CN115103852A - Prame tcr受体和其用途 - Google Patents
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- CN115103852A CN115103852A CN202080087410.8A CN202080087410A CN115103852A CN 115103852 A CN115103852 A CN 115103852A CN 202080087410 A CN202080087410 A CN 202080087410A CN 115103852 A CN115103852 A CN 115103852A
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Abstract
本发明涉及能够结合具有氨基酸序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA‑A2结合形式的PRAME肽的T细胞受体(TCR)。本发明还包括编码TCR的核酸、包含所述核酸的载体和包含所述TCR、所述核酸序列或所述载体的宿主细胞。还包括获得本文所述的TCR的方法、药物或诊断组合物以及在体外检测受试者中癌症的存在的方法。此外,本发明涉及TCR、核酸和/或载体用于产生修饰的淋巴细胞的用途。
Description
技术领域
本发明涉及能够结合具有氨基酸序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式的PRAME肽的T细胞受体(TCR)。本发明还包括编码所述TCR的核酸、包含所述核酸的载体和包含所述TCR、所述核酸序列或所述载体的宿主细胞。还包括获得本文所述的TCR的方法;包含TCR、核酸、载体和/或宿主细胞的药物或诊断组合物;以及在体外检测受试者中癌症的存在的方法,包含TCR、宿主细胞和/或药物组合物。此外,本发明涉及TCR、核酸和/或载体用于产生修饰的淋巴细胞的用途。
背景技术
形成细胞介导的免疫系统的一部分的T淋巴细胞(或T细胞)在根除病原体中起重要作用。T细胞在胸腺中发育并在它们的表面上表达T细胞受体分子,从而容许识别在有核细胞上表达的主要组织相容性复合体(MHC)分子上呈递的肽(抗原呈递)。病原体的抗原即由MHC分子呈递的外源抗原将引发强有力的T细胞应答,而自身抗原通常不会导致T细胞应答,这是因为在所述T细胞的发育期间胸腺中对自身抗原具有特异性的T细胞的负向选择。因此,免疫系统可区分呈递外源抗原或自身抗原的有核细胞,并通过T细胞的强效细胞因子释放和细胞毒性机制特异性靶向和根除感染细胞。
免疫系统的能力已被识别为未来癌症疗法的有前景的工具。在过去的十年里,研究已经开始通过使用过继性细胞转移(ACT)来开发T细胞的独特性质,过继性细胞转移包括施用离体扩增的供体源淋巴细胞。ACT是用于治疗癌症的有吸引力的概念,因为其不需要患者的免疫能力,并且转移的淋巴细胞的特异性可靶向非突变的且因此免疫原性差的肿瘤抗原,所述肿瘤抗原通常不能有效地触发自身T细胞应答。尽管ACT已显示是各种类型的癌症的有前景的治疗,但其作为临床治疗的广泛应用因需要从每个患者中定制分离和表征肿瘤特异性T细胞而受到阻碍,所述定制分离和表征可为困难且耗时的、并且也经常无法产生高亲和力T细胞的过程(Xue等人,Clin Exp Immunol.2005年2月;139(2):167-172;Schmitt等人,Hum Gene Ther.2009年11月;20(11):1240-1248)。
肿瘤抗原特异性T细胞受体(TCR)向原代T细胞的遗传转移可克服ACT目前的一些局限性,因为其容许快速产生具有定义的抗原特异性的肿瘤反应性T淋巴细胞,即使在免疫受损的患者中也是如此。然而,鉴定携带特异性识别肿瘤抗原并在体内展现所需抗肿瘤效应的TCR的合适的T细胞克隆仍是正在进行的研究主题。考虑到2012年全球发生约1410万新的癌症病例且癌症目前是全世界约14.6%的所有人类死亡的病因,迫切需要新颖且高效的治疗选择。本发明的目的是满足上述需要。
PRAME是在众多种肿瘤(优选黑色素瘤)中表达的肿瘤相关抗原。此外,PRAME已描述为诸如葡萄膜黑色素瘤的转移的独立生物标记(Fiedl等人,Clin Cancer Res 2016年3月;22(5):1234-1242)并描述为DLBCL的预后标记(Mitsuhashi等人,Hematology 2014,1/2014)。其在除睾丸外的正常组织中不表达。这种表达模式与其它癌症睾丸(CT)抗原(诸如MAGE、BAGE、GAGE)的表达模式相似。然而,与这些其它CT抗原不同,这种基因也在急性白血病中表达。编码的蛋白用作视黄酸受体的阻遏物,并可能通过这种功能赋予癌细胞生长优点。选择式剪接导致多种转录物变体。还发现PRAME在三阴性乳腺癌中的过表达通过诱导上皮-至-间质转化促进癌细胞运动(Al-Khadairi等人,Journal of TranslationalMedicine 2019;17:9)。已报道在慢性淋巴细胞性白血病中缺失PRAME,然而,这与功能无关,这是因为基因在B细胞中不表达,并且缺失是生理性免疫球蛋白轻链重排的结果。
发明内容
本发明涉及能够特异性识别肿瘤相关抗原PRAME的新颖T细胞受体(TCR)。具体来说,鉴定的TCR特异性识别PRAME氨基酸序列SLLQHLIGL,在本文中也称为PRAMESLL肽。本发明至少部分地基于如下令人惊讶的发现:当与现有技术中已知的PRAME TCR相比时,针对特异性PRAME肽结合的所述分离的T细胞受体具有突出的性质。具体地,能够与PRAME肽SLLQHLIGL结合的本发明的T细胞受体还提供高功能亲合力以及有利的肿瘤细胞识别和杀伤性质。与之相反,所述TCR不识别正常细胞和不相关的肽。此外,T细胞受体识别HLA分子(人类白细胞抗原,HLA)上并且尤其是由HLA亚等位基因HLA-A*02:01、HLA-A*02:02和HLA-A*02:04编码的HLA分子上呈递的肽,甚至容许治疗表达频率较低的呈递PRAMESLL的HLA-A*02等位基因的癌症患者。
在第一方面,本发明涉及能够结合具有氨基酸序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式的PRAME肽的T细胞受体(TCR),其中TCR包括:TCRα链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:6)或与SEQ ID NO:6具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;和/或TCRβ链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:7)或与SEQ ID NO:7具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成。
另一方面,本发明涉及能够结合具有氨基酸序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式的PRAME肽的T细胞受体(TCR),其中TCR包括:
a)TCRα链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:6)或与SEQ ID NO:6具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;TCRα链可变区的CDR1,其包含氨基酸序列SEQ ID NO:2或由所述氨基酸序列组成,以及TCRα链可变区的CDR2,其包含氨基酸序列SEQ ID NO:4或由所述氨基酸序列组成;和
b)TCRβ链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:7)或与SEQ ID NO:7具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;TCRβ链可变区的CDR1,其包含氨基酸序列SEQ ID NO:3或由所述氨基酸序列组成;以及TCRβ链区的CDR2,其包含氨基酸序列SEQ ID NO:5或由所述氨基酸序列组成。
设想HLA-A2是HLA-A*02:01、HLA-A*02:02或HLA-A*02:04编码分子。
具体来说,设想TCR与序列SLLQHLIGL(SEQ ID NO:1)或其优选功能部分或它的HLA-A2结合形式的结合诱导用TCR转导或转染的细胞的IFN-γ分泌。
优选地,如通过IFN-γ免疫测定法测量,半最大相对IFN-γ分泌(EC50值)小于10- 7M。
还设想本发明的TCR包括:
a)TCRα链,其包含具有氨基酸序列SEQ ID NO:2的CDR1、具有氨基酸序列SEQ IDNO:4的CDR2和具有氨基酸序列SEQ ID NO:6的CDR3,和/或
b)TCRβ链,其包含具有氨基酸序列SEQ ID NO:3的CDR1、具有氨基酸序列SEQ IDNO:5的CDR2和具有氨基酸序列SEQ ID NO:7的CDR3。
鉴于本发明,本文提及的TCR可包括TCRα链可变区,其包含氨基酸序列SEQ ID NO:8或由所述氨基酸序列组成;和/或TCRβ链可变区,其包含氨基酸序列SEQ ID NO:9或由所述氨基酸序列组成。
还设想本发明的TCR包括TCRα链恒定区和/或TCRβ链恒定区。
优选地,本发明的TCR包括
a)TCRα链,其包含选自SEQ ID NO:10的氨基酸序列;或与SEQ ID NO:10具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;和/或
b)TCRβ链,其包含选自SEQ ID NO:11的氨基酸序列;或与SEQ ID NO:11具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成。
还设想本发明的TCR包括彼此共价连接以形成TCR异源二聚体或多聚体的至少一个TCRα链和至少一个TCRβ链。
鉴于本发明,设想本文提及的TCR可选自初始TCR、TCR变体、TCR片段或TCR构建体。
在一些实施方案中,本发明的TCR包括任选地选自以下的一种或多种融合组分;Fc受体;Fc结构域,包括IgA、IgD、IgG、IgE和IgM;细胞因子,包括IL-2或IL-15;毒素;抗体或其抗原结合片段,包括抗CD3、抗CD28、抗CDS、抗CD16或抗CD56抗体或其抗结合片段;CD247(CD3-ζ)、CD28、CD137或CD134结构域,或它们的组合,任选地还包括至少一个接头。
本文提及的TCR优选包括至少一个如本文定义的TCRα链;和/或至少一个如本文定义的TCRβ链;和/或针对淋巴细胞表面上的抗原或表位的抗体或单链抗体片段(scFv),其中TCRα链和TCRβ链彼此连接并任选地通过接头与所述抗体或scFv融合。所述抗原可选自CD3、CD28、CD5、CD16或CD56。
本发明的TCR优选包括至少一种分子标记。优选地,本发明的TCR是可溶性的。
另一方面,本发明涉及编码本文提及的TCR的核酸。
所述核酸可包含SEQ ID NO:13、14、15、16、17、18、19、20、21或22的核酸序列。
另一方面,本发明涉及包含本文定义的核酸的载体。
另一方面,本发明涉及包含本文定义的TCR、本文定义的核酸序列或本文定义的载体的宿主细胞。宿主细胞可选自淋巴细胞,包括但不限于细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞。
另一方面,本发明涉及获得本文定义的TCR的方法,其中所述方法包括在引起所述TCR表达的条件下孵育本文定义的宿主细胞,并纯化所述TCR。
另一方面,本发明涉及药物或诊断组合物,其包含以下中的一种或多种:本文定义的TCR;本文定义的核酸;本文定义的载体;和/或本文定义的宿主细胞,以及任选地药物赋形剂。药物组合物还可包含检查点抑制剂。所述检查点抑制剂可选自由以下组成的组:CTLA-4抑制剂、PD-1抑制剂和PD-L1抑制剂、LAG3、ICOS、TIM3、VISTA和CEACAM1抑制剂。
另一方面,本发明涉及用作药物的本文定义的TCR、本文定义的核酸、本文定义的载体和/或本文定义的宿主细胞。优选地,用途是癌症的检测、诊断、预后、预防和/或治疗。在这方面,设想癌症选自由以下组成的组:黑色素瘤、膀胱癌、结肠癌和乳腺癌、肉瘤、前列腺癌、子宫癌、葡萄膜癌、葡萄膜黑色素瘤、鳞状头颈癌、滑膜癌、尤因氏肉瘤(Ewing’ssarcoma)、三阴性乳腺癌、甲状腺癌、睾丸癌、肾癌、胰脏癌、卵巢癌、食管癌、非小细胞肺癌、非霍奇金氏淋巴瘤(non-Hodgkin’s lymphoma)、多发性骨髓瘤、黑色素瘤、肝细胞癌、头颈癌、胃癌、子宫内膜癌、结肠直肠癌、胆道癌、乳腺癌、膀胱癌、骨髓性白血病和急性淋巴母细胞性白血病,优选其中癌症选自由以下组成的组:NSCLC、SCLC、乳腺癌、卵巢癌或结肠直肠癌、肉瘤或骨肉瘤。
此外,设想如本文定义的TCR、核酸、载体和/或宿主细胞在预防和/或治疗癌症中的用途包括:
(a)提供以下中的一种或多种:(i)本文其它地方描述的TCR;(ii)本文其它地方描述的核酸;(iii)本文其它地方描述的载体;(iv)本文其它地方描述的宿主细胞;和(v)本文其它地方描述的药物组合物;和
(b)将(i)至(v)中的至少一种施用给有需要的受试者。
优选地,如本文定义的用于预防和/或治疗癌症的TCR、核酸、载体和/或宿主细胞包括:
(a)提供受试者的样品,所述样品包含淋巴细胞;
(b)提供以下中的一种或多种:(i)本文其它地方描述的TCR;(ii)本文其它地方描述的核酸;(iii)本文其它地方描述的载体;(iv)本文其它地方描述的宿主细胞;和(v)本文其它地方描述的药物组合物;
(c)将步骤(b)的(i)至(v)中的一种或多种引入步骤(b)的淋巴细胞中,从而获得修饰的淋巴细胞,
(d)将步骤(c)的修饰的淋巴细胞施用给有需要的受试者或患者。
另一方面,本发明涉及体外检测受试者中的癌症的存在的方法,所述方法包括:
(a)提供受试者的样品,所述样品包含一种或多种细胞;
(b)使所述样品与以下接触:(i)本文其它地方描述的TCR;(ii)本文其它地方描述的宿主细胞;和/或(iii)本文其它地方描述的药物组合物;从而形成复合体,以及
(c)检测所述复合体,其中检测到所述复合体指示所述受试者中癌症的存在。
另一方面,本发明涉及本文定义的TCR、本文定义的核酸和/或本文定义的载体用于产生修饰的淋巴细胞的用途。
附图说明
图1:肽特异性。向T2细胞负载特异性SLL(SLLQHLIGL)或不相关肽(GLSNTHVL)。然后将这些细胞与TCR转导的T细胞共培养。20小时后,使用IFN-γELISA测量细胞培养上清液中的IFN-γ水平。当负载到T2细胞上时,除阴性对照TCR外的所有TCR转导的效应细胞TCR都显示可识别特异性SLL肽,但不识别不相关肽。
图2:功能亲合力。TCR转基因T细胞群体的功能亲合力测量为在与负载有滴定量的SLL肽(10-5M至10-12M)的T2细胞的共培养物中的半最大相对IFN-γ释放(EC50值)。用TCR027-004转导的细胞显示出比TCR 3825转导的T细胞更高的功能亲合力。
图3A和图3B:TCR识别基序(丝氨酸扫描)。效应物:靶(E:T)比率为1:1(10.000个效应细胞/96孔)的TCR转导的T细胞与负载10-5M肽的T2细胞的体外共培养物。为此,向T2细胞负载仅在一个氨基酸位置变化的肽,所述氨基酸位置由氨基酸丝氨酸连续取代。与TCR克隆3825转导的T细胞(图3B)相比,用TCR 027-004TCR转导的T细胞(图3A)显示具有较少固定位置的不同识别基序。
图4:肿瘤细胞识别。两种TCR转导的T细胞群体(用TCR 027-004或3825转导)均识别PRAMESLL阳性肿瘤细胞系。与3825 TCR转导的T细胞相比,027-004TCR转导的T细胞对PRAMESLL阳性细胞系的识别更高。所测试的TCR中的任一个都不识别PRAMESLL阴性肿瘤细胞。
图5:肿瘤细胞杀伤。所有TCR转导的效应细胞均裂解PRAMESLL阳性(PRAME-pos)肿瘤细胞,且不影响PRAMESLL阴性肿瘤细胞(PRAME-neg)的生长。与用TCR 3825转导的T细胞相比,用TCR 027-004转导的效应细胞显示更好的PRAMESLL阳性细胞系杀伤。
图6:正常细胞识别。TCR转导的T细胞群体不识别未负载的正常细胞,使得分泌高水平的IFN-γ。然而,如果细胞负载有特定PRAMESLL肽,则它们就会被TCR 027-004识别。仅与未负载细胞系RPTEC(内源性PRAME阳性细胞系)的共培养在两种效应物制剂中产生最少IFN-γ。
图7:HLA-A*02等位基因频率。美国/欧洲高加索人群体的等位基因频率(http://www.allelefrequencies.net)。
图8:TCR 027-004的HLA-A*02精细分型。效应物:靶(E:T)比率为1:2(10.000个效应细胞/96孔)的用TCR 027-004转导的T细胞与选择的HLA-A2亚等位基因阳性成淋巴细胞样细胞系(LCL;EBV转变的B细胞)的体外共培养物。所有单独LCL均负载SLL肽(10-5M),以确定独特TCR亚等位基因识别。未负载的靶细胞用作阴性对照。共培养20小时后,使用标准ELISA确定IFN-γ分泌。TCR 027-004高效地识别由10个测试的HLA-A2亚等位基因(A*02:xx)中的3个所呈递的PRAME肽,HLA-A*02亚等位基因A*02:02和A*02:04以与A*02:01相比相当的水平识别。
图9:TCR 3825的HLA-A*02精细分型。E:T比率为1:2(10.000个效应细胞/96孔)的用TCR 3825转导的T细胞与选择的HLA-A*02亚等位基因阳性成淋巴细胞样细胞系(LCL;EBV转变的B细胞)的体外共培养物。所有单独LCL均负载SLL肽(10-5M),以确定独特TCR亚等位基因识别。未负载的靶细胞用作阴性对照。共培养20小时后,使用标准ELISA确定IFN-γ分泌。
对照TCR 3825高效地识别10个测试的HLA-A2亚等位基因(A*02:xx)中的1个所呈递的PRAME肽,即仅识别HLA-A2亚等位基因A*02:01。
图10:图8和图9中所示的结果的汇总。
图11:TCR转导后的效应细胞扩增。在转导当天以及随后在扩增13天后使用血细胞计数器确定效应细胞的细胞数。每个图代表一个供体。TCR ImCorePrefCombi1未显示效应细胞扩增,且因此无法纳入进一步实验。
图12:TCR T23.8-2.1027-004具有与现有技术的TCR不同的识别基序。将TCR转导的效应物(效应细胞)与负载有PRAME-SLL-肽(最右侧)或具有苏氨酸的单个氨基酸取代的SLL-肽变体的T2细胞共培养。作为读出,20小时后收获上清液,并通过IFN-γELISA进行分析。每个图代表一个TCR。X轴上的字母指示氨基酸取代的位置。识别基序的“固定”位置由X轴上的方框突出显示。TCR 46SLL未显示对负载有原始PRAME-SLL肽的T2细胞的识别,且TCRImCore_Scaffold显示对负载有PRAME-SLL的T2细胞的识别降低。为免生疑问,应注意,在本说明书中,本发明的TCR缩写为TCR 027-004,其中全名为TCR T23.8-2.1-027-004。
图13:TCR T23.8-2.1-027-004转导的效应物具有比用现有技术的TCR转导的效应物更高的功能亲合力。将TCR T23.8-2.1-027-004转导的效应物(黑色)和其它TCR转导的效应物(灰色)与负载有滴定量的PRAME-SLL肽的T2细胞共培养。作为读出,20小时后收获上清液,并通过IFN-γELISA进行分析。用虚线指示半最大IFN-γ分泌所需的肽浓度。该图显示代表O.D.值的非线性回归曲线。使用非线性回归分析计算不同TCR转导的效应物的EC50值。每个图代表现有技术的TCR与TCR T23.8-2.1-027-004的比较。
图14:T23.8-2.1-027-004转导的效应物比用现有技术的TCR转导的效应物更强地识别HLA-A*02:01/PRAME双阳性肿瘤细胞系。将用六种不同TCR转导的效应物以及未转导的对照效应物与HLA-A*02:01/PRAME双阳性肿瘤细胞系MeIA375、NCI-H1650和NCI-H1703共培养。20小时后取共培养物的上清液,并通过ELISA分析以确定IFN-γ分泌。
图15:T23.8-2.1-027-004转导的效应物比用现有技术的TCR转导的效应物更有效地介导PRAME阳性肿瘤细胞的裂解。将接种在96孔平底板中的NuclightRed转导的肿瘤细胞系MeIA375和NCI-H1650(HLA-A*02:01阳性/PRAME阳性)与未转导的效应物(以灰色表示)、T23.8-2.1-027-004转导的效应物(黑色圆圈)或用其它TCR转导的效应物共培养144小时。红色荧光的损失使肿瘤细胞凋亡可视化。未转导的效应物用作阴性对照。显示一式三份随时间的红细胞计数(1/mm2)。
具体实施方式
本发明的发明人已经鉴定能够识别表达肿瘤相关抗原PRAME(如SEQ ID NO:33中所绘示的全长PRAME)且尤其氨基酸序列SLLQHLIGL(SEQ ID NO:1)(在本文中也称为PRAMESLL)的细胞的T细胞受体(TCR)克隆。该序列以特定方式被识别,而不相关肽无法被识别(图1)。所述特异性通过仅PRAME阳性癌细胞系的识别来表达(图4和图5),而PRAME阴性和未负载的正常细胞不被所述TCR受体识别。然而,当负载有PRAMESLL肽时,将识别正常细胞(图6)。这种选择性识别可通过T细胞受体的识别基序获得,从而仅显示少数固定位置(图3)。序列SLLQHLIGL(SEQ ID NO:1)的氨基酸LLQ且尤其HLI是该识别基序的一部分。这些氨基酸展现有利的效应物功能,诸如对PRAME肽的多重亲和力(例如功能性亲和力,图2)的高累积强度。
总之,本发明人鉴定的T细胞受体能够特异性识别表达肿瘤相关抗原(TAA)PRAME且特别是PRAMESLL的细胞。所述TCR展现有利的效应物功能,诸如细胞因子产生和靶细胞的细胞溶解。因此,所述T细胞受体是用于高度特异性和有效的癌症治疗的有前景的工具。因此,鉴定的PRAME特异性TCR适用于癌症的过继性T细胞疗法。上述情况容许T细胞离体武装并重新引入供体,在供体中,它们可有效识别并特异性消除表达PRAME的癌细胞(图4和图5)。在这种背景下,识别不同HLA亚等位基因可有利于能够将不同亚等位基因类型的患者纳入覆盖世界群体的不同频率的研究队列(图7)。本文所述的TCR受体识别HLA-A*02:01,以及HLA-A*02:02和HLA-A*02:04编码分子(图8至图10)。因此,对患有表达PRAME的肿瘤的大的癌症患者群体而言,这是一种潜在的癌症治疗。此外,本文提供的新颖TCR的抗原结合区可用于设计包含易于直接施用的其它功能部分(诸如药物、标记或吸引其它免疫细胞的其它结合结构域)的可溶性构建体。
为了根据现有技术进一步证明本发明的TCR的作用,本发明人将TCR识别基序、肿瘤细胞识别、功能亲合力和杀伤能力与从本领域已知的TCR进行比较。选择来自WO2016142783的两种TCR(46SLL和54SLL)、来自WO2018234319的两种TCR(ImCore_Scaffold和ImCorePrefCombi1)以及在WO2018172533中描述的另外两种TCR(R11P3D3和R11P3D3_KE)。表2提供这些选择的克隆及其相应出版物的综述。
从图11可明显看出,TCR ImCorePrefCombi1未显示效应细胞扩增,且因此无法纳入后续实验。在苏氨酸扫描中分析选择的TCR(图12),这可证明形成相应识别基序的氨基酸的不同组成。重要的是,在相同的实验设置中,没有一个选择的TCR在低于本发明的TCR(T23.8-2.1-027-004)的肽浓度下达到相对IFN-γ释放的EC50值。在图13中,现有技术中表现最佳的TCR的EC50值针对本发明的TCR作图。本文所述的TCR T23.8-2.1-027-004在1.16×10-8M的肽浓度下达到EC50值,而与之相比,TCR 54SLL为3.57×10-8M,TCR ImCore_Scaffold为1.31×10-7M。其它TCR的表现并不像本发明的TCR一样好;它们在8.27×10-8M(R11P3D3)和5.73×10-8M(R11P3D3_KE)的肽浓度下达到它们的EC50值。因此,本发明的TCR比现有技术的TCR引发更高的功能亲合力。
为了进一步研究肿瘤细胞识别,将三种表达PRAME的肿瘤细胞系与用不同TCR转导的效应细胞共培养,并在共培养20小时后测量相应IFN-γ释放(图14和表3)。用本发明的TCR转导的效应细胞在与肿瘤细胞系MeIA375、NCI-H1650和NCI-H1703共培养后显示最高的IFN-γ释放。
最后,使用表达PRAME的肿瘤细胞系MeIA375_NuclightRed和NCI-H1650_NuclightRed以分析肿瘤细胞杀伤。如图15和表4中所示,用本发明的TCR转导的效应细胞比用其它现有技术的TCR转导的效应细胞更有效地裂解肿瘤细胞。
从上文提及的数据可得出结论,本发明的TCR具有比现有技术中公开的TCR更高的功能亲合力,最能识别测试的肿瘤细胞系,并且更高效地裂解PRAME阳性肿瘤细胞。
可变区
CDR3结构域
在第一方面,本发明涉及能够结合具有氨基酸序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式的PRAME肽的T细胞受体(TCR),其中TCR包括:TCRα链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:6)或由所述氨基酸序列组成;和/或TCRβ链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:7)或由所述氨基酸序列组成。进一步设想TCR序列变体,所述TCR序列变体包含CDR3α,其包含与SEQ ID NO:6具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列或由所述氨基酸序列组成;和/或CDR3β,其包含与SEQ ID NO:7具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列或由所述氨基酸序列组成,条件是TCR保留在所附实施例中评估的TCR的有利能力,即能够结合本文指定的抗原性靶。
如本文使用的术语“T细胞受体”或“TCR”包括所有语法形式的初始TCR以及TCR变体、片段和构建体。因此,所述术语包括包含TCRα和β链的异源二聚体以及多聚体和单链构建体;任选地包含另外的结构域和/或部分。
TCR以其自然形式作为几种蛋白的复合体存在于T细胞表面上。T细胞受体由两条(独立的)蛋白链构成,所述蛋白链由独立的T细胞受体α和β(TCRα和TCRβ)基因产生并且称为α(α-)和β(β-)链。TCR的每条链具有一个N-末端免疫球蛋白样(Ig)-可变(V)结构域/区、一个Ig-恒定样(C)结构域/区、将链锚定在质膜中的跨膜/跨细胞膜区以及C-末端的短胞质尾区。
抗原特异性是由α和β链的可变区赋予。TCRα链和β链的可变结构域两者均包含三个由框架(FR)区包围的超变或互补决定区(CDR1α/β、CDR2α/β和CDR3α/β)。CDR3是抗原识别和特异性(即识别特定抗原并与之相互作用的能力)的主要决定因素,而CDR1和CDR2主要与呈递抗原肽的MHC分子相互作用。
本文提供的TCR能够识别并特异性识别PRAME,特别是呈其MHC结合形式的PRAME,如将在本文其它地方详细讨论。当抗原肽与MHC分子形成复合体(其可存在于抗原呈递细胞(诸如树突细胞或肿瘤细胞)的表面上,或其可通过例如包被于珠或板上而固定)时,该抗原肽称为以其“MHC结合形式”存在。
初始TCR识别与抗原呈递细胞表面的主要组织相容性复合体(MHC)分子结合(“呈递/展示于其上”)的抗原肽。在MHC分子上呈递的抗原性肽在本文中也称为“肽:MHC复合体”。存在两个不同类别的MHC分子:MHC I和MHC II,其呈递来自不同细胞隔室的肽。MHC I类分子在人体的所有有核细胞的表面上表达,并从细胞内隔室向细胞毒性T细胞展示肽或蛋白片段。在人类中,MHC也称为人类白细胞抗原(HLA)。存在三种主要类型的MHC I类:HLA-A、HLA-B和HLA-C。一旦TCR与其特异性肽:MHC复合体结合,T细胞就会被激活并发挥生物效应物功能。
术语“结合”和“识别”以所有语法形式在本文中可互换使用。特别设想抗原性靶当由MHC I类分子、特别是HLA-A分子、优选HLA-A*02分子结合时,可被本发明的TCR识别。具体来说,当由HLA-A*02:01、HLA-A*02:02或HLA-A*02:04等位基因编码的HLA-分子呈递时,抗原性靶被本发明的TCR识别。所述MHC分子即由HLA-A*02:01、HLA-A*02:02和HLA-A*02:04等位基因编码的分子,可在细胞表面、例如肿瘤细胞表面上或在(固体)载体上呈递。在本发明的上下文中,特别设想PRAMESLL肽当由HLA-A2(其是HLA-A*02:01、HLA-A*02:02或HLA-A*02:04编码分子)结合时,可被本发明的TCR识别。在本发明的一优选实施方案中,TCR当由HLA-A*02:01、HLA-A*02:02和HLA-A*02:04编码分子结合时,可特异性识别PRA MESLL肽,即能够结合所有三种HLA-A*02等位基因编码分子。这意味着,本发明的TCR能够结合由HLA等位基因HLA-A*02:01、HL A-A*02:02和HLA-A*02:04编码的每个分子。然而,并未设想在一名患者中同时识别所有HLA-A2分子,而是将其理解为替代物。
CDR1和CDR2结构域
如前所述,认为TCRα和β链的CDR1和CDR2主要参与MHC识别。存在已知参与HLA-A*02限制性抗原识别的CDR1和CDR2序列的限制“库(pool)”,并且设想本发明的CDR3结构域原则上可与SEQ ID NO:2至5中绘示的CDR1和CDR2结构域中的任一个组合,条件是TCR保留其识别其抗原性靶、优选呈其HLA-A*02(HLA-A*02:01、HLA-A*02:02和HLA-A*02:04)结合形式的能力,与实施例中评估的TCR 3825的程度相似、相同或甚至更高。CDR1和CDR2结构域的有用实例包括CDR1α,其包含如SEQ ID NO:2中所绘示的序列或由所述序列组成;CDR2α,其包含如SEQ ID NO:4中所绘示的序列或由所述序列组成;CDR1β,其包含如SEQ ID NO:3中所绘示的序列或由所述序列组成;以及CDR2β,其包含如SEQ ID NO:5中所绘示的序列或由所述序列组成。所述CDR序列也示于表1中。
根据上文,本发明尤其提供包含两条多肽链的TCR,每条多肽链包含人类可变区,所述人类可变区包含TCR的至少一个互补决定区(即,具体来说CDR3,且优选地CDR1和/或CDR2)。具有特别有利性质的TCR(如所附实施例中所示)包含第一多肽链,所述第一多肽链包括包含氨基酸序列SEQ ID NO:2或由所述氨基酸序列组成的CDR1(CDR1α)、包含氨基酸序列SEQ ID NO:4或由所述氨基酸序列组成的CDR2(CDR2α)以及包含氨基酸序列SEQ ID NO:6或由所述氨基酸序列组成的CDR3(CDR3α);和/或第二多肽链,所述第二多肽链包括包含氨基酸序列SEQ ID NO:3或由所述氨基酸序列组成的CDR1(CDR1β)、包含氨基酸序列SEQ IDNO:5或由所述氨基酸序列组成的CDR2(CDR2β)以及包含氨基酸序列SEQ ID NO:7或由所述氨基酸序列组成的CDR3(CDR3β)。
进一步设想本发明TCR的TCR序列变体,其包含CDR 1α,所述CDR 1α包含与SEQ IDNO:2具有至少约60%同一性、优选与SEQ ID NO:2具有至少约80%同一性的氨基酸序列或由所述氨基酸序列组成;和/或CDR 1β,所述CDR 1β包含与SEQ ID NO:3具有至少约60%同一性、优选与SEQ ID NO:3具有至少80%同一性的氨基酸序列或由所述氨基酸序列组成,条件是TCR保留在所附实施例中评估的TCR的有利能力,即能够结合本文指定的抗原性靶。进一步设想本发明TCR的TCR序列变体,其包含CDR 2α,所述CDR 2α包含与SEQ ID NO:4具有至少约70%同一性、优选与SEQ ID NO:4具有至少约85%同一性的氨基酸序列或由所述氨基酸序列组成;和/或CDR 2β,所述CDR 2β包含与SEQ ID NO:5具有至少约65%同一性、优选与SEQ ID NO:5具有至少80%同一性的氨基酸序列或由所述氨基酸序列组成,条件是TCR保留在所附实施例中评估的TCR的有利能力,即能够结合本文指定的抗原性靶。
完整可变区
本发明进一步提供TCR,所述TCR包括TCRα链可变区,其包含如SEQ ID NO:8中所绘示的氨基酸序列或由所述氨基酸序列组成;和/或TCRβ链可变区,其包含如SEQ ID NO:9中所绘示的氨基酸序列或由所述氨基酸序列组成。所述α和β链序列也示于表1中。
本文还设想TCR序列变体,所述TCR序列变体包含α链可变区,其包含与SEQ ID NO:8具有至少80%同一性、更优选至少85%同一性、更优选90%或95%同一性的氨基酸序列;和/或TCRβ链可变区,其包含与SEQ ID NO:9具有至少80%同一性、更优选至少85%同一性、更优选90%或95%同一性的氨基酸序列或由所述氨基酸序列组成;条件是TCR保留在所附实施例中评估的TCR的有利能力,即能够结合本文指定的抗原性靶。
恒定区
本发明的TCR包括α链恒定区和/或TCRβ链恒定区。恒定区可为人类恒定区或源自另一物种,从而产生“嵌合”TCR。例如,人类α链和/或β链可由它们的鼠类对应物替代(“鼠类化”),已发现这通过支持TCRα和β链的优先配对以及与CD3辅受体的更稳定的缔合来增强人类TCR的表面表达。α链的合适的恒定区可例如选自SEQ ID NO:26(人类)、SEQ ID NO:29(最小鼠类化)和SEQ ID NO:31(鼠类)。β链的合适的恒定区可选自SEQ ID NO:27(人类)、SEQID NO:28(人类)、SEQ ID NO:30(最小鼠类化)和SEQ ID NO:32(鼠类)。SEQ ID NO:27和28中绘示的TCRβ恒定区是有几个氨基酸不同的两种人类序列。应将其理解为替代物。代替完整人类恒定区由它们的鼠类对应物替代,也可仅用人类恒定区中的一些氨基酸交换鼠类恒定区的相应氨基酸(“最少鼠类化”),如本文“TCR序列变体”部分中进一步解释的。此外,本发明设想,恒定区和可变区可以适合于目的的方式组合。在这种情况下,恒定区和可变区可源自人类、小鼠,或通过上述最小鼠类化过程获得。
α及β链
本发明的TCR的有用实例包括包含以下的那些TCR:α链,其包含如SEQ ID NO:10中所绘示的氨基酸序列或由所述氨基酸序列组成,和/或β链,其包含如SEQ ID NO:11中所绘示的氨基酸序列或由所述氨基酸序列组成。
本文还设想TCR序列变体,所述TCR序列变体包含α链,其包含与SEQ ID NO:10具有至少80%同一性、更优选至少85%同一性、更优选90%或95%同一性的氨基酸序列;和/或TCRβ链,其包含与SEQ ID NO:11具有至少80%同一性、更优选至少85%同一性、更优选90%或95%同一性的氨基酸序列或由所述氨基酸序列组成;条件是TCR保留在所附实施例中评估的TCR的有利能力,即能够结合本文指定的抗原性靶。
抗原性靶
本文提供的TCR有利地能够结合(人类)PRAME(SEQ ID NO:1),也称为PRAMESLL。因此,所述TCR对如SEQ ID NO:1中所绘示的PRAME肽、也称为PRAMESLL是特异性的。术语“对……是特异性的”在本发明的上下文中意指TCR特异性结合靶。PRAME(黑色素瘤中优先表达的抗原,Uniprot登录号P78395)也称为MAPE(在肿瘤中优先表达的黑色素瘤抗原)和OIP4(OPA相互作用蛋白4),已报道为功能未知的睾丸癌抗原(CTA)。PRAME是与黑色素瘤、白血病和慢性髓性白血病相关的蛋白编码基因。与该基因相关的基因本体(GO)注释包括视黄酸受体结合。PRAME蛋白作为转录阻遏物发挥作用,从而抑制视黄酸通过视黄酸受体RARA、RARB和RARG的信号传导。其防止视黄酸诱导的细胞增殖、分化和细胞凋亡的停滞。
优选地,本发明的TCR特异性结合其抗原性靶。具体来说,本发明提供能够结合包含在如SEQ ID NO:1中所绘示的PRAME氨基酸序列中的肽的TCR(参见表1)。术语“能够结合”意指所述肽由所述TCR特异性结合。术语“特异性(特异性地)结合”通常指示TCR通过其抗原结合位点与其预期的抗原性靶的结合比与随机、不相关的非靶抗原的结合更容易。特别地,术语“特异性结合”指示TCR对其抗原性靶的结合特异性是其对非靶抗原的结合特异性的至少约5倍、优选10倍、更优选25倍、甚至更优选50倍且最优选100倍或更多。由如SEQ ID NO:1中所绘示的氨基酸序列组成的PRAME肽在本文中也被称为“抗原性靶”或“SLL肽”。因此,由如SEQ ID NO:1中所绘示的氨基酸序列组成的PRAME肽序列是或包含本发明的TCR的靶向表位。
术语“表位”通常是指结合结构域识别的抗原、通常(多)肽上的位点。术语“结合结构域”在其最广泛的意义上是指“抗原结合位点”,即表征与抗原性靶上的特定表位结合/相互作用的分子的结构域。抗原性靶可包括单个表位,但通常包括至少两个表位,并且可包括任何数量的表位,这取决于抗原的大小、构象和类型。术语“表位”通常包括线性表位和构象表位。线性表位是包含在氨基酸一级序列中的邻接表位,并且通常包括至少2个或更多个氨基酸。构象表位是由通过靶抗原(特别是靶(多)肽)的折叠而并置的非邻接氨基酸形成。
本发明人已发现由本发明的TCR识别的最小氨基酸序列对应于PRAME的氨基酸序列(SEQ ID NO:1)。具体来说,如所附实施例中所示,本发明的TCR已显示可(特异性地)识别包含氨基酸序列SLLQHLIGL(SEQ ID NO:1)或它的HLA-A2结合形式或由其组成的氨基酸序列。这种选择性识别可通过T细胞受体的识别基序获得,从而仅显示少数固定位置(图3)。序列SLLQHLIGL(SEQ ID NO:1)的氨基酸LLQ且尤其HLI是该识别基序的一部分。具体来说,设想本文所述的TCR识别上文所提到的氨基酸序列内的至少一个表位。此外,本发明的TCR具有与本领域已知的其它TCR的识别模式显著不同的识别基序(图12)。
设想如本文所述的初始TCR以高功能亲合力结合其抗原性靶(即优选地通过抗原呈递细胞在HLA-A*02:01-、HLA-A*02:02-或HLA-A*02:04编码分子上呈递的PRAME)。术语“功能亲合力”是指TCR表达细胞(特别是如本文所述的表达初始TCR的T细胞)对给定浓度的配体进行体外应答的能力,并且被认为与TCR表达细胞的体内效应物能力相关。根据定义,具有高功能亲合力的TCR表达细胞在体外测试中对非常低的抗原剂量有应答,而具有较低功能亲合力的所述细胞在产生类似于高亲合力TCR表达细胞的免疫应答的免疫应答之前需要更高量的抗原。因此,可将功能亲合力视为TCR表达细胞的激活阈值的定量决定因素。其通过将所述细胞在体外暴露于不同量的同源抗原来确定。具有高功能亲合力的TCR表达细胞对低抗原剂量有应答。
例如,如果TCR表达细胞在与抗原阴性HLA-A2表达靶细胞共培养时分泌至少约200pg/mL或更多(例如200pg/mL或更多、300pg/mL或更多、400pg/ml或更多、500pg/mL或更多、600pg/mL或更多、700pg/mL或更多、1000pg/mL或更多、5,000pg/mL或更多、7,000pg/mL或更多、10,000pg/mL或更多或20,000pg/mL或更多)的干扰素γ(IFN-γ),则通常认为所述TCR表达细胞以“高”功能亲合力与其抗原性靶结合,所述抗原阴性HLA-A2表达靶细胞负载有约10-5M至约10-11M范围内(即,约0.05ng/mL至约5ng/mL、0.05ng/mL、0.1ng/mL、0.5ng/mL、1ng/mL或5ng/mL)的低浓度PRAME肽,并且PRAME肽的分子量为956g/mol。因此,本发明的TCR是高亲和力TCR,其产生如通过IFN-γ免疫测定法测量小于10-7M的半最大相对IFN-γ分泌(EC50值)。优选地,如通过IFN-γ免疫测定法测量,引起的半最大相对IFN-γ分泌(EC50值)小于10-8M(图2)。通过确定每种TCR的EC50值,与本领域公开的其它TCR相比,进一步证明了本发明的TCR的高亲和力(图13)。
本发明包括与序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式的结合诱导用TCR转导或转染的细胞的IFN-γ分泌。当与由HLA-A*02:01-、HLA-A*02:02-或HLA-A*02:04编码分子呈递的氨基酸序列SEQ ID NO:1结合时,与由HLA-A*02:01-、HLA-A*02:02-或HLA-A*02:04编码分子呈递的不相关肽(氨基酸序列GLSNTHVL,绘示于SEQ ID NO:25中)的结合相比,通过效应细胞上表达的本发明的TCR与由HLA-A*02:01-、HLA-A*02:02-或HLA-A*02:04编码分子呈递的氨基酸序列SEQ ID NO:1的结合而诱导的IFN-γ分泌可为100倍、优选500倍、更优选2000倍。IFN-γ分泌可大于例如100pg/ml,诸如大于500pg/ml或大于2000pg/ml。
细胞因子释放(诸如IFN-γ分泌)可使用体外测定进行测量,其中K562细胞(Greiner等人,2006,Blood.2006年12月15日;108(13):4109-17)分别用ivtRNA转染或转导以表达SEQ ID NO:1或不相关肽的氨基酸序列,并与表达待研究的TCR的富含CD8+和/或不富含CD8+的PBMC一起孵育,或在体外测定中使用外部负载有SEQ ID NO:1或不相关肽的T2细胞,并随后与表达待研究的TCR的富含CD8+和/或不富含CD8+的PBMC共孵育。
一些实施方案涉及如本文所述的分离的TCR、如本文所述的多肽或如本文所述的多价TCR复合体,其中通过效应细胞上表达的本发明的TCR与氨基酸序列SEQ ID NO:1或特别是与由HLA-A*02:01-、HLA-A*02:02-或HLA-A*02:04编码分子呈递的氨基酸序列SEQ IDNO:1的结合而诱导的IFN-γ分泌低于预定阈值。所述阈值可通过使用至少2:1的特定效应物与靶比率来确定。“效应细胞”可为外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。通常,效应细胞是免疫效应细胞,诸如T细胞。特定合适的效应细胞包括如本文中别处所述的细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞。
在效应细胞上表达的本发明的TCR与由HLA-A*02:01-、HLA-A*02:02-或HLA-A*02:04编码分子呈递的氨基酸序列SEQ ID NO:1结合时的IFN-γ分泌可在至少10-7M、优选至少10-8M、更优选10-9M的PRAMESLL肽浓度下被诱导。在具体实施方案中,例如当TCR-转基因T细胞与T2细胞的比率为2:1时,通过效应细胞上表达的本发明的TCR与由HLA-A*02:01编码分子呈递的氨基酸序列SEQ ID NO:1的结合而产生的IFN-γ分泌可在至少10-7M、优选至少10-8M、更优选10-9M的PRAMESLL肽浓度下被诱导。用以确定本发明的TCR的特异性结合的其它方法包括由Gertner-Dardenne等人,J Immunol 188(9):4701-4708所述的<51>Cr-释放测定、由Leisegang等人,Clin.Cancer Res 2010.16:2333-2343所述的CD107a/b动员以及由Wilde等人,J Immunol 2012;189:598-605所述的肽:MHC多聚体结合测定。
变体
如前所述,术语“TCR”包括TCR变体,其包括TCR序列变体、片段和构建体。设想所有TCR变体都是本发明的TCR的功能变体。如本文使用的术语“功能性变体”是指与亲代TCR、它的可变区或它的抗原结合区具有实质或显著的序列同一性或相似性的TCR、多肽或蛋白质,并共享其生物活性,即其特异性结合抗原性靶的能力,本发明的亲代TCR对所述抗原性靶具有与本文公开并在所附实施例中评价的TCR相似、相同或甚至更高程度的抗原性特异性。本发明还包括TCR序列变体。
术语“TCR变体”包括本文公开的TCR的“序列变体”,即基本上包含如上所述的本发明的TCR(也称为“亲代”TCR)的氨基酸序列、但与“亲代”TCR氨基酸序列相比含有至少一个氨基酸修饰(即取代、缺失或插入)的变体,条件是变体优选保留本发明的“亲代”TCR的抗原特异性。本发明的TCR序列变体通常是通过将适当的核苷酸改变引入编码“亲代”TCR的核酸中,或通过肽合成来制备。通常,上文所提到的氨基酸修饰可被引入或存在于TCR的可变区或恒定区中,并可用于调节如结合强度和特异性、翻译后加工(例如糖基化)、热力学稳定性、溶解性、表面表达或TCR组装等性质。
如前所述,氨基酸修饰包括例如亲代TCR的氨基酸序列内残基的缺失和/或插入和/或取代。本发明的TCR的示例性插入变体包括所述TCR与酶或另一种功能性多肽的融合产物。本发明的TCR的示例性取代变体是包括α链和/或β链的可变区或CDR、框架区或恒定区中的氨基酸取代的那些取代变体。本文特别设想保守氨基酸取代。保守氨基酸取代在本领域中是已知的,并且包括其中具有某些物理和/或化学性质的一个氨基酸交换为具有相同化学或物理性质的另一氨基酸的氨基酸取代。例如,保守氨基酸取代可为用酸性氨基酸取代另一酸性氨基酸氨基酸(例如Asp或Glu)、用具有非极性侧链的氨基酸取代具有非极性侧链的另一氨基酸(例如Ala、Gly、Val、He、Leu、Met、Phe、Pro、Trp、Vai等)、用一种碱性氨基酸取代另一碱性氨基酸(Lys、Arg等)、用具有极性侧链的氨基酸取代具有极性侧链的另一氨基酸(Asn、Cys、Gin、Ser、Thr、Tyr等)等等,这可例如基于所涉及的残基的极性、电荷、溶解性、疏水性、亲水性和/或两亲性的相似性来进行。
一般来说,设想TCR序列变体包含如本文公开或包含与本文公开的氨基酸序列至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%或相同的氨基酸序列或由所述氨基酸序列组成的CDR1、CDR2、CDR3、α链可变区、β链可变区、α链和/或β链中的至少一个,条件是所述变体展现与所附实施例中评估的TCR相当、相同或改善的结合特征。
如本文使用的术语“序列同一性”指示两个(核苷酸或氨基酸)序列在比对中相同位置处具有相同残基的程度,并且通常以百分比表示。优选地,在所比较的序列的整个长度上确定同一性。因此,恰好相同序列的两个拷贝具有100%同一性,但保守性较低且具有缺失、添加或置换的序列可能具有较低程度的同一性。本领域技术人员将认识到,有几种算法可用于使用标准参数例如Blast(Altschul等人,(1997)Nucleic Acids Res.25:3389-3402)、Blast2(Altschul等人,(1990)J.Mol.Biol.215:403-410)、Smith-Waterman(Smith等人,(1981)J.Mol.Biol.147:195-197)和ClustalW确定序列同一性。
因此,氨基酸序列SEQ ID NO:10或11可例如用作“主题序列”或“参考序列”,而与其不同的CDR3的氨基酸序列可用作“查询序列”。
当根据本公开使用时,术语“位置”意指本文所绘示的氨基酸序列内氨基酸的位置或本文所绘示的核酸序列内核苷酸的位置。如本文使用的术语“相应的”还包括位置不仅由前面的核苷酸/氨基酸的数目决定,而是在序列的周围部分的上下文中考虑。因此,根据本公开的给定氨基酸或核苷酸的位置可由于序列中其它地方的氨基酸或核苷酸的缺失或添加而变化。因此,当一个位置称为“相应的位置”时,根据本公开,应理解,核苷酸/氨基酸可在指定数字方面不同,但是仍然可具有相似的相邻核苷酸/氨基酸。为了确定给定序列中的氨基酸残基(或核苷酸)是否对应于“亲代”氨基酸/核苷酸序列的氨基酸序列中的某个位置,本领域技术人员可使用本领域熟知的方式和方法,例如手动或通过使用计算机程序(诸如本文例示的程序)进行序列比对。
本文中用作对照的TCR变体是TCR受体3825。该变体基于PR AME免疫的小鼠(小鼠ID 3825),其表达针对PRAME的TCR受体,具有如SEQ ID NO:23中所绘示的CDR3α序列(CAVEPGGSYIPTF)、如SEQ ID NO:24中所绘示的CDR3β序列(CASSPGLSYEQYF)。通过具有密码子优化的寡核苷酸的TCR文库,可重组表达和分析该TCR(Weis,Manon(2015):Charakterisierung Antigen-spezifischer T-Zellen nach Induktion in TCR-humanisiertenDissertation,LMU MünchenVeterinary Faculty Ludwigs University of Munich)。
半胱氨酸修饰
已报道在恒定区添加二硫键可加强TCRα和β链的正确配对(Kuball J等人,Blood.2007年3月15日;109(6):2331-8)。因此,本文也设想在恒定区添加一个或多个半胱氨酸键。
鼠类化
如前所述,TCR的鼠类化(即α和β链中的人类恒定区交换为其鼠类对应物)是一种常用于改善宿主细胞中TCR的细胞表面表达的技术。不希望受特定理论的束缚,据认为,鼠类化的TCR与CD3辅受体更有效地缔合;并且/或优先彼此配对并且不太倾向于在离体工程化的人类T细胞上形成混合TCR以表达具有所需抗原特异性的TCR,但仍保留和表达其“原始”TCR。
最近,已鉴定出9个负责鼠类化TCR的改善表达的氨基酸(Som mermeyer和Uckert,J Immunol.2010年6月1日;184(11):6223-31),并设想用TCRα和/或β链恒定区中的一个或所有氨基酸残基取代其鼠类对应物残基。这种技术也称为“最小鼠类化”,并且提供增强细胞表面表达、同时减少氨基酸序列中“外源”氨基酸残基的数量、从而降低免疫原性的风险的优点。
构建体和片段
如本文使用的术语“TCR”还包括TCR构建体。术语“构建体”包括包含本发明的TCR的至少一个抗原结合结构域的蛋白质或多肽,但不一定共享初始TCR的基本结构(即纳入形成异源二聚体的TCRα链和TCRβ链中的可变结构域)。TCR构建体和片段通常通过基因工程的常规方法获得,并且通常被人工构建以包含额外的功能性蛋白质或多肽结构域。根据上文,设想本发明的TCR构建体和片段包含本文别处公开的至少一种CDR3α和/或至少一种CDR3β。本文进一步设想包含至少一个CDR1α、CDR2α、CDR1β、CDR2β、α链可变区、β链可变区、α链和/或β链或它们的组合、任选地与本文例示的其它蛋白质结构域或部分组合的构建体和片段。设想本文提供的TCR构建体和片段能够特异性结合与上文所述并在所附实施例中评估的本发明的TCR相同的抗原性靶。
多聚体
本发明的TCR构建体包括异源二聚体和多聚体,其中至少一个TCRα链可变区或TCRα链和至少一个TCRβ链可变区彼此共价连接以形成TCR异源二聚体或多聚体。如本发明中使用的“多聚体”描述不同亚单元或功能实体的分子,而异源二聚体仅包含两个功能实体。呈其最简单形式的根据本发明的多价TCR构建体包含优选通过接头分子彼此缔合(例如共价或以其它方式连接)的两个或三个或四个或更多个TCR的多聚体。在此上下文中,“共价连接”意指两个分子之间的化学键,其共享描述原子键之间的稳定平衡的电子对。
与球形体、优选均匀珠、更优选聚苯乙烯珠、最优选生物相容性聚苯乙烯珠的合适接头。所述TCR构建体也可包含本发明的TCR和珠,所述珠中纳入了预定义的荧光染料。合适的接头分子包括但不限于多价连接分子,诸如抗生物素蛋白、链霉抗生物素蛋白、中性抗生物素蛋白和外源性抗生物素蛋白,其各自具有四个生物素结合位点。因此,生物素化TCR可形成具有多个TCR结合位点的多聚体。多聚体中TCR的数量取决于TCR的量相对于用于制备多聚体的接头分子的量,并且还取决于任何其它生物素化分子的存在或不存在。示例性多聚体是二聚体、三聚体、四聚体或五聚体或更高级的多聚体TCR构建体。本发明的多聚体还可包含其它功能实体,诸如标记或药物或(固体)载体。
融合蛋白
TCR异源二聚体或多聚体还涉及融合蛋白或多肽,其包含至少一个TCRα链、TCRα链可变区或CDR3α和/或至少一个TCRβ链、TCRβ链可变区或CDR3β;和另外一种或多种融合组分。其可为如本文定义的至少一个TCRα链和/或如本文定义的至少一个TCRβ链和/或针对淋巴细胞表面上的抗原或表位的抗体或单链抗体片段(scFv),并且TCRα链和TCRβ链也彼此连接并任选地通过接头与所述抗体或scFv融合。有用的组分包括Fc受体;Fc结构域(源自IgA、IgD、IgG、IgE和IgM);细胞因子(诸如IL-2或IL-15);毒素;抗体或其抗原结合片段(诸如抗CD3、抗CD28、抗CD5、抗CD16或抗CD56抗体或其抗原结合片段);CD247(CD3-ζ)、CD28、CD137、CD134结构域;或它们的任何组合。
可用作融合组分的示例性抗体片段包括全长抗体的片段,诸如(s)dAb、Fv、Fd、Fab、Fab'、F(ab')2或“r IgG”(“半抗体”);修饰的抗体片段,诸如scFv、二-scFv或联(双)-scFv、scFv-Fc、scFv-拉链、scFab、Fab2、Fab3、双抗体、单链双抗体、串联双抗体(Tandab)、串联二-scFv、串联三-scFv、微小抗体、多抗体(诸如三抗体或四抗体),以及单结构域抗体,诸如仅包含一个可变结构域的纳米抗体或单可变结构域抗体,其可为VHH抗体、VH抗体或VL抗体。
本发明的TCR构建体可与一种或多种抗体或抗体片段融合,从而产生单价、二价和多价(polyvalent/multivalent)构建体,且因此产生仅特异性结合一种靶抗原的单特异性构建体,以及双特异性和多特异性(polyspecific/multispecific)构建体,所述双特异性和多特异性构建体通过不同抗原结合位点特异性结合多于一种靶抗原,例如两种、三种或更多种靶抗原。
任选地,可在本发明的TCR构建体的一个或多个结构域或区之间、即在TCRα链CDR3、TCRα链可变区和/或TCRα链、TCRβ链CDR3、TCRβ链可变区和/或TCRβ链和/或本文所述的一种或多种融合组分之间引入接头。接头是本领域已知的,并且已尤其由Chen等人,AdvDrug Deliv Rev.2013年10月15日;65(10):1357-1369综述。一般而言,接头包括柔性、可切割和刚性接头,并且将根据构建体的类型和预期用途/应用进行选择。例如,对于治疗应用,非免疫原性柔性接头通常是优选的,以确保结构域之间一定程度的柔性或相互作用,同时降低不利的免疫原性反应的风险。所述接头通常由小的非极性氨基酸(例如Gly)或极性氨基酸(例如Ser或Thr)构成,并且包括由Gly和Ser残基组成的“GS”接头。
根据本发明设想的特别有用的TCR构建体是包含以下的那些TCR构建体:至少一个如本文定义的TCRα链、TCRα链可变区或CDR3α、至少一个如本文定义的TCRβ链、TCRβ链可变区或CDR3β,其任选地彼此连接并任选地通过接头与针对淋巴细胞表面上的抗原或表位的至少一种抗体或抗体片段(诸如单链抗体片段(scFv))融合。由抗体或抗体片段(例如scFv)识别的有用抗原性靶包括CD3、CD28、CD5、CD16和CD56。所述构建体通常可具有任何结构,只要“TCR部分”(即TCRα和β链或其可变区或CDR3)保留其识别本文定义的抗原性靶的能力,并且“抗体部分”结合所需的表面抗原或表位,从而招募相应的淋巴细胞并将其靶向靶细胞。所述构建体可有利地用作将展示抗原性靶的抗原呈递细胞(诸如肿瘤细胞)和淋巴细胞(诸如细胞毒性T细胞或NK细胞)接合在一起的“衔接子”。所述融合蛋白的实例是在约55千道尔顿(kDa)的单肽链上根据由不同抗体的两个单链可变片段(scFv)组成的双特异性T细胞衔接器的原理工程化的构建体。因此,本发明的TCR构建体可包含至少一个如本文所述的TCR抗原结合结构域(例如,彼此融合的TCR可变α链和可变β链),其连接至具有所需结合特异性的scFv(或其它结合结构域),例如CD3或CD56。scFv(或其它结合结构域)诸如通过CD3受体结合T细胞,或结合CD56用于NK细胞激活,并且另一个通过在肿瘤细胞上特异性表达的抗原性靶结合肿瘤细胞。本文还设想包含至少一个本文所述的TCR抗原结合结构域、scFv(或其它结合结构域)和另一结构域(例如用于将所述构建体靶向至体内作用位点的结构域(例如Fc结构域))的三抗体。
分离的形式
本发明的TCR可以“分离的”或“基本上纯的”形式提供。“分离的”或“基本上纯的”当在本文中使用时意指TCR已从其产生环境的组分中鉴定、分离和/或回收,使得“分离的”TCR不含或基本上不含来自其产生环境的可干扰其治疗或诊断用途的其它污染组分。污染性组分可包括酶、激素和其它蛋白质溶质或非蛋白质溶质。因此,“分离的”TCR将通过以下方法来制备:通过在引起所述TCR表达的条件下孵育宿主细胞并纯化所述TCR来获得TCR,由此含有至少一个去除或基本上去除这些污染性组分的纯化步骤。上文所提到的定义同样适用于“分离的”多核苷酸/核酸,只要作必要的修改。
可溶性形式
本发明的TCR可以可溶性形式提供。可溶性TCR可用作诊断工具,以及将治疗剂或效应细胞特异性靶向例如表达可溶性TCR识别的抗原性靶的癌细胞的载体或“衔接子”。可溶性TCR(sTCR)通常是包含TCRα链和/或β链或其可变区或CDR的片段或构建体,并任选地通过二硫键稳定或通过合适的接头分子共价连接,例如如上文在本发明的TCR构建体的上下文中所述。它们通常不包含例如跨膜区。在一些情况下,可引入多肽序列中的氨基酸修饰,以增强分子的溶解性,和/或校正α和β链的折叠和配对(如果需要),特别是当在不提供上文所提到的特征的重组宿主中产生时。当使用大肠杆菌(E.coli)作为产生宿主细胞时,例如,TCRα和β链的折叠和配对通常在体外完成。因此,根据本发明的TCR可例如包含额外的半胱氨酸残基,如本文别处所述。
除了额外的半胱氨酸桥,其它有用的修饰包括(例如)添加亮氨酸拉链和/或核糖体跳过序列,例如如Walseng等人(2015),PLoS ONE 10(4):e0119559中描述的来自微小核糖核酸病毒的序列2A,以增加TCRα链和/或β链的折叠、表达和/或配对。
修饰
本发明的TCR可还包括如下文中所述的一个或多个修饰。下文所述的修饰通常是共价修饰,并且可使用本领域已知的标准技术来完成。在一些情况下,可能需要TCR的氨基酸修饰,以有利于引入所述修饰。
分子标记
本发明的TCR、特别是(可溶性)TCR可用至少一种分子标记进行标记。有用的分子标记是本领域已知的,并且可使用常规方法、任选地通过各种长度的接头与TCR或TCR变体偶联。
一般来说,不同的标记属于不同的类别,这取决于检测它们的测定-以下实例包括但不限于:同位素标记物,其可为放射性或重同位素,诸如放射性同位素或放射性核素(例如<3>H、<14>、<15>N、<35>S、<89>Zr、<90>Y、<99>Tc、<111>In、<125>I、<131>I);磁性标记(例如磁性粒子);氧化还原活性部分;光学染料(包括但不限于发色团、磷光体和荧光团),诸如荧光基团(例如FITC、若丹明、镧系磷光体)、化学发光基团以及可为“小分子”荧光团或蛋白质荧光团的荧光团;酶基团(例如辣根过氧化物酶、对-半乳糖苷酶、荧光素酶、碱性磷酸酶;生物素化基团;或由二级报告子识别的预定多肽表位(例如亮氨酸拉链对序列、二级抗体的结合位点、金属结合结构域、表位标签等。)。当TCR、TCR变体或尤其可溶性TCR构建体(诸如包含如本文所述的至少一个TCRα链和/或TCRβ链的那些构建体)旨在用于诊断用途时,特别设想用分子标记进行标记。
功能部分
本发明的TCR、特别是可溶性TCR可通过连接另外的功能部分进行修饰,例如用于降低免疫原性、增加流体动力学大小(溶液中的大小)溶解性和/或稳定性(例如通过增强对蛋白水解降解的保护)和/或延长血清半衰期。
根据本发明使用的示例性功能部分包括与人体中的其它蛋白质(诸如血清白蛋白、免疫球蛋白Fc区或新生儿Fc受体(FcRn)、不同长度的多肽链(例如XTEN技术或)、非蛋白质聚合物,包括但不限于各种多元醇,诸如聚乙二醇(聚乙二醇化)、聚丙二醇、聚氧化烯或聚乙二醇和聚丙二醇的共聚物,或碳水化合物,诸如羟乙基淀粉(例如)或聚唾液酸(例如技术))结合的肽或蛋白质结构域。
其它有用的功能部分包括“自杀”或“安全开关”,其可用于关闭患者体内携带本发明的TCR的效应宿主细胞。实例是由Gargett和Brown Front Pharmacol.2014;5:235描述的诱导型半胱天冬酶9(iCasp9)“安全开关”。简单地说,效应宿主细胞通过众所周知的方法进行修饰以表达半胱天冬酶9结构域,其二聚化取决于小分子二聚体药物(诸如AP1903/CIP),并导致在修饰的效应细胞中快速诱导细胞凋亡。例如,EP2173869(A2)中描述了系统。本领域已知其它“自杀”、“安全开关”的实例,例如单纯疱疹病毒胸苷激酶(HSV-TK),CD20的表达和随后使用抗CD20抗体或myc标签的耗竭(Kieback等人,Proc Natl Acad Sci USA.2008年1月15日;105(2):623-8)。本发明的TCR也可通过引入诱导型所谓“接通”来修饰(例如在WO2019175209A1中所述),其中本发明的TCR的修饰的α和β链仅在与小的二聚体药物相互作用时二聚化,随后产生仅在存在二聚体药物下在细胞表面上表达的功能性TCR。
糖基化
本文还设想糖基化模式改变的TCR。如本领域所知,糖基化模式可取决于氨基酸序列(例如,特定糖基化氨基酸残基的存在或不存在,如下所讨论)和/或产生蛋白质的宿主细胞或生物体。多肽的糖基化通常是N-连接的或O-连接的。N-连接的是指碳水化合物部分与天冬酰胺残基的侧链的连接。将N-连接的糖基化位点添加到结合分子方便地通过改变氨基酸序列来实现,使得其含有一个或多个选自天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸的三肽序列(其中X是除脯氨酸之外的任何氨基酸)。O-连接的糖基化位点可通过向起始序列中添加一个或多个丝氨酸或苏氨酸残基或由所述残基取代来引入。
TCR的糖基化的另一方式是通过糖苷与蛋白质的化学或酶偶联。根据所用的偶联方式,糖可与(a)精氨酸和组氨酸、(b)游离羧基、(c)游离巯基,诸如半胱氨酸的那些巯基、(d)游离羟基,诸如丝氨酸、苏氨酸或羟脯氨酸的那些羟基、(e)芳族残基,诸如苯丙氨酸、酪氨酸或色氨酸的残基或(f)谷氨酰胺的酰胺基连接。
类似地,去糖基化(即去除结合分子上存在的碳水化合物部分)可以化学方式例如通过将TCR暴露于三氟甲磺酸,或以酶促方式通过采用内切和外切糖苷酶来完成。
药物缀合物
还可想到将药物(诸如小分子化合物)添加到TCR中,特别是添加到本发明的可溶性TCR中。连接可通过共价键或诸如通过静电力的非共价相互作用来实现。可采用本领域已知的各种接头以形成药物缀合物。
标签
可修饰本公开的TCR、特别是可溶性TCR,以引入有助于鉴定、追踪、纯化和/或分离相应分子(标签)的额外结构域。所述标签的非限制性实例包括肽动机(peptide motives),已知为Myc标签、HAT标签、HA标签、TAP标签、GST标签、几丁质结合结构域(CBD标签)、麦芽糖结合蛋白(MBP标签)、Flag标签、Strep标签及其变体(例如Strep II标签)、His-标签、CD20、Her2/neu标签、myc标签、FLAG标签、T7标签、HA(血凝素)标签或GFP标签。
表位标签是可纳入本公开的TCR中的标签的有用实例。表位标签是容许结合特异性抗体的短氨基酸片段,因此能够鉴定和跟踪患者体内或培养的(宿主)细胞内可溶性TCR或宿主细胞的结合和移动。表位标签且因此标记的TCR的检测可使用多种不同的技术来完成。所述技术的实例包括:免疫组织化学、免疫沉淀、流式细胞术、免疫荧光显微镜术、ELISA、免疫印迹法(“蛋白质印迹”)和亲和色谱法。表位标签可例如具有6至15个氨基酸、特别是9至11个氨基酸的长度。在本发明的TCR中还可包括多于一个的表位标签。
通过在对标签特异的结合分子(抗体)存在下培养细胞,所述标签还可用于刺激和扩增携带本发明TCR的宿主细胞。
核酸
本发明进一步提供编码本文所述的TCR的核酸或编码如本文所述的TCR的多核苷酸。这些核酸是密码子优化的,这意味着一种蛋白质可由许多可选择的替代核酸序列编码。密码子偏好性(密码子使用偏好)在每种生物中都有所不同,并且其为在异源表达系统中表达重组蛋白带来了挑战,从而导致低且不可靠的表达。对于自体表达也可能是如此,这是因为野生型序列不一定针对表达产率进行优化,但是也针对降解、调节和其它性质进行优化。因此,本文使用密码子优化来提供高效的蛋白质表达。下表1指示编码相应氨基酸序列的核苷酸序列:
表1
具体来说,本文提供编码本发明的TCRα或β链、TCRα或β链可变区、TCR CDR 3α和CDR 3β以及TCR变体、构建体和片段的多核苷酸,并且序列在SEQ ID NO:13、14、15、16、17、18、19、20、21和22中绘示。
如本文使用的术语“多核苷酸”或“核酸”包括多核糖核苷酸和多脱氧核糖核苷酸的序列,例如修饰或未修饰的RNA或DNA,其各自以单链和/或双链形式呈线性或环状,或其混合物,包括杂合分子。因此,根据本发明的核酸包括DNA(诸如dsDNA、ssDNA、cDNA)、RNA(诸如dsRNA、ssRNA、mRNA ivtRNA)、它们的组合或它们的衍生物(诸如PNA)。
多核苷酸可包含常规磷酸二酯键或非常规键(例如,诸如在肽核酸(PNA)中发现的酰胺键)。本发明的多核苷酸还可含有一个或多个修饰的碱基,例如三苯甲基化碱基和不常见的碱基,诸如肌苷。也可想到其它修饰,包括化学修饰、酶修饰或代谢修饰,只要本发明的结合分子可从多核苷酸表达即可。多核苷酸可以如本文别处所定义的分离形式提供。多核苷酸可包括调节序列,诸如转录控制元件(包括启动子、增强子、操作子、阻遏子和转录终止信号)、核糖体结合位点、内含子等。
具体来说,本发明提供多核苷酸,其包含与选自由如SEQ ID NO:13、14、15、16、17、18、19、20、21和22中所绘示的序列组成的组的参考多核苷酸序列至少约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或100%相同的核酸,或由所述核酸组成。
上述多核苷酸可包含或不包含编码例如改变的氨基酸残基的额外或改变的核苷酸序列、指导编码的TCR分泌的信号肽、恒定区或如本文所述的其它异源多肽。所述多核苷酸因此可编码本文所述的结合分子的融合多肽、片段、变体和其它衍生物。
本发明的核酸序列可经密码子优化以在所需宿主细胞(例如人类淋巴细胞)中最佳表达;或用于在特别设想用于表达本发明的可溶性TCR的细菌、酵母或昆虫细胞中表达。密码子优化是指在感兴趣的序列中将在给定物种的高表达基因中通常罕见的密码子与在所述物种的高表达基因中通常常见的密码子交换,所述密码子编码与所交换的密码子相同的氨基酸。因此,最佳密码子的选择取决于宿主基因组的密码子使用以及几种所需和不需要的序列基序的存在。
载体
本文进一步提供载体,其包含一种或多种如本文所述的核酸。“载体”是用作将(外源)遗传物质转移到宿主细胞中的载体的核酸分子,在宿主细胞中,遗传物质可例如复制和/或表达。
术语“载体”包括但不限于质粒、病毒载体(包括逆转录病毒载体、慢病毒载体、腺病毒载体、牛痘病毒载体、多瘤病毒载体和腺病毒相关载体(AAV))、噬菌体、噬粒、粘粒和人工染色体(包括BAC和YAC)。载体本身通常是核苷酸序列,通常是包含插入物(转基因)和作为载体的“主链”的较大序列的DNA序列。工程化载体通常包含用于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)、选择标记和限制性酶切割位点(例如,多重克隆位点,MCS)。载体可另外包含启动子、遗传标记、报告基因、靶向序列和/或蛋白质纯化标签。如本领域技术人员所知,大量合适的载体是本领域技术人员所知的,并且许多是有市售的。
靶向载体
靶向载体可用于通过本领域已知的方法将多核苷酸整合到宿主细胞的染色体中,例如由J.Sambrook等人,Molecular Cloning:A Laboratory Manual(第4版),Cold SpringHarbor Laboratory,Cold Spring Harbor Laboratory Press,New York(2012)所述。简单地说,合适的方式包括同源重组或使用在整合位点特异性靶向序列的杂交重组酶。靶向载体通常是环状的,并且在用于同源重组之前会被线性化。作为替代方案,外源多核苷酸可为通过融合PCR接合的DNA片段或合成构建的DNA片段,然后将其重组到宿主细胞中。也可使用导致随机或非靶向整合的异源重组。
表达载体
本发明的载体也可为表达载体。“表达载体”或“表达构建体”可用于异源多核苷酸序列(例如编码本发明的TCR的那些序列)的转录,以及它们的mRNA在合适的宿主细胞中的翻译。该过程在本文中也称为本发明的TCR的“表达”。
除了复制起点、选择标记和限制性酶切割位点之外,表达载体通常包括一个或多个与待表达的异源多核苷酸可操作连接的调节序列。
术语“调节序列”是指(异源)多核苷酸的可操作连接的编码序列在特定宿主生物体或宿主细胞中表达所必需的核酸序列,并且因此包括转录和翻译调节序列。通常,在原核生物中表达异源多核苷酸序列所需的调节序列包括启动子、任选的操作序列和核糖体结合位点。在真核生物中,通常需要启动子、聚腺苷酸化信号、增强子和任选的剪接信号。此外,也可将特异性起始和分泌信号引入载体中,以容许将感兴趣的多肽分泌到培养基中。
当核酸置于与另一核酸序列、特别是在同一多核苷酸分子上的功能关系中时,所述核酸是“可操作连接的”。例如,当启动子能够实现编码序列的表达时,其与异源基因的编码序列可操作地连接。启动子通常位于编码感兴趣的多肽的基因的上游,并调节所述基因的表达。
哺乳动物宿主细胞表达的示例性调节序列包括指导哺乳动物细胞中高水平的蛋白质表达的病毒元件,诸如源自巨细胞病毒(CMV)(诸如CMV启动子/增强子)、猿猴病毒40(SV40)(诸如SV40启动子/增强子)、腺病毒(例如,腺病毒主要晚期启动子(AdMLP))和多瘤的启动子和/或增强子。如前所述,表达载体还可包括复制起点和可选标记。
如前所提及,本发明的载体可还包含一个或多个选择标记。适用于真核宿主细胞的选择标记包括但不限于单纯疱疹病毒胸苷激酶(tk)、次黄嘌呤-鸟嘌呤磷酸核糖基转移酶(hgprt)和腺嘌呤磷酸核糖基转移酶(aprt)基因。其它基因包括dhfr(甲氨蝶呤抗性)、gpt(霉酚酸抗性)、neo(G-418抗性)和hygro(潮霉素抗性)。载体扩增可用于提高表达水平。一般来说,选择标记基因可直接与待表达的多核苷酸序列连接,或者通过共转变引入同一宿主细胞中。
鉴于上述,本发明因此进一步提供一种或多种本文所述的插入载体(即包括载体)的核苷酸序列。具体来说,本发明提供(可复制的)载体,其包含编码本发明的TCR,或其α或β链,或α或β可变结构域,或可操作地连接到启动子的CDR3α或CDR3β的核苷酸序列。
本领域技术人员将能够基于例如旨在用于TCR表达的宿主细胞容易地选择合适的表达载体。合适的表达载体的实例是病毒载体,诸如逆转录病毒载体,例如MP71载体或逆转录病毒SIN载体;以及慢病毒载体或慢病毒SIN载体。包含编码本发明的TCR的多核苷酸的病毒载体例如能够感染淋巴细胞,设想所述淋巴细胞随后表达异源TCR。合适表达载体的另一实例是睡美人(SB)转位子转位酶DNA质粒系统,SB DNA质粒。本发明的核酸和/或特别是表达构建体也可通过瞬时RNA转染转移到细胞中。
目前用于初始TCR表达的病毒载体通常将一个载体中的TCR-α和TCR-β链基因与内部核糖体进入位点(IRES)序列或源自猪艾柯病毒(tsechovirus)的2A肽序列连接,从而导致在转导细胞内在病毒启动子的控制下表达单个信使RNA(mRNA)分子。
宿主细胞
本发明进一步提供包含本文所述的TCR、核酸或载体的宿主细胞。
根据本发明可使用多种宿主细胞。如本文使用的术语“宿主细胞”包括可为或已经是本文所述的多核苷酸或载体的接受者和/或表达(并且任选地分泌)本发明的TCR的细胞。除非另有明确说明,否则术语“细胞”和“细胞培养物”可互换使用以表示TCR的来源。术语“宿主细胞”还包括宿主细胞系。一般来说,术语“宿主细胞”包括原核或真核细胞,并且还包括但不限于细菌、酵母细胞、真菌细胞、植物细胞和动物细胞,诸如昆虫细胞和哺乳动物细胞,例如鼠类、大鼠、猕猴或人类细胞。
鉴于上文,本发明因此尤其提供包含多核苷酸或载体(例如包含编码如本文所述的TCR或TCR构建体的核苷酸序列的表达载体)的宿主细胞。本发明的多核苷酸和/或载体可使用本领域已知的常规方法、例如通过转染、转变等引入宿主细胞中。
“转染”是将核酸分子或多核苷酸(包括载体)有意引入靶细胞的过程。实例是RNA转染,即将RNA(诸如体外转录的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上打开瞬时孔或“洞”,以容许材料的摄取。转染可使用磷酸钙、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脂质体来进行,所述脂质体与细胞膜融合并将其货物沉积在内部。转染真核宿主细胞的示例性技术包括脂囊泡介导的摄取、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“转变”用于描述核酸分子或多核苷酸(包括载体)向细菌以及向非动物真核细胞(包括植物细胞)的非病毒转移。因此,转变是细菌或非动物真核细胞的遗传改变,所述遗传改变是通过细胞膜从其周围直接摄取并随后纳入外源遗传物质(核酸分子)而产生。转变可通过人工方式来实现。为了发生转变,细胞或细菌必须处于能力状态,这可能作为对诸如饥饿和细胞密度等环境条件的时限反应发生。对于原核转变,技术可包括热休克介导的摄取、细菌原生质体与完整细胞融合、显微注射和电穿孔。植物转变的技术包括土壤杆菌属(Agrobacterium)介导的转移,诸如通过根癌土壤杆菌(A.tumefaciens)、快速推进的钨或金微粒、电穿孔、显微注射和聚乙二醇介导的摄取。
鉴于上述,本发明因此进一步提供包含至少一种如本文所述的多核苷酸序列和/或载体的宿主细胞。
为了表达本发明的TCR,可根据需要选择调节插入的多核苷酸序列的表达并且/或修饰和加工基因产物(即RNA和/或蛋白质)的宿主细胞。基因产物的此类修饰(例如糖基化)和加工(例如切割)对TCR的功能可为重要的。不同的宿主细胞对基因产物的翻译后加工和修饰具有特征性且特异性的机制。可选择适当的细胞系或宿主系统,以确保产物的正确修饰和加工。为此,可使用真核宿主细胞,所述真核宿主细胞具有适当处理基因产物的初级转录物、糖基化和磷酸化的细胞机制。
本文设想提供(a)用于表达和获得特别是呈可溶性形式的本发明的TCR的宿主细胞(“产生宿主细胞”)和(b)表达本发明的TCR并具有效应物功能的宿主细胞(“效应宿主细胞”)。所述“效应宿主细胞”特别可用于治疗应用,并设想用于施用给有需要的受试者。优选的“效应宿主细胞”包括淋巴细胞,诸如细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞。
“产生宿主细胞”
细胞
用于表达本发明的可溶性TCR的“产生宿主细胞”优选能够表达高量的重组蛋白。
根据上文,可想到的表达系统(即包含如上所述的表达载体的宿主细胞)包括用重组噬菌体DNA、质粒DNA或粘粒DNA表达载体转变的微生物,诸如细菌(例如大肠杆菌、枯草芽孢杆菌(B.subtilis));用重组酵母表达载体转变的酵母(例如,酿酒酵母(Saccharomyces)、毕赤酵母(Pichia));用重组病毒表达载体(例如杆状病毒)感染的昆虫细胞系统;用重组病毒表达载体(例如花椰菜花叶病毒(cauliflower mosaic virus),CaMV;烟草花叶病毒,TMV)感染或用重组质粒表达载体(例如Ti质粒)转变的植物细胞系统。具有重组表达构建体的哺乳动物表达系统通常是优选的,所述重组表达构建体含有源自哺乳动物细胞的基因组的启动子(例如金属硫蛋白启动子)或源自哺乳动物病毒的启动子(例如腺病毒晚期启动子;牛痘病毒7.5K启动子、巨细胞病毒(CMV)主要立即早期启动子(MIEP)启动子。合适的哺乳动物宿主细胞可选自已知的细胞系(例如COS、CHO、BLK、293、3T3细胞),然而也可想到使用淋巴细胞,诸如细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞。
可用作“产生宿主细胞”的示例性哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞),包括DHFR减CHO细胞,诸如DG44和DUXBI1、NSO、COS(具有SV40 T抗原的CVI的衍生物)、HEK293(人类肾)和SP2(小鼠骨髓瘤)细胞。其它示例性宿主细胞系包括但不限于HELA(人类子宫颈癌)、CVI(猴肾系)、VERY、BHK(幼小仓鼠肾)、MDCK、293、WI38、R1610(中国仓鼠纤维母细胞)、BALBC/3T3(小鼠纤维母细胞)、HAK(仓鼠肾系)、P3×63-Ag3.653(小鼠骨髓瘤)、BFA-IcIBPT(牛内皮细胞)和RAJI(人类淋巴细胞)。宿主细胞系通常可从商业服务机构、美国组织培养物保藏中心(American Tissue Culture Collection,ATCC)或已公开的文献中获得。
非哺乳动物细胞(诸如细菌、酵母、昆虫或植物细胞)也是容易获得的,并且也可用作如上所述的“产生宿主细胞”。示例性细菌宿主细胞包括肠杆菌科(Enterobacteriaceae),诸如大肠杆菌、沙门氏菌(Salmonella);芽孢杆菌科(Bacillaceae),诸如枯草芽孢杆菌;肺炎球菌(Pneumococcus);链球菌(Streptococcus)和流感嗜血杆菌(Haemophilus influenza)。其它宿主细胞包括酵母细胞,诸如酿酒酵母和巴斯德毕赤酵母(Pichia pastoris)。昆虫细胞包括但不限于草地贪夜蛾(Spodopterafrugiperda)细胞。
根据上文,本发明还提供一种产生和获得如本文所述的TCR的方法,所述方法包括以下步骤:(a)在引起所述TCR表达的条件下孵育宿主细胞(即产生宿主细胞)和(b)纯化所述TCR。
培养
使具有表达载体的宿主细胞在适于产生本文提供的TCR、特别是如本文别处所述的α链和/或β链的条件下生长,并测定α链和/或β链蛋白质合成。为了表达双链TCR,编码α链和β链两者的载体可在宿主细胞中共表达,以表达整个分子。
纯化
一旦本发明的TCR已表达,其就可通过本领域已知的任何纯化方法,例如通过色谱法(例如离子交换色谱法(例如羟磷灰石色谱法)、亲和色谱法,特别是蛋白质A、蛋白质G或凝集素亲和色谱法、粒度分级管柱色谱法)、离心、差示溶解度、疏水相互作用色谱法,或通过用于纯化蛋白质的任何其它标准技术进行纯化。本领域技术人员将能够基于待回收的TCR的单独特征容易地选择合适的纯化方法。
“效应宿主细胞”
如先前所提及,本发明还提供包含本发明的核苷酸序列、载体或TCR的“效应宿主细胞”。所述效应宿主细胞是使用常规方法进行修饰以包含编码本发明的TCR的核酸序列,并设想其特别是在细胞表面上表达本文所述的TCR。出于本发明的目的,“表达本发明的TCR的修饰的宿主细胞”通常是指例如通过如所附实施例中所述的RNA转染而经处理或改变以表达根据本发明的TCR的(效应或产生)宿主细胞。也设想修饰或转染或转导的其它方法,例如本文别处所述的那些方法。因此,术语“修饰的宿主细胞”包括优选表达本发明的TCR的“转染的”、“转导的”和“遗传工程化的”宿主细胞。
优选地,所述“(修饰的)效应宿主细胞”(特别是“(修饰的)效应淋巴细胞”)能够在TCR与其特异性抗原性靶结合时通过细胞内信号转导介导效应物功能。所述效应物功能包括(例如)穿孔蛋白(其在靶细胞膜中产生洞)、颗粒酶(其是在细胞内起作用以触发细胞凋亡的蛋白酶)的释放;Fas配体(其激活携带FAS的靶细胞中的细胞凋亡)的表达以及细胞因子(优选Th1/Tc1细胞因子,诸如IFN-γ、IL-2和TNF-α)的释放。因此,设想经工程化以表达能够在待治疗的受试者中识别并结合其抗原性靶的本发明的TCR的效应物宿主细胞,以执行上文提及的效应物功能,从而杀伤靶(例如癌)细胞。可例如利用检测在与TCR转染的受体T细胞共培养期间荧光标记的靶细胞的消失的CTL荧光杀伤测定(CTL,USA)评价靶细胞的细胞溶解。
鉴于上述,效应宿主细胞优选表达功能性TCR,即其通常包含本文所述的TCRα和β链;以及信号转导亚单位CD3γ、δ、ε和ζ(CD3复合体)。此外,也可能需要表达辅受体CD4或CD8。一般而言,具有参与抗原结合、受体激活和下游信号传导的所需基因(例如Lck、FYN、CD45和/或Zap70)的淋巴细胞、T细胞特别适合作为效应宿主细胞。然而,本文还设想将本发明的TCR表达为“结合结构域”而不含CD3信号转导亚单位和/或上文所提到的下游信号传导分子(即能够识别本文所述的抗原性靶,但不影响由CD3和/或上文所提到的下游信号传导分子介导的功能)的效应宿主细胞。设想所述效应细胞能够识别本文所述的抗原性靶,并任选地实现与CD3信号传导和/或上文所提到的下游信号传导分子的信号传导不相关的其它功能。实例包括表达本发明的TCR并能够(例如)在识别其抗原性靶位时释放细胞毒性颗粒的NK或NKT细胞。
因此,认为细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞是有用的淋巴细胞效应宿主细胞。表达本发明的重组TCR的所述淋巴细胞在本文中也称为“修饰的效应淋巴细胞”。然而,本领域技术人员将容易地认识到,一般而言,可通过本领域已知的重组基因工程化方法将导致所需效应物功能的TCR信号传导路径的任何组分引入合适的宿主细胞中。
效应宿主细胞、特别是淋巴细胞(诸如T细胞)可为从待处理的受试者获得并经转变或转导以表达本发明的TCR的自体宿主细胞。通常,TCR的重组表达将通过使用如所附实施例中所述的病毒载体来实现。用于从患者获得和分离细胞的技术是本领域已知的。
如先前所提及,特别设想本文提供的效应宿主细胞用于治疗应用。可能需要宿主细胞的进一步遗传修饰以提高治疗效能。例如,当使用自体CD8+T细胞作为“效应宿主细胞”时,合适的额外修饰包括内源性TCR、CTLA-4和/或PD-1表达的下调;和/或共刺激分子(诸如CD28、CD134、CD137)的扩增。本领域已经描述了用于实现上文所提到的遗传修饰的方式和方法。
用于宿主细胞的靶向基因组工程化的方法是本领域已知的,并且除了用siRNA的基因敲除之外,还包括使用所谓的“可编程核酸酶”,诸如锌指核酸酶(ZFN)、转录活化剂样效应物核酸酶(TALEN)和源自细菌规律成簇间隔短回文重复序列(CRISPR)-Cas(CRISPR-相关的)系统的RNA引导的工程化核酸酶(RGEN),尤其如Kim&Kim Nature Reviews Genetics15,321-334(2014)中所综述。例如,可编程核酸酶(诸如TALEN)可用于切割编码“不需要的”蛋白质(诸如PD-1、CTLA-4或内源性TCR)的DNA区,从而降低其表达。当T细胞用作(效应)宿主细胞时,内源性TCR的下调具有减少内源性和外源性TCRα/β链的不需要的“错配”的益处。
药物组合物
本发明进一步提供药物组合物,其包含如本文所述的作为一种或多种活性剂的TCR、核酸、载体和/或宿主细胞,以及任选的一种或多种药物赋形剂。因此,本文还设想所述TCR、核酸、载体和宿主细胞用于制备药物组合物或药物的用途。
术语“药物组合物”特别是指适于施用给人类的组合物。然而,该术语通常还包括适合施用给非人类动物的组合物。
本发明设想的药物组合物可还包含一种或多种优选地选自由CTLA-4抑制剂、PD-1抑制剂和PD-L1抑制剂组成的组的检查点抑制剂。所有上文提及的抑制剂都是能够下调免疫应答的免疫检查点抑制剂。细胞毒性淋巴细胞相关蛋白4(CTLA-4)抑制剂是调节性T细胞中组成型表达的蛋白受体,但在激活后仅在常规T细胞中上调。PD-1和PD-L1抑制剂用于抑制程序性死亡-配体1(PD-L1)与其受体程序性细胞死亡蛋白1(PD-1)的缔合。这些细胞表面蛋白的相互作用参与免疫系统的抑制,并在感染后发生,以限制旁观者宿主细胞的杀伤并预防自身免疫性疾病。因此,优选地将所述检查点抑制剂组合到根据本发明的药物组合物中。
本发明包括的其它检查点抑制剂是LAG3、ICOS、TIM3、VISTA和CEACAM1。LAG3是抗原激活的T细胞上的抑制性受体。ICOS蛋白属于CD28和CTLA-4细胞表面受体家族。其形成同型二聚体,并且在细胞-细胞信号传导、免疫应答和细胞增殖调节中发挥重要作用。TIM3或A型肝炎病毒细胞受体编码属于免疫球蛋白超家族的蛋白质和TIM家族的蛋白质。CD4阳性T辅助淋巴细胞基于其细胞因子分泌模式可分为1型(Th1)和2型(Th2)。VISTA或V-Set免疫调节受体编码抑制T细胞应答的免疫调节受体。CEACAM1基因编码癌胚抗原(CEA)基因家族的成员,其属于免疫球蛋白超家族。这些检查点抑制剂也可与药物组合物组合。
药物组合物及其组分(即活性剂和任选的赋形剂)优选是药学上可接受的,即能够引发所需的治疗效应而不在接受者中引起任何不想要的局部或全身效应。本发明的药学上可接受的组合物可例如是无菌的。具体来说,术语“药学上可接受的”可意指经监管机构或其它普遍认可的药典批准用于动物,更具体地用于人类。
上文中描述的活性剂(例如宿主细胞或TCR)优选以治疗有效量存在于药物组合物中。“治疗有效量”意指引发所需治疗效应的活性剂的量。治疗效能和毒性可通过标准程序、例如在细胞培养物或测试动物中测定,例如ED50(在50%群体中治疗有效的剂量)和LD50(对50%群体致死的剂量)。治疗效应与毒性效应之间的剂量比率是治疗指数,并且其可表示为比率ED50/LD50。展现较大治疗指数的药物组合物是优选的。
剂量
TCR多核苷酸、载体或宿主细胞的确切剂量可由本领域技术人员使用已知技术确定。合适的剂量提供足够量的本发明的活性剂,并且优选地治疗有效,即引发所需的治疗效应。
如本领域所知,可能需要针对治疗目的(例如缓解维持与疾病急性发作)、施用途径、时间和频率、施用配制剂的时间和频率、年龄、体重、一般健康状况、性别、饮食、疾病状态的严重程度、药物组合、反应敏感性和对治疗的耐受性/应答进行调整。适用于例如如本文所述的可溶性TCR的剂量范围可使用从细胞培养测定和动物研究中获得的数据确定,并可包括ED50。通常,剂量值可从0.1微克至100000微克变化,最高总剂量约为2克,这取决于施用途径。本发明的活性剂的示例性剂量在约0.01mg/kg至约10mg/kg、约0.1mg/kg至约10mg/kg、约1mg/kg至约10mg/kg、约1mg/kg至约5mg/kg、约0.01mg/kg至约1mg/kg或约0.1mg/kg至约1mg/kg的范围内。文献中提供了关于特定剂量和递送方法的指南。认识到治疗可能需要单次施用治疗有效剂量,或多次施用治疗有效剂量的本发明的活性剂。例如,一些药物组合物可每3-4天、每周或每两周一次、或一个月内一次施用,这取决于特定组合物的配制剂、半衰期和清除率。如前所述,药物组合物可任选地包含一种或多种赋形剂和/或额外活性剂。
赋形剂
术语“赋形剂”包括填充剂、粘合剂、崩解剂、包衣、吸附剂、抗粘附剂、助流剂、防腐剂、抗氧化剂、矫味剂、着色剂、甜味剂、溶剂、共溶剂、缓冲剂、螯合剂、粘度赋予剂、表面活性剂、稀释剂、保湿剂、载体、稀释剂、防腐剂、乳化剂、稳定剂和张力调节剂。选择适用于制备本发明的所需药物组合物的赋形剂在本领域技术人员的知识范围内。用于本发明的药物组合物的示例性载体包括盐水、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用的活性剂、待治疗的疾病和药物组合物的所需配制剂。
额外活性剂
本发明进一步提供药物组合物,其包含一种或多种上述指定的本发明的活性剂(例如宿主细胞或TCR构建体),以及一种或多种适用于治疗和/或预防待治疗的疾病的额外活性剂。适用于组合的活性成分的优选实例包括已知的抗癌药物,诸如顺铂(cis-platin)、美登素(mayt ansine)衍生物、拉奇霉素(rachelmycin)、卡奇霉素(calicheamicin)、多西他赛(docetaxel)、依托泊苷(etoposide)、吉西他滨(gemcitabine)、异环磷酰胺(ifosfamide)、伊立替康(irinotecan)、美法仑(melphalan)、米托蒽醌(mitoxantrone)、索吩姆钠光卟啉II(sorfimer sodiumphotofrin)、替莫唑胺(temozolmide)、托泊替康(topotecan)、葡糖醛酸三甲曲沙(trimetreate glucuronate)、奥里斯他汀E(auristatinE)长春新碱(vincristine)和多柔比星(doxorubicin);以及肽细胞毒素,诸如蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、DNA酶和RNA酶;放射性核素,诸如碘131、铼186、铟111、钇90、铋210和213、锕225和砈213;前药,诸如抗体导向的酶前药;免疫刺激剂,诸如IL-2、趋化因子(诸如IL-8、血小板因子4、黑色素瘤生长刺激蛋白等)、抗体或其片段(诸如抗CD3抗体或其片段)、补体激活剂、异种蛋白结构域、同种异体蛋白结构域、病毒/细菌蛋白结构域和病毒/细菌肽。
施用
多种途径可用于施用根据本发明的药物组合物。通常,施用是亲本(parentally)完成。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。
配制剂
本发明的药物组合物可配制成各种形式,这尤其取决于所用的活性剂(例如可溶性TCR),例如呈固体、液体、气体或冻干形式,并且尤其可呈软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液、气溶胶、颗粒、丸剂、悬浮剂、乳液、胶囊、糖浆、液体、酏剂、提取物、酊剂或液体提取物的形式,或者呈特别适合于所需施用方法的形式。本身已知用于产生药物的方法在第22版Remington’s Pharmaceutical Sciences(Ed.Maack Publishing Co,Easton,Pa.,2012)中指示,并且可包括例如常规混合、溶解、制粒、制糖衣、磨细、乳化、包封、包埋或冻干方法。包含例如如本文所述的宿主细胞或可溶性TCR的药物组合物通常以液体形式提供,并且优选包含药学上可接受的缓冲剂。
在制备本发明的药物组合物之后,可将它们置于适当容器中并标记用于所指示病状的治疗。例如,此类标记应包括施用的量、频率和方法。
治疗
鉴于上文,本发明因此提供如本文所述的用作检测、诊断、预后、预防和/或治疗癌症的药物的TCR、核酸、载体和/或宿主细胞。
TCR、核酸、载体和/或宿主细胞通常可用于疾病或病症的治疗检测、诊断、预后、预防和/或治疗。术语“治疗”以其所有语法形式包括有需要的受试者的治疗性或预防性治疗。“治疗性或预防性治疗”包括旨在完全预防临床和/或病理表现的预防性治疗或旨在改善或缓解临床和/或病理表现的治疗性治疗。因此,术语“治疗”也包括疾病的改善或预防。
当使用本发明的药物组合物时设想治疗的所述疾病优选地选自由以下组成的组的癌症:黑色素瘤、膀胱癌、结肠癌和乳腺癌、肉瘤、前列腺癌、子宫癌、葡萄膜癌、葡萄膜黑色素瘤、鳞状头颈癌、滑膜癌、尤因氏肉瘤、三阴性乳腺癌、甲状腺癌、睾丸癌、肾癌、胰脏癌、卵巢癌、食管癌、非小细胞肺癌、非霍奇金氏淋巴瘤、多发性骨髓瘤、黑色素瘤、肝细胞癌、头颈癌、胃癌、子宫内膜癌、结肠直肠癌、胆道癌、乳腺癌、膀胱癌、骨髓性白血病和急性淋巴母细胞性白血病,优选其中癌症选自由以下组成的组:NSCLC、SCLC、乳腺癌、卵巢癌或结肠直肠癌、肉瘤或骨肉瘤。
术语“受试者”或“个体”或“动物”或“患者”在本文中可互换使用,以指需要疗法的任何受试者,特别是哺乳动物受试者。哺乳动物受试者通常包括人类、非人类灵长类动物、狗、猫、豚鼠、兔、大鼠、小鼠、马、牛、牛等。然而,应容易地理解,本文提供的TCR、核酸、载体、宿主细胞和药物组合物尤其设想用于治疗人类受试者,特别是HLA-A2阳性受试者。
直接施用
对于疗法,本发明的TCR(特别是本发明的可溶性TCR)、核酸、载体(诸如病毒载体)或宿主细胞可直接施用给有需要的受试者。因此,本发明提供用于检测、诊断、预测、预防和/或治疗癌症的方法中的TCR、核酸、载体或宿主细胞。所述方法可包括以下步骤:(a)提供本发明的(i)TCR、(ii)核酸、(iii)载体、(iv)宿主细胞和/或(v)药物组合物中的一种或多种;以及(b)将(i)-(v)中的一种或多种施用给有需要的受试者。任选地,所述方法可包括癌症疗法(例如辐射)或施用一种或多种抗癌剂的又一步骤。
离体治疗
根据本发明的治疗还可包括以下步骤:(a)提供受试者的样品,所述样品包含淋巴细胞;(b)提供本发明的(i)TCR、(ii)核酸、(ii)载体、(iv)宿主细胞和/或(v)药物组合物中的一种或多种,(c)将步骤(b)的(i)至(v)中的一种或多种引入步骤(a)的淋巴细胞中,从而获得修饰的淋巴细胞,(d)将步骤(c)的修饰的淋巴细胞施用给有需要的受试者或患者。
特别设想步骤(a)中提供的淋巴细胞是如上文所述的“效应宿主细胞”,并且有利地选自T细胞、NK细胞和/或NKT细胞,尤其是CD8+T细胞;并且可在先前步骤中通过本领域已知的常规方法从受试者的样品(特别是血液样品)获得。然而,也可想到使用优选能够表达本发明的TCR并发挥如本文所述的所需生物效应物功能的其它淋巴细胞。此外,通常选择所述淋巴细胞以与受试者的免疫系统相容,即它们将优选不引发免疫原性应答。例如,可想到使用“通用受体细胞”,即可在体外生长和扩增的发挥所需生物效应物功能的通用相容性淋巴细胞。因此,所述细胞的使用将避免需要获得和提供步骤(a)中受试者自身的淋巴细胞。
步骤(c)的离体引入可通过将本文所述的核酸或载体通过电穿孔引入淋巴细胞,或通过用病毒载体(诸如如先前在效应宿主细胞上下文中所述的慢病毒或逆转录病毒载体)感染淋巴细胞来进行。其它可想到的方法包括使用转染试剂,诸如脂质体,或瞬时RNA转染。通过例如(逆)病毒载体或瞬时RNA转染将抗原特异性TCR基因转移到(原代)T细胞中代表了产生肿瘤相关抗原特异性T细胞的有前景的工具,所述肿瘤相关抗原特异性T细胞随后可被重新引入供体,在所述供体中,它们特异性地靶向并破坏表达所述抗原的肿瘤细胞。在本发明中,所述肿瘤相关抗原是如本文定义的PRAME,特别是其HLA-A*02结合形式。
根据本发明的治疗还可包括以下步骤:(a)提供受试者的样品,所述样品包含淋巴细胞;而所述治疗由以下组成:(b)提供(i)TCR、(ii)核酸、(iii)载体、(iv)宿主细胞和(v)药物组合物中的一种或多种;(c)将步骤(b)的(i)至(v)中的一种或多种引入步骤的淋巴细胞中,从而获得修饰的淋巴细胞,(d)将步骤(c)的修饰的淋巴细胞施用给有需要的受试者或患者。
鉴于上文,因此,本发明的另一方面是如本文别处所述的TCR、核酸序列、载体和/或宿主细胞用于产生修饰的淋巴细胞的用途。用于将例如核酸和载体引入淋巴细胞的方式和方法已在本文别处描述。
诊断组合物
本发明还提供诊断组合物,其包含作为一种或多种诊断剂的如本文所述的TCR、核酸、载体和/或宿主细胞。通常,所述诊断剂将包括用于检测其与其抗原性靶结合的构件,例如如在本发明的TCR构建体的上下文中所述的标记。关于宿主细胞,例如可想到使用修饰的宿主细胞,其包含在抗原识别时释放的染料或造影剂(而不是细胞毒性颗粒)。
用途
本发明设想上文中所述的诊断剂用于检测、诊断和/或预测受试者的癌症的用途,其可在体内或体外完成。
因此,本发明提供用于在体内检测、诊断受试者的癌症的诊断组合物,所述组合物包含作为诊断剂的本发明的TCR、核酸、载体和/或宿主细胞。所述方法通常包括(a)将所述诊断剂施用给受试者,以及(b)检测所述诊断剂与其抗原性靶的结合。
此外,本发明提供体外检测、诊断和/或预测受试者的癌症的方法。根据本发明,还提供检测受试者的癌症的存在的方法,所述方法包括以下步骤:(a)提供受试者的样品,所述样品包含一种或多种细胞;(b)使所述样品与本发明的TCR、宿主细胞和/或药物组合物接触;从而形成复合体,以及(c)检测所述复合体。设想所述复合体指示诊断剂与其抗原性靶的结合,并且指示表达所述抗原性靶的(癌)细胞的存在。
在两种方法中,诊断剂与其抗原性靶的结合通过使用本领域已知的常规方法是可检测的,并且尤其将取决于所使用的特异性诊断剂。可与本发明的诊断剂偶联的合适的标记在与标记的TCR构建体相关的部分中例示。
此外,本发明设想包括如本文所述的TCR、核酸或载体用于产生修饰的淋巴细胞的用途。如本文别处所述,优选的淋巴细胞包括但不限于细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞。
必须注意,除非上下文另有明确说明,否则如本文使用的单数形式“一”(“a”、“an”)和“所述”包括多个指示物。因此,例如,对“试剂”的提及包括一种或多种所述不同试剂,对“所述方法”的提及包括提及本领域普通技术人员已知的等同步骤和方法,可对其进行修改或取代用于本文所述的方法。
除非另外指示,否则一系列要素之前的术语“至少”应理解为指该系列中的每个要素。本领域技术人员将认识到,或者能够仅使用常规实验来确定,本文所述的本发明的具体实施方案的许多等同物。本发明旨在包括所述等同物。
本文使用的术语“和/或”包括“和”、“或”和“由所述术语连接的要素的所有或任何其它组合”的含义。
如本文使用的术语“约”或“大约”意指在给定值或范围的20%以内,优选10%以内,更优选5%以内。然而,它也包括具体数字,例如“约20”包括20。
术语“小于”或“大于”包括具体数字。例如,小于20意指小于或等于。类似地,超过或大于分别意指超过或等于,或大于或等于。
在整个说明书和随后的权利要求中,除非上下文另有要求,否则词语“包含(comprise)”以及诸如“包含(comprises)”和“包含(comprising)”的变化形式应理解为暗示包括所陈述的整数或步骤或整数或步骤的组,而不排除任何其它整数或步骤或整数或步骤的组。当在本文中使用时,术语“包含(comprising)”可用术语“含有(containing)”或“包括(including)”取代,或者有时当在本文中使用时,用术语“具有”取代。
当在本文中使用时,“由……组成”排除在权利要求要素中未指定的任何要素、步骤或成分。当在本文中使用时,“基本上由……组成”不排除实质上不影响权利要求的基本和新颖特征的材料或步骤。
在本文的每种情况下,术语“包括”、“基本上由……组成”和“由……组成”中的任一个都可用另两个术语中的任一个替代。
应理解,本发明不限于本文所述的特定方法、方案、材料、试剂和物质等并且因此可变化。本文所用的术语仅仅是为了描述特定实施方案目的,而不旨在限制本发明的范围,本发明的范围仅由权利要求来限定。
本说明书全文引用的所有出版物和专利(包括所有专利、专利申请、科学出版物、制造商的指示、说明书等)无论是上文还是下文,都通过引用整体并入本文。本文中的任何内容都不应理解为承认本发明无权凭借先前的发明先于此类公开。如果通过引用并入的材料与本规范相矛盾或不一致,则本说明书将取代任何此类材料。
从下面的实施例中将获得对本发明及其优点的更好理解,所提供的实施例仅用于说明的目的。实施例并不旨在以任何方式限制本发明的范围。
本发明的实施例
以下实施例说明了本发明,但不应理解为限制本发明的范围。
表2:实施例中测试的TCR的概述。
实施例1:肽特异性
在37℃下,用浓度为10-5M的特异性SLL肽(SLLQHLIGL)或不相关肽(GLSNTHVL)负载T2细胞1.5小时。然后将这些细胞与TCR转导的T细胞以1:1的效应物:靶比率(使用10.000个效应细胞/96孔)共培养。20小时后,使用标准IFN-γELISA测量细胞培养上清液中的IFN-γ水平。除阴性对照(negative control,neg.contr.)TCR外,所有TCR转导的效应细胞当负载在T2细胞上时,都显示对特异性SLL肽、而非不相关肽的识别(图1)。
实施例2:功能亲合力
本实验的目标是测量SLL肽特异性TCR的功能亲和力。功能亲合力是指诸如转基因TCR和pMHC复合体之间的单独非共价结合相互作用的多重亲合力的累积强度。TCR转基因T细胞群体的功能性亲和力测量为与负载有分级(滴定)量的SLL肽(10-5M至10-12M;负载在37℃下执行1.5小时)的T2细胞(效应物:靶为1:1,10.000个效应细胞/96孔)的共培养物中的半最大相对IFN-γ释放(EC50值)。
使用的读出是共培养20小时后的标准IFN-γELISA(使用三次多项式外推4000pg以上的值)。
结果:
与3825TCR转导的T细胞相比,027-004TCR转导的T细胞显示更高的功能亲合力,指示对极低量的靶肽的敏感性更高(图2)。
与用本领域公开的TCR转导的T细胞相比,027-004TCR转导的T细胞显示更高的功能亲合力,指示对极低量的靶肽的敏感性更高(图13)。
实施例3:TCR识别基序(丝氨酸和苏氨酸扫描)
本实验的目的是评价SLL表位序列中的关键残基,所述关键残基对于由TCR的直接识别或与HLA-A*02:01编码分子的肽结合是必不可少的。氨基酸取代扫描用于定义表位序列中的关键氨基酸,每当这些残基更换为氨基酸丝氨酸或苏氨酸时,所述关键氨基酸会消除由TCR的识别。这些“固定”氨基酸可用于定义独特TCR识别基序。丝氨酸或苏氨酸残基用于系统地替代PRAME肽中的单独氨基酸(丝氨酸和苏氨酸扫描)。
TCR转导的T细胞与T2细胞的体外共培养物分别以1:1的E:T比率(10.000个效应细胞/96孔)负载(在37℃下1.5小时)10-5M的不同肽。
读出:共培养20小时后的标准IFN-γELISA(使用三次多项式外推4000pg以上的值)。
结果:
在丝氨酸扫描中,与3825TCR转导的T细胞相比,027-004TCR转导的T细胞显示具有较少固定位置的不同识别基序(图3)。
在苏氨酸扫描中,027-004TCR转导的T细胞显示与本领域公开的其它TCR不同的识别基序(图12)。
表3:用于肿瘤细胞识别的靶细胞的概述。*数据源自http://celll ines.tron-mainz.de/。
表4:用于肿瘤细胞杀伤的靶细胞的概述。*数据源自http://celll ines.tron-mainz.de/。
实施例4:肿瘤细胞识别和肿瘤细胞杀伤
对于肿瘤细胞识别,将用TCR 027-004或TCR 3825转导的效应细胞与PRAMESLL阳性或PRAMESLL阴性肿瘤细胞以1:1的E:T比率(10.000个效应细胞/96孔)在37℃、6%CO2下共培养20小时。使用标准IFN-γELISA确定效应细胞的IFN-γ分泌(使用三次多项式外推4000pg以上的值)。
结果:
与3825TCR转导的T细胞相比,TCR 027-004转导的效应细胞显示对肿瘤细胞(例如MeIA375)的识别更好(图4)。
与用本领域已知的TCR转导的T细胞相比,TCR 027-004转导的效应细胞显示对肿瘤细胞(MeIA375、NCI-H1650和NCI-H1703)的识别更好(图14)。
在每孔添加20.000个效应细胞后,添加肿瘤细胞(在647V的情况下为2.500个细胞,对于所有其它肿瘤细胞系为5.000个细胞),并将培养板转移至IncuCyte装置,并在37℃和6%CO2下在100小时内监测红色荧光细胞的扩增,每4小时拍摄照片。
所有TCR转导的效应细胞裂解PRAMESLL阳性肿瘤细胞(PRAME-pos),并且不影响PRAMESLL阴性肿瘤细胞(PRAME-neg)的生长。
结果:
与3825TCR转导的T细胞相比,TCR 027-004转导的效应细胞显示对肿瘤细胞(例如MeIA375)的杀伤更好(图5)。
与用本领域已知的TCR转导的T细胞相比,TCR 027-004转导的效应细胞显示对肿瘤细胞(MeIA375和NCI-H1650)的杀伤更好(图15)。
实施例5:正常细胞识别
这组实验的目标是评价可由PRAME特异性TCR转导的效应细胞引起的潜在中靶/脱瘤和脱靶毒性。为此,测试表达HLA-A*02:01的原代细胞和代表必需组织或器官的诱导的多潜能干细胞(iPS)源细胞系是否由TCR转导的T细胞识别。
根据单独靶细胞类型以调整的E:T比率进行体外共培养实验(40.000个效应细胞/96孔)。根据单独靶的性质,在共培养开始前1至7天,以按照制造商的指示的细胞密度接种细胞,并在平底孔中以单层培养。在培养基中使用低剂量IFN-γ诱导神经元上的HLA-A2表达。
通过定量即时聚合酶链式反应(qPCR)分析所有测试的正常细胞的PRAME mRNA表达,以区分中靶/脱瘤毒性与潜在的脱靶毒性。负载10-5M肽的靶细胞用作内部阳性对照(SLL肽)。
读出:共培养20小时后的标准IFN-γ/IL-2ELISA。
结果:TCR转导的T细胞群体不以导致高水平的IFN-γ产生的方式识别未负载的正常细胞。然而,如果细胞负载有特异性SLL肽,则它们就会被识别。仅与未负载的RPTEC的共培养物在两个样品中都产生最少IFN-γ产生,这是因为已知这种细胞类型中PRAME的已知内源性表达(图6)。
实施例6:HLA-A*02精细分型
实验的目标是确定常见HLA-A2亚等位基因(HLA-A*02:xx;等位基因命名根据:www.hla.alleles.org)而非HLA-A*02:01,它们能够呈递PRAMESLL表位并可由单独SLL特异性TCR识别(HLA限制性精细分型)。因此,表达这些识别的HLA-A2亚等位基因的患者也可纳入研究队列(图7)。
将E:T比率为1:2(10.000个效应细胞/96孔)的TCR转导的T细胞与选择的HLA-A2亚等位基因阳性成淋巴细胞样细胞系(LCL;EBV转变的B细胞)在37℃、6%CO2下体外共培养20小时。使用一个供体的TCR转导的PBL作为效应细胞。在37℃下,对所有单独LCL小鼠负载10- 5M SLL肽1.5小时,并与相应的效应细胞共培养,并测试IFN-γ分泌,以确定转导的T细胞的独特TCR亚等位基因识别。未负载的靶细胞用作阴性对照。
读出:共培养20小时后的标准IFN-γELISA。
结果:027-004高效地识别10个测试的HLA-A2亚等位基因A*02:xx)中的3个所呈递的PRAME肽。HLA-A2亚等位基因A*02:02和A*02:04的识别水平与A*02:01相当。对照3825高效地识别由10个测试的HLA-A2亚等位基因(A*02:xx)中的1个所呈递的PRAME肽,即识别HLA-A2亚等位基因A*02:01(图8-10)。
参考文献:
Altschul,et al.,(1997)Nucleic Acids Res.25:3389-3402,
Altschul,et al.,(1990)J.Mol.Biol.215:403-410,
Chen et al.,Adv Drug Deliv Rev.2013 Oct.15;65(10):1357-1369
Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press,NewYork(2012)
EP2173869(A2)
Gargett and Brown Front Pharmacol.2014;5:235
Kieback et al,Proc Natl Acad Sci USA.2008 Jan.15;105(2):623-8
Maack Publishing Co,Easton,Pa.,2012
Sambrook et al.,Molecular Cloning:A Laboratory Manual(4th edition),
Schmitt et al.,Hum Gene Ther.2009 November;20(11):1240-1248
Smith,et al.,(1981)J.Mol.Biol.147:195-197
Sommermeyer and Uckert,J Immunol.2010 Jun.1;184(11):6223-31
Walseng et al.,(2015),PLoS ONE 10(4):e0119559
Weis,Manon(2015):Charakterisierung Antigen-spezifischer T-Zellen nachInduktion in TCR-humanisiertenDissertation,LMU MünchenVeterinary Faculty Ludwigs University of Munich.
Xue et al.,Clin Exp Immunol.2005 February;139(2):167-172;
Fiedl et al.,Clin Cancer Res 2016 March;22(5):1234-1242 for DLBCL
Mitsuhashi et al.,Hematology 2014,1/2014
Al-Khadairi et al.,Journal of Translational Medicine 2019;17:9
WO2019/175209A1
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Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
20 25 30
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
35 40 45
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
50 55 60
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
65 70 75 80
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
85 90 95
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
100 105 110
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
115 120 125
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135 140
<210> 27
<211> 177
<212> PRT
<213> 人工(artificial)
<220>
<223> TCR β-01恒定,源自人类
<400> 27
Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
1 5 10 15
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
50 55 60
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
65 70 75 80
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
85 90 95
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
100 105 110
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
115 120 125
Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly Val Leu Ser
130 135 140
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
145 150 155 160
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
165 170 175
Phe
<210> 28
<211> 179
<212> PRT
<213> 人工(artificial)
<220>
<223> TCR β-02恒定,源自人类
<400> 28
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
1 5 10 15
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
50 55 60
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
65 70 75 80
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
85 90 95
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
100 105 110
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
115 120 125
Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser
130 135 140
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
145 150 155 160
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
165 170 175
Ser Arg Gly
<210> 29
<211> 140
<212> PRT
<213> 人工(artificial)
<220>
<223> TCR α恒定,源自小鼠
<400> 29
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
1 5 10 15
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
20 25 30
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
35 40 45
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
50 55 60
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
65 70 75 80
Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp Val
85 90 95
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
100 105 110
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
115 120 125
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135 140
<210> 30
<211> 179
<212> PRT
<213> 人工(artificial)
<220>
<223> TCR β恒定,源自小鼠
<400> 30
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
1 5 10 15
Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
50 55 60
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
65 70 75 80
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
85 90 95
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
100 105 110
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
115 120 125
Ala Asp Cys Gly Ile Thr Ser Arg Ser Tyr His Gln Gly Val Leu Ser
130 135 140
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
145 150 155 160
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
165 170 175
Ser Arg Gly
<210> 31
<211> 136
<212> PRT
<213> 人工(artificial)
<220>
<223> TCR α murC恒定,鼠类化
<400> 31
Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser
1 5 10 15
Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn
20 25 30
Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr Val
35 40 45
Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp
50 55 60
Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn
65 70 75 80
Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu
85 90 95
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser Val
100 105 110
Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu
115 120 125
Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 32
<211> 173
<212> PRT
<213> 人工(artificial)
<220>
<223> TCR β murC恒定,鼠类化
<400> 32
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Thr Leu Phe Glu Pro
1 5 10 15
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys
50 55 60
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
65 70 75 80
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
85 90 95
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
100 105 110
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
115 120 125
Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu
130 135 140
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
145 150 155 160
Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser
165 170
<210> 33
<211> 509
<212> PRT
<213> 人工(artificial)
<220>
<223> PRAME全长,源自人类
<400> 33
Met Glu Arg Arg Arg Leu Trp Gly Ser Ile Gln Ser Arg Tyr Ile Ser
1 5 10 15
Met Ser Val Trp Thr Ser Pro Arg Arg Leu Val Glu Leu Ala Gly Gln
20 25 30
Ser Leu Leu Lys Asp Glu Ala Leu Ala Ile Ala Ala Leu Glu Leu Leu
35 40 45
Pro Arg Glu Leu Phe Pro Pro Leu Phe Met Ala Ala Phe Asp Gly Arg
50 55 60
His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr Cys
65 70 75 80
Leu Pro Leu Gly Val Leu Met Lys Gly Gln His Leu His Leu Glu Thr
85 90 95
Phe Lys Ala Val Leu Asp Gly Leu Asp Val Leu Leu Ala Gln Glu Val
100 105 110
Arg Pro Arg Arg Trp Lys Leu Gln Val Leu Asp Leu Arg Lys Asn Ser
115 120 125
His Gln Asp Phe Trp Thr Val Trp Ser Gly Asn Arg Ala Ser Leu Tyr
130 135 140
Ser Phe Pro Glu Pro Glu Ala Ala Gln Pro Met Thr Lys Lys Arg Lys
145 150 155 160
Val Asp Gly Leu Ser Thr Glu Ala Glu Gln Pro Phe Ile Pro Val Glu
165 170 175
Val Leu Val Asp Leu Phe Leu Lys Glu Gly Ala Cys Asp Glu Leu Phe
180 185 190
Ser Tyr Leu Ile Glu Lys Val Lys Arg Lys Lys Asn Val Leu Arg Leu
195 200 205
Cys Cys Lys Lys Leu Lys Ile Phe Ala Met Pro Met Gln Asp Ile Lys
210 215 220
Met Ile Leu Lys Met Val Gln Leu Asp Ser Ile Glu Asp Leu Glu Val
225 230 235 240
Thr Cys Thr Trp Lys Leu Pro Thr Leu Ala Lys Phe Ser Pro Tyr Leu
245 250 255
Gly Gln Met Ile Asn Leu Arg Arg Leu Leu Leu Ser His Ile His Ala
260 265 270
Ser Ser Tyr Ile Ser Pro Glu Lys Glu Glu Gln Tyr Ile Ala Gln Phe
275 280 285
Thr Ser Gln Phe Leu Ser Leu Gln Cys Leu Gln Ala Leu Tyr Val Asp
290 295 300
Ser Leu Phe Phe Leu Arg Gly Arg Leu Asp Gln Leu Leu Arg His Val
305 310 315 320
Met Asn Pro Leu Glu Thr Leu Ser Ile Thr Asn Cys Arg Leu Ser Glu
325 330 335
Gly Asp Val Met His Leu Ser Gln Ser Pro Ser Val Ser Gln Leu Ser
340 345 350
Val Leu Ser Leu Ser Gly Val Met Leu Thr Asp Val Ser Pro Glu Pro
355 360 365
Leu Gln Ala Leu Leu Glu Arg Ala Ser Ala Thr Leu Gln Asp Leu Val
370 375 380
Phe Asp Glu Cys Gly Ile Thr Asp Asp Gln Leu Leu Ala Leu Leu Pro
385 390 395 400
Ser Leu Ser His Cys Ser Gln Leu Thr Thr Leu Ser Phe Tyr Gly Asn
405 410 415
Ser Ile Ser Ile Ser Ala Leu Gln Ser Leu Leu Gln His Leu Ile Gly
420 425 430
Leu Ser Asn Leu Thr His Val Leu Tyr Pro Val Pro Leu Glu Ser Tyr
435 440 445
Glu Asp Ile His Gly Thr Leu His Leu Glu Arg Leu Ala Tyr Leu His
450 455 460
Ala Arg Leu Arg Glu Leu Leu Cys Glu Leu Gly Arg Pro Ser Met Val
465 470 475 480
Trp Leu Ser Ala Asn Pro Cys Pro His Cys Gly Asp Arg Thr Phe Tyr
485 490 495
Asp Pro Glu Pro Ile Leu Cys Pro Cys Phe Met Pro Asn
500 505
Claims (30)
1.一种能够结合PRAME肽的T细胞受体(TCR),所述PRAME肽具有氨基酸序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式,其中所述TCR包括:
a)TCRα链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:6)或与SEQ ID NO:6具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;TCRα链可变区的CDR1,其包含氨基酸序列SEQ ID NO:2或由所述氨基酸序列组成;以及TCRα链可变区的CDR2,其包含氨基酸序列SEQ ID NO:4或由所述氨基酸序列组成,以及
b)TCRβ链可变区的CDR3,其包含氨基酸序列(SEQ ID NO:7)或与SEQ ID NO:7具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;TCRβ链可变区的CDR1,其包含氨基酸序列SEQ ID NO:3或由所述氨基酸序列组成;以及TCRβ链可变区的CDR2,其包含氨基酸序列SEQ ID NO:5或由所述氨基酸序列组成。
2.根据权利要求1所述的TCR,其中所述HLA-A2是HLA-A*02:01、HLA-A*02:02或HLA-A*02:04编码分子。
3.根据权利要求1或2所述的TCR,其中与序列SLLQHLIGL(SEQ ID NO:1)或其一部分或它的HLA-A2结合形式的结合诱导用所述TCR转导或转染的细胞的IFN-γ分泌。
4.根据权利要求1至3中任一项所述的TCR,其中如通过IFN-γ免疫测定法测量,半最大IFN-γ分泌小于10-7M。
5.根据前述权利要求中任一项所述的TCR,其中所述TCR包括:
a)TCRα链,其包含具有氨基酸序列SEQ ID NO:2的CDR1、具有氨基酸序列SEQ ID NO:4的CDR2和具有氨基酸序列SEQ ID NO:6的CDR3,以及
b)TCRβ链,其包含具有氨基酸序列SEQ ID NO:3的CDR1、具有氨基酸序列SEQ ID NO:5的CDR2和具有氨基酸序列SEQ ID NO:7的CDR3。
6.根据前述权利要求中任一项所述的TCR,所述TCR包括
a)TCRα链可变区,其包含氨基酸序列SEQ ID NO:8或由所述氨基酸序列组成,以及
b)TCRβ链可变区,其包含氨基酸序列SEQ ID NO:9或由所述氨基酸序列组成。
7.根据前述权利要求中任一项所述的TCR,所述TCR包括
a)TCRα链,其包含选自SEQ ID NO:10的氨基酸序列或与SEQ ID NO:10具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成;以及
b)TCRβ链,其包含选自SEQ ID NO:11的氨基酸序列或与SEQ ID NO:11具有至少80%同一性、优选至少85%同一性、更优选90%或95%同一性的氨基酸序列,或由所述氨基酸序列组成。
8.根据前述权利要求中任一项所述的TCR,所述TCR包括彼此共价连接以形成TCR异源二聚体或多聚体的至少一个TCRα链和至少一个TCRβ链。
9.根据前述权利要求中任一项所述的TCR,所述TCR选自初始TCR、TCR变体、TCR片段或TCR构建体。
10.根据前述权利要求中任一项所述的TCR,所述TCR还包括一或多种任选地选自以下的融合组分:Fc受体;Fc结构域,包括IgA、IgD、IgG、IgE和IgM;细胞因子,包括IL-2或IL-15;毒素;抗体或其抗原结合片段,包括抗CD3、抗CD28、抗CDS、抗CD16或抗CD56抗体或其抗原结合片段;CD247(CD3-ζ)、CD28、CD137、CD134结构域或它们的组合,任选还包括至少一种接头。
11.根据前述权利要求中任一项所述的TCR,所述TCR包括
a)至少一个如权利要求1至10中任一项所限定的TCRα链;和/或
b)至少一个如权利要求1至10中任一项所限定的TCRβ链;和/或
c)针对淋巴细胞表面上的抗原或表位的抗体或单链抗体片段(scFv),
其中所述TCRα链和TCRβ链彼此连接,并且任选地通过接头与所述抗体或scFv融合。
12.根据权利要求11所述的TCR,其中所述抗原选自CD3、CD28、CD5、CD16或CD56。
13.根据前述权利要求中任一项所述的TCR,所述TCR还包括至少一种分子标记。
14.根据前述权利要求中任一项所述的TCR,所述TCR是可溶性的。
15.一种核酸,所述核酸编码根据前述权利要求中任一项所述的TCR。
16.根据权利要求15所述的核酸,所述核酸包含SEQ ID NO:13、14、15、16、17、18、19、20、21或22的核酸序列。
17.一种载体,所述载体包含根据权利要求15或16所述的核酸。
18.一种宿主细胞,所述宿主细胞包含根据权利要求1至14中任一项所述的TCR、根据权利要求15或16所述的核酸序列或根据权利要求17所述的载体。
19.根据权利要求18所述的宿主细胞,所述宿主细胞选自淋巴细胞,包括但不限于细胞毒性T淋巴细胞(CTL)、CD8+T细胞、CD4+T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、γ/δ-T细胞。
20.一种获得根据前述权利要求中任一项所述的TCR的方法,所述方法包括
a)在引起所述TCR表达的条件下孵育根据权利要求18或19所述的宿主细胞,
b)纯化所述TCR。
21.一种药物或诊断组合物,所述药物或诊断组合物包含以下中的一种或多种:
a)根据权利要求1至14中任一项所述的TCR;
b)根据权利要求15或16所述的核酸;
c)根据权利要求17所述的载体;和/或
d)根据权利要求18或19所述的宿主细胞,
以及任选药学赋形剂。
22.根据权利要求21所述的药物组合物,所述药物组合物还包含检查点抑制剂。
23.根据权利要求22所述的药物组合物,其中所述检查点抑制剂选自由以下组成的组:CTLA-4抑制剂、PD-1抑制剂和PD-L1抑制剂。
24.根据权利要求1至14中任一项所述的TCR、根据权利要求15或16所述的核酸、根据权利要求17所述的载体和/或根据权利要求18或19所述的宿主细胞,其用作药物。
25.根据权利要求1至14中任一项所述的TCR、根据权利要求15或16所述的核酸、根据权利要求17所述的载体和/或根据权利要求18或19所述的宿主细胞,其用于癌症的检测、诊断、预后、预防和/或治疗。
26.如权利要求25所述的使用的TCR、核酸、载体和/或宿主细胞,其中所述癌症优选选自由以下组成的组:黑色素瘤、膀胱癌、结肠癌和乳腺癌、肉瘤、前列腺癌、子宫癌、葡萄膜癌、葡萄膜黑色素瘤、鳞状头颈癌、滑膜癌、尤因氏肉瘤、三阴性乳腺癌、甲状腺癌、睾丸癌、肾癌、胰脏癌、卵巢癌、食管癌、非小细胞肺癌、非霍奇金氏淋巴瘤、多发性骨髓瘤、黑色素瘤、肝细胞癌、头颈癌、胃癌、子宫内膜癌、结肠直肠癌、胆道癌、乳腺癌、膀胱癌、骨髓性白血病和急性淋巴母细胞性白血病,优选其中所述癌症选自由以下组成的组:NSCLC、SCLC、乳腺癌、卵巢癌或结肠直肠癌、肉瘤或骨肉瘤。
27.如权利要求25所述的使用的TCR、核酸、载体和/或宿主细胞,其中癌症的预防和/或治疗包括:
a)提供以下中的一种或多种
(i)根据权利要求1至14中任一项所述的TCR;
(ii)根据权利要求15或16所述的核酸;
(iii)根据权利要求17所述的载体;
(iv)根据权利要求18或19所述的宿主细胞;和
(v)根据权利要求21至23中任一项所述的药物组合物;以及
b)将(i)至(v)中的至少一种施用给有需要的受试者。
28.如权利要求25至27中任一项所述的使用的TCR、核酸、载体和/或宿主细胞,其中癌症的预防和/或治疗包括:
a)提供受试者的样品,所述样品包含淋巴细胞;
b)提供以下中的一种或多种
(i)根据权利要求1至14中任一项所述的TCR;
(ii)根据权利要求15或16所述的核酸;
(iii)根据权利要求17所述的载体;
(iv)根据权利要求18或19所述的宿主细胞;和
(v)根据权利要求21至23中任一项所述的药物组合物;
c)将步骤(b)的(i)至(v)中的一种或多种引入步骤(a)的所述淋巴细胞中,从而获得修饰的淋巴细胞,
d)将步骤(c)的所述修饰的淋巴细胞施用给有需要的受试者或患者。
29.一种体外检测受试者中癌症的存在的方法,所述方法包括:
(a)提供受试者的样品,所述样品包含一种或多种细胞;
(b)使所述样品与以下接触
(i)根据权利要求1至14中任一项所述的TCR;
(ii)根据权利要求18或19所述的宿主细胞;和/或
(iii)根据权利要求21所述的药物组合物;
从而形成复合体,以及
(c)检测所述复合体,
其中检测到所述复合体指示所述受试者中所述癌症的所述存在。
30.根据权利要求1至14中任一项所述的TCR、根据权利要求15或16所述的核酸和/或根据权利要求17所述的载体用于产生修饰的淋巴细胞的用途。
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PE20200614A1 (es) | 2017-07-14 | 2020-03-11 | Immatics Biotechnologies Gmbh | Molecula de polipeptido con especificidad dual mejorada |
IL308257A (en) | 2021-05-05 | 2024-01-01 | Immatics Biotechnologies Gmbh | Antigen binding proteins that uniquely bind PRAME |
CN117279931A (zh) * | 2021-05-07 | 2023-12-22 | 基因医疗免疫疗法有限责任公司 | Prame特异性t细胞受体与嵌合共刺激受体的组合 |
WO2023175069A1 (en) * | 2022-03-16 | 2023-09-21 | Medigene Immunotherapies Gmbh | Tcr constant region pairing library for pramevld tcrs |
WO2023175070A1 (en) * | 2022-03-16 | 2023-09-21 | Medigene Immunotherapies Gmbh | Tcr constant region pairing library |
WO2024049476A1 (en) * | 2022-08-31 | 2024-03-07 | Immunocore Limited | Compositions and methods for treating cancer that demonstrates decreasing levels of ctdna in a subject |
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EP2006376A1 (en) | 2007-06-21 | 2008-12-24 | Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH | Fusion protein comprising a caspase domain and a nuclear hormone receptor binding domain and methods and uses thereof |
JP2018510627A (ja) | 2015-03-10 | 2018-04-19 | レイデン ユニバーシティ メディカル センター | メラノーマ優先発現抗原に対して向けられたt細胞レセプターおよびその使用 |
CA3022129A1 (en) * | 2016-06-17 | 2017-12-21 | Medigene Immunotherapies Gmbh | T cell receptors and uses thereof |
DE102017106305A1 (de) | 2017-03-23 | 2018-09-27 | Immatics Biotechnologies Gmbh | Neue T-Zellrezeptoren und deren Verwendung in Immuntherapien gegen prame-positive Krebsarten |
GB201709866D0 (en) | 2017-06-20 | 2017-08-02 | Immunocore Ltd | T cell receptors |
EP3731876A4 (en) * | 2017-12-28 | 2022-04-06 | Gritstone bio, Inc. | ANTIGEN-BINDING PROTEINS DIRECTED AGAINST COMMON ANTIGENS |
JP7412006B2 (ja) | 2018-03-14 | 2024-01-12 | メディジーン イミュノテラピーズ ゲーエムベーハー | 誘導性t細胞レセプター及びその使用 |
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BR112022009707A2 (pt) | 2022-08-09 |
EP4061827A1 (en) | 2022-09-28 |
CU20220029A7 (es) | 2023-01-16 |
AU2020385604A1 (en) | 2022-06-30 |
JP2023503416A (ja) | 2023-01-30 |
CO2022008396A2 (es) | 2023-06-20 |
US20220401484A1 (en) | 2022-12-22 |
WO2021099360A1 (en) | 2021-05-27 |
MX2022005922A (es) | 2022-09-02 |
KR20220104204A (ko) | 2022-07-26 |
CL2022001305A1 (es) | 2023-04-28 |
CA3161817A1 (en) | 2021-05-27 |
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