CN114437214B - 靶向lir1的抗体及其用途 - Google Patents
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- CN114437214B CN114437214B CN202011208654.5A CN202011208654A CN114437214B CN 114437214 B CN114437214 B CN 114437214B CN 202011208654 A CN202011208654 A CN 202011208654A CN 114437214 B CN114437214 B CN 114437214B
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Abstract
靶向LIR1的抗体及其用途。本发明提供靶向LIR1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LIR1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LIR1的抗体,及其在预防和/或治疗和/或诊断疾病中的用途。
背景技术
白细胞免疫球蛋白样受体(Leukocyte Immunoglobulin-like Receptor,LIR)也称为LILRB、免疫球蛋白样转录物(Immunoglobulin-like transcripts,ILT)或单核细胞-巨噬细胞抑制性受体(Monocyte-macrophage inhibitory receptor,MIR)。LIR一般包含2-4个胞外免疫球蛋白结构域、跨膜结构域和2-4个胞质免疫受体基于酪氨酸的抑制基序(ITIM)。LIR家族共有13个成员,其中LIR1能够结合抗原呈递细胞上的MHC I类分子,进而传导抑制信号以抑制免疫细胞的激活。据报道,LIR1在人胃癌细胞中表达,并且可增强肿瘤生长。此外,还发现LIR1可以控制炎症应答和细胞毒性,以有助于集中免疫应答并限制自身反应性。
本发明旨在提供一种靶向LIR1的抗体,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LIR1抗体,其包含:(1)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;或(2)如SEQ ID NO:10所示的CDR-L1、如SEQ ID NO:11所示的CDR-L2、如SEQ ID NO:12所示的CDR-L3、如SEQ IDNO:13所示的CDR-H1、如SEQ ID NO:14所示的CDR-H2、如SEQ ID NO:15所示的CDR-H3。
在一个实施方案中,所述LIR1抗体与选自SEQ ID NO:7和16所示的氨基酸序列具有至少90%同一性的轻链可变区,和与选自SEQ ID NO:8和17所示的氨基酸序列具有至少90%同一性的重链可变区。
在一个实施方案中,所述LIR1抗体包含选自SEQ ID NO:7和16所示的轻链可变区和选自SEQ ID NO:8和17的重链可变区。在一个实施方案中,所述LIR1抗体包含如SEQ IDNO:7所示的轻链可变区和如SEQ ID NO:8所示的重链可变区;或如SEQ ID NO:16所示的轻链可变区和如SEQ ID NO:17所示的重链可变区。
在一个实施方案中,所述LIR1抗体的氨基酸序列选自SEQ ID NO:9和18。
本发明还提供编码上述LIR1抗体的核酸分子。因此,在一个实施方案中,编码所述LIR1抗体的核酸分子与选自SEQ ID NO:19-20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LIR1抗体能够特异性结合LIR1抗原。优选地,编码所述LIR1抗体的核酸分子选自SEQ ID NO:19-20。
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LIR1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LIR1抗体或多特异性抗体的核酸分子的载体,以及表达所述LIR1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受体,其包含一种或多种NK抑制性配体、跨膜结构域和信号传导结构域,其中所述NK抑制性配体包含如上所述的LIR1抗体或含有所述LIR1抗体的多特异性抗体,其中所述信号传导结构域包含一个或多个共刺激结构域。
在一个实施方案中,所述嵌合受体包含两种NK抑制性配体,其中第一NK抑制性配体是如上所述的LIR1抗体,第二NK抑制性配体选自:(1)靶向以下NK抑制性受体的抗体或其片段:NKG2A、NKG2B、CD94、LIR2、LIR3、KIR2DL1、KIR2DL2/3、KIR3DL1、CEACAM1、LAIR1和KLRG1;或(2)HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL、唾液酸、PD-L1、PD-L2、CD155、CD112、CD113、Gal-9、FGL1,和它们包含的NK抑制性受体结合区。
在一个实施方案中,本发明的嵌合受体中的所述信号传导结构域由一个或多个共刺激结构域组成。即,不包含初级信号传导结构域,例如来自FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d的初级信号传导结构域。
在另一个实施方案中,本发明的嵌合受体的信号传导结构域还可以包含初级信号传导结构域,例如CD3ζ胞内区。
本发明还提供编码如上所定义的靶向LIR1的嵌合受体的核酸分子,以及包含所述核酸分子的载体。
本发明还提供一种工程化免疫细胞,其表达本发明的包含LIR1抗体的嵌合受体,并且其中至少一种MHC相关基因的表达被抑制或沉默。
在一个实施方案中,所述MHC相关基因选自:HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
在一个实施方案中,所述表达本发明的包含LIR1抗体的嵌合受体的工程化免疫细胞进一步包括至少一种TCR/CD3基因的表达被抑制或沉默,所述TCR/CD3基因的实例包括例如TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ。
在一个实施方案中,本发明提供的工程化免疫细胞还表达靶向肿瘤抗原的嵌合抗原受体。
在一个实施方案中,所述免疫细胞选自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LIR1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抗体、多特异性抗体、抗体偶联物或嵌合受体。
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抗体、嵌合受体、多特异性抗体、工程化细胞或抗体偶联物,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LIR1表达相关的疾病的方法,包括向受试者施用如上所述的抗体、嵌合受体、多特异性抗体、抗体偶联物、工程化免疫细胞或药物组合物。
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。
LIR1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)。本发明的抗体也包含重组抗体、人抗体、人源化抗体、鼠源抗体、嵌合抗体及其抗原结合部分。
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 sitetopography,”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。
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LIR1抗体是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。事实上,如果使用较短的接头(例如在5-10个氨基酸之间),则可以防止链内折叠。关于接头的大小和组成的选择,参见例如,Hollinger等人,1993Proc NatlAcad.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。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,本发明的LIR1抗体包含(1)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;或(2)如SEQ ID NO:10所示的CDR-L1、如SEQ ID NO:11所示的CDR-L2、如SEQ ID NO:12所示的CDR-L3、如SEQ ID NO:13所示的CDR-H1、如SEQ ID NO:14所示的CDR-H2、如SEQ ID NO:15所示的CDR-H3。
在一个实施方案中,所述LIR1抗体包含与选自SEQ ID NO:7和16的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%的序列同一性的轻链可变区,和与SEQ ID NO:8和17所示的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%的序列同一性的重链可变区。优选地,所述LIR1抗体包含选自SEQ ID NO:7和16所示的轻链可变区和选自SEQ ID NO:8和17所示的重链可变区。更优选地,所述LIR1抗体包含如SEQ ID NO:7所示的轻链可变区和如SEQ ID NO:8所示的重链可变区;或如SEQ ID NO:16所示的轻链可变区和如SEQ ID NO:17所示的重链可变区。
在一个实施方案中,所述LIR1抗体的氨基酸序列如SEQ ID NO:9或18所示。
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。
在在一个方面,本发明还提供包含如上所述LIR1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。
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LIR1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LIR1抗体的核酸分子与选自SEQ ID NO:19-20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LIR1抗体能够特异性结合LIR1抗原。优选地,编码所述LIR1抗体的核酸分子如SEQ ID NO:19-20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LIR1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LIR1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LIR1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。
嵌合受体
在另一方面,本发明还提供包含如上所述的LIR1抗体的嵌合受体。由于LIR1是一种NK抑制性受体,因此包含LIR1抗体的嵌合受体可以用于抑制NK细胞的杀伤作用。
在一个实施方案中,本发明提供一种嵌合受体,其包含一种或多种NK抑制性配体、跨膜结构域和信号传导结构域,其中所述NK抑制性配体包含如上所述的LIR1抗体或含有所述LIR1抗体的多特异性抗体,其中所述信号传导结构域包含一个或多个共刺激结构域。
在一个实施方案中,所述嵌合受体包含多种NK抑制性配体,例如两种NK抑制性配体,其中第一NK抑制性配体是如上所述的LIR1抗体,第二NK抑制性配体是靶向其他NK抑制性受体的抗体或其片段,和/或其他NK抑制性受体的天然配体或其包含的NK抑制性受体结合区。
在一个实施方案中,所述第二NK抑制性配体是选自靶向以下NK抑制性受体的抗体或其片段:NKG2/CD94组分(例如NKG2A、NKG2B、CD94);杀伤细胞Ig样受体(KIR)家族成员(例如KIR2DL1、KIR2DL2/3、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2和KIR3DL3);白细胞Ig样受体(LIR)家族成员(例如LIR2、LIR3、LIR5和LIR8);NK细胞受体蛋白1(NKR-P1)家族成员(例如NKR-P1B和NKR-P1D);免疫检查点受体(例如PD-1、TIGIT和CD96、TIM3、LAG3);癌胚抗原相关的细胞黏附分子1(CEACAM1);唾液酸结合性免疫球蛋白样凝集素(SIGLEC)家族成员(例如SIGLEC7和SIGLEC9);白细胞相关的免疫球蛋白样受体1(LAIR1);Ly49家族成员(例如Ly49A、Ly49C、Ly49F、Ly49G1和Ly49G4)和杀伤细胞凝集素样受体G1(KLRG1)。更优选地,所述第二NK抑制性配体选自靶向以下NK抑制性受体的抗体或其片段:NKG2A、NKG2B、CD94、LIR2、LIR3、KIR2DL1、KIR2DL2/3、KIR3DL1、CEACAM1、LAIR1和KLRG1。还更优选地,所述第二NK抑制性配体选自靶向以下NK抑制性受体的抗体或其片段:NKG2A、CD94、KIR2DL1、KIR2DL2/3、KIR3DL1、CEACAM1、LAIR1和KLRG1。
在一个实施方案中,所述第二NK抑制性配体是其他NK抑制性受体的天然配体或其包含的NK抑制性受体结合区,例如HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL、唾液酸、免疫检查点配体(例如PD-L1/PD-L2、CD155、CD112、CD113、Gal-9、FGL1等),和它们包含的NK抑制性受体结合区。优选地,所述第二NK抑制性配体选自HLA-E、HLA-F、HLA-G、钙黏素、PD-L1、PD-L2,或它们包含的NK抑制性受体结合区。更优选的,所述第二NK抑制性配体选自HLA-E胞外区、HLA-G胞外区、E-钙黏素胞外区、PD-L1胞外区和PD-L2胞外区。更优选的,所述第二NK抑制性配体是E-钙黏素胞外区,其包含EC1和EC2,更优选包含EC1、EC2、EC3、EC4和EC5。
如本文所用,术语“跨膜结构域”是指能够使嵌合受体在免疫细胞(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“共刺激结构域”是指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胞内区: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:27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:28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:25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:26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,所述信号传导结构域由一个或多个共刺激结构域组成(即,不包含初级信号传导结构域,例如来自FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d的初级信号传导结构域)。在另一个实施方案中,本发明的嵌合受体的信号传导结构域还可以包含初级信号传导结构域,例如CD3ζ胞内区。在优选的实施方式中,所述CD3ζ胞内区与SEQ ID NO:29或31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:30或32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和抗体的任何寡肽或多肽。具体地,铰链区用来为配体结合结构域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:37、39或41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:38、40或42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,本发明的CR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:33或35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 IDNO:34或36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CR含有如本文所提供的LIR1抗体或含有所述LIR1抗体的多特异性抗体、CD8α跨膜区和信号传导结构域,所述信号传导结构域包含选自CD28和4-1BB的共刺激结构域。优选地,所述信号传导结构域由选自CD28和4-1BB的共刺激结构域组成。在另一个实施方案中,所述信号传导结构域还包含CD3ζ胞内区。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。
本发明还提供编码如上所定义的靶向LIR1的嵌合受体的核酸分子,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
由于LIR1能够与HLA-I类分子结合,进而抑制免疫细胞例如NK细胞的激活。因此引入外源性的LIR1抗体能够通过结合LIR1来实现抑制NK细胞杀伤作用的效果,这在某些情况下(例如HLA-I类分子缺失或制备通用型CAR-T细胞的情况下)尤其有用。
因此在一个方面,本发明还提供一种工程化免疫细胞,其表达本发明的包含LIR1抗体的嵌合受体,并且其中至少一种MHC相关基因的表达被抑制或沉默。
如本文所用,MHC相关基因包括MHC基因本身(例如,MHC-I类分子和MHC-II类分子),以及与MHC基因相互作用或调控其表达的基因。MHC-I类分子的实例包括但不限于HLA-A、HLA-B、HLA-C、B2M。MHC-II类分子的实例包括但不限于HLA-DPA1、HLA-DQA1和HLA-DRA。与MHC基因相互作用或调控其表达的基因的实例包括但不限于TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK和CIITA。
因此,在一个实施方案中,使MHC相关基因的表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
在一个实施方案中,所述表达本发明的包含LIR1抗体的嵌合受体的工程化免疫细胞进一步包括至少一种TCR/CD3基因的表达被抑制或沉默,所述TCR/CD3基因的实例包括例如TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ。
在一个优选的实施方案中,所述表达本发明的嵌合受体的工程化免疫细胞包括至少一种TCR/CD3基因和至少一种MHC相关基因的表达被抑制或沉默,其中所述至少一种TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ和它们的组合;所述至少一种MHC相关基因选自HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
在一个优选的实施方案中,所述至少一种TCR/CD3基因选自TRAC、TRBC和它们的组合,所述至少一种MHC相关基因选自B2M、RFX5、RFXAP、RFXANK、CIITA和它们的组合。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和B2M的表达被抑制或沉默。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和CIITA的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M和CIITA的表达被抑制或沉默。在一个优选的实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M和RFX5的表达被抑制或沉默。
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,包括但不限于例如通过大范围核酸酶、锌指核酸酶、TALE核酸酶或CRISPR系统中的Cas酶介导DNA断裂、或通过反义寡核苷酸、RNAi、shRNA等技术使基因失活。
在一个实施方案中,本发明提供的工程化免疫细胞还表达靶向肿瘤抗原的嵌合抗原受体。
在一个实施方案中,所述嵌合抗原受体靶向选自以下的肿瘤抗原:TSHR、CD19、CD123、CD22、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-l lRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、NCAM、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gplOO、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、Claudin18.2、NKG2D和它们的任意组合。优选地,所述靶标选自:CD19、CD20、CD22、BAFF-R、CD33、EGFRvIII、BCMA、GPRC5D、PSMA、ROR1、FAP、ERBB2(Her2/neu)、MUC1、EGFR、CAIX、WT1、NY-ESO-1、CD79a、CD79b、GPC3、Claudin18.2、NKG2D和它们的任意组合。根据待靶向的抗原,本发明的CAR可以被设计为包括对该抗原具有特异性的配体结合结构域。例如,如果CD19是待靶向的抗原,则CD19抗体可用作本发明的配体结合结构域。
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。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。
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,本发明提供多种工程化免疫细胞,其中一种免疫细胞表达本发明所述的嵌合受体,另一种免疫细胞表达靶向其他NK抑制性受体的第二嵌合受体。在该实施方案中,所述第二嵌合受体包含第二NK抑制性配体、跨膜结构域和信号传导结构域,其中所述第二NK抑制性配体、跨膜结构域和信号传导结构域的定义如在“嵌合受体”一节中所述。还在另一个实施方案中,将一种免疫细胞改造为表达包含LIR1抗体的嵌合受体,并且将另一种免疫细胞改造为表达靶向肿瘤抗原的嵌合抗原受体。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LIR1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LIR1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),Nucleic Acids 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LIR1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LIR1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LIR1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LIR1抗体和与所述LIR1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抗体、多特异性抗体、嵌合受体或抗体偶联物。
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抗体、多特异性抗体、嵌合受体、工程化免疫细胞或抗体偶联物,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。包含例如本文所述的免疫细胞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LIR1表达相关的疾病的方法,包括向受试者施用如上所述的抗体、嵌合受体、多特异性抗体、抗体偶联物、工程化免疫细胞或药物组合物。
在一个实施方案中,与LIR1表达相关的疾病包括但不限于:急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、红白血病、急性巨核细胞白血病;慢性白血病,例如慢性髓细胞白血病、慢性淋巴细胞白血病、慢性单核细胞白血病;和其他特殊类型的白血病例如毛细胞白血病、幼淋巴细胞白血病、浆细胞白血病、成人T细胞白血病、嗜酸性粒细胞白血病、嗜碱性粒细胞白血病等)、母细胞性浆细胞样树突状细胞瘤、恶性淋巴组织增生疾病、Waldenstrom巨球蛋白血症、淋巴瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤,例如B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(NHL)、小淋巴细胞性(SL)NHL、中间级/滤泡性NHL、中间级扩散性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小型非裂化细胞性NHL、大肿块病NHL)、套细胞淋巴瘤、AIDS相关淋巴瘤、伯基特氏淋巴瘤、弥散性大B细胞淋巴瘤、滤泡性淋巴瘤、MALT淋巴瘤、边缘区淋巴瘤、浆母细胞性淋巴瘤、浆细胞样树突状细胞瘤等)、NK细胞淋巴瘤、大颗粒淋巴细胞增殖性疾病、NK细胞白血病、白血病(包括急性白血病,例如急性淋巴细胞白血病、急性髓细胞白血病、急性非淋巴细胞白血病诸如急性粒细胞白血病(包括未分化型和部分分化型)、骨髓发育不良、多发性骨髓瘤、骨髓增生异常、移植后淋巴细胞增生性紊乱(PTLD)、组织细胞坏死性淋巴结炎、假性淋巴瘤、伴有毛细胞的脾淋巴瘤、脑神经胶质瘤、胚细胞瘤、肉瘤、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和CNS癌症、乳腺癌、腹膜癌、宫颈癌、绒毛膜癌、结肠和直肠癌、结缔组织癌症、消化系统的癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌(包括胃肠癌)、胶质母细胞瘤(GBM)、肝癌、肝细胞瘤、上皮内肿瘤、肾癌、喉癌、肝肿瘤、肺癌(例如小细胞肺癌、非小细胞肺癌、腺状肺癌和鳞状肺癌)、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、前列腺癌、间皮瘤、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统的癌症、唾液腺癌、皮肤癌、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌、子宫或子宫内膜癌、泌尿系统的恶性肿瘤、外阴癌。优选地,可以用本发明的工程化免疫细胞或药物组合物治疗的疾病选自:单核/巨噬细胞功能异常疾病、白血病、淋巴瘤、多发性骨髓瘤、脑神经胶质瘤、胰腺癌、胃癌等。
在另一个实施方案中,当本发明的包含抗LIR1抗体的嵌合受体与靶向肿瘤抗原的嵌合抗原受体在免疫细胞中共同表达或将分别表达两者的免疫细胞组合施用时,可以治疗的疾病取决于嵌合抗原受体靶向的肿瘤抗原。例如,当本发明的包含抗LIR1抗体的嵌合受体与靶向CD19的嵌合抗原受体共同表达或施用时,可以治疗的疾病是与CD19表达相关的疾病,例如B细胞恶性肿瘤,包括急性淋巴细胞白血病(B-ALL)、慢性B-淋巴细胞白血病(B-CLL),B细胞霍奇金氏淋巴瘤(B-HL)和非霍奇金氏淋巴瘤(B-NHL)等。在该实施方案中,包含抗LIR1抗体的嵌合受体用于抑制NK细胞对回输的工程化免疫细胞的杀伤,而嵌合抗原受体用于通过与肿瘤抗原的结合来定向杀伤靶细胞。
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:示出了包含LIR1抗体的UNKi-T细胞的scFv表达水平。
图2:示出了包含LIR1抗体的UNKi-T细胞对NK细胞杀伤作用的抑制效果。用Two-way ANOVA分析,并用T test进行统计学分析。**表示P值小于0.01,达到显著水平。
具体实施方式
实施例1.制备LIR1抗体
将含有LIR1蛋白胞外区序列克隆到带有His标签的pCP载体上,将测序正确的质粒瞬时感染CHO细胞,培养8-10天后收获细胞培养液,采用亲和层析方式进行蛋白纯化,获得人源LIR1蛋白胞外区,作为免疫原。
采用6-8周雌性Balb/c小鼠进行初次和加强免疫,采用ELISA和FACS检测血清中蛋白免疫原的抗体效价和特异性,综合评定后对小鼠进行最后一次强化免疫。3-4天后处死小鼠,收集脾细胞,将其按照一定比例与小鼠骨髓瘤细胞(SP2/0)混合,并将增殖后的杂交瘤细胞经由FACS和ELISA方法鉴定后筛选到阳性细胞株。经过多轮亚克隆鉴定,最终获得可稳定分泌LIR1抗体的两株杂交瘤细胞,将两株细胞上清中的抗体进行纯化后,获得LIR1-1和KIR1-2抗体。
采用胰蛋白酶进行酶解抗体,通过DNA数据采集获得高质量的一级和二级谱图,将谱图用peaks软件进行de novo解析后获得初步的氨基酸序列结果;采用多种蛋白酶对抗体进行酶解,MSE采集数据后可获得所有肽段峰以及每个肽段各个价态完整和碎裂的信息;将获得的更加全面的质谱数据与初步的氨基酸序列进行匹配,最终获得的两个LIR1单链抗体的氨基酸序列如下表1所示。
表1.LIR1 scFv的序列
LIR1 scFv-1 | LIR1 scFv-2 | |
CDR-L1 | SEQ ID NO:1 | SEQ ID NO:10 |
CDR-L2 | SEQ ID NO:2 | SEQ ID NO:11 |
CDR-L3 | SEQ ID NO:3 | SEQ ID NO:12 |
CDR-H1 | SEQ ID NO:4 | SEQ ID NO:13 |
CDR-H2 | SEQ ID NO:5 | SEQ ID NO:14 |
CDR-H3 | SEQ ID NO:6 | SEQ ID NO:15 |
VL | SEQ ID NO:7 | SEQ ID NO:16 |
VH | SEQ ID NO:8 | SEQ ID NO:17 |
scFv | SEQ ID NO:9 | SEQ ID NO:18 |
实施例2.制备表达包含LIR1抗体的嵌合受体的UNKi-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):B2m信号肽(SEQ ID NO:33)、抗LIR1 scFv-1(SEQ IDNO:9)、IgG4铰链区(SEQ ID NO:41)、CD8α跨膜区(SEQ ID NO:21)、CD28共刺激结构域(SEQID NO:25),获得LIR1-1质粒,并通过测序确认目标序列在质粒中的正确插入。
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:35)、抗LIR1 scFv-2(SEQ IDNO:18)、CD28铰链区(SEQ ID NO:39)、CD28跨膜区(SEQ ID NO:23)、4-1BB共刺激结构域(SEQ ID NO:27),获得LIR1-2质粒,并通过测序确认目标序列在质粒中的正确插入。
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,获得表达包含LIR1抗体的嵌合受体的T细胞。
然后采用CRISPR/Cas9系统敲除野生型T细胞(即NT细胞)和所述表达包含LIR1抗体的嵌合受体的T细胞中的TCR/CD3组分(具体为TRAC基因)和MHC相关基因(具体为B2M和RFX5),分别获得Mock T细胞、LIR1-UNKi-1-T细胞(包含LIR1-1质粒)和LIR1-UNKi-2-T细胞(包含LIR1-2质粒)。并使用FITC Mouse Anti-Human CD3(BD Pharmingen,货号555916)抗体、PE mouse anti-human HLA-I(R&D货号FAB7098P)和APC anti-human DR,DP,DQ(biolegend,货号361714)抗体,通过流式细胞仪检测UNKi-T细胞、Mock T细胞和NT细胞中的CD3/HLA-I/HLA-II的表达效率,结果如下表2所示。
表2.UNKi-T细胞中的基因表达效率
细胞名称 | TCR/CD3 | B2M/HLA-I | RFX5/HLA-II |
LIR1-UNKi-1-T | 3.5% | 17.6% | 10.9% |
LIR1-UNKi-2-T | 4.3% | 16.9% | 10.3% |
Mock T | 2.6% | 15.8% | 9.3% |
NT | 98% | 98% | 83% |
从表1可以看出,本发明制备的UNKi-T细胞以及Mock T细胞中的CD3/HLA-I/HLA-II的表达被有效抑制或沉默。
用recombinant human LILRB1 protein(sino biological,货号16014-H02H)作为一抗,APC anti-human IgG Fc(biolegend,货号409306)作为二抗检测LIR1-UNKi-1 T细胞和LIR1-UNKi-2 T细胞中scFv的表达,结果如图1所示。从图1可以看出,本发明制备的UNKi-T细胞的抗LIR1 scFv均有效表达。
用Far-Red(invitrogen,货号C34564)标记本发明制备的UNKi-T细胞和Mock-T细胞。然后按照1x104个细胞/孔的浓度将标记好的UNKi-T细胞和Mock T细胞铺入96孔板,并以2:1的效靶比加入NK92细胞进行共培养。16-18小时后,用流式细胞仪检测培养物中T细胞的比例,进而计算NK细胞对T细胞的杀伤率,结果如图2所示。
可以看出,与Mock T相比,本实施例制备的两种表达包含LIR1抗体的嵌合受体的UNKi-T细胞均能显著降低NK细胞对T细胞的杀伤作用。
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。
Claims (24)
1.一种靶向LIR1的抗体,其包含:
(1)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;或
(2)如SEQ ID NO:10所示的CDR-L1、如SEQ ID NO:11所示的CDR-L2、如SEQ ID NO:12所示的CDR-L3、如SEQ ID NO:13所示的CDR-H1、如SEQ ID NO:14所示的CDR-H2、如SEQ ID NO:15所示的CDR-H3。
2.权利要求1所述的抗体,其包含与选自SEQ ID NO:7和16所示的氨基酸序列具有至少90%同一性的轻链可变区和与选自SEQ ID NO:8和17所示的氨基酸序列具有至少90%同一性的重链可变区。
3.权利要求1所述的抗体,其中所述LIR1抗体的氨基酸序列选自SEQ ID NO:9和18。
4.一种核酸分子,其编码权利要求1-3任一项所述的抗体。
5.权利要求4所述的核酸分子,其与选自SEQ ID NO:19-20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LIR1抗体能够特异性结合LIR1抗原。
6.一种多特异性抗体,其包含权利要求1-3任一项所述的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6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1-3任一项所述的抗体或权利要求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1-3任一项所述的抗体或权利要求6或7所述的多特异性抗体。
10.一种嵌合受体,其包含一种或多种NK抑制性配体、跨膜结构域和信号传导结构域,其中所述NK抑制性配体包含权利要求1-3任一项所述的抗体或权利要求6或7所述的多特异性抗体,所述信号传导结构域包含一个或多个共刺激结构域。
11.权利要求10所述的嵌合受体,所述嵌合受体包含两种NK抑制性配体,其中第一NK抑制性配体包含权利要求1-3任一项所述的抗体或权利要求6或7所述的多特异性抗体,第二NK抑制性配体选自:(1)靶向以下NK抑制性受体的抗体或其片段:NKG2A、NKG2B、CD94、LIR2、LIR3、KIR2DL1、KIR2DL2/3、KIR3DL1、CEACAM1、LAIR1和KLRG1;和/或(2)HLA-E、HLA-F、HLA-G、钙黏素、胶原蛋白、OCIL、唾液酸、PD-L1、PD-L2、CD155、CD112、CD113、Gal-9、FGL1,和它们包含的NK抑制性受体结合区。
12.权利要求10或11所述的嵌合受体,其中所述信号传导结构域由一个或多个共刺激结构域组成。
13.权利要求10或11所述的嵌合受体,其中所述信号传导结构域还包含CD3ζ胞内区。
14.权利要求10-13任一项所述的嵌合受体,其中所述共刺激结构域选自CD28或4-1BB胞内区。
15.一种工程化免疫细胞,其表达权利要求10-14任一项所述的嵌合受体,并且其中至少一种MHC相关基因的表达被抑制或沉默。
16.权利要求15所述的工程化免疫细胞,其中所述MHC相关基因选自:HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA和它们的组合。
17.权利要求15或16所述的工程化免疫细胞,其中所述工程化免疫细胞进一步包括至少一种TCR/CD3基因的表达被抑制或沉默,所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε和CD3ζ。
18.权利要求15-17任一项所述的工程化免疫细胞,其中所述工程化免疫细胞还表达靶向肿瘤抗原的嵌合抗原受体。
19.权利要求15-18任一项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。
20.一种抗体偶联物,其包含权利要求1-3任一项所述的抗体或权利要求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。
21.权利要求20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。
22.一种检测试剂盒,其包含权利要求1-3任一项所述的抗体、权利要求6或7所述的多特异性抗体、权利要求10-14任一项所述的嵌合受体,或权利要求20或21所述的抗体偶联物。
23.一种药物组合物,包含权利要求1-3任一项所述的抗体、权利要求6或7所述的多特异性抗体、权利要求10-14任一项所述的嵌合受体、权利要求15-19任一项所述的工程化免疫细胞或权利要求20或21所述的抗体偶联物,和一种或多种药学上可接受的赋形剂。
24.权利要求1-3任一项所述的抗体、权利要求6或7所述的多特异性抗体、权利要求10-14任一项所述的嵌合受体、权利要求15-19任一项所述的工程化免疫细胞、权利要求20或21所述的抗体偶联物或权利要求23所述的药物组合物在制备用于治疗和/或预防和/或诊断与LIR1表达相关的疾病的药物中的用途。
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WO2016065329A1 (en) * | 2014-10-24 | 2016-04-28 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions and methods for inducing phagocytosis of mhc class i positive cells and countering anti-cd47/sirpa resistance |
CN109790213A (zh) * | 2016-07-29 | 2019-05-21 | 德克萨斯大学体系董事会 | 用于鉴定lilrb阻断抗体的方法 |
CN111315778A (zh) * | 2017-08-23 | 2020-06-19 | 蜻蜓疗法股份有限公司 | 结合nkg2d、cd16和肿瘤相关抗原的蛋白质 |
WO2020136145A2 (en) * | 2018-12-26 | 2020-07-02 | Innate Pharma | Leucocyte immunoglobulin-like receptor neutralizing antibodies |
CN111867614A (zh) * | 2018-01-18 | 2020-10-30 | 艾达奈特公司 | 抗lilrb抗体及其用途 |
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WO2016065329A1 (en) * | 2014-10-24 | 2016-04-28 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions and methods for inducing phagocytosis of mhc class i positive cells and countering anti-cd47/sirpa resistance |
CN109790213A (zh) * | 2016-07-29 | 2019-05-21 | 德克萨斯大学体系董事会 | 用于鉴定lilrb阻断抗体的方法 |
CN111315778A (zh) * | 2017-08-23 | 2020-06-19 | 蜻蜓疗法股份有限公司 | 结合nkg2d、cd16和肿瘤相关抗原的蛋白质 |
CN111867614A (zh) * | 2018-01-18 | 2020-10-30 | 艾达奈特公司 | 抗lilrb抗体及其用途 |
WO2020136145A2 (en) * | 2018-12-26 | 2020-07-02 | Innate Pharma | Leucocyte immunoglobulin-like receptor neutralizing antibodies |
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