CN104853765A - 肿瘤特异性t细胞受体 - Google Patents
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Abstract
本发明涉及用于制备新型T细胞受体(TCR)的方法,所述新型T细胞受体在免疫治疗(特别是过继性T细胞转移)中提供降低的不良事件的风险。根据本发明方法制备的TCR对肿瘤细胞为特异的并且不与健康组织反应。另外提供编码本发明的TCR的核酸、包含本发明的TCR的载体和宿主细胞以及它们在治疗肿瘤性疾病中的用途。
Description
发明领域
本发明涉及用于制备新型T细胞受体(TCR)的方法,所述新型T细胞受体提供降低的免疫治疗(特别是过继性T细胞转移)中的不良事件的风险。根据本发明方法制备的TCR对肿瘤细胞为特异的并且不与健康组织反应。另外提供编码本发明的TCR的核酸、包含本发明的TCR的载体和宿主细胞以及这些化合物在治疗肿瘤性疾病中的用途。
描述
虽然在被诊断患有癌症的患者可用的诊断和治疗选项中取得显著的技术进步,但预后经常仍然是不良的,许多患者不能被治愈。免疫疗法拥有为被诊断患有各种肿瘤的患者提供有效的且靶向的治疗的希望,同时根除恶性肿瘤细胞而不会损害正常组织的潜力。理论上,免疫系统的T细胞能够识别对肿瘤细胞特异的蛋白模式并且通过多种效应机理介导其破坏。过继性T细胞治疗为利用并放大患者自身T细胞的根除肿瘤的能力,然后将这些效应物以使得它们有效地消除残余的肿瘤而不会损害健康组织的状态返回至患者的尝试。虽然该方法对肿瘤免疫学领域不是新的,但过继性T细胞治疗的临床使用中的许多缺点阻碍该方法在癌症治疗中的全面使用。
TCR为免疫球蛋白超家族的异二聚体细胞表面蛋白质,其与参与介导信号传导的CD3复合物的不变蛋白质相关。TCR以αβ和γδ形式存在,所述形式为结构上类似的,但具有完全不同的解剖学定位以及可能具有完全不同的功能。天然异二聚体αβTCR的细胞外部分由两条多肽组成,所述多肽中的每一条都具有膜近端的恒定结构域和膜远端的可变结构域。恒定结构域和可变结构域中的每一种都包括链内二硫键。可变结构域含有与抗体的互补决定区(CDR)类似的高度多态的环。TCR基因治疗的使用克服许多当前的障碍。其允许患者自身的T细胞备有期望的特异性并在短的时段内生成足够数目的T细胞,从而避免它们的耗尽。TCR将被转导入中央型记忆T细胞或具有干细胞特性的T细胞,这可以确保转移后较好的持久性和功能。将TCR工程改造的T细胞输注入通过化疗或辐射而使淋巴细胞减少的癌症患者,这允许有效的植入但抑制免疫抑制。表达人MHC分子和多种人TCR库的转基因小鼠用作迅速分析肽抗原是否为免疫原性(即它们能由MHC分子有效地处理和呈递吗?在免疫之后,它们能有效地诱导T细胞响应吗?)的工具(Li等人,2010Nat Med)。
使用人TCR转基因小鼠,并非由小鼠基因组编码的任何人肽序列都适合于免疫并且将产生具有最佳亲和力的TCR。最佳亲和力意指T细胞限于人自身的MHC分子并将肽抗原识别为外来物,如代表不能耐受的库。通过使用肽/MHC多聚体,可分选转基因小鼠的特异性T细胞,如通过单细胞PCR分离人TCR,优化TCR用于有效表达同时避免与内源性TCR的错配并用于用病毒载体转导患者的T细胞(Uckert等人,2008Cancer Immunol Immunother;Kammertoens T等人,2009Eur J Immunol)。
ATT的关键问题为靶向正确的抗原以预防肿瘤复发和毒性副作用。考虑到大数目的推定的肿瘤抗原,这听起来简单。然而,大多数为肿瘤相关的(自身)抗原(TAA)。正常细胞也表达TAA。通常不分析罕见但重要细胞的表达。此外,TAA表达在指定个体的肿瘤/转移内可为异质的。因此,靶向TAA具有对长期响应无效并破坏正常组织的风险。
如针对Melan-A/MART-1、gp100、HER-2和癌胚抗原的TCR(或嵌合抗体受体;CAR)工程改造的T细胞的临床试验支持该假设。
Morgan RA和同事提供了一名患有过表达ERBB2的癌症的患者的病例报告,所述患者通过将用识别ERBB2的嵌合抗原受体转导的T细胞输注入患者来治疗。在输注15分钟后,患者经历呼吸性窘迫和显著的肺浸润。患者在5天后死亡。该显著结果强调在过继性T细胞治疗的背景下毒性不良作用的问题。
另一方法利用小鼠的免疫、T细胞和来自这些细胞的T细胞受体的随后分离以便转导肿瘤患者自体的外周淋巴细胞。转导的淋巴细胞经扩增,然后再输注。虽然观察到肿瘤消退,但患者仍显示正常细胞的破坏(Johnson LA等人,2009Blood)。
Parkhurst和同事(2010Mol Ther)基因工程改造患有标准治疗难以治疗的转移性结肠直肠癌的患者的自体的T淋巴细胞。改变T淋巴细胞以表达针对癌胚抗原(CEA)的鼠T细胞受体。报告再次显示肿瘤的消退,然而在所有患者中具有严重的短暂性炎性结肠炎作为副作用。
因此,有效的过继性T细胞治疗对于许多(如果不是大部分)肿瘤相关抗原的显著毒性为可预测的。
鉴于上述背景技术的主要缺点,本发明的目标为提供过继性T细胞治疗的新型方法,当基因工程改造的T细胞受体被引入自体淋巴细胞并再输注入人患者时,其可克服免疫治疗中观察到的严重的副作用。本发明的更具体的目标为提供特异性靶向肿瘤细胞而非健康细胞的新型抗原识别构建体。
在本发明的第一方面,以上目标通过用于制备人T细胞受体(TCR)或T细胞的方法解决,所述人T细胞受体或T细胞对肿瘤细胞为特异的并且减少过继性T细胞治疗中的不良作用,所述方法包括以下方法步骤:
a.提供表达未重排的人TCR基因座的宿主生物体,
b.用包含对肿瘤特异性抗原(TSA)特异的表位的肽免疫所述宿主生物体,
c.从所述宿主生物体或细胞中分离对所述人突变的TSA具有活性的T细胞克隆,
d.任选地,从所述T细胞克隆分离TCR,
其中所述TSA从体细胞突变的抗原类别中选出。
本发明的令人惊讶的发现是,与本领域现有方法相比,如果突变的驱动癌症的癌基因,特别是体细胞突变的抗原类别中的TSA,通过过继性T细胞治疗(ATT)靶向,则本领域现状中已知的TAA的许多问题为已解决的。除了癌症病毒编码的抗原以外,突变的抗原为唯一的肿瘤特异性抗原。
当然,根据本文所述的本发明方法制备的TCR不但在过继性T细胞治疗中提供其有利的作用,而且在任何其它治疗性方法提供其有利的作用,其中使用TCR与其靶标的特异性结合。
由于其降低的在过继性T细胞治疗中观察到的不良作用的风险,根据本发明的方法分离的TCR优于本领域现有的抗原识别构建体。在过继性T细胞转移背景下的不良作用主要是由于自身免疫反应或脱靶反应。本发明特别意在通过提供T细胞来解决前面的问题,所述T细胞对肿瘤细胞为高度特异的并且不介导针对患者的健康组织的免疫反应。本发明寻求减少在人自体的或同种异体的淋巴细胞输注后的不良事件可为不同的。在本发明的优选实施方案中,当在过继性T细胞治疗中用于诱导健康组织损伤时,通过本发明获得的TCR提供降低的风险,所述健康组织损伤可能导致水肿和坏死。
在本发明的一个优选实施方案中,所述宿主生物体还包含用于表达人主要组织相容性复合物(MHC)I或II类等位基因的转基因。优选地,MHC为人白细胞抗原(HLA)型,其为已知的或疑似能够呈递所述突变的TSA。甚至更优选的为在所述宿主生物体中表达的HLA型为已知的或疑似能够呈递来源于所述突变的TSA的肽。该肽应包含含有突变的氨基酸序列,所述突变特别存在于与相同蛋白质的相应的未突变(野生型)版本相反的突变的TSA中。
与MHC I类相应的HLA包括A型、B型和C型。HLA I类复合物呈递在呈递细胞内处理的肽(包括外来肽,诸如病毒肽(如果出现的话))。通常,此类HLA I类肽是长度为约9个氨基酸的小的聚合物。与MHC II类相应的HLA包括DP型、DM型、DOA型、DOB型、DQ型和DR型。HLA II类复合物呈递源自细胞外的抗原。它们的长度可为12至18个氨基酸。负责呈递选择的抗原的HLA等位基因的特性为本领域通常已知的方法。
在根据本发明使用的所述宿主生物体中-在不是人的情况下-未重排的人TCR基因座优选以所述宿主生物体的基因组中的一个或多个转基因存在。优选地,这些基因座编码TCRα和β链,并且优选地包含多个,理想上所有人TCR V、D、J和/或C基因。
对于根据本发明的方法,所述宿主生物体具有适应性免疫系统和/或能够增加所述人TCR基因座内的VDJC重排优选为必要条件。此外,优选能够表达异源性TCR的宿主生物体。在本发明的某些优选实施方案中,所述宿主生物体为转基因动物,优选为哺乳动物,更优选为非人哺乳动物,最优选为小鼠、大鼠、驴、兔、野兔或猴或本领域已知的为用于生成T细胞的宿主的任何动物。
在涉及以上方法的本发明的此类实施方案的背景下,并且其中使用非人宿主生物体,此类非人宿主生物体优选地还包括失活的内源性TCR基因座,优选地,其中所述内源性TCR基因座编码所述非人宿主生物体的TCRα和β链。
在本发明的一个非常具体的实施方案中,所述宿主-生物体为“ABabDII”小鼠。术语“ABabDII”小鼠是指如在Li等人,2010;16:1029-34Nature Medicine中所述制备的转基因动物。当然,应理解用与Li等人所述相同的方法制备的任何其它转基因动物也应涵盖为本文所述的本发明的实施方案中使用的合适的宿主生物体。
替代实施方案涉及方法,其中用如本文所述的肽免疫人,例如健康个体或患有肿瘤性疾病的人患者。在该实施方案中,可从人受试者的血液分离T细胞,随后进行免疫过程。该实施方案具有优势:改良的T细胞受体在人,理想为自体T细胞上表达,所述T细胞然后可在过继性T细胞治疗中用于再输注。
在本发明方法的背景下用于免疫宿主生物体的肽包含与所对应的野生型细胞蛋白质的氨基酸序列相比,至少一个氨基酸残基为突变的氨基酸序列。本发明涉及肿瘤特异性抗原的用途,因此,在肿瘤细胞的形成中为突变的并且因此呈该特异性突变形式的蛋白质仅存在于肿瘤细胞中。然而,正常的健康细胞仍可表达最初未突变的(野生型)蛋白质。因此,对于本文所述的本发明,特别优选的是用于免疫的肽在其序列中包含突变,所述突变将TSA与最初未突变的细胞蛋白质相区分。用于本发明方法中的优选的肽包含SEQ ID No.1至27中显示的任何序列。在本发明的优选实施方案中,用于免疫的肽包含SEQ ID No.1中显示的氨基酸序列。
可将在肿瘤细胞中特异性表达但在健康组织中不表达的抗原分类成四种类型:(I)在肿瘤-形成期间通过肿瘤细胞内的点突变或易位形成突变的抗原。那些抗原严格为肿瘤特异的。在本发明的背景下,这些抗原被称为肿瘤特异性抗原(TSA)。(II)癌症/种系抗原通常仅在成熟生物体的生殖细胞内表达而不在健康的体细胞组织中表达。然而,在癌细胞中,由于表观遗传调节的丧失,生殖细胞特异性基因可被活化。(III)分化抗原在肿瘤及其健康祖细胞中表达。针对此类抗原的CTL响应经常导致自身免疫反应。(IV)过表达的TAA在健康细胞中仅显示少量表达,而在肿瘤中那些抗原被强烈地活化。对于本发明,优选的是仅使用第一类型的抗原。
对于本发明包括通过任何种类的突变形成的TSA。仅出于说明性原因,描述了以下类型的突变:氨基酸置换、缺失、添加、插入或化学或翻译后修饰。此外,包括染色体易位以及仅在肿瘤细胞中表达的剪接变体,例如所述剪接变体通过导致新的剪接位点的非特异性剪接突变出现。
对于免疫过程,所述肽可具有任何长度。然而,最低要求是存在含有上述突变序列的表位。本发明的优选的肽的长度为100个氨基酸,优选为50个氨基酸,更优选为30个氨基酸,甚至更优选为8至16个氨基酸。准确的肽长度可取决于TSA被MHC I类还是MHC II类呈递而变化。
为了增强宿主生物体的免疫,优选的是将佐剂与肽一起使用。佐剂为例如但不限于此,CpG和/或弗氏不完全佐剂。在用肽进行初始免疫后,将所述宿主生物体用所述肽和/或选择的佐剂优选处理至少一次或两次、三次或四次。弗氏佐剂为油溶液(矿物油),其中用于免疫的抗原被乳化。弗氏不完全佐剂,如本发明中优选使用的,不含有任何分支杆菌组分。
在免疫过程中以及之后,所述宿主生物体应形成表达针对本发明的TSA特异的重排的T细胞受体的T细胞。然后,在优选的实施方案中,此类T细胞克隆从所述宿主生物体中分离。例如细胞可从脾细胞、淋巴结细胞或血液中分离。可例如经由CD4或CD8的表面表达选择T细胞克隆,这取决于TSA表位是MHC I类还是II类。从宿主生物体分离单个T细胞克隆的方法是本领域技术人员熟知的。本发明不限制用于分离T细胞的特定方法。然而,在本发明的一个优选实施方案中,在分离后,对所述T细胞或所述T细胞克隆表达能结合本发明的方法中使用的TSA的TCR进行进一步测试。这优选地使用TSA特异性HLA四聚体通过四聚体结合(染色)来完成。任选地,与未突变版本的细胞蛋白质相比,也测试分离的T细胞或T细胞克隆对TSA的特异性。为此,比较T细胞对包含突变的肽以及对包含野生型版本的肽的反应性。在优选的实施方案中,根据本发明的方法分离此类T细胞或T细胞克隆,其对TSA具有高度选择性而对未突变版本的细胞蛋白质不具有高度选择性。
本发明的另一个实施方案涉及如本文所述的方法,其中在分离T细胞或T细胞克隆之后,克隆TCR序列。在该实施方案中,步骤d中的方法,如上文所述,包括以下其它方法步骤(i)由所述T细胞克隆制备cDNA,(ii)扩增所述cDNA,以及(iii)将各个TCRα和β基因克隆入载体。优选地,将用于转导人外周血淋巴细胞的逆转录病毒载体用作本发明的TCR的媒介物。用于此类克隆程序的途径和方法为技术人员熟知的。
在本发明的另一个优选实施方案中,使用的TSA在肿瘤细胞或肿瘤疾病中表达。
如本文所用,术语“肿瘤”或“肿瘤疾病”意指良性肿瘤和恶性肿瘤两者或赘生物并且包括黑素瘤、淋巴瘤、白血病、癌和肉瘤。肿瘤组织的说明性实例为皮肤肿瘤,诸如恶性黑素瘤和蕈样霉菌病;血液系统肿瘤,诸如白血病,例如,急性淋巴母细胞性白血病、急性髓细胞白血病或慢性髓细胞白血病;淋巴瘤,诸如霍奇金疾病或恶性淋巴瘤;妇科肿瘤,诸如卵巢肿瘤和子宫肿瘤;泌尿系肿瘤诸如前列腺肿瘤、膀胱肿瘤或睾丸肿瘤的那些;软组织肉瘤、骨肉瘤或非骨肉瘤、乳腺肿瘤;垂体肿瘤、甲状腺肿瘤和肾上腺皮质肿瘤;胃肠肿瘤诸如食道肿瘤、胃肿瘤、肠肿瘤和结肠肿瘤的那些;胰腺肿瘤和肝肿瘤;喉乳头状瘤(laryngeae papillomestasas)以及肺肿瘤。在本发明背景下的优选肿瘤选自黑素瘤、肺肿瘤、子宫内膜肿瘤、神经胶质瘤、淋巴瘤、白血病或前列腺肿瘤。
可经历本文所述的本发明方法的示例性TSA-不限制本发明-在Krauthammer等人,2012(Nature Genetics)中描述。由HLA A2型呈递的优选选择的TSA为RAC1、RAC2、RHOT1、MAP2K1、MAP2K2、Nos1、EGFR、SMCA4、STK11、ARID1A、RBM10、U2AF1、EP300、CHD4、FBXW7、H3F3A、KLHL6、SPOP或MED12。其各个突变的表位序列在下文实施例部分提供。
本发明的目标通过编码根据本发明方法获得的或可获得的TCR的核酸分子进一步解决。本发明中进一步提供编码本发明的TCR的各个α或β链,或编码本发明的TCR的可变结构域或恒定结构域,或编码本发明的TCR的片段的核酸分子,优选地,其中TCR的此类片段仍具有结合其TSA的活性/能力。除此之外,核酸分子任选地具有其它序列,所述其它序列对于核酸序列的蛋白质表达,特别是哺乳动物/人中的表达,最优选为免疫细胞中的表达是必需的。使用的核酸可包含在适合于允许表达与细胞中的TCR相应的核酸序列的载体中。
还提供包含本文以上所述的核酸分子的载体或细胞,特别是,其中所述载体用于医学中。还提供包含根据本发明的载体的细胞。
在另一方面,本发明提供T细胞受体(TCR)或其片段,如通过本发明的方法获得或可获得的。在该背景下,特别优选的是本发明的TCR为显示减少免疫治疗中不良作用的TCR。本发明的TCR优选不靶向健康细胞或组织,其表达用于生成TCR的未突变(野生型)版本的TSA。在优选的实施方案中,当给予受试者时,本发明的TCR不诱导坏死事件并且不会增加对健康细胞或组织的免疫响应。本发明的优选的TCR为对SEQ ID No.1中显示的表位特异的TCR。
优选地,根据本发明的TCR可以为本文在以下所述的TCR。
本发明的另一实施方案涉及单链TCR(scTCR),优选αβ-scTCR,其来源于本发明的TCR的序列。单链TCR(scTCR)为由单条氨基酸链组成的人工构建体。scTCR可包含第一TCR链(如,[α]链)的可变区的多肽以及整个(全长)第二TCR链(如,[β]链)的多肽,或反之亦然。此外,scTCR可任选地含有一个或多个接头,所述接头将两条或更多条多肽连接在一起。接头可为,例如,将两条单链连接在一起的肽,如本文所述。
还提供本发明的此类scTCR或本发明的其它TCR源的分子,其与诸如IL-2、IL-7或IL-15的人细胞因子融合。本发明的TCR也可以多聚体复合物提供,所述多聚体复合物包含至少两个scTCR或TCR分子,其中所述scTCR或TCR分子例如通过引入的生物素-链霉亲和素官能团互连。
本发明的另一方面提供宿主细胞,其包含如本文以上所述的载体、核酸或TCR分子。在本发明的优选实施方案中,宿主细胞为人细胞,优选为人T淋巴细胞,其对CD4或CD8的表达为阳性的。本发明的此类宿主细胞优选通过根据本发明的核酸或载体的转导获得。将核酸分子引入T细胞的转导方法为本领域熟知的并且包括但不限于此病毒转导媒介物。
在本发明的替代方面,提供通过用于制备人T细胞受体(TCR)的方法获得的或可获得的T细胞,所述人T细胞受体对于肿瘤细胞为特异的并且减少过继性T细胞治疗中的不良作用,如本文以上所述。此类T细胞取决于本发明的方法中使用的宿主生物体,例如人或非人T细胞,优选为表达人TCR的非人T细胞。
在其它方面,本发明所提供的化合物用于医学,例如用于治疗癌性疾病,特别是,其中癌性疾病特征为所述突变的TSA的特异性表达。最优选地,本发明的化合物用于涉及过继性T细胞转移的癌症治疗中。
本发明的另一方面涉及治疗人受试者,特别是患有肿瘤疾病的人受试者的方法。治疗方法包括将任何上述化合物施用至需要此种治疗的患者。本发明的化合物的施用可以例如涉及将本发明的T细胞输注入所述患者。优选地,此类T细胞为用本发明的核酸或TCR体外转导的患者自体的T细胞。
因此还提供药物组合物,其包含根据本发明的TCR或TCR片段,或根据本发明的核酸、载体、宿主细胞或分离的T细胞。在优选实施方案中,将药物组合物用于免疫治疗。
可用于本发明的药学上可接受的载体或稀释剂的实例包括稳定剂诸如SPGA,碳水化合物(如山梨糖醇、甘露醇、淀粉、蔗糖、葡萄糖、葡聚糖),蛋白质诸如白蛋白或酪蛋白,含有诸如牛血清或脱脂乳的试剂的蛋白质以及缓冲液(如磷酸盐缓冲液)。
在本发明的方法中优选用于获得本发明的TCR的肿瘤抗原列于下表1和2(突变被指示为括号中表位内的氨基酸交换):
表1:
在优选的实施方案中,本发明的上述TCR涉及以下TCR分子:
本发明涉及包含CDR3区的TCRα链,所述CDR3区具有SEQ IDNO:28、30、32、33、36、38或40中任一项所显示的序列。优选的为包含可变结构域的TCRα链,所述可变结构域具有SEQ ID NO 42、44、46、47、50、52或54中任一项所显示的序列。
本发明涉及包含CDR3区的TCRβ链,所述CDR3区具有SEQ IDNO:29、31、34、35、37、39或41中任一项所显示的序列。优选的为包含可变结构域的TCRβ链,所述可变结构域具有SEQ ID NO 43、45、48、49、51、53或55中任一项所显示的序列。
本发明的优选实施方案涉及根据如本文所述的任一种方法分离或制备(获得)特异性TCR。本发明的此类TCR优选为特异性靶向选自表1或2的突变的抗原的TCR。Rac-1或TRRAP突变的抗原为优选的。更具体地,具有特异性结合于突变的Rac-1表位FSGEYIPTV或突变的TRAPP表位KLVFGSVFL的能力的此类TCR为优选的。
本发明的优选的TCR通过存在包含SEQ ID NO.28至41中显示的任何一种氨基酸序列的CDR3区进一步表征。根据本发明的Rac-1TCR,α或β链,优选地包含具有SEQ ID NO:28至39中任一项所显示的序列的CDR3。根据本发明的优选的TRRAP TCR特征为选自SEQID NO:40或41中所显示的序列的CDR3氨基酸序列的存在。
更优选的为具有包含SEQ ID NO:28中显示的CDR3序列的α链以及包含SEQ ID NO:29中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:30中显示的CDR3序列的α链以及包含SEQ IDNO:31中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:32中显示的CDR3序列的α链以及包含SEQ ID NO:34中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:32中显示的CDR3序列的α链以及包含SEQ ID NO:35中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:33中显示的CDR3序列的α链以及包含SEQ ID NO:34中显示的CDR3序列的β链的α/βTCR;具有包含SEQID NO:33中显示的CDR3序列的α链以及包含SEQ ID NO:35中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:36中显示的CDR3序列的α链以及包含SEQ ID NO:37中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:38中显示的CDR3序列的α链以及包含SEQ ID NO:39中显示的CDR3序列的β链的α/βTCR;具有包含SEQ ID NO:40中显示的CDR3序列的α链以及包含SEQ IDNO:41中显示的CDR3序列的β链的α/βTCR。
本发明TCR中包含的TCR链可以进一步包含至少一种,优选两种,最优选所有三种存在于TCR 1至7的任一种的可变区之一的CDR区。含有所有三种CDR区的所述可变区的序列在SEQ ID NO 42至55中显示。
在另一个优选的实施方案中,本发明的TCR包含α和/或β链的至少一种可变区,其选自本文以下在表3中所述的本发明的TCR T1至T7中任一种的α或β链的可变区。
在本发明的背景下分离的TCR包含以下可变区(CDR3区被加下划线):
Rac-1 TCR:
TRAV20*02-CAVQTSQGGSEKLVF-TRAJ57*01
TRBV4-1*01-CASSQDASGIYYEQYF-TRBD2*02-TRBJ2-7*01
TRAV13-1*01-CAASRGGAQKLVF-TRAJ54*01
TRBV3-1*01-CASSQLAGGPLYNEQFF-TRBD2*02-TRBJ2-1*01
TRAV5*01-CAESKRFSDGQKLLF-TRAJ16*01
TRAV12-2*02-CAAQSARQLTF-TRAJ22*01
TRBV20-1*01(/02)-CSARDLITDTQYF-TRBJ2-3*01
TRBV3-1*01-CASSPWQETQYF-TRBJ2-5*01
TRAV13-1*01 CAASLGSGNTPLVF TRAJ29*01
TRBV28*01 CASSLHSGRDTQYF TRBJ2-3*01 TRBD2*02
TRAV13-2*01 CAENRGANSKLTF TRAJ56*01 F
TRBV12-3*01 CASSFTGGFYGYTF TRBJ1-2*01 TRBD1*01
TRRAP TCR:
TRAV17*01-CATDWYTGANSKLTF-TRAJ56*01
TRBV6-2*01-CASSYSGYEQYF-TRBD1*01-TRBJ2-7*01
本发明的一个其它优选的实施方案提供TCRα和/或β链或其片段,其包含选自SEQ ID NO 42至55的序列。优选地,本发明的TCR为异二聚体TCR,其包含含有SEQ ID NO 42序列的α链以及含有SEQID NO 43序列的β链,或包含含有SEQ ID NO 44序列的α链以及含有SEQ ID NO 45序列的β链,或包含含有SEQ ID NO 46序列的α链以及含有SEQ ID NO 48序列的β链,或包含含有SEQ ID NO 46序列的α链以及含有SEQ ID NO 49序列的β链,或包含含有SEQ ID NO 47序列的α链以及含有SEQ ID NO 48序列的β链,或包含含有SEQ IDNO 47序列的α链以及含有SEQ ID NO 49序列的β链,或包含含有SEQ ID NO 50序列的α链以及含有SEQ ID NO 51序列的β链,或包含含有SEQ ID NO 52序列的α链以及含有SEQ ID NO 53序列的β链,或包含含有SEQ ID NO 54序列的α链以及含有SEQ ID NO 55序列的β链。
在本发明的甚至更优选的方面中,本发明的TCR为包含选自下表3中TCR T1至T7中任一种的TCR链的至少一种TCRα或β链的TCR。最优选的是,本发明的TCR为选自本文在以下表3中所述的T1至T7中任一种的α/βTCR。
在一些实施方案中,本发明的上述TCR可以含有改变的氨基酸序列。优选的是,由本发明涵盖的TCR链与如本文公开的TCR序列或TCRα或β链序列、SEQ ID NO:42至55中任一项的TCR可变区或CDR3序列具有至少70%、80%、90%、95%、96%、97%、98%或99%的同一性。最优选地,本发明的TCR包含α和/或β链,其与表3中所述的TCR T1至T7中任一种的α/β链具有至少90%或95%或99%的同一性。
优选地,上述TCR对在表1或2中公开的Rac-1或TRRAP的突变的抗原为特异的,尤其当在细胞,诸如肿瘤细胞或抗原呈递细胞上呈递时。本发明进一步包括的是本发明的TCR或TCR链的功能性片段。术语“TCR或TCR链的功能性片段”应指全长受体分子的片段,特征在于片段来源于该分子并且保持相同的结合突变的TAA的能力。
在其它方面,如已在上文公开,本发明还涉及编码本发明的TCR分子的核酸以及包含这些核酸的细胞或表达本发明的TCR的细胞。本发明进一步涉及TCR蛋白质或核酸或细胞在之前本文描述的不同的方法或用途中的使用。
本发明的方面优选涉及用本发明的方法和各种物质治疗肿瘤性疾病。优选的疾病为癌症,其特征为本文公开的任一种突变的TAA的表达。优选的是特征为Rac-1或TRRAP的突变的表位的表达的疾病。用对Rac-1突变的抗原或TRRAP突变的抗原特异的本发明的TCR治疗的优选的疾病选自癌性增生性疾病,如肺癌、乳腺癌、宫颈癌、结肠癌、胃癌、肾癌、白血病、肝癌、淋巴瘤、卵巢癌、胰腺癌、前列腺癌、直肠癌、肉瘤、皮肤癌、睾丸癌和子宫癌。Rac1特异性TCR的特别优选的疾病为黑素瘤和非小细胞肺癌。
现将参考附图和序列在以下实施例中进一步描述本发明,然而,本发明不限于此。出于本发明的目的,本文引用的所有参考通过引用以其整体并入。在图和序列中:
图1:显示在ABabDII小鼠中对HLA-A201限制的突变的RAC1P29S表位的特异性CD8+T细胞响应。
SEQ ID No 1至27:显示表1中所述的HLA A2型限制的TSA的突变的表位序列。
SEQ ID No 28至41:显示本发明的TCR的CDR3结构域序列。
SEQ ID No 42至55:显示本发明的TCR 1至7的可变区。
实施例
在本发明背景下可用的且优选的示例性肿瘤特异性抗原表位在表2中提供。
基因 | 蛋白质 | HLA A2.01表位* |
黑素瘤 | ||
RAC1: | Ras相关的C3肉毒毒素底物1 | FP/SGEYIPTV |
RAC2: | Ras相关的C3肉毒毒素底物1 | FP/LGEYIPTV |
RHOT1: | 线粒体Rho GTPase 1 | FP/LEEVPPRA |
MAP2K1: | 双特异性有丝分裂原活化的蛋白激酶1 | E/KIKLCDFGV |
MAP2K2: | 双特异性有丝分裂原活化的蛋白激酶2 | E/KIKLCDFGV |
S/FLDQVLKEA | ||
Nos1: | 一氧化氮合酶 | KS/LQAYAKTL |
肺肿瘤 | ||
EGFR: | 表皮生长因子受体 | VLG/ASGAFGT |
SMCA4: | 转录激活剂BRG1 | LLSTRAG/WGL |
STK11: | 丝氨酸/苏氨酸蛋白激酶 | FQP/LPEIANGL |
ARID1A: | 含有富含AT相互作用结构域的蛋白质1A | MW/LVDRYLAFT |
FE/VMSKHPGL | ||
RBM10: | RNA结合蛋白质10 | I/FLGALAPYA |
U2AF1: | 剪接因子U2AF 26kDa亚基 | RHGDRCS/FRL |
子宫内膜肿瘤 | ||
EP300: | 组蛋白乙酰转移酶p300 | LMDGR/WDAFL |
LMDGR/QDAFL | ||
CHD4 | 染色质域解旋酶DNA结合蛋白4 | NLEEL/VFHLL |
FBXW7: | 含有F-box/WD重复的蛋白质7 | TLYGHTF/SAV |
TLYGHTFA/TV | ||
神经胶质瘤 | ||
H3F3A: | 组蛋白H3.3 | QLATKAARK/M |
KSAPSTG/VGV | ||
CLL | ||
KLHL6: | Kelch样蛋白质6 | KF/LDDAGLSL |
前列腺肿瘤 | ||
SPOP: | 斑型POZ蛋白质 | YLSLY/NLLLV |
YLSLY/CLLLV | ||
FVQGKDWGF/V | ||
FVQGKDWGF/L | ||
MED12: | RNA聚合酶II转录亚基12的介质 | VLYD/EQPRHV |
*野生型/突变的氨基酸
实施例1:针对FSGEYIPTV表位的RAC1特异性TCR
为了生成具有RAC1TSA特异性TCR的T细胞,使用缺乏其内源性TCR基因座且表达人TCR库的小鼠。转基因小鼠(ABabDII小鼠)的制备和建立在别处详细描述(Li LP,Lampert JC,Chen X,LeitaoC,Popovic J,Muller W等人,Transgenic mice with a diverse human Tcell antigen receptor repertoire.Nat Med.2010;16:1029-34.)。
将ABabDII小鼠用突变的RAC1P29S表位(见上文)免疫两次。在最后一次免疫后七天,将混合的脾和淋巴结细胞在体外用RAC1突变体或野生型肽刺激并分析CD3、CD8和细胞内IFN-γ的表达。图1显示CD3+细胞群内的CD8+和IFN-γ+细胞(由数值指示百分比)。在圆括号内,给出了CD8+T细胞群内的CD8+和IFN-γ+T细胞的百分比。
实施例2:本发明的RAC1和TRRAP特异性TCR
表3:可分离以下TCR:
TCR | 抗原 | 肽/纯化 | TCR序列 | CDR3* |
T1 | Rac-1 | FSGEYIPTV | TRAV20*02-CAVQTSQGGSEKLVF-TRAJ57*01 | 28 |
IFNg-CAPTURE | TRBV4-1*01-CASSQDASGIYYEQYF-TRBD2*02-TRBJ2-7*01 | 29 | ||
T2 | Rac-1 | FSGEYIPTV | TRAV13-1*01-CAASRGGAQKLVF-TRAJ54*01 | 30 |
IFNg-CAPTURE | TRBV3-1*01-CASSQLAGGPLYNEQFF-TRBD2*02-TRBJ2-1*01 | 31 | ||
T3/T4 | Rac-1 | FSGEYIPTV | TRAV5*01-CAESKRFSDGQKLLF-TRAJ16*01 | 32 |
A2-TETRAMER | TRAV12-2*02-CAAQSARQLTF-TRAJ22*01 | 33 | ||
TRBV20-1*01(/02)-CSARDLITDTQYF-TRBJ2-3*01 | 34 | |||
TRBV3-1*01-CASSPWQETQYF-TRBJ2-5*01 | 35 | |||
T5 | Rac-1 | FSGEYIPTV | TRAV13-1*01CAASLGSGNTPLVF TRAJ29*01 | 36 |
A2-TETRAMER | TRBV28*01CASSLHSGRDTQYF TRBJ2-3*01TRBD2*02 | 37 | ||
T6 | Rac-1 | FSGEYIPTV | TRAV13-2*01CAENRGANSKLTF TRAJ56*01F | 38 |
A2-TETRAMER | TRBV12-3*01CASSFTGGFYGYTF TRBJ1-2*01TRBD1*01 | 39 | ||
T7 | TRRAP | KLVFGSVFL | TRAV17*01-CATDWYTGANSKLTF-TRAJ56*01 | 40 |
IFNg-CAPTURE | TRBV6-2*01-CASSYSGYEQYF-TRBD1*01-TRBJ2-7*01 | 41 |
*序列标识符
表3提供本发明的分离的TCR的α和β链的序列(T1至T7)。序列通过已知的TCR等位基因序列以及本发明的TCR的特异性CDR3氨基酸序列提供。TCR等位基因命名法来源于TCR等位基因数据库IMGT
(http://www.imgt.org/vquest/refseqh.html#VQUEST)Lefranc,M.-P.and Lefranc,G.The T cell receptor FactsBook Academic Press,London,UK(398页),(2001)。
TCR 1至7的TCR链的可变区在SEQ ID No 42至55中提供。
对于T3/T4,发明人发现,尤其是链组合TRAV5/TRBV20-1(SEQID NO:32和34)对Rac1四聚体显示良好的结合。
Claims (30)
1.用于制备人T细胞受体(TCR)的方法,所述人T细胞受体对肿瘤细胞为特异的并且在过继性T细胞治疗中具有降低的不良作用,所述方法包括:
a.提供表达未重排的人TCR基因座的宿主生物体,
b.用包含对肿瘤特异性抗原(TSA)特异的表位的肽免疫所述宿主生物体,
c.从所述宿主生物体分离对人突变的TSA具有活性的T细胞克隆,
d.任选地,从所述T细胞克隆分离所述TCR,
其中所述TSA从体细胞突变的抗原类别中选出。
2.根据权利要求1所述的方法,其中所述宿主生物体还包含用于表达人主要组织相容性复合物(MHC)I类或II类的转基因,所述人主要组织相容性复合物优选已知呈递所述突变的TSA的人白细胞抗原(HLA)型。
3.根据权利要求1或2所述的方法,其中所述未重排的人TCR基因座在所述宿主生物体的基因组中以一种或多种转基因存在。
4.根据权利要求1至3中任一项所述的方法,其中所述人TCR基因座编码TCRα和β链,并且优选地包含多个TCR V、D、J和/或C基因。
5.根据权利要求1至4中任一项所述的方法,其中所述宿主生物体具有适应性免疫系统和/或能够增加VDJC重排并且表达异源性TCR;优选地,所述宿主生物体为转基因动物,优选哺乳动物,更优选非人哺乳动物,最优选小鼠、大鼠、驴、兔、野兔或猴。
6.根据权利要求1至3中任一项所述的方法,其中所述宿主生物体还包含失活的内源性TCR基因座,优选地,其中所述内源性TCR基因座编码TCRα和β链。
7.根据权利要求1至4中任一项所述的方法,其中所述宿主生物体为ABabDII小鼠。
8.根据权利要求1至7中任一项所述的方法,其中所述肽包含与所对应的野生型细胞蛋白质的氨基酸序列相比,至少一个氨基酸残基为突变的氨基酸序列。
9.根据权利要求8所述的方法,其中突变选自所述至少一个氨基酸残基的置换、缺失、添加、插入、染色体易位、或化学或翻译后修饰。
10.根据权利要求1至9中任一项所述的方法,其中所述肽的长度为100个氨基酸,优选50个氨基酸,更优选30个氨基酸,甚至更优选8至16个氨基酸。
11.根据权利要求1至10中任一项所述的方法,其中在步骤b中,将CpG和弗氏不完全佐剂另外地施用至所述宿主生物体以增强免疫效率。
12.根据权利要求1至11中任一项所述的方法,其中在初始免疫后,用所述肽加CpG以及弗氏不完全佐剂将所述宿主生物体处理至少一次或多次。
13.根据权利要求1至12中任一项所述的方法,其中所述T细胞克隆从所述宿主生物体的脾细胞、淋巴结细胞或血液中分离。
14.根据权利要求1至13中任一项所述的方法,其中步骤d包括以下的其它方法步骤:(i)由所述T细胞克隆制备cDNA,(ii)扩增所述cDNA,以及(iii)将各个TCRα和β基因克隆入载体。
15.根据权利要求14所述的方法,其中所述载体为用于转导人外周血淋巴细胞的逆转录病毒载体。
16.根据权利要求1至15中任一项所述的方法,其中所述突变的TSA在选自黑素瘤、肺肿瘤、子宫内膜肿瘤、神经胶质瘤、淋巴瘤、白血病或前列腺肿瘤的肿瘤中表达。
17.根据权利要求1至15中任一项所述的方法,其中所述突变的TAA选自RAC1、RAC2、RHOT1、MAP2K1、MAP2K2、Nos1、EGFR、SMCA4、STK11、ARID1A、RBM10、U2AF1、EP300、CHD4、FBXW7、H3F3A、KLHL6、SPOP或MED12。
18.核酸分子,其编码权利要求1至17中任一项所述的方法获得的TCR,或其α或β链,或其可变结构域或恒定结构域,或其具有结合所述突变的TSA的能力的片段。
19.包含权利要求18所述的核酸的载体。
20.通过权利要求1至17中任一项所述的方法可获得的TCR,或其α或β链,或其可变结构域或恒定结构域,或其具有结合所述突变的TAA抗原片段的能力的片段。
21.包含α和/或β链的TCR,其中所述α和/或β链包含SEQ ID NO:28至41中任一项的至少一种CDR3结构域。
22.根据权利要求21所述的TCR,其中所述TCR包含选自表3的TCR T1至T7中任一种的TCR单链的可变区的至少一种可变区,优选地,其中所述可变区包含SEQ ID NO 42至55中任一项的序列。
23.宿主细胞,其包含权利要求19所述的载体,权利要求18所述的核酸或权利要求20至22中任一项所述的TCR。
24.根据权利要求23所述的宿主细胞,其为人细胞,优选T细胞。
25.根据权利要求23所述的宿主细胞,其为CD4或CD8阳性T细胞。
26.通过权利要求1至17中任一项所述的方法可获得的非人T细胞。
27.根据权利要求26所述的非人T细胞,其中所述T细胞为表达人TCR的非人T细胞。
28.用于医学中的权利要求18所述的核酸分子,权利要求19所述的载体,权利要求20至22中任一项所述的TCR或权利要求23至25中任一项所述的宿主细胞。
29.用于治疗癌性疾病的权利要求28所述的核酸分子、载体、TCR或宿主细胞,特别是其中所述癌性疾病特征为所述突变的TSA的特异性表达。
30.根据权利要求29所述的核酸分子、载体、TCR或宿主细胞,其中所述治疗涉及过继性T细胞治疗。
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EP2925349A1 (en) | 2015-10-07 |
EP2925349B1 (en) | 2019-05-08 |
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WO2014083173A1 (en) | 2014-06-05 |
AU2020200092A1 (en) | 2020-01-30 |
JP6615612B2 (ja) | 2019-12-04 |
CA2891967A1 (en) | 2014-06-05 |
GB2508414A (en) | 2014-06-04 |
JP2015536665A (ja) | 2015-12-24 |
CN104853765B (zh) | 2019-06-28 |
US20150307585A1 (en) | 2015-10-29 |
AU2013351062B2 (en) | 2018-03-22 |
US10683336B2 (en) | 2020-06-16 |
AU2013351062A1 (en) | 2015-06-04 |
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