗体的Fc段负责多种不同的效应功能如ADCC和CDC,但不参与抗原的结合。
抗体的″Fv″段指的是含有完整抗原结合位点的最小抗体片段。Fv片段由一条轻链的可变区和一条重链的可变区组成。
″单链Fv抗体″或″scFv″是指由轻链可变区与重链可变区直接相连或通过一个肽链连接而成的工程抗体(Huston JS等,Proc Natl Acad Sci USA,85:5879(1988))。
″单链抗体Fv-Fc″或″scFv-Fc″是指由连接到某抗体Fc段的scFv组成的工程抗体。
″骆驼化单域抗体(Camelized single domain antibody)″,″重链抗体″或″HCAb(Heavy-chain-only antibodies,HCAb)″都是指含有两个VH域而不含有轻链的抗体(Riechmann L.和Muyldermans S.,J Immunol Methods.231(1-2):25-38(1999);Muyldermans S.,J Biotechnol.74(4):277-302(2001);W094/04678;W094/25591;U.S.Patent No.6,005,079)。重链抗体最初从驼科(骆驼、单峰驼和美洲驼)衍生得到。虽然缺失轻链,骆驼化抗体(camelized antibodies)有确证的抗原结合全部功能(HamersCasterman C.等,Nature 363(6428):446-8(1993);Nguyen VK.等,″Heavy-chainantibodies in Camelidae:a case of evolutionary innovation,Immunogenetics.54(1):39-47(2002);Nguyen VK.等,Immunology.109(1):93-101(2003))。重链抗体的可变区(VH域)是已知的最小的获得性免疫产生的抗原结合单位(Koch-Nolte F.等,FASEB J.21(13):3490-8.Epub(2007))。
″纳米抗体″是指一种抗体片段,其由一个来自重链抗体的VH域和两个恒定区CH2和CH3组成。
″双功能抗体(diabody)″包括带有两个抗原结合位点的小抗体片段,其中该片段含有在同一条多肽链上相连的VH域和VL域(请参见,Holliger P.等,Proc Natl Acad SciU S A.90(14):6444-8(1993);EP404097;W093/11161)。两个域之间衔接物很短,使同一条链上的两个域不能互相配对,从而迫使两个域与另一条链的互补域配对,形成两个抗体结合位点。这两个抗体结合位点可靶向结合相同或不同的抗原(或抗原表位)。
″域抗体″是指仅含有一条重链可变区或一条轻链可变区的抗体片段。在某些情况下,两个或多个VH域由一个多肽衔接物共价结合并形成双价域抗体。双价域抗体的两个VH域可靶向作用于相同或不同的抗原。
在某些实施方式中,″(dsFv)2″含有三条肽链:两个VH基因间通过一条多肽衔接物相连,并通过二硫键与两个VL基团结合。
在某些实施方式中″双特异性ds双功能抗体″含有VL1-VH2(由一个多肽衔接物相连)和VH1-VL2(也是由一个多肽衔接物相连),两者在VH1和VL1间通过二硫键结合。
″双特异性dsFv″或″dsFv-dsFv″含有三条多肽链:VH1-VH2基团,其中两者的重链通过多肽衔接物(如:长的弹性衔接物)相连,并通过二硫键分别与VL1和VL2基团结合,每对通过二硫键配对的重链轻链具有不同的抗原特异性。
在某些实施方式中,″scFv二聚体″是双价双功能抗体或双价单链抗体(BsFv),含有二聚化的两个VH-VL(由多肽衔接物连接)基团,其中一个基团的VH与另一个基团的VL协作形成两个结合位点,这两个结合位点可靶向结合相同抗原(或抗原表位)或不同抗原(或抗原表位)。在另一些实施方式中,″scFv二聚体″是双特异性双功能抗体,含有相互连接的VL1-VH2(由多肽衔接物连接)和VH1-VL2(由多肽衔接物连接),其中VH1和VL1协作,VH2和VL2协作,且每个协作的配对具有不同的抗原特异性。
本申请中使用的术语″全人源″当用于抗体或抗原结合片段时,是指所述抗体或抗原结合片段具有某氨基酸序列或由所述氨基酸序列组成,所述氨基酸序列对应于由人或人免疫细胞生产的、或从例如利用人源抗体库的转基因非人动物等非人来源衍生的抗体的氨基酸序列,或者其他编码人源抗体的序列。在某些实施方式中,全人源抗体不包含来源于非人抗体的氨基酸残基(特别是抗原结合残基)。
本申请中使用的术语″人源化″当用于抗体或抗原结合片段时,是指包括来源于非人动物的CDR、来源于人的FR区,以及来源于人的恒定区(当适用时)的抗体或抗原结合片段。由于人源化的抗体或抗原结合片段具有降低的免疫原性,其在某些实施方式中可用作人的治疗剂。在一些实施方式中,所述非人动物是哺乳动物例如小鼠、大鼠、兔、山羊、绵羊、豚鼠或仓鼠。在一些实施方式中,所述人源化抗体或抗原结合片段除了CDR序列是非人源的以外,基本上全部由人源序列组成。在一些实施方式中,所述来源于人的FR区可以包括与其来自的人源抗体相同的氨基酸序列,或其可以包括一些氨基酸改变,例如,不超过10,9、8、7、6、5、4、3、2或1个氨基酸改变。在一些实施方式中,该氨基酸改变可以仅存在于重链FR区、仅存在于轻链FR区或同时存在于两个链中。在一些优选实施方式中,所述人源化抗体包括人源FR1-3和人源JH和JK。
本申请中使用的术语″嵌合″是指具有来源于一种物种的重链和/或轻链的一部分,和所述重链和/或轻链其余部分来源于不同物种的抗体或抗原结合片段。在一个示例性的例子中,嵌合抗体可以包括来源于人的恒定区和来源于非人动物例如小鼠的可变区。
术语“癌胚抗原细胞粘附分子5”(CEACAM5,简称为CEA,又称为CD66e;参见例如,AAA51967.1/GI:180223,702个氨基酸)是具有约180kDa分子量的糖蛋白。CEACAM5含有7个Ig-like结构域,这7个结构域包括单一N端Ig可变域和与Ig恒定域同源的6个结构域(A1-B1-A2-B2-A3-B3)。CEACAM经由羧基端的糖基磷脂酰肌醇(GPI)锚与细胞膜连接。
本申请中的″特异性结合″或″特异性的结合″是指两分子间的非随机结合反应,如抗体和抗原间的反应。在某些实施方式中,本申请的抗体或其抗原结合片段与人和/或猴癌胚抗原细胞粘附分子5特异性结合,并且其结合亲和力(KD)≤10-6M。本申请中的KD是指解离速度与结合速度的比值(koff/kon),可通过表面等离子共振的方法测定,例如使用如Biacore的仪器。
本申请中的″选择性结合″是指,本申请的抗体或其抗原结合片段与CEACAM5蛋白特异性结合,但基本上不结合或者以显著更低的水平结合其他CEACAM蛋白,例如CEACAM1蛋白,CEACAM3蛋白,CEACAM7蛋白。
在某些实施方式中,本申请所述的抗体的重链恒定区为人IgG1型。在某些实施方式中,本申请所述的抗体的轻链恒定区为κ链。在某些实施方式中,本申请所述的抗体的重链和轻链恒定区分别为人IgG1和κ链。
在本申请中当″保守置换″用于氨基酸序列时,是指将一个氨基酸残基用另一个具有相似理化性质的侧链的氨基酸残基替代。例如,可以在疏水侧链氨基酸残基间(例如Met、Ala、Val、Leu和Ile)、中性亲水侧链残基间(例如Cys、Ser,Thr、Asn和Gln)、酸性侧链残基间(例如Asp、Glu)、碱性侧链氨基酸间(例如His、Lys和Arg)或芳香侧链残基间(例如Trp、Tyr和Phe)进行保守置换。本领域已知保守置换通常不会引起蛋白构象结构的显著变化,因此能够保留蛋白质的生物活性。
当″百分比序列同一性″用于氨基酸序列(或核酸序列)时,是指在进行序列比对,并且必要时引入间隔使相同氨基酸(或核酸)数目达到最多后,在候选序列中,与参比序列相同的氨基酸(或核酸)残基占所述候选序列的氨基酸(或核酸)残基的百分比。所述氨基酸残基的保守置换可以认为或可以不认为是相同残基。可以通过本领域公开的工具对序列进行比对以确定氨基酸(或核酸)序列的百分比序列同一性。本领域技术人员可以使用所述工具的默认参数或根据比对的需要适当调整参数,例如通过挑选合适的算法。
本申请中使用的“T细胞”包括CD4+T细胞、CD8+T细胞、T辅助1型T细胞、T辅助2型T细胞、T辅助17型T细胞和抑制性T细胞。
本申请中使用的″效应功能″是指抗体的Fc区与其效应器例如C1复合物和Fc受体结合的生物活性。示例性的效应功能包括抗体与C1复合物上的C1q相互作用诱导的补体依赖性细胞毒性(CDC)、抗体的Fc区与效应细胞上的Fc受体结合诱导的抗体依赖性细胞介导的细胞毒性(ADCC)以及吞噬。
本申请中的“癌症”或“癌病症”是指任何由肿瘤或恶性细胞生长、增殖或转移所介导,并引发实体瘤和非实体瘤如白血病的医学状况。本申请中的″肿瘤″是指肿瘤和/或恶性细胞的实体物质。
对某种状况的″治疗″或″疗法″包括预防或减轻某种状况,降低某种状况兴起或发展的速度,减少发展出某种状况的风险,预防或延迟与某种状况相关的症状发展,减少或终止与某种状况相关的症状,产生某种状况的完全或部分的逆转,治愈某种状况,或以上的组合。对于癌症来说,″治疗″或″疗法″可以指抑制或减缓肿瘤或恶性细胞生长,繁殖,或转移,或以上的某些组合。对于肿瘤来说,″治疗″或″疗法″包括清除全部或部分的肿瘤,抑制或减缓肿瘤生长和转移,预防或延缓肿瘤的发展,或以上的某些组合。
″被分离″的物质已经经人工由自然状态改变。如果自然界中出现某种″被分离″的物质或成分,那么其已经被改变或脱离其原始状态,或二者均有发生。例如,某一活体动物体内天然存在的多核苷酸或多肽是未被分离的,但如果这些多核苷酸或多肽与之在天然状态下共存的物质足够分离并以足够纯的状态存在,则可以认为是″被分离″。在某些实施方式中,抗体和抗原结合片段的纯度为至少90%、93%、95%、96%、97%、98%、99%,其可由电泳方法(如SDS-PAGE、等电聚焦、毛细管电泳),或色谱法(如离子交换色谱法或反相HPLC)确定。
本申请中″载体″是指,可将编码某蛋白的多核苷酸操作性地插入其中并使该蛋白获得表达的一种运载工具。载体可用于转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内得以表达。举例来说,载体包括:质粒、噬菌粒、柯斯质粒、人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1衍生的人工染色体(PAC)、噬菌体如λ噬茵体或M13噬菌体,以及动物病毒等。用作载体的动物病毒种类有逆转录病毒(包括慢病毒、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40))。载体可含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。载体还可包括协助其进入细胞的成分,包括但不限于,病毒颗粒、脂质体或蛋白外壳。
本申请中″宿主细胞″是指导入外源多核苷酸和/或载体的细胞。本申请所述的宿主细胞包括但不限于,原核细胞例如大肠杆菌或枯草菌,真菌细胞例如酵母细胞或曲霉菌,昆虫细胞例如S2果蝇细胞或Sf9,或者动物细胞例如纤维原细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,BHK细胞,HEK 293细胞或人细胞。
本申请中″嵌合抗原受体″简称CAR,是指可以识别特定抗原(例如肿瘤抗原)的细胞表面受体,其包含能够识别特定抗原的胞外域(例如,识别并结合特定抗原的抗体的抗原结合片段)和能够将细胞外的信号传递到细胞内部的胞内域(也称为胞内信号转导区,例如CD3的δ链或FcεRIγ的胞内部分)。携带并表达此类嵌合抗原受体的T细胞即被称为CAR-T细胞,其能够通过胞外域识别并结合特定抗原以及表达所述特定抗原的细胞(例如肿瘤细胞),并通过胞内域的信号转导作用,激活免疫应答,释放大量的多种效应因子,高效杀伤表达所述特定抗原的细胞(例如肿瘤细胞),从而发挥治疗作用(例如治疗肿瘤)。
基于现有技术的不足,本申请的主要目的之一在于,提供一种特异性更强、选择性更好的抗CEACAM5抗体。本申请还提供了所述抗体的制备方法和用途,本申请的抗CEACAM5抗体可以用于检测和/或治疗肿瘤。
本申请的抗体
在一个方面,本申请提供了一种特异性结合CEACAM5蛋白的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
(a)包含下述3个互补决定区(CDRs)的重链可变区(VH):
(i)VH CDR1,其由下述序列组成:SEQ ID NO:1,或与其相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个或3个氨基酸的置换、缺失或添加)的序列,
(ii)VH CDR2,其由下述序列组成:SEQ ID NO:2,或与其相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个或3个氨基酸的置换、缺失或添加)的序列,和(iii)VHCDR3,其由下述序列组成:SEQ ID NO:3,或与其相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个或3个氨基酸的置换、缺失或添加)的序列;
和/或,
(b)包含下述3个互补决定区(CDRs)的轻链可变区(VL):
(iv)VL CDR1,其由下述序列组成:SEQ ID NO:4,或与其相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个或3个氨基酸的置换、缺失或添加)的序列,
(v)VL CDR2,其由下述序列组成:SEQ ID NO:5,或与其相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个或3个氨基酸的置换、缺失或添加)的序列,和
(vi)VL CDR3,其由下述序列组成:SEQ ID NO:6,或与其相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个或3个氨基酸的置换、缺失或添加)的序列。
在某些实施方案中,(i)-(vi)任一项中所述的置换为保守置换。
在某些实施方案中,(i)-(vi)任一项中所述的CDR根据Kabat编号系统定义。
在某些实施方案中,所述抗体或其抗原结合片段包含:如下3个重链CDRs:序列为SEQ ID NO:1的VH CDR1,序列为SEQ ID NO:2的VH CDR2,序列为SEQ ID NO:3的VH CDR3;和/或,如下3个轻链CDRs:序列为SEQ ID NO:4的VL CDR1,序列为SEQ ID NO:5的VLCDR2,序列为SEQ ID NO:6的VLCDR3。在某些实施方案中,所述的重链CDR和轻链CDR根据Kabat编号系统定义。
在一个方面,本申请提供了一种特异性结合CEACAM5蛋白的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:如SEQ ID NO:7所示的重链可变区(VH)中含有的3个CDR;和/或,如SEQ ID NO:8所示的轻链可变区(VL)中含有的3个CDR。在某些实施方案中,所述VH中含有的3个CDR和/或所述VL中含有的3个CDR由Kabat、IMGT或Chothia编号系统定义。
在某些实施方案中,所述抗体或其抗原结合片段包含:
(a)重链可变区(VH),其包含选自下列的氨基酸序列:
(i)SEQ ID NO:7所示的序列;
(ii)与SEQ ID NO:7所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NO:7所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;
和/或
(b)轻链可变区(VL),其包含选自下列的氨基酸序列:
(iv)SEQ ID NO:8所示的序列;
(v)与SEQ ID NO:8所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(vi)与SEQ ID NO:8所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。
在某些实施方案中,(ii)或(v)中所述的置换是保守置换。
在某些示例性实施方案中,所述抗体或其抗原结合片段包含:包含如SEQ ID NO:7所示的序列的VH和包含如SEQ ID NO:8所示的序列的VL。
本申请的抗体或其抗原结合片段可以包含来源于哺乳动物(例如,鼠或人)免疫球蛋白的恒定区序列或其变体,所述变体与其所源自的序列相比具有一个或多个氨基酸的置换、缺失或添加或其任意组合(例如,至多20个、至多15个、至多10个、或至多5个氨基酸的置换、缺失或添加或其任意组合;例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加或其任意组合)。
在某些实施方案中,本申请的抗体或其抗原结合片段的重链包含人免疫球蛋白的重链恒定区(CH)或其变体,所述变体与其所源自的序列相比具有一个或多个氨基酸的置换、缺失或添加或其任意组合(例如,至多20个、至多15个、至多10个、或至多5个氨基酸的置换、缺失或添加或其任意组合;例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加或其任意组合);和/或,
在某些实施方案中,本申请的抗体或其抗原结合片段的轻链包含人免疫球蛋白的轻链恒定区(CL)或其变体,所述变体与其所源自的序列相比具有一个或多个氨基酸的置换、缺失或添加或其任意组合(例如,至多20个、至多15个、至多10个、或至多5个氨基酸的置换、缺失或添加或其任意组合;例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加或其任意组合)。
在一些实施方案中,所述重链恒定区(CH)的变体与其所源自的序列相比可以具有一个或多个氨基酸的保守置换(例如1个,2个,3个,4个或5个氨基酸的保守置换)。
在一些实施方案中,所述轻链恒定区(CL)的变体与其所源自的序列相比可以具有一个或多个氨基酸的保守置换(例如1个,2个,3个,4个或5个氨基酸的保守置换)。
在某些实施方案中,所述重链恒定区是IgG重链恒定区,例如IgG1、IgG2、IgG3或IgG4重链恒定区。在某些实施方案中,所述重链恒定区是人IgG1、IgG2、IgG3或IgG4重链恒定区。
在某些实施方案中,所述轻链恒定区是κ轻链恒定区。在某些实施方案中,所述轻链恒定区是人κ轻链恒定区。
在某些示例性实施方案中,本申请的抗体或其抗原结合片段包含SEQ ID NO:9所示的重链恒定区(CH);和/或,SEQ ID NO:11所示的轻链恒定区(CL)。
在某些实施方案中,所述抗原结合片段选自Fab、Fab’、(Fab’)2、Fv、二硫键连接的Fv、scFv、双抗体(diabody)和单域抗体(sdAb)。
在某些实施方案中,所述抗体为鼠源抗体、嵌合抗体、人源化抗体、双特异性抗体或多特异性抗体。
本申请的抗体或其抗原结合片段具有选自下列的一种或多种活性:
(1)特异性结合CEACAM5蛋白或表达CEACAM5蛋白的细胞;
(2)基本上不与CEACAM1、CEACAM3、CEACAM6、CEACAM7蛋白或表达CEACAM1、CEACAM3、CEACAM6、CEACAM7蛋白的细胞结合;
(3)与CEACAM8蛋白或表达CEACAM8蛋白的细胞仅具有微弱的结合,其结合亲和力显著低于与CEACAM5蛋白或表达CEACAM5蛋白的细胞的结合亲和力;
(4)具有ADCC活性;
(5)能够抑制或杀伤表达CEACAM5蛋白的肿瘤细胞(例如结肠癌细胞,胃癌细胞),具有治疗肿瘤的活性。
在某些实施方案中,本申请的抗体或其抗原结合片段带有标记。在某些实施方案中,所述抗体或其抗原结合片段带有可检测的标记,例如酶(例如辣根过氧化物酶)、放射性核素、荧光染料、发光物质(如化学发光物质)或生物素。
在某些实施方式中,本申请提供了示例性的抗CEACAM5抗体UM05-6L。
本领域技术人员应理解可以将前述CDR序列进行修饰以包含一个或更多氨基酸的取代,由此得到提高的生物学活性例如提高的与人癌胚抗原细胞粘附分子5的结合亲和性。例如,可以利用噬菌体展示技术生产并表达抗体变体库(例如Fab或FcFv变体),随后筛选与CEACAM5有亲和性的抗体。另一个例子中,可以用计算机软件模拟所述抗体与CEACAM5的结合并鉴别抗体上形成结合界面的氨基酸残基。可以避免这些残基的替代以防止结合亲和性降低,或可以靶向这些残基进行替代以形成更强的结合。在某些实施方式中,CDR序列中的至少一个(或全部)取代是保守替代。
在某些实施方式中,所述抗体或抗原结合片段包括一个或多个CDR序列,这些序列具有与SEQ ID NO:1-6的序列至少80%(例如至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)的序列同一性,并且同时保留了与其亲本抗体相似或甚至更高的与CEACAM5的结合亲和性。所述亲本抗体具有基本相同的序列,但其相应的CDR序列与SEQ ID NO:1-6所列的序列具有100%序列同一性。
在一些实施方式中,本申请所述的抗体或抗原结合片段能够以≤10-7M的结合亲和性(KD)与CEACAM5特异性结合,其可通过表面等离子共振法测量。结合亲和性值可以用KD值表示,其通过当抗原和抗原结合分子的结合达到平衡时的解离速率与结合速率的比值(koff/kon)计算得到。所述抗原结合亲和性(例如KD)可以通过本领域已知的适宜方法适宜地确定,例如包括使用仪器如Biacore的等离子共振结合法。
在某些实施方式中,本申请所述抗体或抗原结合片段与CEACAM5以1ng/mL-10μg/mL的EC50(即半数结合浓度)结合。抗体或抗原结合片段与CEACAM5的结合可以通过本领域已知的方法如夹心法如ELISA,Western印迹,FACS或其他结合试验测定。在示例性的例子中,将待测抗体(即一抗)与固定化的CEACAM5或表达CEACAM5的细胞结合,随后洗掉未结合抗体,引入标记的二抗,其能够与一抗结合,因此能够检测出结合的二抗。当使用固定化的癌胚抗原细胞粘附分子5时,可在酶标仪板上进行所述检测,或当使用表达CEACAM5的细胞时,可使用FACS分析进行所述检测。
在某些实施方式中,本申请所述的抗体或抗原结合片段以10ng/mL-10μg/mL(使用FACS分析测定)的ECS0(即50%的有效浓度)与CEACAM5结合。
所述抗体是CEACAM5特异性的。在某些实施方式中,所述抗体任选地不与CEACAM1、CEACAM3、CEACAM6、CEACAM7结合,且以显著低于与CEACAM5的结合亲和性结合CEACAM8。
在一些实施方式中,本申请所述的抗体能与具有免疫原性的物质联用,如肿瘤细胞、纯化的肿瘤抗原和用编码免疫刺激因子转染的细胞、肿瘤疫苗。此外,所述抗CEACAM5抗体和其抗原结合片段可以包括在联用治疗中,包括标准化学疗法和放射疗法、基于靶点的小分子疗法、其他新兴免疫检查点调节剂疗法。在一些实施方式中,所述抗体和其抗原结合片段可以用作抗体-药物缀合物、双特异性或多价抗体的基础分子。
在一些实施方式中,本申请所述的抗体和其抗原结合片段是骆驼化单域抗体(camelized single chain domain antibody)、双功能抗体(diabody)、scFv、scFv二聚体、BsFv、dsFv、(dsFv)2、dsFv-dsFv′、Fv片段、Fab、Fab′、F(ab′)2、ds双功能抗体(ds diabody)、纳米抗体、域抗体或双价域抗体。
在一些实施方式中,本申请所述的抗体包括免疫球蛋白恒定区。在一些实施方式中,免疫球蛋白恒定区包括重链和/或轻链恒定区。所述重链恒定区包括CH1、CH1-CH2或CH1-CH3区。在一些实施方式中,免疫球蛋白恒定区可以进一步包括一个或多个修饰以获得所需的性质。例如,可以将所述恒定区修饰,以降低或消除一种或多种效应功能,增强FcRn受体结合或引入一个或多个半胱氨酸残基。
在某些实施方式中,所述抗体及其抗原结合片段进一步包含缀合物。可以设想,本申请中的抗体或其抗原结合片段可与多种缀合物连接(见例如″Conjugate Vaccines″、Contributions to Microbiology and Immunology、J.M.Cruse and R.E.Lewis、Jr.(eds.)、Carger Press、New York(1989))。这些缀合物可以通过共价结合、亲和结合、嵌入、同等结合(coordinate binding)、络合、结合、混合或加入等其他方式与所述抗体或抗原结合片段连接。在某些实施方式中,本申请公开的抗体和抗原结合片段可以通过工程的方法使其含有表位结合部分以外的特定位点,这些位点可用来结合一种或多种缀合物。例如,这样的位点可包含一种或多种反应性氨基酸残基,例如半胱氨酸残基和组氨酸残基,用于协助与结合物的共价连接。在某些实施方式中,抗体可间接连于缀合物,或通过另一个缀合物相连。例如,所述抗体或其抗原结合片段可结合生物素,然后间接结合第二个缀合物,其与亲和素相连。所述缀合物可以是可检测的标记、药代动力学修饰部分、纯化部分或细胞毒性部分。可检测的标记的例子可以包括荧光标记(例如荧光素、罗丹明、丹酰、藻红蛋白或德克萨斯红)、酶底物标记物(例如辣根过氧化物酶、碱性磷酸酶、荧光素酶、葡糖淀粉酶、溶菌酶、糖氧化酶或β-D半乳糖昔酶)、稳定同位素或者放射性同位素、发色团部分、地高辛、生物素/亲和素、DNA分子或金以进行检测。在某些实施方式中,所述缀合物可以是药代动力学修饰部分如PEG,其帮助延长抗体的半衰期。其他适宜的聚合物包括例如羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、乙二醇/丙二醇共聚物等。在某些实施方式中,所述缀合物可以是纯化部分例如磁珠。″细胞毒性部分″可以是对细胞有害的或可能损坏或杀死细胞的任何试剂。细胞毒性部分的示例包括,但不限于,紫杉醇、细胞松弛素B、短杆菌肽D、溴化乙绽、吐根碱、丝裂霉素、依托泊昔、替尼泊甘、长春新碱、长春碱、秋水仙碱、阿霉素、柔红霉素、二羟基炭疽菌素二酮、米托蒽醌、光神霉素、放线菌素D、l-去氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普茶洛尔、嘌呤霉素及其类似物、抗代谢物(例如,甲氨喋呤、6-巯基嘌呤、6-巯鸟嘌呤、阿糖胞苷、5氟尿嘧啶达卡巴)、烷化剂(例如氮芥、塞替派苯丁酸氮芥、美法仑、卡莫司汀(BSNU)和洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲霉素、丝裂霉素C和顺-二氯二胺铂(DDP)顺铂)、蒽环类抗生素(例如柔红霉素(以前的道诺霉素)和阿霉素)、抗生素(例如更生霉素(以前称为放线菌素)、博来霉素、光神霉素和氨茵霉素(AMC))以及抗有丝分裂剂(例如长春新碱和长春碱)。
核酸分子和重组方法
本申请的抗体可以以本领域已知的各种方法来制备,例如通过基因工程重组技术来获得。例如,可通过化学合成或PCR扩增获得编码本申请抗体或其抗原结合片段的DNA分子。将所得DNA分子插入表达载体内,然后转染宿主细胞。然后,在特定条件下培养转染后的宿主细胞,并表达本申请的抗体或其抗原结合片段。
本申请的抗原结合片段可以通过水解完整的抗体分子获得(参见Morimoto etal.,J.Biochem.Biophys.Methods 24:107-117(1992)and Brennan et al.,Science 229:81(1985))。另外,这些抗原结合片段也可以直接由重组宿主细胞产生(reviewed inHudson,Curr.Opin.Immunol.11:548-557(1999);Little et al.,Immunol.Today,21:364-370(2000))。比如,Fab’片段可以直接从宿主细胞中获得;可以将Fab’片段化学偶联形成F(ab’)2片段(Carter et al.,Bio/Technology,10:163-167(1992))。另外,Fv、Fab或F(ab’)2片段也可以直接从重组宿主细胞培养液中直接分离得到。本领域的普通技术人员完全知晓制备这些抗原结合片段的其它技术。
在某些具体的实施方案中,本申请提供的抗CEACAM5抗体或其抗原结合的制备方法包括以下步骤:
1)以过表达癌胚抗原细胞粘附分子5的CHO细胞株为抗原免疫的Balb/c小鼠为材料,提取脾细胞,与小鼠骨髓瘤细胞系SP2/0-AG14融合,获得可表达抗CEACAM5抗体或其抗原结合片段的杂交瘤细胞株;
2)在由步骤1)得到的杂交瘤细胞株中克隆表达抗CEACAM5抗体或其抗原结合片段的基因;
3)提供表达载体,所述表达载体包含步骤2)所克隆得到的基因以及与所述基因操作性相连的表达调控序列;
4)用步骤3)所述的表达载体转化宿主细胞;
5)培养步骤4)得到的宿主细胞;
6)分离纯化得到单克隆抗体。
在另一方面,本申请提供了用于上述制备方法的杂交瘤细胞株。
本申请制备了分泌特异性抗CEACAM5抗体的人-鼠杂交瘤,利用分子生物学技术克隆了该抗体的重链和轻链序列(百分之百人的基因),构建了抗人癌胚抗原细胞粘附分子5人源单克隆抗体,并由CHO细胞来表达生产抗体。这些抗体作为药物与现有抗体比较,具有更强的结合能力和特异性。
在另一个方面,本申请提供了一种分离的核酸分子,其包含编码本申请的抗体或其抗原结合片段,或其重链可变区和/或轻链可变区的核苷酸序列。在某些实施方案中,所述核酸分子包含如SEQ ID NO:14和/或SEQ ID NO:15所示的核苷酸编码序列。
在另一个方面,本申请提供了一种载体(例如克隆载体或表达载体),其包含如上所述的分离的核酸分子。在某些实施方案中,本申请的载体是质粒,粘粒,噬菌体等。
在某些实施方案中,所述载体包含编码本申请的抗体或其抗原结合片段的重链可变区的第一核苷酸序列,和/或编码本申请的抗体或其抗原结合片段的轻链可变区的第二核苷酸序列。在某些实施方案中,所述第一核苷酸序列和第二核苷酸序列被提供在相同或不同的载体上。
在另一个方面,本申请提供了一种宿主细胞,其包含如上所述的分离的核酸分子或载体。在某些实施方案中,所述宿主细胞是哺乳动物细胞。在某些实施方案中,所述宿主细胞是人、鼠、羊、马、狗或猫的细胞。在某些实施方案中,所述宿主细胞是中国仓鼠卵巢细胞。
在另一个方面,提供了制备本申请的抗体或其抗原结合片段的方法,其包括,在允许所述抗体或其抗原结合片段表达的条件下,培养如上所述的宿主细胞,和从培养的宿主细胞培养物中回收所述抗体或其抗原结合片段。
在另一个方面,本申请还提供了双特异性或多特异性分子,其包含所述的抗体或其抗原结合片段。在某些实施方案中,所述双特异性或多特异性分子特异性结合CEACAM5,并且额外地特异性结合一个或多个其他靶标。在某些实施方案中,所述双特异性或多特异性分子还包含至少一种具有针对第二靶标的第二结合特异性的分子(例如第二抗体)。
在另一个方面,本申请还提供了免疫缀合物,其包含所述的抗体或其抗原结合片段以及连接于所述抗体或其抗原结合片段的治疗剂。在某些实施方案中,所述治疗剂选自细胞毒剂。在某些实施方案中,所述治疗剂选自烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂,及其任意组合。在某些实施方案中,所述免疫缀合物是抗体-药物偶联物(ADC)。
使用本领域公知的遗传工程学技术,可以将本申请所述抗体及其抗原结合片段的氨基酸序列转换成相应的DNA编码序列。由于遗传密码的简并性,转换所得的DNA序列可以不完全一致,而编码的蛋白序列保持不变。
使用本领域公知的重组技术,可以将包括编码所述抗体及其抗原结合片段的多核苷酸的载体引入宿主细胞用于克隆(扩增DNA)或基因表达。在另一实施方式中,所述抗体及其抗原结合片段可通过本领域公知的同源重组的方法制得。多种载体可供选择。载体组分通常包括,但不限于,以下的二种或多种:信号序列、复制起始点、一种或多种标记基因、增强序列、启动子(例如:SV40、CMV、EF-1a)和转录终止序列。
在一些实施方式中,所述载体系统包括哺乳动物、细菌、酵母系统等,并将包括质粒例如但不限于pALTER、pBAD、pcDNA、pCal、pL、pELpGEMEX、pGEX、pCLpCMV、pEGFP、pEGFT,pSV2、pFUSE、pVITRO,pVIVO、pMAL、pMONO、pSELECT、pUNO、pDUO、Psg5L、pBABE、pWPXL、pBI、p15TV-L、pPro18、pTD、pRS420、pLexA、pACT2等其他可从实验室获得或市售的载体。适宜的载体可以包括质粒或病毒载体(例如复制缺陷型逆转录病毒、腺病毒和腺相关病毒)。
可以将包括编码所述抗体及其抗原结合片段的多核苷酸的载体引入宿主细胞用于克隆或基因表达。本申请中适用于克隆或表达所述载体中的DNA的宿主细胞为原核细胞、酵母或上述高级真核细胞。适用于本申请用途的原核细胞包括真细菌,如革兰氏阴性菌或革兰氏阳性菌,例如肠杆菌科(如大肠杆菌),肠杆菌属,欧文氏菌属,克雷白氏杆菌属,变形杆菌属,沙门氏菌属,如,鼠伤寒沙门(氏)杆菌,沙雷氏菌属,如粘质沙雷氏菌,以及志贺氏菌属,及杆菌属如枯草芽孢杆菌和地衣芽孢杆菌,假单胞菌如绿肽杆菌和链霉菌。
除了原核细胞以外,真核微生物如丝状真菌或酵母也可作宿主细胞克隆或表达编码抗体的载体。酿酒酵母,或面包酵母是最常用的低等真核宿主微生物。但是,许多其他属、种和株都比较常用且在本申请中适用,如粟酒裂殖酵母;克鲁维酵母属宿主如,乳酸克鲁维酵母、脆壁克鲁维酵母(ATCC12424)、保加利亚克鲁维酵母(ATCC16045)、魏氏克鲁维酵母(ATCC24178)、克鲁雄酵母(ATCC56500)、果蝇克鲁维酵母(ATCC36906)、耐热克鲁维酵母和马克斯克鲁维酵母:解脂耶氏酵母(EP402226);巴斯德毕赤酵母(EP183070);假丝酵母:里氏木霉(EP244234);链孢霉;西方许旺酵母,如:西方许旺酵母;和丝状真菌,如:脉孢菌、青霉菌、弯颈霉和曲霉菌,如:钩巢曲霉和黑曲霉。
本申请中提供的适用于表达糖基化抗体或其抗原结合片段的宿主细胞由多细胞生物衍生得到。无脊椎细胞的实例包括植物和昆虫细胞。已发现多种杆状病毒株(baculoviral strains)及其变体以及对应的许可性昆虫宿主细胞(permissive insecthost cells),来自于诸如以下的宿主:草地夜蛾(毛虫)、埃及斑蚊(蚊子)、白纹伊蚊(蚊子)、黑腹果蝇(果蝇)及家蚕。多种用于转染的病毒株为公众可得,例如苜蓿银纹夜蛾核型多角体病毒和家蚕核型多角体病毒的Bm-5变种,这些病毒都可在本申请中使用,特别是用于转染草地夜蛾细胞。棉花、玉米、土豆、大豆、矮牵牛花、西红柿和烟草的植物细胞培养也可用作宿主。
但是,最感兴趣的是脊椎细胞,且脊椎细胞的培养(组织培养)已经成为常规操作。可用的哺乳动物宿主细胞实例有,SV40转化的猴肾细胞CV1系(COS-7,ATCC CRL 1651);人胚胎肾细胞系(293或悬浮培养的293细胞亚克隆,Graham et al.,].Gen Virol.36:59(1977));幼地鼠肾细胞(B血,ATCC CCL 10);中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub etal.,Proc.Natl.Acad.Sci.USA 77:4216(1980));小鼠睾丸支持细胞(TM4,Mather J.P.,Biol.Reprod.23:243-252(1980));猴肾细胞(CV1ATCC CCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL2);犬肾细胞(MDCK,ATCC CCL 34);布法罗大鼠肝细胞(BRL 3A,ATCC CRL 1442);人肺细胞(W138,ATCC CCL75);人肝细胞(HepG2,HB 8065);小鼠乳腺瘤(MMT 060562,ATCC CCL51);TRI细胞(Mather等,AnnalsN.Y.Acad.Sci.383:44-68(1982));MRC 5细胞;FS4细胞;及人肝癌细胞系HepG2)。在某些优选的实施方式中,所述宿主细胞是293F细胞。
用上述的可产生所述抗体及其抗原结合片段的表达或克隆载体转化宿主细胞,并将其在常规的营养培养基中培养,所述营养培养基经修饰后适宜于诱导启动子、选择转化细胞或扩增编码目的序列的基因。
本申请中用于产生所述抗体及其抗原结合片段的宿主细胞可在多种本领域公知的培养基中培养。所述培养基还可含有本领域公知的适当浓度的任何其他必要的添加剂。所述培养基的条件,如温度、pH值等类似条件,为选择用于表达的宿主细胞此前所使用的条件,为普通技术人员所熟知。
在使用重组技术时,所述抗体可在胞内、壁膜空间生成,或直接分泌到培养基中。如果所述抗体在胞内生成,首先除去宿主细胞或裂解片断的颗粒残骸,例如,可通过离心或超声的方法。Carter et al.,Bio/Technology 10:163-167(1992)描述了将分泌到大肠杆菌壁膜空间的抗体分离的方法。简要地说,在醋酸铀(pH 3.5)、EDTA和苯甲磺酣氟(PMSF)存在的条件下化开细胞糊(cell paste)约30分钟以上。离心除去细胞碎片。如所述抗体分泌到培养基中,则通常首先使用市售的蛋白浓度过滤器,如IAmicon或Millipore Pelliconultrafiltration unit,浓缩该表达系统的上清液。在任何前述的步骤中都可加入蛋白酶抑制剂如PMSF以抑制蛋白降解,以及抗生素以防止偶然污染物的生长。
从所述细胞中制得的抗体可采用纯化方法进行纯化,例如羟磷灰石色谱、凝胶电泳、透析、DEAE-纤维素离子交换色谱柱、硫酸铵沉淀、盐析以及亲和色谱,其中亲和色谱为优选的纯化技术。所述抗体的种类以及所述抗体中存在任何免疫球蛋白的Fc结构域决定了蛋白A作为亲和配体是否适合。蛋白A可用于纯化基于人γ1、γ2或γ4重链的抗体(Lindmark et al.,J.Immunol.Meth.62:13(1983))。蛋白G适用于所有鼠源异构体和人γ3(Guss et al.,EMBO J.5:15671575(1986))。琼脂糖是最常用的亲和配体附着基质,但也可选用其他基质。机械力稳定的基质如可控孔度玻璃或聚(苯乙烯)苯与用琼脂糖相比可实现更快的流速和更短的处理时间。如该抗体含有CH3结构域,则可用Bakerbond ABX.TM树脂进行纯化(J.T.Baker,Phillipsburg,N.J.)。也可根据需要获得的抗体确定其他蛋白纯化的技术,如离子交换柱中的分馏、乙醇沉淀、反相HPLC、硅胶色谱、基于阴离子或阳离子交换树脂的肝素琼脂糖凝胶色谱(如聚天冬氨酸柱)、层析聚焦、SDS-PAGE、以及硫酸铵沉淀。
在任意初步纯化步骤之后,可用低pH疏水相互作用色谱的方法处理含有感兴趣的抗体和杂质的混合物,用pH约2.5-4.5的洗脱缓冲液,优选地在低盐浓度下进行(例如,从约0到0.25M盐浓度)。
药物组合物及治疗用途
在另一个方面,本申请提供了一种药物组合物,其含有本申请的抗体或其抗原结合片段、本申请的双特异性或多特异性分子或者本申请的免疫缀合物以及药学上可接受的载体和/或赋形剂。
在某些实施方案中,所述药物组合物还可以包含另外的药学活性剂。
在某些实施方案中,所述另外的药学活性剂是具有抗肿瘤活性的药物,例如烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂、放射增敏剂、抗血管生成剂、细胞因子、分子靶向药物、免疫检查点抑制剂或溶瘤病毒。
在某些实施方案中,所述抗体或其抗原结合片段、双特异性或多特异性分子或免疫缀合物与所述另外的药学活性剂作为分离的组分或作为同一组合物的组分提供。本申请的抗体或其抗原结合片段与所述另外的药学活性剂可以同时、分开或相继施用。
本申请进一步提供了包括所述抗体的药物组合物和一个或多个药学上可接受的载体。
用在本申请公开的药物组合物中的药用可接受载剂可包括,例如,药用可接受的液体、凝胶或固体载剂、水相介质、非水相介质、抗微生物物质、等渗物质、缓冲液、抗氧剂、麻醉剂、悬浮剂/分散剂、整合剂、稀释剂、佐剂、辅料或无毒辅助物质,其他本领域公知的组分或以上的多种组合。
适用的组分可包括,例如,抗氧剂、填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、矫味剂、增稠剂、着色剂、乳化剂或稳定剂例如糖和环糊精。适用的抗氧剂可包括,例如,甲硫氨酸、抗坏血酸、EDTA、硫代硫酸钠、铂、过氧化氢酶、柠檬酸、半胱氨酸、巯基甘油、巯基乙酸、巯基山梨醇、丁基甲基茴香醚、丁基化羟基甲苯和/或没食子酸丙酯。在一种含有本申请公开的抗体的组合物中包括一种或多种抗氧剂如甲硫氨酸,可将降低所述抗体的氧化。对氧化作用的减少可防止或减少结合亲和力的降低,从而提高抗体稳定性并延长保质期。
进一步的说,药用可接受的载剂可包括,例如,水相介质如氯化钠注射液、林格氏液注射液、等渗葡萄糖注射液、无菌水注射液、或葡萄糖和乳酸林格注射液、非水介质例如:植物来源的不挥发性油、棉花子油、玉米油、芝麻油、或者花生油、细菌抑制或真菌抑制浓度下的抗菌物质、等渗剂如氯化钠或葡萄糖、缓冲液如磷酸盐或枸橼酸盐缓冲液,抗氧化剂如硫酸氢钠,局部麻醉剂如盐酸普鲁卡因,助悬剂和分散剂如羧甲基纤维素钠、羟丙基甲基纤维素或聚乙烯吡咯烷酮,乳化剂如聚山梨醇酯80(吐温-80)、整合试剂如EDTA(乙二胺四乙酸)或EGTA(乙二醇双(2-氨基乙基醚)四乙酸)、乙醇、聚乙二醇、丙二醇、氢氧化钠、盐酸、柠檬酸或乳酸。作为载剂的抗菌剂可加入多次剂量容器中的药物组合物中,其包括酚类或甲酚、汞制剂、苯甲醇、氯代丁醇、甲基和丙基对羟基苯甲酸酯、噻汞撒、氯苯甲烷铵和氯苯乙铵。适用的辅料可包括,例如,水、盐、葡萄糖、甘油或乙醇。适用的无毒辅助物质可包括,例如,乳化剂、pH值缓冲剂、稳定剂、增溶剂,或者醋酸钠、去水山梨糖醇月桂酸酯、三乙醇胺油酸酯或者环糊精之类的物质。
所述药物组合物可以是液体溶液、悬浮液、乳剂、丸剂、胶囊、片剂、持续释放制剂或粉末。口服制剂可以包括标准载体如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、聚乙烯吡咯烷酮、糖精钠、纤维素、碳酸镁等。
在某些实施方式中,所述药物组合物被制剂成可注射的组合物。可注射的药物组合物可以任何常规的形式制备,例如,液体溶剂、悬浮剂、乳化剂或适用于产生液体溶剂、悬浮剂或乳化剂的固体形式。注射制剂可包括现用的无菌和/或无热原溶液、使用前现与溶剂结合的无菌干燥的可溶物,如冻干粉,包括皮下片、注射即用的无菌悬浮剂、使用前现与介质结合的无菌干燥不溶产品,和无菌和/或无热原的乳剂。溶剂可以为水相或非水相。
在某些实施方式中,单位剂量的注射制剂包装在一个安瓿、一支管或一支带有针的针筒中。本领域悉知,所有注射给药的制剂应为无菌无热原。
在某些实施方式中,通过将本申请公开的抗体或其抗原结合片段溶解于某适当的溶剂中可制备无菌冻干的粉末。所述溶剂可含有一种可提高粉或由粉末制得的重组溶液的稳定性,或改善粉末或重组溶液的其他药理组分。适用的辅料包括,但不限于,水、葡萄糖、三梨糖醇、果糖、玉米糖浆、木糖醇、甘油、葡萄糖、黑糖或其他适用的物质。溶剂可含有缓冲液,如枸橼酸缓冲液、磷酸钠或磷酸钾缓冲液或其他本技术熟练人员公知的缓冲液,在一种实施方式中,缓冲液的pH为中性。在本领域公知的标准条件下进行对所述溶液进行随后的过滤除菌,然后冻干制得理想的制剂。在一种实施方式中,将所得的溶剂分装至小管中冻干。每支小管可容纳单次剂量或多次剂量的所述抗CEACAM5抗体或其抗原结合片段或其组合物。每支小管中的装入量可略微高于每次剂量所需或多次剂量所需(例如10%过量),从而保证取样精确和给药精确。冻干粉可在适当的条件下储存,如在约4℃到室温范围。
用注射用水将冻干粉重溶得到用于注射给药的制剂。在一种实施方式中,可将冻干粉加至无菌无热原水或其他适用的液体载剂中重溶。精确的量由选择的疗法决定,可根据经验值决定。
抗体衍生化和免疫缀合物
本申请的抗体或其抗原结合片段可进行衍生化,例如被连接至另一个分子(例如另一个多肽或蛋白)。通常,抗体或其抗原结合片段的衍生化(例如,标记)不会不利影响其对CEACAM5的结合。因此,本申请的抗体或其抗原结合片段还意欲包括此类衍生化的形式。例如,可以将本申请的抗体或其抗原结合片段功能性连接(通过化学偶合、基因融合、非共价连接或其它方式)于一个或多个其它分子基团,例如另一个抗体(例如,形成双特异性抗体),检测试剂,药用试剂,和/或能够介导抗体或抗原结合片段与另一个分子结合的蛋白或多肽(例如,抗生物素蛋白或多组氨酸标签)。此外,本申请的抗体或其抗原结合片段还可以用化学基团进行衍生,例如聚乙二醇(PEG),甲基或乙基,或者糖基。这些基团可用于改善抗体的生物学特性,例如增加血清半衰期。
因此,在一个方面,本申请提供一种免疫缀合物,其包含本申请所述的抗体或其抗原结合片段以及连接于所述抗体或其抗原结合片段的治疗剂;
在某些实施方案中,所述治疗剂选自细胞毒剂;
在某些实施方案中,所述治疗剂选自烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂,及其任意组合;优选地,所述免疫缀合物是抗体-药物偶联物(ADC)。
试剂盒及检测用途
本申请的抗体或其抗原结合片段能够特异性结合CEACAM5蛋白,并且基本上不与CEACAM1、CEACAM3、、CEACAM6、CEACAM7蛋白结合,仅与CEACAM8蛋白有较弱的结合,因此,本申请的抗体或其抗原结合片段在检测中具有更高的特异性和准确性。
因此,在另一个方面,本申请提供了一种试剂盒,其包括本申请的抗体或其抗原结合片段、或本申请的缀合物。
在某些实施方案中,所述抗体或其抗原结合片段带有可检测的标记,例如酶(例如辣根过氧化物酶)、放射性核素、荧光染料、发光物质(如化学发光物质)或生物素。
在某些实施方案中,所述试剂盒还包括第二抗体,其特异性识别所述的抗体或其抗原结合片段。
在某些实施方案中,所述第二抗体还包括可检测的标记,例如酶(例如辣根过氧化物酶)、放射性核素、荧光染料、发光物质(如化学发光物质)或生物素。
在某些实施方案中,本申请的试剂盒可以进一步包含用于使相应可检测的标记被检测到的试剂。例如,当所述可检测的标记为酶时,所述试剂盒还可以包含相应酶的显色底物,例如用于辣根过氧化物酶的邻苯二胺(OPD)、四甲基联苯胺(TMB)、ABTS或鲁米诺类化合物,或用于碱性磷酸酶的对硝基苯磷酸酯(p-NPP)或AMPPD。例如当所述可检测的标记为化学发光试剂(例如吖啶酯类化合物)时,所述试剂盒还可以包含用于化学发光的预激发液和/或激发液。
在另一个方面,本申请还提供了所述的抗体或其抗原结合片段在制备试剂盒中的用途,所述试剂盒用于检测肿瘤是否能够通过靶向CEACAM5的抗肿瘤疗法来治疗。
在某些实施方案中,所述抗体或其抗原结合片段带有可检测的标记。
在某些实施方案中,所述CEACAM5是人CEACAM5。
在某些实施方案中,所述肿瘤选自非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿(mycosis fungoids)、默克尔细胞癌和其它恶性血液病、如经典型霍奇金淋巴瘤(CHL)、原发性纵膈大B细胞淋巴瘤、T细胞/组织细胞的富B细胞淋巴瘤、EBV阳性和阴性PTLD和EBV相关弥漫性大B细胞淋巴瘤(DLBCL)、浆母细胞性淋巴瘤、结外NK/T细胞淋巴瘤、鼻咽癌和HHV8相关原发性渗出性淋巴瘤、霍奇金淋巴瘤,中枢神经系统(CNS)肿瘤,例如原发性CNS淋巴瘤,脊轴肿瘤,脑干神经胶质瘤。
本申请提供了包括所述抗体或其抗原结合片段的试剂盒。在一些实施方式中,所述试剂盒用于检测在生物样品中的CEACAM5的存在情况或水平。所述生物样品可以包括细胞或组织。
在一些实施方式中,所述试剂盒包括与可检测标记缀合的抗体或其抗原结合片段。在一些实施方式中,所述试剂盒包括未标记的抗体,并进一步包括能够与未标记的抗体结合标记的二抗。所述试剂盒可以进一步包括使用说明和在试剂盒中将每个组件分隔开的包装。
在一些实施方式中,所述抗体与底物或仪器连接用于夹心测定如ELISA或免疫色谱测定。适用的底物或仪器可以是例如微孔板和试纸。
嵌合抗原受体
在另一个方面,本申请还提供了嵌合抗原受体,其包含所述的抗体或其抗原结合片段的抗原结合结构域。
在某些实施方案中,所述抗原结合结构域包含所述的抗体或其抗原结合片段的重链可变区和轻链可变区。
在某些实施方案中,所述抗原结合结构域是scFv。
在某些实施方案中,所述抗原结合受体包含所述的抗体的抗原结合片段。
在某些实施方案中,所述抗原结合受体由免疫效应细胞(例如T细胞)所表达。
在另一个方面,本申请还提供了分离的核酸分子,其编码所述的嵌合抗原受体。
在另一个方面,本申请还提供了载体,其包含所述的分离的核酸分子;在某些实施方案中,其用于制备嵌合抗原受体T细胞。
在另一个方面,本申请还提供了宿主细胞,其包含所述的分离的核酸分子或载体;
优选地,所述宿主细胞是免疫效应细胞(例如,T细胞或NK细胞);
优选地,所述宿主细胞是嵌合抗原受体T细胞(CAR-T)。
检测方法与治疗方法
在许多恶性肿瘤中,CEACAM5的过度表达可以作为肿瘤生物标志物。因此,测量患者血液中的CEACAM5可用于癌症的预后和控制,CEACAM5的靶向治疗也成为潜在的癌症治疗方法。而本申请的抗体(例如,UM05-6L)能够高亲和、高特异的结合CEACAM5蛋白,并具有ADCC活性,能够抑制肿瘤生长,杀灭肿瘤细胞。
因此,在另一个方面,本申请还提供了一种抑制表达CEACAM5的肿瘤细胞生长和/或杀伤所述肿瘤细胞的方法,其包括将所述肿瘤细胞与有效量的所述的抗体或其抗原结合片段,或所述的双特异性或多特异性分子,或所述的免疫缀合物,或所述的药物组合物,或所述的嵌合抗原受体,或所述的宿主细胞接触。
在另一个方面,本申请还提供了一种用于降低CEACAM5在细胞表面的表达水平的方法,其包括将所述细胞与所述的抗体或其抗原结合片段,或所述的双特异性或多特异性分子,或所述的免疫缀合物,或的药物组合物,或所述的嵌合抗原受体,或所述的宿主细胞接触,使得CEACAM5在所述细胞表面的表达水平降低;其中,所述细胞在其表面表达CEACAM5。
在某些实施方案中,所述细胞是表达CEACAM5的肿瘤细胞。
在另一个方面,本申请还提供了一种用于在受试者(例如人)中预防和/或治疗肿瘤的方法,所述方法包括向有此需要的受试者施用有效量的所述的抗体或其抗原结合片段,或所述的双特异性或多特异性分子,或所述的免疫缀合物,或所述的药物组合物,或所述的嵌合抗原受体,或所述的宿主细胞。
在某些实施方案中,所述肿瘤表达CEACAM5。
在某些实施方案中,所述肿瘤涉及表达CEACAM5的肿瘤细胞。在某些实施方案中,所述CEACAM5在所述肿瘤细胞表面上表达。
在某些实施方案中,所述肿瘤选自非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿(mycosis fungoids)、默克尔细胞癌和其它恶性血液病、如经典型霍奇金淋巴瘤(CHL)、原发性纵膈大B细胞淋巴瘤、T细胞/组织细胞的富B细胞淋巴瘤、EBV阳性和阴性PTLD和EBV相关弥漫性大B细胞淋巴瘤(DLBCL)、浆母细胞性淋巴瘤、结外NK/T细胞淋巴瘤、鼻咽癌和HHV8相关原发性渗出性淋巴瘤、霍奇金淋巴瘤,中枢神经系统(CNS)肿瘤,例如原发性CNS淋巴瘤,脊轴肿瘤,脑干神经胶质瘤。
在某些实施方案中,所述受试者为哺乳动物,例如人。
在某些实施方案中,所述方法还包括施用另外的具有抗肿瘤活性的药物,例如烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂、放射增敏剂、抗血管生成剂、细胞因子、分子靶向药物、免疫检查点抑制剂或溶瘤病毒。
在某些实施方案中,所述方法还包括施用另外的抗肿瘤疗法,例如手术、化学治疗、放射治疗、靶向治疗、免疫治疗、激素治疗、基因治疗或姑息治疗。
在另一个方面,本申请还提供了所述的抗体或其抗原结合片段,或所述的双特异性或多特异性分子,或所述的免疫缀合物,或所述的药物组合物,或所述的嵌合抗原受体,或所述的宿主细胞,在制备药物中的用途,所述药物用于在受试者(例如人)中预防和/治疗肿瘤。
在某些实施方案中,药物还包含另外的药学活性剂。
在某些实施方案中,所述另外的药学活性剂是具有抗肿瘤活性的药物,例如烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂、放射增敏剂、抗血管生成剂、细胞因子、分子靶向药物、免疫检查点抑制剂或溶瘤病毒。
在某些实施方案中,所述肿瘤表达CEACAM5。
在某些实施方案中,所述肿瘤涉及表达CEACAM5的肿瘤细胞;优选地,所述CEACAM5在所述肿瘤细胞表面上表达。
在某些实施方案中,所述肿瘤选自非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿(mycosis fungoids)、默克尔细胞癌和其它恶性血液病、如经典型霍奇金淋巴瘤(CHL)、原发性纵膈大B细胞淋巴瘤、T细胞/组织细胞的富B细胞淋巴瘤、EBV阳性和阴性PTLD和EBV相关弥漫性大B细胞淋巴瘤(DLBCL)、浆母细胞性淋巴瘤、结外NK/T细胞淋巴瘤、鼻咽癌和HHV8相关原发性渗出性淋巴瘤、霍奇金淋巴瘤,中枢神经系统(CNS)肿瘤,例如原发性CNS淋巴瘤,脊轴肿瘤,脑干神经胶质瘤。
在某些实施方案中,所述受试者为哺乳动物,例如人。
在另一个方面,本申请还提供了一种检测CEACAM5(例如人CEACAM5)在样品中的存在或其量的方法,其包括以下步骤:
(1)将所述样品与所述的抗体或其抗原结合片段接触;
(2)检测所述抗体或其抗原结合片段与CEACAM5之间复合物的形成或检测所述复合物的量。
在某些实施方案中,所述抗体或其抗原结合片段带有可检测的标记。
在某些实施方案中,所述CEACAM5是人CEACAM5。
在另一个方面,本申请还提供了一种用于检测肿瘤是否能够通过靶向CEACAM5的抗肿瘤疗法来治疗的方法,其包括以下步骤:
(1)将含有所述肿瘤细胞的样品与所述的抗体或其抗原结合片段接触;
(2)检测所述抗体或其抗原结合片段与CEACAM5之间复合物的形成。
在某些实施方案中,所述抗体或其抗原结合片段带有可检测的标记。
在某些实施方案中,所述CEACAM5是人CEACAM5。
在某些实施方案中,所述肿瘤选自非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿(mycosis fungoids)、默克尔细胞癌和其它恶性血液病、如经典型霍奇金淋巴瘤(CHL)、原发性纵膈大B细胞淋巴瘤、T细胞/组织细胞的富B细胞淋巴瘤、EBV阳性和阴性PTLD和EBV相关弥漫性大B细胞淋巴瘤(DLBCL)、浆母细胞性淋巴瘤、结外NK/T细胞淋巴瘤、鼻咽癌和HHV8相关原发性渗出性淋巴瘤、霍奇金淋巴瘤,中枢神经系统(CNS)肿瘤,例如原发性CNS淋巴瘤,脊轴肿瘤,脑干神经胶质瘤。
本申请还提供了治疗方法,包括将治疗有效量的本申请所述的抗体施用给需要其的受试者。
本申请中提供的抗体的治疗有效剂量依赖于本领域公知的多种因素,例如体重、年龄、过往病史、现用治疗、对象的健康状况和交叉感染的潜力、过敏、超敏和副作用,以及给药途径和肿瘤发展的程度。本领域熟练人员(例如医生或兽医)可根据这些或其它条件或要求按比例降低或升高剂量。
在某些实施方式中,本申请提供的抗体可在治疗有效剂量约0-01mg/kg到约100mg/kg之间给药。在某些实施方式中,所述抗体以约50mg/kg或更少的剂量给药,在某些实施方式中,给药剂量为10mg/kg或更少、5mg/kg或更少、1mg/kg或更少、0.5mg/kg或更少或0.1mg/kg或更少。某特定剂量可在多个间隔给药,例如每天一次、每天两次或更多、每月两次或更多、每周一次、每两周一次、每三周一次、每月一次或每两月或更多月一次。在某些实施方式中,给药剂量可随治疗进程变化。例如,在某些实施方式中,初始给药剂量可比后续给药剂量高。在某些实施方式中,给药剂量在治疗进程中根据给药对象的反应进行调整。
给药方案可通过调整达到最优反应(如治疗反应)。例如,可进行单剂量给药或在一段时间分多个分隔的剂量给药。
本申请中公开的抗体可通过本领域公知的给药方式给药,例如注射给药(如,皮下注射、腹腔注射、静脉注射,包括静脉滴注,肌肉注射或皮内注射)或非注射给药(如,口服给药、鼻腔给药、舌下给药、直肠给药或外用给药)。
在某些实施方式中,所述抗体可用于治疗与其分子机制相关的病症,包括肿瘤和癌症,例如非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿(mycosis fungoids)、默克尔细胞癌和其它恶性血液病、如经典型霍奇金淋巴瘤(CHL)、原发性纵膈大B细胞淋巴瘤、T细胞/组织细胞的富B细胞淋巴瘤、EBV阳性和阴性PTLD和EBV相关弥漫性大B细胞淋巴瘤(DLBCL)、浆母细胞性淋巴瘤、结外NK/T细胞淋巴瘤、鼻咽癌和HHV8相关原发性渗出性淋巴瘤、霍奇金淋巴瘤,中枢神经系统(CNS)肿瘤,例如原发性CNS淋巴瘤,脊轴肿瘤,脑干神经胶质瘤。
使用方法
本申请进一步提供了使用所述抗体的方法。
在一些实施方式中,本申请提供了在个体中治疗与所述抗体机制相关的状况或病症的方法,包括施用治疗有效量的本申请所述的抗体。
本申请公开的抗体可单独给药或与一种或多种其他治疗手段或物质联合给药。例如,本申请公开的抗体可与化疗、放疗、癌症治疗手术(如肿瘤切除术)、抗病毒药物、一种或多种抗呕吐药或其他化疗导致的并发症的疗法、或任何其他用于癌症或病毒的治疗物质进行联用。在某些这样的实施方式中,本申请公开的抗体与一种或多种治疗物质联用时,可与所述的一种或多种治疗物质同时给药,在某些这样的实施方式中,所述的抗体可作为同一个药物组合物的一部分同时给药。但是,与其他治疗物质″联用″的抗体不需要同时给药或与该治疗物质在同一组合物中给药。本申请中″联用″的含义还包括在另一个治疗物质之前或之后给药的抗体也被认为是与该治疗物质″联用″,即使所述抗体与第二种物质通过不同给药方式给药。在可能的情况下,与本申请公开的抗体联用的其他治疗物质可参照该其他治疗物质的产品说明书的方法用药,或参照、外科医生的案头参考书2003(Physicians′Desk Reference,57th Ed;Medical Economics Company;ISBN:1563634457;第57版(2002年11月)),或参照其他本领域公知的方法。
在某些实施方式中,所述治疗物质能够诱导或增强针对癌症的免疫反应。例如,肿瘤疫苗可以用于诱导对某些肿瘤或癌症的免疫应答。细胞因子治疗可以用于提高将肿瘤抗原向免疫系统的递呈。细胞因子治疗的示例包括但不限于干扰素如干扰素α、β和γ,集落刺激因子如巨噬细胞CSF、粒细胞巨噬细胞CSF和粒细胞CSF,白介素如IL-1、IL-1a、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7,IL-8、IL-9、IL-10、IL-11和IL-12,肿瘤坏死因子如TNF-α和TNF-β。还可以使用灭活免疫抑制目标的试剂,如PD-1抗体、TGF-β抑制剂、IL-10抑制剂和Fas配体抑制剂。另一组试剂包括激活针对肿瘤或癌细胞的免疫响应的那些试剂,例如,提高T细胞激活(如T细胞共刺激信号通路如CTLA-4、ICOS、OX40、4-1BB等通路)的那些,以及提高树突细胞功能和抗原递呈的那些。
以下实施例旨在更好地说明本申请,且不应理解为限制本申请的范围。所有下述的特定组合物、材料和方法,其整体或部分都在本申请的范围内。这些特定的组合物、材料和方法不是为了限制本申请,而只是为说明在本申请的范围内的特定的实施方式。本领域熟练技术人员可不添加创造性及不偏离本申请范围而开发出等同的组合物、材料和方法。应理解,在对本申请的方法作出的多种改动可以仍然包括在本申请范围内。发明人意在将这样的变动包括在本申请的范围内。
序列信息
本申请所涉及的部分序列的信息如下面的表1所示。
表1.部分序列的信息
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有益效果
本申请的单克隆抗体(例如UM05-6L抗体)能够以高特异性和高选择性与CEACAM5蛋白或表达CEACAM5蛋白的细胞结合,并且其基本不与CEACAM1、CEACAM3、CEACAM6、CEACAM7蛋白结合,仅与CEACAM8蛋白有较弱的结合。同时,抗体UM05-6L还具有ADCC活性。基于抗体UM05-6L所构建的UM05-6L-CAR能够表达于人T细胞表面,在体内能够识别肿瘤细胞,分泌细胞因子,具有强烈的抑制肿瘤作用。因此,本申请的单克隆抗体(例如UM05-6L抗体)较高的临床应用价值。
附图说明
图1显示了本申请构建的过表达CEACAM5的CHO细胞株的过表达倍数;与常规的CHO细胞相比,本申请构建的CHO细胞株过表达倍数达904倍。
图2显示了抗体UM05-6L与CEACAM5蛋白结合的ELISA实验结果图。
图3显示了抗体UM05-6L与LOVO细胞结合能力的检测结果。
图4a-4b显示了抗体UM05-6L的ADCC报告基因活性;其中,图4a显示了阳性对照(Erbitux抗体)和阴性对照的ADCC报告基因活性,图4b显示了UM05-6L的ADCC报告基因活性。
图5a-5b显示了流式细胞的检测结果;图5a为对照T细胞(Mock T)的表达效率,图5b为UM05-6L-CAR的表达效率。
图6显示了UM05-6L-CAR-T与肿瘤细胞混合后细胞因子IFNγ(左图)和IL-2(右图)的分泌结果。
图7显示了UM05-6L-CAR-T细胞对肿瘤细胞KATO3的杀伤结果。
图8显示了UM05-6L-CAR-T细胞经肿瘤细胞LS174T刺激后的扩增结果。
图9显示了UM05-6L-CAR-T在小鼠体内对肿瘤的抑制结果。
图10显示了接受UM05-6L-CAR-T的小鼠体内IFNγ的释放情况。
具体实施方式
现参照下列意在举例说明本申请(而非限定本申请)的实施例来描述本申请。
除非特别指明,本申请中所使用的分子生物学实验方法和免疫检测法,基本上参照J.Sambrook等人,分子克隆:实验室手册,第2版,冷泉港实验室出版社,1989,以及F.M.Ausubel等人,精编分子生物学实验指南,第3版,John Wiley & Sons,Inc.,1995中所述的方法进行;限制性内切酶的使用依照产品制造商推荐的条件。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。本领域技术人员知晓,实施例以举例方式描述本申请,且不意欲限制本申请所要求保护的范围。
实施例1:抗人CEACAM5蛋白的单克隆抗体的获得
本申请构建了过表达CEACAM5蛋白的CHO细胞株。简言之,将CEACAM5的质粒(北京义翘神州科技有限公司,HG11077-UT)转染入CHO细胞株(ATCC)并表达。该质粒带有潮霉素(Hygromycin)抗性,因此稳定转染具有该质粒的细胞可以在含有Hygromycin的培养基中稳定传代。挑取细胞并测量CEACAM5的表达量,如图1所示,经FACS检测得到的CHO-CEACAM5细胞,其CEACAM5的过表达倍数达904倍。
用CHO-CEACAM5细胞和从肿瘤病人中提纯的CEACAM5蛋白(上海领潮生物,L2C01001)按表2的免疫方案对6只5-8周龄Balb/c mice小鼠(上海斯莱克)进行免疫。
表2.小鼠免疫方案
日期 | 操作 | 抗原 | 佐剂 |
第1天 | 腹腔注射免疫 | CHO-CEACAM5细胞 | CFA |
第26天 | 腹腔注射免疫 | CHO-CEACAM5细胞 | IFA |
第49天 | 腹腔注射免疫 | CHO-CEACAM5细胞 | IFA |
第91天 | 腹腔注射免疫 | CEACAM5蛋白 | Gerbu(MM3001) |
第104天 | 腹腔注射免疫 | CEACAM5蛋白 | Gerbu(MM3001) |
第105天 | 腹腔注射免疫 | CEACAM5蛋白 | Gerbu(MM3001) |
第106天 | 腹腔注射免疫 | CEACAM5蛋白 | Gerbu(MM3001) |
免疫结束后第二天,取免疫小鼠的脾细胞与SP2/0-AG14细胞(ATCC)进行杂交瘤细胞融合,并取适量融合后的细胞铺至96孔板。融合后10天左右取各孔上清,以ELISA法检测杂交瘤细胞分泌的小鼠抗体与人CEACAM5的结合活性。
进一步的,取ELISA检测得到的强阳性孔中的上清,以流式细胞术检测与LOVO细胞(中国科学院上海细胞生物学研究所)的结合活性,得到了具有较高LOVO细胞结合活性的杂交瘤细胞。将这部分细胞进行亚克隆获得单克隆细胞。表3所示的是部分杂交瘤细胞的检测数据。
表3.杂交瘤细胞与CEACAM的结合结果
杂交瘤细胞 | ELISA OD值 | LOVO FACS结合 |
1-2C5 | 1.0690 | 12.1 |
1-9G3 | 1.0390 | 7.01 |
3-2F3 | 1.4480 | 11 |
3-6F5 | 1.3520 | 6.51 |
3-8C10 | 2.3030 | 137 |
3-8G8 | 1.9270 | 82.9 |
2A10A5 | 2.392 | / |
2A10C4 | 2.434 | / |
选择其中结合活性较好的杂交瘤细胞3-8G8进行测序,经测序获得了一株抗体,命名为UM05-6,使用Kabat编号系统(Kabat等,Sequences of Proteins of ImmunologicalInterest,第五版,Public Health Service,美国国立卫生研究院,贝塞斯达、马里兰州(1991),第647-669页)确定了UM05-6抗体的CDR序列,具体如表4所示。
表4.UM05-5可变区序列
实施例2:人鼠嵌合抗体的制备
根据表4中UM05-6的序列,设计并表达了人鼠嵌合抗体,将其命名为UM05-6L。简言之,将编码小鼠抗体的VH和VL序列分别连接至编码人IgG1重链的恒定区序列(其氨基酸序列如SEQ ID NO:9,核苷酸序列如SEQ ID NO:10所示,)和κ链的恒定区序列(其氨基酸序列如SEQ ID NO:11,核苷酸序列如SEQ ID NO:12所示),得到人鼠嵌合抗体UM05-6L。
将编码抗体重链、轻链的核苷酸序列分别克隆到哺乳动物细胞表达载体pcDNA3.4上。将重链表达载体和轻链表达载体按2∶1的摩尔比用Lipofectamine 2000转染试剂(Invitrogen)转染入HEK293细胞,并在37℃、5%二氧化碳条件下培养7天。收集培养液上清,并用Protein A亲和层析法提纯上清中的抗体。纯化后的抗体经PBS溶液透析和冷冻干燥浓缩后,保存于-20℃。
实施例3:抗体与CEACAM5蛋白的结合
将浓度为1μg/mL的人CEACAM5蛋白溶液以100μL/well包被96孔高亲和力板,4℃,振荡过夜。第二天先以300μL PBST(Tween20:0.5‰)洗涤3次,之后用100μL/well的5%BSA/PBS封闭1小时,室温振荡。300μLPBST洗涤3次。用PBS配制抗体样品的梯度稀释溶液。以100μL/孔加入96孔板,室温振荡1小时。300μL PBST洗涤3次。配制二抗羊抗人(goat anti-human)IgG HRP溶液,以100μL/孔加入96孔板,室温振荡30min。300μL PBST洗涤4次。加入100μL/孔TMB,显色20min。加入100μL/孔0.6N H2SO4,终止显色,检测OD450nm。经检测,结果如图2所示,嵌合抗体UM05-6L与CEACAM5蛋白结合的EC50为47.47ng/mL。
实施例4:抗体与表达CEACAM5的细胞的结合
用流式细胞仪(FACS)检测抗体与天然表达人CEACAM5蛋白的LOVO肿瘤细胞或过表达不同CEACAM蛋白细胞的结合情况。简单来说,首先收集细胞,PBS洗涤一遍后计数,稀释成2*106/ml细胞悬液;分别取10μl抗体工作液加入100μl细胞悬液中,4℃避光孵育30min;PBS洗涤2次后,加入对应的荧光标记二抗Goat-anti-Human IgG(H+L)(Invitrogen),4℃避光孵育30min,PBS洗涤2次后,以400μl FACS buffer悬起,以FACS检测抗体与细胞的结合情况。
检测了嵌合抗体UM05-6L和对照抗体UM05-8(本实验室通过杂交瘤法自制的抗CEACAM5抗体)的上清在浓度为3μg/mL时与不同细胞的结合情况。其中,SW620-CEACAM1为过表达CEACAM1蛋白的细胞,SW620-CEACAM3为过表达CEACAM3蛋白的细胞,CHO-CEACAM6为过表达CEACAM6蛋白的细胞,CHO-CEACAM7为过表达CEACAM7蛋白的细胞,CHO-CEACAM8为过表达CEACAM8蛋白的细胞。以抗体与LOVO细胞(其表达CEACEM5)的结合活性(即,FACS的检测值)为100%作为基准,计算抗体与不同细胞(其表达不同CEACAM蛋白)的相对结合活性,检测结果如表5所示。
表5.抗体与LOVO细胞和过表达不同CEACAM蛋白的细胞的结合情况
细胞名称 | UM05-6L | UM05-8 |
LOVO | 100.00% | 100.00% |
SW620-CEACAM1 | 1.20% | 120.47% |
SW620-CEACAM3 | 0.84% | 91.56% |
CHO-CEACAM6 | 1.35% | 69.61% |
CHO-CEACAM7 | 0.36% | 13.71% |
CHO-CEACAM8 | 15.23% | 61.60% |
从表5中可以看到,嵌合抗体UM05-6L具有尤为突出的选择性:其以高亲和力结合CEACAM5,但与CEACAM1、CEACAM3、CEACAM6、CEACAM7均无明显结合,且与CEACAM8仅有较弱的结合。而普通的抗体(如对照抗体UM05-8),在与CEACAM5结合的同时,能够以较高水平与CEACAM1、CEACAM3、CEACAM6、CEACAM7、CEACAM8结合,不具有选择性。
进一步的,我们用FACS检测了嵌合抗体UM05-6L与天然表达人CEACAM5的LOVO肿瘤细胞的EC50。结果如图3所示,嵌合抗体UM05-6L与LOVO细胞结合EC50为276.1ng/mL。综合上述结果,嵌合抗体UM05-6L具有非常优良的与CEACAM5结合的亲和力、特异性和选择性。
实施例5:抗体的ADCC活性
使用LOVO细胞为靶细胞,将LOVO细胞按20000个/孔密度接种于96孔细胞培养板,37℃,5%CO2孵育过夜。第二天,将抗体UM05-6L和阳性对照抗体Erbitux按照20μg/ml配制于培养基中,并按3倍倍比稀释8个浓度。吸尽LOVO细胞上清培养基,将以指定浓度稀释的抗体(阳性对照抗体Erbitux,嵌合抗体UM05-6L或阴性对照无关抗体)按照30μL/孔加入LOVO细胞中。接着,将效应细胞Jurkat/ADC(南京诺艾新生物技术有限公司)按照120000个/30μL/孔铺到LOVO细胞孔中,37℃,5%CO2孵育16-20h。孵育结束后以Bright-Glo试剂盒(Promega,cat.E2620)检测效应细胞中luciferase表达水平。该luciferase水平代表了效应细胞的ADCC活化程度。图4a显示了阳性对照Erbitux抗体和阴性对照的ADCC报告基因活性,图4b显示了UM05-6L的ADCC报告基因活性。综合上述结果可知,UM05-6L的具有较强的ADCC活性,EC50为0.57μg/mL。
实施例6:靶向CEACAM5的CAR-T细胞的构建
我们基于第二代及第三代的CAR-T结构,以抗CEACAM5单链抗体作为CAR-T识别抗体,采用1个或多个41BB,CD28,OX40等共刺激原件进行了不同CEA-CAR的结构设计,并构建相应的慢病毒质粒用于生成可感染细胞并表达相应CAR的慢病毒。该慢病毒可以用于感染自肿瘤病人外周血分离到的T细胞,产生在细胞膜表面表达相应CAR受体的CAR-T细胞。这种CAR-T细胞可以有效识别和杀伤表达CEACAM5的肿瘤细胞。在体外和体内实验中都看到了该细胞免疫疗法具有非常好的安全性和有效性。
将如SEQ ID NO:13所示的单链抗体UM05-6L scFv(以VH-G4S3-VL顺序)与序列CD8α-CD137-CD3ζ-p2A-tEGFR相连接,从而构建嵌合抗原受体CAR,然后将编码所述CAR的核苷酸序列克隆至慢病毒载体(吉凯基因,GV401)中,将载体命名为UM05-6L-CAR。表达框为EF1a启动子-CAR-2A-tEGFR-WPRE。
将UM05-6L-CAR慢病毒载体与包装质粒瞬时转染293T细胞16小时,更换培养基,继续培养24-48小时,收集培养基上清(含慢病毒),于-80℃保存。
将来源于健康人的PBMC细胞,用CD3/28抗体激活24小时后;按照MOI=3∶1将慢病毒与T细胞混合培养96小时,用PE荧光标记的Cetuximab检测UM05-6L-CAR的表达。结果如图5所示,与对照相比(图5a),UM05-6L-CAR(图5b)可很好的表达于人T细胞表面。
实施例7:靶向CEACAM5的CAR-T细胞的功能检测
1、细胞因子释放检测
将UM05-6L-CAR-T细胞和表达CEACAM5的肿瘤细胞(例如KATO3和LS174T)混合,并设置培养基对照(即仅使用UM05-6L-CAR-T细胞)和CEACAM5阴性细胞对照(即使用UM05-6L-CAR-T细胞和不表达CEACAM5的细胞,例如RKO细胞);将两种细胞按照1∶1混合培养16小时后,检测上清中IFNγ和IL2的释放。结果如图6所示,UM05-6L-CAR-T可以识别表达CEACAM5的细胞系并释放细胞因子IFNγ和IL-2。
2、肿瘤细胞杀伤检测
将UM05-6L-CAR-T与表达CEACAM5的肿瘤细胞(例如KATO3)按照指定的E∶T比例(30∶1,10∶1,3∶1,1∶1,0.3∶1)混合培养于96孔培养板中。利用Promega LDH检测试剂盒检测培养上清中乳酸脱氢酶(LDH)的释放记录数据。肿瘤细胞杀伤计算结果图7所示,由图中可以看出UM05-6L-CAR-T可以高效的、剂量依赖的杀伤肿瘤细胞。
3、肿瘤细胞刺激的增殖实验
将UM05-6L-CAR-T细胞与表达CEACAM5的肿瘤细胞(例如LS174T),按照E∶T=1∶1混合培养72小时(without IL2 supplement),通过细胞计数检测其增殖。结果如图8所示,UM05-6L-CAR-T在经过表达CEACAM5的肿瘤细胞刺激时,可高效扩增。
实施例8:LS174T肿瘤模型的体内药效实验
将LS174T细胞(ATCC CL-187)按照1×107/只接种于NSG小鼠(百奥赛图)皮下,待肿瘤体积达到200-400mm3时,经尾静脉分别给予PBS对照、未经修饰的T细胞对照(Mock T)或UM05-6L CAR-T,给与的剂量分别为100μl、1×107个细胞、1×107tEGFR+个细胞,记录瘤体积变化并分析外周血中IFNγ的释放。结果如图9和图10所示,UM05-6L在小鼠体内识别LS174T肿瘤细胞,并释放大量IFNγ,产生强烈的肿瘤抑制作用。
SEQUENCE LISTING
<110> 上海吉倍生物技术有限公司
<120> 一种抗CEACAM5的单克隆抗体及其制备方法和用途
<130> IDC210301
<150> 201910481112.6
<151> 2019-06-04
<160> 15
<170> PatentIn version 3.5
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Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 10
<211> 993
<212> DNA
<213> artificial
<220>
<223> 编码IgG1重链恒定区的核苷酸序列
<400> 10
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggaccccc 420
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960
cagaagagcc tctccctgtc tccgggtaaa tga 993
<210> 11
<211> 107
<212> PRT
<213> artificial
<220>
<223> κ链的恒定区
<400> 11
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 12
<211> 324
<212> DNA
<213> artificial
<220>
<223> 编码κ链恒定区的核苷酸序列
<400> 12
cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60
ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120
tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180
agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240
aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagttcgcc cgtcacaaag 300
agcttcaaca ggggagagtg ttga 324
<210> 13
<211> 238
<212> PRT
<213> artificial
<220>
<223> VH-G4S3-VL
<400> 13
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Leu Asn Trp Val Lys Gln Ser Pro Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Ile Asn Asp Phe Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ser Tyr
65 70 75 80
Met Ala Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Tyr Asp Gly Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala
130 135 140
Ser Leu Gly Asp Thr Ile Thr Ile Thr Cys His Ala Ser Gln Asn Ile
145 150 155 160
Asn Val Trp Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Lys
165 170 175
Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser
195 200 205
Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Ser
210 215 220
Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 14
<211> 348
<212> DNA
<213> artificial
<220>
<223> VH基因
<400> 14
gaggtccagc tgcaacaatc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60
tcctgtaagg cttctggata cacgttcact gactactact tgaactgggt aaaacagagc 120
cctggaaaga gccttgagtg gattggaaac attaatccta tcaatgattt tactacctac 180
aaccagaagt tcaaggccaa ggccacattg actgtagaca agtcctctac cacttcctac 240
atggcgctcc gcagcctgac atctgaggac tctgcagtct attactgtac aagatatgat 300
ggttacttcg cctactgggg ccaaggcacc actctcacag tctcctca 348
<210> 15
<211> 321
<212> DNA
<213> artificial
<220>
<223> VL基因
<400> 15
gacatccaga tgaaccagtc tccatccagt ctgtctgcat cccttggaga cacaattacc 60
atcacttgcc atgccagtca gaacattaat gtttggttaa gctggtacca gcagaaacca 120
ggaaatattc ctaaactatt gatctataag gcttccaatt tgcacacagg cgtcccatca 180
aggtttagtg gcagtggatc tggaacaggt ttcacattaa ccatcagcag cctgcagcct 240
gaagacattg ccacttacta ctgtcaacag ggtcaaagtt atccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa a 321
Claims (53)
1.特异性结合CEACAM5蛋白的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含:
(a)包含下述3个互补决定区的重链可变区(VH):
(i)VH CDR1,其由下述序列组成:SEQ ID NO:1;
(ii)VH CDR2,其由下述序列组成:SEQ ID NO:2;和
(iii)VH CDR3,其由下述序列组成:SEQ ID NO:3;
和
(b)包含下述3个互补决定区的轻链可变区(VL):
(iv)VL CDR1,其由下述序列组成:SEQ ID NO:4;
(v)VL CDR2,其由下述序列组成:SEQ ID NO:5;和
(vi)VL CDR3,其由下述序列组成:SEQ ID NO:6。
2.权利要求1的抗体或其抗原结合片段,其特征在于,(i)-(vi)中任一项所述的CDR根据Kabat编号系统定义。
3.权利要求1或2的抗体或其抗原结合片段,其中,所述抗体或其抗原结合片段包含:
(a)重链可变区,其包含SEQ ID NO:7所示的氨基酸序列;
和
(b)轻链可变区,其包含SEQ ID NO:8所示的氨基酸序列。
4.权利要求1或2的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段具有SEQ ID NO:7所示序列的重链可变区和SEQ ID NO:8所示序列的轻链可变区。
5.权利要求1或2所述的抗体或其抗原结合片段,其中,所述抗体或其抗原结合片段包含来源于人免疫球蛋白的重链恒定区和轻链恒定区。
6.权利要求5的抗体或其抗原结合片段,其中,所述抗体或其抗原结合片段的重链恒定区是IgG重链恒定区,包括IgG1、IgG2、IgG3或IgG4重链恒定区;所述轻链恒定区是κ轻链恒定区。
7.权利要求5的抗体或其抗原结合片段,其中,所述抗体或其抗原结合片段包含SEQ IDNO:9所示的重链恒定区和/或SEQ ID NO:11所示的轻链恒定区。
8.权利要求1或2所述的抗体或其抗原结合片段,其中,所述抗原结合片段选自Fab、Fab’、(Fab’)2、Fv、双抗体、单域抗体;和所述抗体为鼠源抗体、嵌合抗体或人源化抗体。
9.权利要求1或2所述的抗体或其抗原结合片段,其中,所述抗体或其抗原结合片段带有检测标记:酶、放射性核素、荧光染料、发光物质或生物素。
10.分离的核酸分子,其编码权利要求1-9任一项所述的抗体或其抗原结合片段。
11.权利要求10所述的核酸分子,所述核酸分子包含SEQ ID NO:14或SEQ ID NO:15中所示的核苷酸序列。
12.载体,其包含权利要求10-11所述的核酸分子。
13.权利要求12的载体,所述载体为克隆载体或表达载体。
14.宿主细胞,其包含权利要求10-11任一的核酸分子或权利要求12-13任一的载体。
15.制备权利要求1-9任一项所述的抗体或其抗原结合片段的方法,其包括,在允许所述抗体或其抗原结合片段表达的条件下,培养权利要求14所述的宿主细胞,和从培养的宿主细胞培养物中回收所述抗体或其抗原结合片段。
16.权利要求15的方法,所述宿主细胞是哺乳动物细胞。
17.权利要求16的方法,所述宿主细胞为人、鼠、羊、马、狗或猫的细胞。
18.权利要求16的方法,所述宿主细胞为中国仓鼠卵巢细胞。
19.双特异性或多特异性分子,其包含权利要求1-9任一项所述的抗体或其抗原结合片段,所述双特异性或多特异性分子特异性结合CEACAM5,并且额外地特异性结合一个或多个第二靶标。
20.权利要求19的双特异性或多特异性分子,所述双特异性或多特异性分子的第二靶标是抗体。
21.免疫缀合物,其包含权利要求1-9任一项所述的抗体或其抗原结合片段以及连接于所述抗体或其抗原结合片段的治疗剂。
22.权利要求21的免疫缀合物,所述治疗剂选自细胞毒剂。
23.权利要求21的免疫缀合物,所述治疗剂选自烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂,及其任意组合。
24.权利要求21的免疫缀合物,所述免疫缀合物是抗体-药物偶联物。
25.药物组合物,其包含权利要求1-9任一项所述的抗体或其抗原结合片段,或权利要求19-20所述的双特异性或多特异性分子或者权利要求21所述的免疫缀合物,以及药学上可接受的载体和/或赋形剂。
26.权利要求25的药物组合物,其还包含另外的药学活性剂;所述另外的药学活性剂是具有抗肿瘤活性的药物。
27.权利要求26的药物组合物,所述抗肿瘤活性的药物是烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂、放射增敏剂、抗血管生成剂、细胞因子、分子靶向药物、免疫检查点抑制剂或溶瘤病毒。
28.权利要求26的药物组合物,所述抗体或其抗原结合片段、双特异性或多特异性分子、或免疫缀合物,与所述另外的药学活性剂作为分离的组分或作为同一组合物的组分提供。
29.试剂盒,其含有权利要求1-9任一项所述的抗体或其抗原结合片段。
30.权利要求29的试剂盒,所述抗体或其抗原结合片段带有检测标记:酶、放射性核素、荧光染料、发光物质或生物素。
31.权利要求29的试剂盒,所述试剂盒还包括第二抗体,其特异性识别权利要求1-9任一项所述的抗体或其抗原结合片段。
32.权利要求31的试剂盒,所述第二抗体还包括检测标记:酶、放射性核素、荧光染料、发光物质或生物素。
33.嵌合抗原受体,其包含权利要求1-9任一项所述的抗体或其抗原结合片段的抗原结合结构域,所述抗原结合结构域包含权利要求1-9任一项所述的抗体或其抗原结合片段的重链可变区和轻链可变区。
34.权利要求33的嵌合抗原受体,其中,所述抗原结合结构域是scFv。
35.权利要求33的嵌合抗原受体,其中,所述抗原结合结构域包含权利要求1-9任一项所述的抗原结合片段。
36.权利要求33-35任一项的嵌合抗原受体,其中,所述抗原结合结构域由免疫效应细胞所表达。
37.分离的核酸分子,其编码权利要求33-36任一项所述的嵌合抗原受体。
38.载体,其包含权利要求37所述的分离的核酸分子。
39.权利要求38的载体,其用于制备嵌合抗原受体T细胞。
40.宿主细胞,其包含权利要求37述的分离的核酸分子或权利要求38-39所述的载体。
41.权利要求40的宿主细胞,所述宿主细胞是免疫效应细胞。
42.权利要求41的宿主细胞,所述宿主细胞是T细胞或NK细胞。
43.权利要求40的宿主细胞,所述宿主细胞是嵌合抗原受体T细胞。
44.权利要求1-9任一项所述的抗体或其抗原结合片段,或权利要求19-20任一所述的双特异性或多特异性分子,或权利要求21-24任一所述的免疫缀合物,或权利要求25-28任一所述的药物组合物,或权利要求33-36任一所述的嵌合抗原受体,或权利要求40-43任一所述的宿主细胞在制备药物中的用途,所述药物用于预防和/或治疗肿瘤。
45.权利要求44的用途,其中,所述药物用于抑制表达CEACAM5的肿瘤细胞生长和/或杀伤所述肿瘤细胞。
46.权利要求44的用途,其中,制备的药物还包含另外的药学活性剂。
47.权利要求46的用途,所述另外的药学活性剂是具有抗肿瘤活性的药物,包括烷化剂、有丝分裂抑制剂、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂、酪氨酸激酶抑制剂、放射性核素剂、放射增敏剂、抗血管生成剂、细胞因子、分子靶向药物、免疫检查点抑制剂或溶瘤病毒。
48.权利要求47的用途,所述肿瘤表达CEACAM5。
49.权利要求48的用途,所述CEACAM5在肿瘤细胞表面表达。
50.权利要求49的用途,所述肿瘤选自非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿或默克尔细胞癌。
51.权利要求1-9任一项所述的抗体或其抗原结合片段在制备试剂盒中的用途,所述试剂盒用于检测肿瘤是否能够通过靶向CEACAM5的抗肿瘤疗法来治疗。
52.权利要求51的用途,所述抗体或其抗原结合片段带有检测标记。
53.权利要求51的用途,所述肿瘤选自非小细胞肺癌、小细胞肺癌、肾细胞癌、结肠直肠癌、卵巢癌、乳癌、胰脏癌、胃癌、膀胱癌、食管癌、间皮瘤、黑色素瘤、头颈部癌、甲状腺癌、肉瘤、前列腺癌、成胶质细胞瘤、子宫颈癌、胸腺癌、白血病、淋巴瘤、骨髓瘤、蕈样肉芽肿或默克尔细胞癌。
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BR112021024544A2 (pt) | 2022-02-08 |
WO2020244526A1 (zh) | 2020-12-10 |
US20220235142A1 (en) | 2022-07-28 |
CN113906052B (zh) | 2024-02-13 |
CN113474372A (zh) | 2021-10-01 |
WO2020244528A1 (zh) | 2020-12-10 |
JP2022535553A (ja) | 2022-08-09 |
CN113906052A (zh) | 2022-01-07 |
AU2020289301A1 (en) | 2022-01-27 |
CA3142635A1 (en) | 2020-12-10 |
KR20220016943A (ko) | 2022-02-10 |
EP3981793A4 (en) | 2023-06-07 |
JP2022536114A (ja) | 2022-08-12 |
EP3981793A1 (en) | 2022-04-13 |
US20220242968A1 (en) | 2022-08-04 |
TW202110895A (zh) | 2021-03-16 |
TW202100560A (zh) | 2021-01-01 |
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