CN114605538A - 靶向cd19的人源化抗体及其用途 - Google Patents
靶向cd19的人源化抗体及其用途 Download PDFInfo
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Abstract
本发明提供靶向CD19的人源化抗体,以及包含它的多特异性抗体、嵌合受体、抗体偶联物、药物组合物和试剂盒,以及它们在诊断/治疗/预防与CD19表达相关的疾病中的用途。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及靶向CD19的人源化抗体,及其在预防和/或治疗和/或诊断疾病中的用途。
背景技术
CD19是一种由556个氨基酸组成的I型跨膜蛋白,属于免疫球蛋白超家族成员,在B淋巴细胞以及滤泡树突状细胞表面表达。CD19与CD21、CD81和CD225形成B细胞受体复合物来调节B细胞的发育、增殖和分化,其中CD19发挥主要的信号传导作用。由于CD19只在正常和恶性B细胞中表达,几乎不在其他组织中表达,并且CD19在B细胞恶性转化过程中不丢失,对于难治性/复发性病例仍有效,使得CD19成为诊断和治疗B细胞恶性肿瘤的有效靶标。目前,靶向CD19的ADC和CAR-T细胞疗法均已在临床上显示出针对B细胞恶性肿瘤的良好治疗效果。
本发明旨在提供一种靶向CD19的人源化抗体,及其在疾病预防和/或治疗和/或诊断中的用途。
发明内容
在第一个方面,本发明提供一种靶向CD19的人源化抗体,其包含轻链可变区和重链可变区,其中所述轻链可变区包含如SEQ ID NO:1所示的CDR-L1、如SEQ ID NO:2所示的CDR-L2、如SEQ ID NO:3所示的CDR-L3,所述重链可变区包含如SEQ ID NO:4所示的CDR-H1、如SEQ ID NO:5所示的CDR-H2、如SEQ ID NO:6所示的CDR-H3,并且所述轻链可变区与SEQID NO:10或12所示的氨基酸序列具有至少90%同一性,所述重链可变区与SEQ ID NO:11或13的氨基酸序列具有至少90%同一性。
在一个实施方案中,所述CD19人源化抗体包含选自SEQ ID NO:10和12的轻链可变区和选自SEQ ID NO:11和13的重链可变区。
在一个实施方案中,所述CD19人源化抗体包含选自SEQ ID NO:22和23的接头。
在一个实施方案中,所述CD19人源化抗体的氨基酸序列选自SEQ ID NO:14-17。
本发明还提供编码上述CD19人源化抗体的核酸分子。因此,在一个实施方案中,编码所述CD19人源化抗体的核酸分子与选自SEQ ID NO:18-21的核苷酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%序列同一性,并且其编码的CD19人源化抗体能够特异性结合CD19抗原。优选地,编码所述CD19人源化抗体的核酸分子选自SEQ ID NO:18-21。
在另一个方面,本发明还提供一种多特异性抗体(优选双特异性抗体或三特异性抗体),其包含如上所述的CD19人源化抗体和一个或多个与其他抗原特异性结合的第二抗体或其抗原结合部分。
在一个实施方案中,第二抗体或其抗原结合部分可以具有任何抗体或抗体片段形式,例如全长抗体、Fab、Fab'、(Fab')2、Fv、scFv、scFv-scFv、微抗体、双抗体或sdAb。
本发明还提供包含编码上述CD19人源化抗体或多特异性抗体的核酸分子的载体,以及表达所述CD19人源化抗体或多特异性抗体的宿主细胞。
在另一个方面,本发明还提供一种嵌合抗原受体,其包含本发明所述的CD19人源化抗体、跨膜结构域和胞内信号传导结构域。优选地,所述嵌合抗原受体还包含一个或多个共刺激结构域。在一个实施方案中,本发明的嵌合抗原受体还可以包含靶向其他肿瘤抗原的第二抗体或其抗原结合部分。
本发明还提供编码如上所定义的靶向CD19的嵌合抗原受体的核酸分子,以及包含所述核酸分子的载体。
本发明还提供包含如上所定义的靶向CD19的嵌合抗原受体的细胞,优选免疫细胞,例如T细胞、NK细胞、NKT细胞、巨噬细胞、树突细胞。
在另一个方面,本发明还提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和第二功能性结构,其中所述第二功能性结构选自Fc、放射性同位素、延长半衰期的结构部分、可检测标记物和药物。
在一个实施方案中,所述延长半衰期的结构部分选自:所述延长半衰期的结构部分选自白蛋白的结合结构、转铁蛋白的结合结构、聚乙二醇分子、重组聚乙二醇分子、人血清白蛋白、人血清白蛋白的片段和结合人血清白蛋白的白多肽(包括抗体)。在一个实施方案中,可检测标记物选自荧光团、化学发光化合物、生物发光化合物、酶、抗生素抗性基因和造影剂。在一个实施方案中,所述药物选自细胞毒素和免疫调节剂。
在另一个方面,本发明还提供一种检测试剂盒,其包含本发明所述的人源化抗体、多特异性抗体、抗体偶联物、嵌合抗原受体或工程化免疫细胞。
在另一个方面,本发明还提供一种药物组合物,其包含本发明所述的人源化抗体、嵌合抗原受体、多特异性抗体、抗体偶联物或工程化免疫细胞,和一种或多种药学上可接受的赋形剂。
在另一个方面,本发明还提供一种治疗和/或预防和/或诊断与CD19表达相关的疾病的方法,包括向受试者施用如上所述的人源化抗体、嵌合抗原受体、多特异性抗体、抗体偶联物或药物组合物。
发明详述
除非另有说明,否则本文中所使用的所有科学技术术语的含义与本发明所属领域的普通技术人员通常所了解的相同。
CD19人源化抗体
如本文所用,术语“抗体”具有本领域技术人员所理解的最广泛的含义,并且包括单克隆抗体(包含完整抗体)、多克隆抗体、多价抗体、多特异性抗体(例如双特异性抗体)、和能够表现期望的生物活性的携带一个或多个CDR序列的抗体片段或合成多肽。本发明所述抗体可为任何种类(例如IgG、IgE、IgM、IgD、IgA等)或亚类(例如IgG1、IgG2、IgG2a、IgG3、IgG4、IgA1、IgA2等)。
通常,完整抗体包括通过二硫键连接在一起的两条重链和两条轻链,每条轻链通过二硫键被连至各自的重链,呈“Y”形结构。每条重链包含重链可变区(VH)和重链恒定区,其中重链可变区包含三个互补决定区(CDR):CDR-H1、CDR-H2和CDR-H3,重链恒定区包含三个恒定结构域:CH1、CH2和CH3。每条轻链包含轻链可变区(VL)和轻链恒定区,其中轻链可变区包含三个CDR:CDR-L1、CDR-L2和CDR-L3,轻链恒定区包含一个恒定结构域CL。在重链/轻链可变区中,CDR被更保守的框架区(FR)隔开。重链/轻链的可变区负责与抗原的识别和结合,恒定区则可以介导抗体与宿主组织或因子的结合,包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分。
可以使用许多本领域熟知的编号方案容易地确定给定CDR或FR的精确氨基酸序列边界,这些方案包括:Kabat等人(1991),“Sequences ofProteins of ImmunologicalInterest,”第5版Public Health Service,NationalInstitutes of Health,贝塞斯达,马里兰州(“Kabat”编号方案);Al-Lazikani等人,(1997)JMB273,927-948(“Chothia”编号方案);MacCallum等人,J.Mol.Biol.262:732-745(1996),“Antibody-antigeninteractions:Contact analysis and binding sitetopograpy,”J.Mol.Biol.262,732-745”(“Contact”编号方案);Lefranc MP等人,“IMGTunique numbering forimmunoglobulin and T cell receptor variable domains andIg superfamily V-likedomains,”Dev Comp Immunol,2003年1月;27(1):55-77(“IMGT”编号方案);Honegger A和Plückthun A,“Yet another numbering scheme forimmunoglobulin variable domains:an automatic modeling and analysis tool,”JMol Biol,2001年6月8日;309(3):657-70(“Aho”编号方案);和Martin等人,“Modelingantibody hypervariable loops:a combinedalgorithm,”PNAS,1989,86(23):9268-9272(“AbM”编号方案)。
给定CDR或FR的边界可能取决于用于鉴定的方案而不同。例如,Kabat方案是基于结构比对,而Chothia方案是基于结构信息。Kabat和Chothia方案的编号都是基于最常见的抗体区域序列长度,其中通过插入字母提供插入(例如“30a”)并且在一些抗体中出现缺失。这两种方案将某些插入和缺失(“插入缺失(indel)”)放置在不同的位置,从而产生不同的编号。Contact方案是基于对复杂晶体结构的分析,并且在许多方面与Chothia编号方案相似。AbM方案是介于Kabat与Chothia定义之间的折衷,其基于Oxford Molecular的AbM抗体建模软件所使用的方案。
因此,除非另有规定,否则应当理解,给定抗体或其区域(如其可变区)的“CDR”涵盖由任何上述方案或其他已知方案所定义的CDR。例如,在指定特定的CDR(例如CDR3)含有给定氨基酸序列的情况下,应理解,这样的CDR还可以具有由任何上述方案或其他已知方案所定义的相应CDR(例如CDR3)的序列。同样,除非另有规定,否则应当理解给定抗体或其区域(如其可变区)的FR涵盖由任何上述方案或其他已知方案所定义的FR。本申请中用于界定CDR和FR边界的编号方案采用Chothia方案。
如本文所用,“人源化”抗体是指其中所有或基本上所有CDR氨基酸残基源自非人CDR并且所有或基本上所有FR氨基酸残基源自人FR。非人抗体的“人源化形式”是指所述非人抗体的变体,其经历人源化以通常降低对人的免疫原性,同时保留亲本非人抗体的特异性和亲和力。在一些实施方案中,人源化抗体中的一些FR残基被来自非人抗体(例如,衍生CDR残基的抗体)的相应残基取代,例如以恢复或改善抗体特异性或亲和力。
人源化抗体及其制备方法是本领域技术人员熟知的,参见例如Almagro和Fransson,Front.Biosci.13:1619-1633(2008)。可用于人源化的人类框架区包括但不限于:使用“最佳拟合”方法选择的框架区;源自轻链或重链可变区的特定亚组的人类抗体的共有序列的框架区;人类成熟(体细胞突变)框架区或人类种系框架区;以及筛选FR文库得到的框架区。
如本文所用,术语“抗体片段”或“抗原结合部分”仅包含完整抗体的一部分,一般包含完整抗体的抗原结合位点并因此保留结合抗原的能力。本发明中的抗体片段的实例包括但不限于:Fab、Fab'、F(ab')2、Fd片段、Fd′、Fv片段、scFv、二硫键-连接的Fv(sdFv)、抗体的重链可变区(VH)或轻链可变区(VL)、线性抗体、具有两个抗原结合位点的“双体”、单结构域抗体、纳米抗体、所述抗原的天然配体或其功能性片段等。因此,本发明的“抗体”涵盖如上定义的抗体片段。
在一个实施方案中,本发明的CD19人源化抗体选自IgG、Fab、Fab′、F(ab′)2、Fv、scFv、Fd、Fd′、sdFv、线形抗体、双体、单结构域抗体和纳米抗体,优选是scFv。“单链抗体”和“scFv”在本文中可互换使用,是指由抗体重链可变区(VH)和轻链可变区(VL)通过接头连接而成的抗体。可以选择接头的最佳长度和/或氨基酸组成。接头的长度会明显影响scFv的可变区折叠和相互作用情况。关于接头的大小和组成的选择,参见例如,Hollinger等人,1993Proc Natl Acad.Sci.U.S.A.90:6444-6448;美国专利申请公布号2005/0100543、2005/0175606、2007/0014794;以及PCT公布号WO2006/020258和WO2007/024715,其全文通过引用并入本文。常用的接头例如GSTSGSGKPGSGEGSTKG(SEQ ID NO:22)、GGGGSGGGGSGGGGS(SEQ ID NO:23)。scFv可以包含以任何顺序连接的VH和VL,例如VH-接头-VL或VL-接头-VH。
在一个实施方案中,本发明提供一种CD19人源化抗体,其包含轻链可变区和重链可变区,其中所述轻链可变区包含如SEQ ID NO:1所示的CDR-L1、如SEQ ID NO:2所示的CDR-L2、如SEQ ID NO:3所示的CDR-L3,所述重链可变区包含如SEQ ID NO:4所示的CDR-H1、如SEQ ID NO:5所示的CDR-H2、如SEQ ID NO:6所示的CDR-H3,并且所述轻链可变区与选自SEQ ID NO:10和12的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%的序列同一性或与SEQ ID NO:10和12相比具有一个或几个(例如最多10个、最多9个、最多8个、最多7个、最多6个、最多5个、最多4个、最多3个、最多2个)氨基酸的保守性修饰,所述重链可变区与SEQ ID NO:11和13所示的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%的序列同一性与SEQ ID NO:11和13相比具有一个或几个(例如最多10个、最多9个、最多8个、最多7个、最多6个、最多5个、最多4个、最多3个、最多2个)氨基酸的保守性修饰。
在一个实施方案中,所述CD19人源化抗体包含选自SEQ ID NO:10和12的轻链可变区和选自SEQ ID NO:11和13所示的重链可变区。
在一个实施方案中,所述CD19人源化抗体的氨基酸序列选自SEQ ID NO:14-17。
如本文所用,术语“序列同一性”表示两个(核苷酸或氨基酸)序列在比对中在相同位置处具有相同残基的程度,并且通常表示为百分数。优选地,同一性在被比较的序列的整体长度上确定。因此,具有完全相同序列的两个拷贝具有100%同一性。本领域技术人员知晓,可以使用一些算法来确定序列同一性,例如Blast(Altschul等(1997)Nucleic AcidsRes.25:3389-3402)、Blast2(Altschul等(1990)J.Mol.Biol.215:403-410)、Smith-Waterman(Smith等(1981)J.Mol.Biol.147:195-197)和ClustalW。
如本文所用,术语“保守性修饰”是指不会明显影响或改变含有该氨基酸序列的抗体或抗体片段的结合特征的氨基酸修饰。这些保守性修饰包括氨基酸的取代、添加及缺失。修饰可以通过本领域中已知的标准技术,如定点诱变和PCR介导的诱变而引入本发明的抗体中。氨基酸的保守性取代是氨基酸残基被具有类似侧链的氨基酸残基置换的取代。具有类似侧链的氨基酸残基家族已在本领域中有定义,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)及芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。保守性修饰可以例如基于极性、电荷、溶解度、疏水性、亲水性和/或所涉及残基的两亲性质的相似性来进行选择。
在在一个方面,本发明还提供包含如上所CD19人源化抗体的多特异性抗体(优选双特异性抗体或三特异性抗体),其还包含一个或多个与其他抗原特异性结合的第二抗体。
如本文所用,术语“多特异性”是指抗原结合蛋白具有多表位特异性(即,能够特异性结合一个生物分子上的两个、三个或更多个不同的表位或能够特异性结合两个、三个或更多个不同的生物分子上的表位)。如本文所用,术语“双特异性”表示抗原结合蛋白具有两种不同的抗原结合特异性。
在一个实施方案中,第二抗体可以具有任何抗体或抗体片段形式,例如全长抗体、Fab、Fab'、(Fab')2、Fv、scFv、scFv-scFv、微抗体、双抗体或sdAb。
因此,在一个实施方案中,所述第二抗体靶向选自以下的抗原:BCMA、CD4、CD5、CD7、CD8、CD14、CD15、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD194、CD80、CD126、CD138、B7、MUC-1、Ia、HM1.24、HLA-DR、腱生蛋白、血管生成因子、VEGF、PIGF、ED-B纤连蛋白、致癌基因、致癌基因产物、CD66a-d、坏死抗原、Ii、IL-2、T101、TAC、IL-6、ROR1、TRAIL-R1(DR4)、TRAIL-R2(DR5)、tEGFR、Her2、L1-CAM、间皮素、CEA、乙型肝炎表面抗原、抗叶酸受体、CD24、CD30、CD44、EGFR、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、ErbB二聚体、EGFR vIII、FBP、FCRL5、FCRH5、胎儿乙酰胆碱受体、GD2、GD3、G蛋白偶联受体C型家族5D(GPRC5D)、HMW-MAA、IL-22R-α、IL-13R-α2、kdr、κ轻链、Lewis Y、L1-细胞粘附分子(L1-CAM)、黑色素瘤相关抗原(MAGE)-A1、MAGE-A3、MAGE-A6、黑色素瘤优先表达抗原(PRAME)、生存素、EGP2、EGP40、TAG72、B7-H6、IL-13受体a2(IL-13Ra2)、CA9、CD171、G250/CAIX、HLA-A1、HLA-A2、NY-ESO-1、PSCA、叶酸受体-a、CD44v6、CD44v7/8、avb6整合素、8H9、NCAM、VEGF受体、5T4、胎儿AchR、NKG2D配体、双抗原、与通用标签相关的抗原、癌症-睾丸抗原、MUC1、MUC16、NY-ESO-1、MART-1、gp100、癌胚胎抗原、VEGF-R2、癌胚抗原(CEA)、前列腺特异性抗原、PSMA、Her2/neu、雌激素受体、孕酮受体、肝配蛋白B2、CD123、c-Met、GD-2、O-乙酰化GD2(OGD2)、CE7、Wilms肿瘤1(WT-1)、细胞周期蛋白A2、CCL-1、hTERT、MDM2、CYP1B、WT1、活素、AFP、p53、细胞周期蛋白(D1)、CS-1、BAFF-R、TACI、CD56、TIM-3、CD123、细胞周期蛋白(如细胞周期蛋白A1(CCNA1))和/或病原体特异性抗原、生物素化分子、由HIV、HCV、HBV和/或其他病原体表达的分子;和/或新表位或新抗原。
核酸、载体、宿主细胞
在另一方面中,本发明涉及编码本发明的CD19抗体或多特异性抗体的核酸分子。本发明的核酸可为RNA、DNA或cDNA。根据本发明的一个实施方案,本发明的核酸是基本上分离的核酸。
在一个实施方案中,编码所述CD19抗体的核酸分子与选自SEQ ID NO:18-21的核苷酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%序列同一性,并且其编码的CD19抗体能够特异性结合CD19。优选地,编码所述CD19抗体的核酸分子如SEQ ID NO:18-21所示。
本发明的核酸也可呈载体形式,可存在于载体中和/或可为载体的一部分,该载体例如质粒、粘端质粒或YAC。载体可尤其为表达载体,即可提供CD19抗体在体外和/或体内(即在适合宿主细胞、宿主有机体和/或表达系统中)表达的载体。该表达载体通常包含至少一种本发明的核酸分子,其可操作地连接至一个或多个适合的表达调控元件(例如启动子、增强子、终止子等)。对所述调控元件及其序列进行选择以便在特定宿主中表达是本领域技术人员熟知的。对本发明的CD19抗体的表达有用或必需的调控元件及其他元件的具体实例包括但不限于启动子、增强子、终止子、整合因子、选择标记物、前导序列、报告基因。
在另一方面中,本发明还提供表达本发明的CD19抗体、多特异性抗体和/或含有本发明的核酸或载体的宿主细胞。本发明的优选宿主细胞为细菌细胞、真菌细胞或哺乳动物细胞。
适合的细菌细胞包括革兰氏阴性细菌菌株(例如大肠杆菌(Escherichia coli)菌株、变形杆菌属(Proteus)菌株及假单胞菌属(Pseudomonas)菌株)及革兰氏阳性细菌菌株(例如芽孢杆菌属(Bacillus)菌株、链霉菌属(Streptomyces)菌株、葡萄球菌属(Staphylococcus)菌株及乳球菌属(Lactococcus)菌株)的细胞。
适合的真菌细胞包括木霉属(Trichoderma)、脉孢菌属(Neurospora)及曲菌属(Aspergillus)的物种的细胞;或者包括酵母属(Saccharomyces)(例如酿酒酵母(Saccharomyces cerevisiae))、裂殖酵母属(Schizosaccharomyces)(例如粟酒裂殖酵母(Schizosaccharomyces pombe))、毕赤酵母属(Pichia)(例如巴斯德毕赤酵母(Pichiapastoris)及嗜甲醇毕赤酵母(Pichia methanolica))及汉森酵母属(Hansenula)的物种的细胞。
适合的哺乳动物细胞包括例如HEK293细胞、CHO细胞、BHK细胞、HeLa细胞、COS细胞等。
然而,本发明也可使用两栖类细胞、昆虫细胞、植物细胞及本领域中用于表达异源蛋白的任何其他细胞。
重组受体
在另一方面,本发明还提供包含如上所述的CD19人源化抗体的重组受体,例如重组TCR受体或嵌合抗原受体。优选地,本发明还提供包含如上所述的CD19人源化抗体的嵌合抗原受体。
如本文所用,术语“嵌合抗原受体”或“CAR”是指人工构建的杂合多肽,该杂合多肽一般包括配体结合结构域(例如抗体的抗原结合部分)、跨膜结构域、任选的共刺激结构域和细胞内信号传导结构域,各个结构域之间通过接头连接。CAR能够利用抗体的抗原结合特性以非MHC限制性的方式将T细胞和其它免疫细胞的特异性和反应性重定向至所选择的靶标。
在一个实施方案中,本发明提供一种嵌合抗原受体,其包含如上所述的CD19人源化抗体或含有所述CD19人源化抗体的多特异性抗体、跨膜结构域和胞内信号传导结构域。
如本文所用,术语“跨膜结构域”是指能够使嵌合抗原受体在免疫细胞(例如淋巴细胞、NK细胞或NKT细胞)表面上表达,并且引导免疫细胞针对靶细胞的细胞应答的多肽结构。跨膜结构域可以是天然或合成的,也可以源自任何膜结合蛋白或跨膜蛋白。当嵌合抗原受体与靶抗原结合时,跨膜结构域能够进行信号传导。特别适用于本发明中的跨膜结构域可以源自例如TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154及其功能性片段。或者,跨膜结构域可以是合成的并且可以主要地包含疏水性残基如亮氨酸和缬氨酸。优选地,所述跨膜结构域源自CD8α链或CD28,其与SEQ ID NO:24或26所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:25或27所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
如本文所用,术语“胞内信号传导结构域”是指转导效应子功能信号并指导细胞进行指定功能的蛋白质部分。在一个实施方案中,本发明的嵌合抗原受体包含的胞内信号传导结构域可以是T细胞受体和共受体的胞内区序列,其在抗原受体结合以后一同起作用以引发信号传导,以及这些序列的任何衍生物或变体和具有相同或相似功能的任何合成序列。胞内信号传导结构域可以包含许多免疫受体酪氨酸激活基序(ImmunoreceptorTyrosine-based Activation Motifs,ITAM)。本发明的胞内信号传导结构域的非限制性施例包括但不限于FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d等的胞内区。在优选的实施方式中,本发明CAR的信号传导结构域可以包含CD3ζ胞内区,其与SEQ IDNO:32或34所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:33或35所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的嵌合抗原受体还可以包含位于抗体和跨膜结构域之间的铰链区。如本文所用,术语“铰链区”一般是指作用为连接跨膜结构域至抗体的任何寡肽或多肽。具体地,铰链区用来为抗体提供更大的灵活性和可及性。铰链区可以包含最多达300个氨基酸,优选10至100个氨基酸并且最优选25至50个氨基酸。铰链区可以全部或部分源自天然分子,如全部或部分源自CD8、CD4或CD28的胞外区,或全部或部分源自抗体恒定区。或者,铰链区可以是对应于天然存在的铰链序列的合成序列,或可以是完全合成的铰链序列。在优选的实施方式中,所述铰链区包含CD8α、CD28、FcγRIIIα受体、IgG4或IgG1的铰链区部分,更优选CD8α、CD28或IgG4铰链,其与SEQ ID NO:40、42或44所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:41、43或45所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,嵌合抗原受体还可以包含一个或多个共刺激结构域。共刺激结构域可以是来自共刺激分子的细胞内功能性信号传导结构域,其包含所述共刺激分子的整个细胞内部分,或其功能片段。“共刺激分子”是指在T细胞上与共刺激配体特异性结合,由此介导T细胞的共刺激反应(例如增殖)的同源结合配偶体。共刺激分子包括但不限于1类MHC分子、BTLA和Toll配体受体。本发明的共刺激结构域的非限制性施例包括但不限于源自以下蛋白质的共刺激信号传导结构域:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18(LFA-1)、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM以及ZAP70。优选地,本发明CAR的共刺激结构域来自4-1BB、CD28或4-1BB+CD28。在一个实施方案中,4-1BB共刺激结构域与SEQ ID NO:30所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:31所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个实施方案中,CD28共刺激结构域与SEQ ID NO:28所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:29所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的CAR还可以包含信号肽,使得当其在细胞例如T细胞中表达时,新生蛋白质被引导至内质网并随后引导至细胞表面。信号肽的核心可以含有长的疏水性氨基酸区段,其具有形成单个α-螺旋的倾向。在信号肽的末端,通常有被信号肽酶识别和切割的氨基酸区段。信号肽酶可以在移位期间或完成后切割,以产生游离信号肽和成熟蛋白。然后,游离信号肽被特定蛋白酶消化。可用于本发明的信号肽是本领域技术人员熟知的,例如衍生自B2M、CD8α、IgG1、GM-CSFRα等的信号肽。在一个实施方案中,可用于本发明的信号肽来自B2M或CD8α,其与SEQ ID NO:36或38所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQID NO:37或39所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,所述CAR含有如本文所提供的CD19人源化抗体或含有所述CD19人源化抗体的多特异性抗体、CD28或CD8α跨膜区、CD28和/或4-1BB共刺激结构域,和CD3ζ胞内信号传导结构域。在该实施方案中,所述CAR还可以进一步包含来自B2M、CD8α、IgG1或GM-CSFRα的信号肽。
在一个实施方案中,根据需要,所述CAR还可以包含靶向其他肿瘤抗原的第二抗体或其抗原结合片段。所述其他肿瘤抗原的实例包括但不限于:BCMA、CD4、CD5、CD7、CD8、CD14、CD15、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD194、CD80、CD126、CD138、B7、MUC-1、Ia、HM1.24、HLA-DR、腱生蛋白、血管生成因子、VEGF、PIGF、ED-B纤连蛋白、致癌基因、致癌基因产物、CD66a-d、坏死抗原、Ii、IL-2、T101、TAC、IL-6、ROR1、TRAIL-R1(DR4)、TRAIL-R2(DR5)、tEGFR、Her2、L1-CAM、间皮素、CEA、乙型肝炎表面抗原、抗叶酸受体、CD24、CD30、CD44、EGFR、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、ErbB二聚体、EGFR vIII、FBP、FCRL5、FCRH5、胎儿乙酰胆碱受体、GD2、GD3、G蛋白偶联受体C型家族5D(GPRC5D)、HMW-MAA、IL-22R-α、IL-13R-α2、kdr、κ轻链、Lewis Y、L1-细胞粘附分子(L1-CAM)、黑色素瘤相关抗原(MAGE)-A1、MAGE-A3、MAGE-A6、黑色素瘤优先表达抗原(PRAME)、生存素、EGP2、EGP40、TAG72、B7-H6、IL-13受体a2(IL-13Ra2)、CA9、CD171、G250/CAIX、HLA-A1、HLA-A2、NY-ESO-1、PSCA、叶酸受体-a、CD44v6、CD44v7/8、avb6整合素、8H9、NCAM、VEGF受体、5T4、胎儿AchR、NKG2D配体、双抗原、与通用标签相关的抗原、癌症-睾丸抗原、MUC1、MUC16、NY-ESO-1、MART-1、gp100、癌胚胎抗原、VEGF-R2、癌胚抗原(CEA)、前列腺特异性抗原、PSMA、Her2/neu、雌激素受体、孕酮受体、肝配蛋白B2、CD123、c-Met、GD-2、O-乙酰化GD2(OGD2)、CE7、Wilms肿瘤1(WT-1)、细胞周期蛋白A2、CCL-1、hTERT、MDM2、CYP1B、WT1、活素、AFP、p53、细胞周期蛋白(D1)、CS-1、BAFF-R、TACI、CD56、TIM-3、CD123、细胞周期蛋白(如细胞周期蛋白A1(CCNA1))和/或病原体特异性抗原、生物素化分子、由HIV、HCV、HBV和/或其他病原体表达的分子;和/或新表位或新抗原。
本发明还提供编码如上所定义的靶向CD19的嵌合抗原受体的核酸分子,以及包含所述核酸分子的载体。
如本文所用,术语“载体”是用作将(外源)遗传材料转移到宿主细胞中的媒介核酸分子,在该宿主细胞中所述核酸分子可以例如复制和/或表达。载体一般包括靶向载体和表达载体。“靶向载体”是通过例如同源重组或使用特异性靶向位点处序列的杂合重组酶将分离的核酸递送至细胞内部的介质。“表达载体”是用于异源核酸序列(例如编码本发明的嵌合抗原受体多肽的那些序列)在合适的宿主细胞中的转录以及它们的mRNA的翻译的载体。可用于本发明的合适载体是本领域已知的,并且许多可商购获得。在一个实施方案中,本发明的载体包括但不限于质粒、病毒(例如逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV、多瘤病毒和腺相关病毒(AAV)等)、噬菌体、噬菌粒、粘粒和人工染色体(包括BAC和YAC)。载体本身通常是核酸分子,通常是包含插入物(转基因)的DNA序列和作为载体“骨架”的较大序列。工程化载体通常还包含在宿主细胞中自主复制的起点(如果需要多核苷酸的稳定表达)、选择标记和限制酶切割位点(如多克隆位点,MCS)。载体可另外包含启动子、多聚腺苷酸尾(polyA)、3’UTR、增强子、终止子、绝缘子、操纵子、选择标记、报告基因、靶向序列和/或蛋白质纯化标签等元件。在一个具体的实施方案中,所述载体是体外转录的载体。
工程化免疫细胞
在一个方面,本发明还提供表达本发明所述重组受体(例如TCR或CAR)的工程化免疫细胞。
如本文所用,术语“免疫细胞”是指免疫系统的具有一种或多种效应子功能(例如,细胞毒性细胞杀伤活性、分泌细胞因子、诱导ADCC和/或CDC)的任何细胞。例如,免疫细胞可以是T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞和/或NKT细胞。在一个实施方案中,免疫细胞衍生自干细胞,例如成体干细胞、胚胎干细胞、脐带血干细胞、祖细胞、骨髓干细胞、诱导多能干细胞、全能干细胞或造血干细胞等。优选地,免疫细胞是T细胞。T细胞可以是任何T细胞,如体外培养的T细胞,例如原代T细胞,或者来自体外培养的T细胞系例如Jurkat、SupT1等的T细胞,或获得自受试者的T细胞。受试者的实例包括人、狗、猫、小鼠、大鼠及其转基因物种。T细胞可以从多种来源获得,包括外周血单核细胞、骨髓、淋巴结组织、脐血、胸腺组织、来自感染部位的组织、腹水、胸膜积液、脾组织及肿瘤。T细胞也可以被浓缩或纯化。T细胞可以处于任何发育阶段,包括但不限于,CD4+/CD8+T细胞、CD4+辅助T细胞(例如Th1和Th2细胞)、CD8+T细胞(例如,细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞、αβ-T细胞等。T细胞也可以是自体T细胞或异体T细胞。在一个优选的实施方案中,免疫细胞是人T细胞。可以使用本领域技术人员已知的多种技术,如Ficoll分离从受试者的血液获得T细胞。免疫细胞可以来源于待治疗的患者(即,自体细胞),也可以来源于健康供体(即,同种异体细胞)。
采用本领域已知的常规方法(如通过转导、转染、转化等)可以将编码嵌合抗原受体的核酸序列引入免疫细胞。“转染”是将核酸分子或多核苷酸(包括载体)引入靶细胞的过程。一个例子是RNA转染,即将RNA(比如体外转录的RNA,ivtRNA)引入宿主细胞的过程。该术语主要用于真核细胞中的非病毒方法。术语“转导”通常用于描述病毒介导的核酸分子或多核苷酸的转移。动物细胞的转染通常涉及在细胞膜中打开瞬时的孔或“洞”,以允许摄取材料。可以使用磷酸钙、通过电穿孔、通过细胞挤压或通过将阳离子脂质与材料混合以产生与细胞膜融合并将它们的运载物沉积入内部的脂质体,进行转染。用于转染真核宿主细胞的示例性技术包括脂质囊泡介导的摄取、热休克介导的摄取、磷酸钙介导的转染(磷酸钙/DNA共沉淀)、显微注射和电穿孔。术语“转化”用于描述核酸分子或多核苷酸(包括载体)向细菌中、也向非动物真核细胞(包括植物细胞)中的非病毒转移。因此,转化是细菌或非动物真核细胞的基因改变,其通过细胞膜从其周围直接摄取并随后并入外源遗传材料(核酸分子)而产生。转化可以通过人工手段实现。为了发生转化,细胞或细菌必须处于感受态的状态。对于原核转化,技术可包括热休克介导的摄取、与完整细胞的细菌原生质体融合、显微注射和电穿孔。将核酸或载体引入免疫细胞后,本领域技术人员可以通过常规技术对所得免疫细胞进行扩增和活化。
在一个实施方案中,为减少移植物抗宿主病的风险,所述工程化免疫细胞还包含至少一种选自以下的基因的表达被抑制或沉默:CD52、GR、dCK、TCR/CD3基因(例如TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ)、MHC相关基因(HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA)和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。优选地,所述工程化免疫细胞还包含至少一种选自以下的基因的表达被抑制或沉默:TRAC、TRBC、HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA、PD1、LAG3、TIM3、CTLA4,更优选TRAC、TRBC、HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA。
抑制基因表达或使基因沉默的方法是本领域技术人员熟知的。例如,可以使用反义RNA、RNA诱饵、RNA适体、siRNA、shRNA/miRNA、反式显性阴性蛋白(TNP)、嵌合/抗体偶联物、趋化因子配体、抗感染性细胞蛋白、细胞内抗体(sFv)、核苷类似物(NRTI)、非核苷类似物(NNRTI)、整合酶抑制剂(寡核苷酸、二核苷酸和化学剂)和蛋白酶抑制剂来抑制基因的表达。另外,也可以通过例如大范围核酸酶、锌指核酸酶、TALE核酸酶或CRISPR系统中的Cas酶介导DNA断裂,从而使基因沉默。
在一个实施方案中,提供多种免疫细胞,每种免疫细胞被改造为表达一种或多种嵌合抗原受体。例如,在一些实施方案中,将一种免疫细胞改造为表达结合和/或靶向CD19的嵌合抗原受体(例如包含本发明所述CD19人源化抗体的CAR),并且将另一种细胞改造为表达结合和/或靶向其他抗原的嵌合抗原受体。在一个实施方案中,免疫细胞也可以表达多特异性嵌合抗原受体,其靶向包括CD19在内的一种或多种抗原。例如,这种多特异性嵌合抗原受体可以包含靶向CD19的多特异性抗体,或者同时包含本发明所述的CD19人源化抗体和靶向其他肿瘤抗原的抗体。在此类实施方案中,所述多种工程化免疫细胞可以一起或单独施用。在一个实施方案中,所述多种免疫细胞可以在同一组合物中或在不同组合物中。细胞的示例性组合物包括本申请以下章节中所描述的组合物。
抗体偶联物
在一个方面,本发明提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和第二功能性结构,其中所述第二功能性结构选自Fc、放射性同位素、延长半衰期的结构部分、可检测标记物和药物。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和Fc。如本文所用,术语“Fc”用于定义免疫球蛋白重链的C末端区,其包括天然Fc和变体Fc。“天然Fc”是指包含通过消化完整抗体产生的、无论是单体形式或是多聚体形式的非抗原结合片段的分子或序列。产生天然Fc的免疫球蛋白源优选来源于人类。天然Fc片段由可以通过共价连接(例如二硫键)和非共价连接而连接为二聚体或多聚体形式的单体多肽构成。根据类别(例如IgG、IgA、IgE、IgD、IgM)或亚型(例如IgG1、IgG2、IgG3、IgA1、IgGA2)的不同,天然Fc分子单体亚基之间具有1-4个分子间二硫键。天然Fc的一个实例是通过用木瓜蛋白酶消化IgG产生的二硫键连接的二聚体(参见Ellison等(1982),NucleicAcids Res.10:4071-9)。本文所用的术语“天然Fc”一般是指单体、二聚体和多聚体形式。“变体Fc”是指由于至少一个本文定义的“氨基酸修饰”而与“天然”或“野生型”Fc的氨基酸序列不同的氨基酸序列,也称为“Fc变体”。因此,“Fc”也包括单链Fc(scFc),即,由多肽接头连接的两个Fc单体组成的单链Fc,其能够自然折叠成功能性二聚体Fc区域。在一个实施方案中,所述Fc优选是人免疫球蛋白的Fc,更优选是人IgG1的Fc。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和放射性同位素。可用于本发明的放射性同位素的实例包括但不限于At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212、99mTc、123I、18F和68Ga。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和延长半衰期的结构部分,所述延长半衰期的结构部分选自白蛋白的结合结构、转铁蛋白的结合结构、聚乙二醇分子、重组聚乙二醇分子、人血清白蛋白、人血清白蛋白的片段和结合人血清白蛋白的白多肽(包括抗体)。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和可检测标记物。术语“可检测标记物”在本文中意指产生可检测信号的化合物。例如,可检测标记物可以是MRI造影剂、闪烁扫描造影剂、X射线成像造影剂、超声造影剂、光学成像造影剂。可检测标记物的实施例包括荧光团(如荧光素、Alexa或花青)、化学发光化合物(如鲁米诺)、生物发光化合物(如荧光素酶或碱性磷酸酶)、酶(如辣根过氧化物酶、葡萄糖-6-磷酸酶、β-半乳糖苷酶)、抗生素(例如卡那霉素、氨苄霉素、氯霉素、四环素等)抗性基因和造影剂(如纳米颗粒或钆)。本领域技术人员可以根据所用的检测系统选择合适的可检测标记物。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的CD19人源化抗体和与所述CD19人源化抗体偶联的药物,例如细胞毒素或免疫调节剂(即,抗体药物偶联物)。通常药物通过共价与抗体连接,并且通常依赖于接头。在一个实施方案中,所述药物是细胞毒素。在另一个实施方案中,所述药物是免疫调节剂。细胞毒素的实例包括但不限于甲氨蝶呤、氨基蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶、达卡巴嗪、氮芥、噻替派、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、1-甲基亚硝基脲、环磷酰胺、氮芥、白消安、二溴甘露醇、链佐星、丝裂霉素、顺-二氯二胺铂(II)(DDP)、顺铂、卡铂、佐柔比星、多柔比星、地托比星、卡米诺霉素、伊达比星、表柔比星、米托蒽醌、放线菌素D、博来霉素、刺孢霉素、光辉霉素、安曲霉素(AMC)、长春新碱、长春花碱、紫杉醇、蓖麻毒素、假单胞菌外毒素、吉西他滨、细胞松弛素B、短杆菌肽D、溴乙锭、依米丁、依托泊苷、替尼泊苷、秋水仙素、二羟基蒽二酮、1-脱氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普萘洛尔、嘌呤霉素、丙卡巴肼、羟基脲、天冬酰胺酶、皮质类固醇、米托坦(O,P'-(DDD))、干扰素,以及它们的组合。免疫调节剂的实例包括但不限于更昔洛韦、依那西普、他克莫司、西罗莫司、伏环孢素、环孢灵、雷帕霉素、环磷酰胺、硫唑嘌呤、霉酚酸酯、甲氨蝶呤、糖皮质素及其类似物、细胞因子、干细胞生长因子、淋巴毒素、肿瘤坏死因子(TNF)、造血因子、白介素(例如IL-1、IL-2、IL-3、IL-6、IL-10、IL-12、IL-18及IL-21)、集落刺激因子(例如G-CSF及(GM-CSF)、干扰素(例如干扰素-α、干扰素-β及干扰素-γ)、命名为“S1因子”的干细胞生长因子、红细胞生成素和血小板生成素,或其组合。
试剂盒和药物组合物
在另一个方面,本发明还提供一种检测试剂盒,其包含本发明所述的人源化抗体、多特异性抗体、抗体偶联物、嵌合抗原受体或工程化免疫细胞。
在另一个方面,本发明还提供一种药物组合物,其包含本发明所述的人源化抗体、嵌合抗原受体、多特异性抗体、抗体偶联物或工程化免疫细胞,和一种或多种药学上可接受的赋形剂。
如本文所用,术语“药学上可接受的赋型剂”是指在药理学和/或生理学上与受试者和活性成分相容(即,能够引发所需的治疗效果而不会引起任何不希望的局部或全身作用)的载体和/或赋形剂,其是本领域公知的(参见例如Remington's PharmaceuticalSciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)。药学上可接受的赋型剂的实例包括但不限于填充剂、粘合剂、崩解剂、包衣剂、吸附剂、抗粘附剂、助流剂、抗氧化剂、调味剂、着色剂、甜味剂、溶剂、共溶剂、缓冲剂、螯合剂、表面活性剂、稀释剂、润湿剂、防腐剂、乳化剂、包覆剂、等渗剂、吸收延迟剂、稳定剂和张力调节剂。本领域技术人员已知选择合适的赋型剂以制备本发明期望的药物组合物。用于本发明的药物组合物中的示例性赋型剂包括盐水、缓冲盐水、葡萄糖和水。通常,合适的赋形剂的选择尤其取决于所使用的活性剂、待治疗的疾病和药物组合物的期望剂型。
根据本发明的药物组合物可适用于多种途径施用。通常,通过胃肠外完成施用。胃肠外递送方法包括局部、动脉内、肌内、皮下、髓内、鞘内、心室内、静脉内、腹膜内、子宫内、阴道内、舌下或鼻内施用。
根据本发明的药物组合物也可以制备成各种形式,如固态、液态、气态或冻干形式,特别可以是软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液、气雾剂、颗粒、丸剂、混悬剂、乳剂、胶囊、糖浆、酏剂、浸膏剂、酊剂或流浸膏提取物的形式,或者是特别适用于所需施用方法的形式。本发明已知的用于生产药物的过程可包括例如常规混合、溶解、制粒、制糖衣、研磨、乳化、包封、包埋或冻干过程。例如本文所述的药物组合物通常以溶液形式提供,并且优选包含药学上可接受的缓冲剂。
根据本发明的药物组合物还可以与一种或多种适用于治疗和/或预防待治疗疾病的其它药剂组合施用。适用于组合的药剂的优选实例包括已知的抗癌药物,比如顺铂、美登素衍生物、雷查霉素(rachelmycin)、卡里奇霉素(calicheamicin)、多西紫杉醇、依托泊苷、吉西他滨、异环磷酰胺、伊立替康、美法仑、米托蒽醌、sorfimer卟啉钠II(sorfimersodiumphotofrin II)、替莫唑胺、拓扑替康、葡萄糖醛酸曲美沙特(trimetreateglucuronate)、奥利斯他汀E(auristatin E)、长春新碱和阿霉素;肽细胞毒素,比如蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、DNA酶和RNA酶;放射性核素,比如碘131、铼186、铟111、铱90、铋210和213、锕225和砹213;前药,比如抗体定向的酶前药;免疫刺激剂,比如血小板因子4、黑色素瘤生长刺激蛋白等;抗体或其片段,比如抗CD3抗体或其片段,补体活化剂,异种蛋白结构域,同种蛋白结构域,病毒/细菌蛋白结构域和病毒/细菌肽。此外,本发明的药物组合物也可以与其他一种或多种治疗方法,例如化疗、放疗组合使用。
治疗/预防/诊断用途
在另一个方面,本发明还提供一种治疗和/或预防和/或诊断与CD19表达相关的疾病的方法,包括向受试者施用如上所述的人源化抗体、嵌合抗原受体、多特异性抗体、抗体偶联物或药物组合物。
在一个实施方案中,与CD19表达相关的疾病是选自以下的B细胞淋巴瘤:急性淋巴母细胞白血病(ALL)、AIDS相关淋巴瘤、ALK阳性大B细胞淋巴瘤、伯基特淋巴瘤、慢性淋巴细胞白血病(CLL)、经典霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤、血管内大B细胞淋巴瘤、HHV8相关多中心Castleman病引起的大B细胞淋巴瘤、淋巴瘤样肉芽肿、淋巴浆细胞性淋巴瘤、套细胞淋巴瘤(MCL)、边缘区B细胞淋巴瘤(MZL)、粘膜相关淋巴组织淋巴瘤(MALT)、淋巴结边缘区B细胞淋巴瘤(NMZL)、结节性淋巴细胞为主的霍奇金淋巴瘤、非霍奇金淋巴瘤、浆母细胞性淋巴瘤、原发性中枢神经系统淋巴瘤、原发性渗出性淋巴瘤、脾边缘区淋巴瘤(SMZL)和瓦氏巨球蛋白血症或其组合。
在一个优选的实施方案中,B细胞淋巴瘤是急性淋巴母细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤、套细胞淋巴瘤(MCL)、边缘区B细胞淋巴瘤(MZL)、粘膜相关淋巴组织淋巴瘤(MALT)和非霍奇金淋巴瘤。
下面将参考附图并结合实例来详细说明本发明。需要说明的是,本领域的技术人员应该理解本发明的附图及其实施例仅仅是为了例举的目的,并不能对本发明构成任何限制。在不矛盾的情况下,本申请中的实施例及实施例中的特征可以相互组合。
附图说明
图1:示出了CAR-T细胞中的人源化CD19 scFv的表达水平。
图2:示出了不同效靶比下CAR-T细胞对Nalm6靶细胞的杀伤效果。
图3:示出了CAR-T细胞与靶细胞Nalm6或非靶细胞293F共培养后的细胞因子释放水平。
具体实施方式
实施例1.制备CD19人源化抗体
基于鼠源FMC63制备人源化抗体。克隆FMC63包含如SEQ ID NO:1所示的CDR-L1、如SEQ ID NO:2所示的CDR-L2、如SEQ ID NO:3所示的CDR-L3、如SEQ ID NO:4所示的CDR-H1、如SEQ ID NO:5所示的CDR-H2、如SEQ ID NO:6所示的CDR-H3,其轻链可变区序列如SEQ IDNO:7所示,重链可变区序列如SEQ ID NO:8所示,全长scFv氨基酸序列如SEQ ID NO:9所示。制备人源化抗体的具体方法如下:保留原始抗体的CDR区序列不变,根据germlinealignment的结果以及抗体结构模拟的结果,重链和轻链分别选择不同的人源抗体模版,并在人源化之后的框架区进行回复突变,以保证人源化抗体的亲和力和特异性。最终得到2个人源化轻链可变区序列hVL1(SEQ ID NO:10)和hVL2(SEQ ID NO:12),以及2个人源化重链可变区序列hVH1(SEQ ID NO:11)和hVH2(SEQ ID NO:13)。将上述轻链可变区和重链可变区进行组合,获得4个单链抗体:hCD19-1(hVH1-接头-hVL1,氨基酸序列如SEQ ID NO:14所示,核苷酸序列如SEQ ID NO:18所示)、hCD19-2(hVL1-接头-hVH1,氨基酸序列如SEQ ID NO:15所示,核苷酸序列如SEQ ID NO:19所示)、hCD19-3(hVH2-接头-hVL2,氨基酸序列如SEQ IDNO:16所示,核苷酸序列如SEQ ID NO:20所示)、hCD19-4(hVL2-接头-hVH2,氨基酸序列如SEQ ID NO:17所示,核苷酸序列如SEQ ID NO:21所示)。
实施例2.制备包含CD19人源化抗体的CAR-T细胞
合成编码以下蛋白的序列,并将其克隆至pLVX载体(Public Protein/PlasmidLibrary(PPL),货号:PPL00157-4a):CD8α信号肽(SEQ ID NO:)、CD19人源化抗体(选自SEQID NO:)、CD8α铰链区(SEQ ID NO:)、CD8α跨膜区(SEQ ID NO:)、4-1BB胞内区(SEQ IDNO:)、CD3ζ胞内信号传导结构域(SEQ ID NO:),并通过测序确认目标序列的正确插入。其中,hCAR19-1 CAR包含的抗CD19 scFv的氨基酸序列如SEQ ID NO:14所示;hCAR19-2 CAR包含的抗CD19 scFv的氨基酸序列如SEQ ID NO:15所示;hCAR19-3 CAR包含的抗CD19 scFv的氨基酸序列如SEQ ID NO:16所示;hCAR19-4 CAR包含的抗CD19 scFv的氨基酸序列如SEQID NO:17所示。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)稀释上述质粒后,再根据质粒:病毒包装载体:病毒包膜载体=4:2:1的比例加入包装载体psPAX2(Addgene,货号12260)和包膜载体pMD2.G(Addgene,货号12259)。然后,加入120ul X-treme GENE HP DNA转染试剂(Roche,货号06366236001),立即混匀,于室温下孵育15min,然后将质粒/载体/转染试剂混合物逐滴加入到293T细胞的培养瓶中。在24小时和48小时收集病毒,将其合并后,超速离心(25000g,4℃,2.5小时)获得浓缩的慢病毒。
用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,并在37℃和5%CO2下继续培养1天。然后,加入浓缩的慢病毒,持续培养3天后,获得表达不同CD19人源化scFv的CAR T细胞,未经修饰的野生型T细胞用作阴性对照(NT)。
使用Biotin-SP(long spacer)AffiniPure Goat Anti-human IgG,F(ab')2Fragment Specific(min X Hu,Bov,Hrs Sr Prot)(jackson immunoresearch,货号109-065-097)作为一抗,APC Streptavidin(BD Pharmingen,货号554067)或PE Streptavidin(BD Pharmingen,货号554061)作为二抗,通过流式细胞仪检测hCAR19-1 T细胞、hCAR19-2T细胞、hCAR19-3 T细胞和hCAR19-4上的scFv的表达水平,结果如图1所示。
可以看出,本发明制备的CAR T细胞中的CD19人源化scFv均可以有效表达。
实施例3:CAR T细胞对靶细胞的杀伤效果和细胞因子释放
3.1 CAR-T细胞对靶细胞的杀伤效果
当T细胞对靶细胞有杀伤时,靶细胞的数量就会减少。将T细胞和带有可表达荧光素酶的靶细胞共培养后,靶细胞数量减少的同时,分泌的荧光素酶也会随之减少。荧光素酶可以催化荧光素转化为氧化性荧光素,而在此氧化过程中,会产生生物发光,并且这种发光的强度将取决于靶细胞表达的荧光素酶的水平。因此,检测的荧光强度能够反应T细胞对靶细胞的杀伤能力。
为了检测CAR-T细胞对靶细胞的杀伤能力,首先以1x104/孔将携带荧光素基因的Nalm6靶细胞铺入96孔板中,然后以10:1、5:1和2.5:1的效靶比(即效应T细胞与靶细胞之比)将CAR T细胞和NT细胞铺入到96孔板进行共培养,16-18小时后利用酶标仪测定荧光值。根据计算公式:(靶细胞荧光均值-样品荧光均值)/靶细胞荧光均值×100%,计算得到杀伤效率,结果如图2所示。
可以看出,与NT相比,本发明的CAR T细胞对靶细胞均有特异性杀伤。
3.2 CAR-T细胞的细胞因子释放
T细胞杀伤靶细胞时,靶细胞数量减少的同时也会释放细胞因子。根据以下步骤,使用酶联免疫吸附法(ELISA)来测定本发明的CAR T细胞杀伤靶细胞时细胞因子IL2和IFNγ的释放水平。
(1)收集细胞共培养上清液
以1x105/孔将靶细胞铺于96孔板中,然后以1:1的比例将CAR T和NT细胞(阴性对照)与靶细胞Nalm6或非靶细胞293F共培养,18-24小时后收集细胞共培养上清液。
(2)ELISA检测上清中IL-2和IFN-γ的分泌量
使用捕获抗体Purified anti-human IL2 Antibody(Biolegend,货号500302)或Purified anti-human IFN-γAntibody(Biolegend,货号506502)包被96孔板4℃孵育过夜,然后移除抗体溶液,加入250μL含有2%BSA(sigma,货号V900933-1kg)的PBST(含0.1%吐温的1XPBS)溶液,37℃孵育2小时。然后用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。每孔加入50μL细胞共培养上清液或标准品,并在37℃孵育1小时,然后用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。然后向各孔分别加入50μL检测抗体Anti-Interferongamma抗体[MD-1](Biotin)(abcam,货号ab25017),在37℃孵育1小时后,用250μL PBST(含0.1%吐温的1XPBS)清洗板3次。再加入HRP Streptavidin(Biolegend,货号405210),在37℃孵育30分钟后,弃上清液,加入250μL PBST(含0.1%吐温的1XPBS),清洗5次。向各孔加入50μL TMB底物溶液。使反应在室温下于暗处发生30分钟,之后向各孔中加入50μL 1mol/LH2SO4以停止反应。在停止反应的30分钟内,使用酶标仪检测450nm处吸光度,并根据标准曲线(根据标准品的读值和浓度绘制)计算细胞因子的含量,结果如图3所示。
可以看出,本发明的CAR T细胞的细胞因子释放水显著高于对照的NT细胞。
需要说明的是,以上仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。本领域技术人员理解的是,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 南京北恒生物科技有限公司
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<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L2
<400> 2
His Thr Ser Arg Leu His Ser
1 5
<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L3
<400> 3
Gln Gln Gly Asn Thr Leu Pro Tyr Thr
1 5
<210> 4
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H1
<400> 4
Gly Val Ser Leu Pro Asp Tyr
1 5
<210> 5
<211> 5
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H2
<400> 5
Trp Gly Ser Glu Thr
1 5
<210> 6
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H3
<400> 6
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
1 5 10
<210> 7
<211> 107
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> fmc63 vL
<400> 7
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 8
<211> 120
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> fmc63 VH
<400> 8
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 9
<211> 242
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> fmc63 scFv
<400> 9
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
115 120 125
Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
130 135 140
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
145 150 155 160
Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
165 170 175
Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
195 200 205
Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
210 215 220
Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
225 230 235 240
Ser Ser
<210> 10
<211> 106
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hVL-1
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105
<210> 11
<211> 120
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hVH-1
<400> 11
Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Val Leu
65 70 75 80
Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 12
<211> 106
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hVL-2
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile
100 105
<210> 13
<211> 120
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hVH-2
<400> 13
Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Val Leu
65 70 75 80
Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 14
<211> 241
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-1
<400> 14
Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Val Leu
65 70 75 80
Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Leu Tyr His Thr Ser Arg Leu His Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile
<210> 15
<211> 241
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-2
<400> 15
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
115 120 125
Gly Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr
130 135 140
Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln
145 150 155 160
Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala Val Ile Trp Gly Ser Glu
165 170 175
Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys
180 185 190
Asp Thr Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro
195 200 205
Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg His Tyr Tyr Tyr Gly Gly
210 215 220
Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser
225 230 235 240
Ser
<210> 16
<211> 241
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-3
<400> 16
Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Val Leu
65 70 75 80
Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu
225 230 235 240
Ile
<210> 17
<211> 241
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-4
<400> 17
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
115 120 125
Gly Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr
130 135 140
Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln
145 150 155 160
Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala Val Ile Trp Gly Ser Glu
165 170 175
Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys
180 185 190
Asp Thr Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro
195 200 205
Val Asp Thr Ala Thr Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly
210 215 220
Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser
225 230 235 240
Ser
<210> 18
<211> 723
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-1 scFv
<400> 18
caggtaacct tgaaagaatc aggcccagtc ctggtaaagc cgacggagac attgacgctg 60
acctgcacag tcagtggagt gtcattgccc gattatggtg tctcttggat tcgccagcct 120
cctggcaagg ctcttgaatg gttggctgtc atctggggca gtgagactac ttattataac 180
agtgcgttga aatcccggct gactattagt aaagatactt ccaaaagcca agtagtcctc 240
actatgacaa acatggatcc tgtagacacg gctacttatt attgtgcacg gcattactac 300
tacggcggct cttatgctat ggattactgg ggtcaaggaa caatggttac tgtttcatct 360
ggcggcgggg ggtcaggtgg gggtggttcc gggggtggtg gtagtgacat ccaaatgaca 420
caatctccga gtagtctctc cgcaagtgtg ggcgatcgag ttacaattac ttgtcgagcc 480
tcacaggaca tatctaagta cttgaattgg taccaacaga agccggggaa ggcaccaaag 540
ttgctgctgt atcacactag tagattgcat agtggggtgc cctcaagatt cagtggaagt 600
ggatcaggca ctgattacac tttgactatt agtagtctgc aacaggaaga cttcgcaacg 660
tactattgtc agcaaggtaa caccttgccg tacacattcg gtcaaggtac caaagtggaa 720
att 723
<210> 19
<211> 723
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-2 scFv
<400> 19
gatattcaga tgacccaaag tccgtctagc ttgtcagcct ccgtagggga cagagttacg 60
ataacttgta gagcttcaca ggatatatca aagtacctta attggtatca acaaaagcct 120
ggtaaagccc cgaagcttct cctttaccat acgtctcgac tccactccgg tgtcccttct 180
cgcttcagtg gttctgggag tgggaccgac tatacattga ccatctcttc tttgcaacaa 240
gaggacttcg ctacgtatta ctgtcagcaa ggtaatactc ttccgtatac tttcggacaa 300
ggcacgaaag tagaaattgg tggtggcggt tcaggcgggg gtggaagcgg ggggggtggg 360
tctcaggtca ccttgaagga atctggacct gttctggtga agcctacaga aactttgaca 420
ctgacatgca ccgtctctgg tgtatcattg ccggactacg gtgtgtcatg gattaggcaa 480
ccgcctggaa aagccttgga atggctcgcc gtcatctggg ggtctgagac gacctattac 540
aactcagcgt tgaagtcacg cctcacgatt tcaaaggaca cgtctaaatc acaagtggtt 600
ttgacaatga ctaacatgga cccggtcgat acggctactt actactgcgc tcgccactat 660
tattatgggg ggtcctatgc gatggactat tggggacagg gcacaatggt gacagtctca 720
agc 723
<210> 20
<211> 723
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-3 scFv
<400> 20
caggtgacat tgaaagagtc cggacctgtt ctcgtcaaac cgacggagac gctcaccctt 60
acatgcacgg tcagtggcgt ctcactgcca gattatgggg tttcttggat aagacagccc 120
cctggcaagg cccttgaatg gcttgcggtc atctggggtt ctgaaacaac atattataac 180
agtgcactca aatcacgcct tacgatttca aaggatacaa gtaaatctca agttgttctg 240
accatgacga atatggatcc agtggacacc gcgacgtact attgcgcgaa acattactac 300
tacggcggaa gctacgctat ggactattgg ggacaaggaa cgatggtcac tgtctctagc 360
ggcgggggtg gaagtggagg agggggatca gggggaggag gaagtgacat tcaaatgacg 420
cagtctccta gttcagtctc tgcatctgtg ggcgacagag tcacgattac ctgtagggca 480
agccaggata tctctaagta ccttaattgg tatcaacaaa aaccagggaa ggccccgaag 540
cttcttatct accatacaag ccgactccat agtggggttc cctcacgatt tagcgggtct 600
ggctctggta cagacttcac tctcactatt agtagcctgc aaccagagga cttcgcaacc 660
tactactgcc agcagggaaa cactcttcca tatacattcg gacagggaac ccggctcgag 720
att 723
<210> 21
<211> 723
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> hCD19-4 scFv
<400> 21
gatatacaaa tgacgcagtc tccatcatcc gtatccgcca gcgtaggaga tagagtcacc 60
atcacatgtc gcgcgagtca ggacatcagc aaatacctca attggtacca gcaaaagccc 120
ggcaaggctc caaaattgct gatataccat acgagtaggt tgcacagtgg agtacccagt 180
agattttctg ggtcagggag tggcacagat ttcacgctga caataagtag tcttcaacct 240
gaagatttcg caacctatta ctgtcaacaa ggtaatacgc tgccgtacac gtttggtcag 300
ggtacgaggc tcgaaatcgg tggcggggga agtggaggtg gtggatctgg gggtgggggc 360
tctcaagtta ctttgaaaga gagtggacca gtgctcgtaa agcctacgga gacgcttacc 420
cttacgtgca cagtatctgg ggtgagtctc ccagattacg gtgtaagttg gatacgccag 480
ccgccgggga aagccttgga atggctcgca gtgatttggg gatccgaaac tacctattac 540
aatagcgccc ttaaatccag gctgactatt tccaaagaca cgagcaaatc ccaggtcgtc 600
cttaccatga caaacatgga cccagttgac accgctacct actactgtgc gaaacattat 660
tactacggtg ggagctatgc tatggactac tggggccaag gcacaatggt cactgttagt 720
agc 723
<210> 22
<211> 18
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 接头
<400> 22
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 23
<211> 15
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 接头
<400> 23
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 24
<211> 25
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 24
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys Lys
20 25
<210> 25
<211> 75
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 25
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gcaaa 75
<210> 26
<211> 27
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 26
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 27
<211> 81
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 27
ttttgggtcc tcgtcgtagt tggaggggta cttgcctgtt atagcctcct ggttaccgta 60
gcatttatta tattctgggt g 81
<210> 28
<211> 41
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28共刺激结构域
<400> 28
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 29
<211> 123
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28共刺激结构域
<400> 29
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcc 123
<210> 30
<211> 40
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 30
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
1 5 10 15
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
20 25 30
Glu Glu Glu Glu Gly Gly Cys Glu
35 40
<210> 31
<211> 120
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 31
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 60
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 120
<210> 32
<211> 113
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 32
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 33
<211> 339
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 33
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgc 339
<210> 34
<211> 114
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 34
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg
<210> 35
<211> 342
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 35
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctttaacg agctcaatct aggacgaaga gaggagttcg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg cagagaagga agaaccctca ggaaggcctg 180
tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 240
gagcgccgga ggggcaaggg gcacgatggc cttttccagg gtctcagtac agccaccaag 300
gacacctttg acgcccttca catgcaggcc ctgccccctc gc 342
<210> 36
<211> 20
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 36
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala
20
<210> 37
<211> 60
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 37
atgtcccgct ctgttgcttt ggctgtgctg gcccttttgt cccttagcgg actggaggcc 60
<210> 38
<211> 21
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 38
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 39
<211> 63
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 39
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 40
<211> 45
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 40
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 41
<211> 135
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 41
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 42
<211> 39
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 42
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 43
<211> 117
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 43
attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc 60
catgtgaaag ggaaacacct ttgtccaagt cccctatttc ccggaccttc taagccc 117
<210> 44
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 44
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 45
<211> 36
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 45
gaaagcaaat acgggccgcc gtgtccaccc tgtccg 36
Claims (20)
1.一种靶向CD19的人源化抗体,其包含轻链可变区和重链可变区,其中所述轻链可变区包含如SEQ ID NO:1所示的CDR-L1、如SEQ ID NO:2所示的CDR-L2、如SEQ ID NO:3所示的CDR-L3,所述重链可变区包含如SEQ ID NO:4所示的CDR-H1、如SEQ ID NO:5所示的CDR-H2、如SEQ ID NO:6所示的CDR-H3,并且所述轻链可变区与SEQ ID NO:10或12所示的氨基酸序列具有至少90%同一性,所述重链可变区与SEQ ID NO:11或13的氨基酸序列具有至少90%同一性。
2.权利要求1所述的人源化抗体,其包含选自SEQ ID NO:10和12所示的轻链可变区和选自SEQ ID NO:11和13的重链可变区。
3.权利要求1所述的人源化抗体,其包含选自SEQ ID NO:22和23的接头。
4.权利要求1所述的人源化抗体,其中所述人源化抗体的氨基酸序列选自SEQ ID NO:14-17。
5.一种核酸分子,其编码权利要求1-4任一项所述的人源化抗体。
6.一种多特异性抗体,其包含权利要求1-4任一项所述的人源化抗体和一个或多个与其他抗原特异性结合的第二抗体或其抗原结合部分。
7.权利要求5所述的多特异性抗体,其中所述第二抗体或其抗原结合部分选自全长抗体、Fab、Fab'、(Fab')2、Fv、scFv、scFv-scFv、微抗体、双抗体或sdAb。
8.一种载体,其包含编码权利要求1-4任一项所述的人源化抗体或权利要求6或7所述的多特异性抗体的核酸分子。
9.一种宿主细胞,其表达权利要求1-4任一项所述的人源化抗体或权利要求6或7所述的多特异性抗体。
10.一种嵌合抗原受体,其包含权利要求1-4任一项所述的人源化抗体或权利要求6或7所述的多特异性抗体、跨膜结构域和胞内信号传导结构域。
11.权利要求9所述的嵌合抗原受体,其中所述跨膜结构域源自TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137或CD154。
12.权利要求9所述的嵌合抗原受体,其中所述胞内信号传导结构域选自FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d的胞内区。
13.权利要求9所述的嵌合抗原受体,其还包含一个或多个共刺激结构域,所述共刺激结构域选自TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18(LFA-1)、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM和ZAP70的共刺激信号传导结构域。
14.一种工程化免疫细胞,其包含权利要求10-13任一项所述的嵌合抗原受体。
15.权利要求14所述的工程化免疫细胞,其选自T细胞、NK细胞、NKT细胞、巨噬细胞、树突细胞。
16.一种抗体偶联物,其包含权利要求1-4任一项所述的人源化抗体或权利要求6或7所述的多特异性抗体,和第二功能性结构,其中所述第二功能性结构选自Fc、放射性同位素、延长半衰期的结构部分、可检测标记物和药物。
17.权利要求16所述的抗体偶联物,其中所述延长半衰期的结构部分选自:白蛋白的结合结构、转铁蛋白的结合结构、聚乙二醇分子、重组聚乙二醇分子、人血清白蛋白、人血清白蛋白的片段和结合人血清白蛋白的白多肽;所述可检测标记物选自荧光团、化学发光化合物、生物发光化合物、酶、抗生素抗性基因和造影剂;所述药物选自细胞毒素和免疫调节剂。
18.一种检测试剂盒,其包含权利要求1-4任一项所述的人源化抗体、权利要求6或7所述的多特异性抗体、权利要求10-3任一项所述的嵌合抗原受体、权利要求14或15所述的工程化免疫细胞、或权利要求16或17所述的抗体偶联物。
19.一种药物组合物,包含权利要求1-4任一项所述的人源化抗体、权利要求6或7所述的多特异性抗体、权利要求10-3任一项所述的嵌合抗原受体、权利要求14或15所述的工程化免疫细胞、或权利要求16或17所述的抗体偶联物,和一种或多种药学上可接受的赋形剂。
20.权利要求1-4任一项所述的人源化抗体、权利要求6或7所述的多特异性抗体、权利要求10-3任一项所述的嵌合抗原受体、权利要求14或15所述的工程化免疫细胞、或权利要求16或17所述的抗体偶联物、或权利要求19所述的药物组合物在制备用于治疗和/或预防和/或诊断与CD19表达相关的疾病的药物中的用途。
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US18/255,049 US20240018236A1 (en) | 2020-12-08 | 2021-12-07 | Cd19-targeting humanized antibody and use thereof |
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