CN113474367A - 结合cd3和hla-a*02限制性肽的半衰期延长的immtac - Google Patents
结合cd3和hla-a*02限制性肽的半衰期延长的immtac Download PDFInfo
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Abstract
本发明涉及可溶性多结构域结合分子,其包含:对抗原、免疫球蛋白Fc结构域或白蛋白结合部分具有特异性的T细胞受体(TCR);和免疫效应结构域。此类多结构域结合分子是有利的,因为它们在保留功能的同时显示出改善的半衰期。
Description
技术领域
本发明涉及可溶性多结构域结合分子,其包含:对抗原、免疫球蛋白Fc结构域或白蛋白结合部分具有特异性的T细胞受体(T cell receptor,TCR);和免疫效应子结构域。这种多结构域结合分子是有利的,因为它们在保留功能的同时显示出改善的半衰期。
背景技术
许多基于蛋白质(包括抗体片段和融合蛋白)的疗法,在给药后会迅速从体内清除。它们的循环半衰期短通常归因于它们的小尺寸,这使得通过肾脏过滤被有效清除,并且缺乏对细胞内降解的防护。在这种情况下,需要频繁给药或长时间输注以在延长的时间内维持药物的有效浓度。为了改进用药,已采用几种策略来延长循环半衰期。这些策略包括通过连接柔性亲水性分子,例如碳水化合物或PEG(聚乙二醇)来增加蛋白质的流体动力学半径,以及通过连接抗体Fc结构域或血清白蛋白经由新生Fc受体(Fc receptor,FcRn)进行回收利用(Konnteman,Curr Opin Biotechnol.2011Dec;22(6):868-76)。
利用FcRn介导的再循环的策略特别有吸引力,因为在体内诱导免疫原性的风险较低,并且可以实现长的半衰期延长。例如,据报道,在连接Fc结构域后,格式的T细胞接合双特异性抗体的半衰期超过200小时(Lorenczewski,et al.,Blood 2017.130(Suppl1),2815)。类似地,据报道,合并白蛋白结合结构域的形式的双特异性抗体具有超过四天的半衰期(Wesche et al.,Cancer Res 2018;78(13Suppl):Abstract nr 3814)。
包含与抗CD3抗体片段融合的可溶性T细胞受体的融合蛋白是一类新型T细胞接合双特异性融合蛋白,其体内半衰期为6小时至8小时(Sato et al.,2018J Clin Onc 201836,no.15_suppl 9521-9521;Middleton et al.,J Clin Onc 2016 34,no.15_suppl3016-3016)。与传统的抗体不同,T细胞受体旨在识别源自细胞内抗原并由人类白细胞抗原(肽-HLA)呈递到细胞表面的短肽。抗原呈递细胞和T细胞上的肽-HLA复合物之间的有效免疫突触形成依赖于固定的相互作用几何学,这种固定的相互作用几何学会受到膜内距离增加的干扰(Choudhuri et al.,2005Nature Jul 28;436(7050):578-82)。
发明内容
需要能够介导有效免疫突触形成的具有增加的半衰期的T细胞接合双特异性蛋白。与本领域的预期相反,本发明人发现,将TCR-抗-CD3融合蛋白与抗体Fc区或白蛋白结合部分融合出乎意料地导致了有效的免疫突触形成。
在第一方面,提供一种多结构域结合分子,其包含:
i)与T细胞接合免疫效应子相连的肽-主要组织相容性复合物(Peptide-majorhistocompatibility complex,pMHC)结合部分;和
ii)半衰期延长结构域,该半衰期延长结构域包含免疫球蛋白Fc或白蛋白结合结构域。
优选地,pMHC结合部分是T细胞受体(TCR)或TCR样抗体,该T细胞受体(TCR)或TCR样抗体包含TCR和/或抗体可变结构域和至少一个恒定结构域。优选地,pMHC结合部分包含至少一个免疫球蛋白恒定结构域。优选地,恒定结构域可以对应于来自TCRα链或TCRβ链的恒定结构域(分别为TRAC或TRBC)。可选择地,pMHC结合部分的TCR恒定结构域可以被来自抗体轻链或重链的恒定结构域(CL、CH1、CH2、CH3或CH4)替换。恒定结构域可以是全长的或者可以被截短。可以截短TCR恒定结构域以去除跨膜结构域。在恒定结构域被截短的情况下,优选只去除膜相关部分。相对于天然恒定结构域,可以向恒定结构域的氨基酸序列中引入额外的突变。恒定区还可以包括使得能够通过例如两个半胱氨酸残基之间的二硫键进行二聚化的天然存在的或引入的残基。
本发明人意外地发现包含pMHC结合部分、免疫效应子结构域和免疫球蛋白Fc结构域或白蛋白结合部分的多结构域结合分子仍然是功能性的。鉴于本领域的知识,即TCR-pMHC相互作用依赖于固定的结合几何学并且TCR触发对膜间距离的增加是敏感的,这尤其令人惊讶(Garboczi et al.,Nature.1996Nov 14;384(6605):134-41;Choudhuri et al.,2005Nature Jul 28;436(7050):578-82;Rudolph et al.,Annu Rev Immunol.2006;24:419-66)。事实上,动力学离析模型提出,TCR触发是TCR-CD3复合物在紧密接触区域内束缚的结果,在该区域中,酪氨酸磷酸化因为酪氨酸磷酸酶(例如CD45)受到尺寸依赖性排斥而取得优势(Choudhuri et al.,2005Nature Jul 28;436(7050):578-82;Davis et al.,NatImmunol.2006Aug;7(8):803-9)。因此,小尺寸的TCR-pMHC复合物(大约)和固定的结合几何学被认为对于免疫突触形成和TCR触发很重要。基于该知识,技术人员将认为,本发明的抗原结合多肽将预期会导致不良的免疫突触形成、TCR-pMHC结合几何学的干扰以及最终无效的TCR触发。
pMHC结合部分可以是TCR样抗体。优选地,pMHC结合部分包含TCR样抗体的可变结构域。抗体不会天然地识别pMHC;然而,众所周知,可以工程化对pMHC具有特异性的抗体。此类抗体称为TCR样抗体或TCR模拟抗体(Chang et al.,Expert Opin Biol Ther.2016Aug;16(8):979-87和Dahan et al.,Expert Rev Mol Med.2012Feb 24;14:e6)。
TCR可以是异二聚体α/β或γ/δTCR多肽对。可替代地,TCR可以是单链α/β或γ/δTCR多肽。TCR可变结构域的氨基酸序列可以对应于自然界中发现的那些,或者它们可以相对于天然TCR包含一个或多个突变。可以进行此类突变以增加TCR对给定抗原的亲和力。另外地或可替代地,可以合并突变以提高稳定性和可生产性。
TCR可以与与肽抗原形成复合物的MHC结合。优选地,肽抗原是任何疾病相关抗原。优选地,肽抗原是任何肿瘤相关抗原。肽抗原可以是如WO2011001152、WO2017109496、WO2017175006和WO2018234319中所述的衍生自GP100、NYESO、MAGEA4或PRAME的肽。
TCR可以具有如WO2011001152、WO2017109496、WO2017175006和WO2018234319中定义的氨基酸序列。
T细胞接合免疫效应子结构域可以是CD3效应子结构域。T细胞接合免疫效应子可以是通过与CD3和/或TCR/CD3复合物的相互作用来活化T细胞的抗体scFv(或类似大小的抗体样支架)。CD3效应子包括但不限于抗CD3抗体或抗体片段,特别是抗CD3 scFv或抗体样支架。其他免疫效应子包括但不限于:细胞因子(比如IL-2和IFN-γ);超级抗原及其突变体;趋化因子(例如IL-8、血小板因子4、黑色素瘤生长刺激蛋白);与免疫细胞(如T细胞或NK细胞)上的抗原结合的抗体(例如抗CD28分子或抗CD16分子或任何位于免疫突触的分子),包括其片段、衍生物和变体;以及补体活化剂。
半衰期延长结构域可以与pMHC结合部分的C末端或N末端连接,或与T细胞接合免疫效应子的C末端或N末端连接。
半衰期延长结构域可以包含免疫球蛋白Fc。免疫球蛋白Fc结构域可以是任何抗体Fc区。Fc区是抗体的尾部区域,该区域与细胞表面Fc受体和补体系统的一些蛋白质相互作用。Fc区通常包含两条均具有两个或三个重链恒定结构域(称为CH2、CH3和CH4)的多肽链,以及铰链区。这两条链通过铰链区内的二硫键连接。来自免疫球蛋白亚类IgG1、IgG2和IgG4的Fc结构域结合FcRn并经历FcRn介导的再循环,这赋予了长的循环半衰期(3周至4周)。IgG与FcRn的相互作用已定位于覆盖部分CH2和CH3结构域的Fc区。用于本发明的优选免疫球蛋白Fc结构域包括但不限于来自IgG1或IgG4的Fc结构域。优选地,Fc结构域来源于人序列。Fc区还可以优选地包括促进二聚化的KiH突变,以及防止与活化受体(即功能沉默分子)相互作用的突变。免疫球蛋白Fc结构域可以与其他结构域(即TCR或免疫效应子)的C末端或N末端融合。免疫球蛋白Fc可以通过接头与其他结构域(即TCR或免疫效应子)融合,可替代地,可以不使用接头。接头序列通常是柔性的,因为它们主要由氨基酸(比如不具有可能限制柔性的庞大侧链的甘氨酸、丙氨酸和丝氨酸)组成。可替代地,具有更大刚性的接头可能是可取的。可以容易地确定可用的或最佳长度的接头序列。通常接头序列的长度小于约12个氨基酸,例如小于10个或为2-10个氨基酸。接头的长度可以为约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个氨基酸。可用于本发明的多结构域结合分子的合适接头的实例包括但不限于:GGGSGGGG、GGGGS、GGGSG、GGSGG、GSGGG、GSGGGP、GGEPS、GGEGGGP和GGEGGGSEGGGS(如WO2010/133828中所述的)。当免疫球蛋白Fc与TCR融合时,它可以通过接头或不通过接头与α链或β链融合或与α链和β链融合。此外,Fc的各个链可以与TCR的各个链融合。
优选地,Fc区可以源自IgG1或IgG4亚类。这两条链可以包含CH2和CH3恒定结构域以及全部或部分铰链区。铰链区可以基本上或部分对应于来自IgGl、IgG2、IgG3或IgG4的铰链区。铰链可以包括全部或部分核心铰链结构域和全部或部分下铰链区。优选地,铰链区包含至少一个连接两条链的二硫键。
Fc区可以包含相对于WT Fc序列的突变。突变包括替换、插入和删除。可以为了引入所需的治疗特性而进行此类突变。例如,为了促进异源二聚化,可以将杵臼结构(Knobsinto holes,KiH)突变工程化到CH3结构域中。在这种情况下,将一条链工程化为包含庞大的突出残基(即杵(Knob)),例如Y,而将另一条链工程化为包含一个互补的口袋(即臼(Hole))。KiH突变的合适位置是本领域已知的。另外地或可替代地,可以引入消除或减少与Fcy受体的结合和/或增加与FcRn的结合、和/或阻止Fab臂交换或去除蛋白酶位点的突变。另外地或可替代地,可以出于产生原因进行突变,例如去除或替换可能经历翻译后修饰(例如糖基化)的氨基酸。
示例包括:
IgG4(下划线残基表示相对于野生型序列的突变)
“杵”
YGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLYCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK
“臼”
YGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLTSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK
IgG1(下划线残基表示相对于野生型序列的突变)
“杵”
VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLYCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
“臼”
VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
半衰期延长结构域可以包含白蛋白结合结构域。如本领域中已知的,白蛋白具有19天的长循环半衰期,部分原因在于其大小高于肾阈值以及由于其特异性相互作用和经由FcRn的再循环。与白蛋白连接是一种众所周知的改善治疗分子体内循环半衰期的策略。白蛋白可以通过使用特定的白蛋白结合结构域以非共价方式连接,或通过缀合或直接遗传融合以共价方式连接。Sleep et al.,Biochim Biophys Acta.2013Dec;1830(12):5526-34中给出了利用与白蛋白的连接来改善半衰期的治疗分子的例子。
白蛋白结合结构域可以是能够与白蛋白结合的任何部分,包括任何已知的白蛋白结合部分。白蛋白结合结构域可以选自特异性结合白蛋白的内源性或外源性配体、有机小分子、脂肪酸、肽和蛋白质。优选的白蛋白结合结构域的例子包括:短肽,例如Dennis etal.,J Biol Chem.2002Sep 20;277(38):35035-43中描述的(例如肽QRLMEDICLPRWGCLWEDDF);经工程化以结合白蛋白的蛋白质,例如抗体、抗体片段和抗体样支架,例如由GSK商品化提供的(O'Connor-Semmes et al.,Clin PharmacolTher.2014Dec;96(6):704-12)和由Ablynx商品化提供的(Van Roy et al.,Arthritis Res Ther.2015May 20;17:135);以及基于在自然界中发现的白蛋白结合结构域(如链球菌蛋白G蛋白(Stork et al.,Eng Des Sel.2007Nov;20(11):569-76))的蛋白质,例如由Affibod商品化提供的优选地,白蛋白是人血清白蛋白(Human serumalbumin,HSA)。白蛋白结合结构域对人白蛋白的亲和力可以在皮摩尔至微摩尔的范围内。鉴于人血清中白蛋白的浓度极高(35mg/ml-50mg/ml,大约0.6mM),据计算,在体内基本上所有的白蛋白结合结构域都将与白蛋白结合。
白蛋白结合部分可以与其他结构域(即TCR或免疫效应子)的C末端或N末端连接。白蛋白结合部分可以通过接头与其他结构域(即TCR或免疫效应子)连接。接头序列通常是柔性的,因为它们主要由氨基酸(比如不具有可能限制柔性的庞大侧链的甘氨酸、丙氨酸和丝氨酸)组成。可替代地,具有更大刚性的接头可能是可取的。可以容易地确定可用的或最佳长度的接头序列。通常接头序列的长度小于约12个氨基酸,例如小于10个或为2-10个氨基酸。接头的长度可以为约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个氨基酸。可用于本发明的多结构域结合分子的合适接头的实例包括但不限于:GGGSGGGG、GGGGS、GGGSG、GGSGG、GSGGG、GSGGGP、GGEPS、GGEGGGP和GGEGGGSEGGGS(如WO2010/133828中所述的)。当白蛋白结合部分与TCR连接时,它可以通过接头或不通过接头与α链或β链连接或与α链和β链连接。
根据第一方面的多结构域结合分子可以用作药物。
在另一方面,提供了包含根据第一方面的多结构域结合分子的药物组合物。
在又一方面,提供了编码根据第一方面的多结构域结合分子的核酸。还提供了包含该方面的核酸的表达载体。另外,提供了一种宿主细胞,该宿主细胞包含该方面的核酸或载体,其中编码多结构域结合分子的核酸作为单个开放阅读框或分别编码α链和β链的两个不同的开放阅读框存在。
在另一方面中,提供一种制备根据第一方面的多结构域结合分子的方法,该方法包括将如上所述的宿主细胞维持在可选的用于核酸表达的条件下以及分离多结构域抗原结合多肽。
再一方面,提供了一种治疗方法,该治疗方法包括向有需要的患者给药根据第一方面的多结构域结合分子。
本文公开的任何分子的表型沉默变体属于本发明的范围内。如本文所用,术语“表型沉默变体”应理解为是指合并除了上述那些之外的一个或多个其他氨基酸变化(包括替换、插入和缺失)的变体,该变体具有与相应的不含所述变化的分子相似的表型。为了本申请的目的,表型包含结合亲和力(KD和/或结合半衰期)和特异性。优选地,除了结合亲和力和特异性之外,可溶性多结构域结合分子的表型包括免疫活化的效力和纯化产率。
表型沉默变体可包含一个或多个保守替换和/或一个或多个无害替换(toleratedsubstitution)。无害替换意指那些不落入如下所提供的保守的定义但仍然是表型沉默的替换。技术人员知道各种氨基酸具有相似的性质并因此是“保守的”。蛋白质、多肽或肽的一个或多个这样的氨基酸通常可以被一个或多个其他这样的氨基酸替换,而不会消除该蛋白质、多肽或肽的所需活性。
因此,氨基酸甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸(具有脂肪族侧链的氨基酸)通常可以互相替换。在这些可能的替换中,优选使用甘氨酸和丙氨酸来互相替换(因为它们具有相对短的侧链),以及使用缬氨酸、亮氨酸和异亮氨酸来互相替换(因为它们具有较大的疏水脂肪族侧链)。通常可以互相替换的其他氨基酸包括:苯丙氨酸、酪氨酸和色氨酸(具有芳香族侧链的氨基酸);赖氨酸、精氨酸和组氨酸(具有碱性侧链的氨基酸);天冬氨酸和谷氨酸(具有酸性侧链的氨基酸);天冬酰胺和谷氨酰胺(具有酰胺侧链的氨基酸);以及半胱氨酸和甲硫氨酸(具有含硫侧链的氨基酸)。应当理解,本发明范围内的氨基酸替换可以使用天然存在的或非天然存在的氨基酸来进行。例如,本文考虑可以用乙基基团取代丙氨酸上的甲基基团,和/或可以对肽骨架进行微小的改变。无论是否使用天然氨基酸或合成氨基酸,优选仅存在L-氨基酸。
这种性质的替换通常被称为“保守”或“半保守”氨基酸替换。因此,本发明延伸至如下这样的分子的用途,该分子包含上述任意氨基酸序列,但在该序列中具有一个或多个保守替换和/或一个或多个无害替换,使得该TCR的氨基酸序列与本文公开的TCR序列具有至少90%的同一性,例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的同一性。
如本领域已知的“同一性”是通过比较序列所确定的两个或更多个多肽序列或两个或更多个多核苷酸序列之间的关系。在本领域中,同一性也意指多肽或多核苷酸序列(视情况而定)之间的序列相关程度,如通过这种序列的串之间的匹配所确定。虽然存在许多测量两个多肽序列或两个多核苷酸序列之间的同一性的方法,但通常用于确定同一性的方法是在计算机程序中编码化的。用于确定两个序列之间的同一性的优选计算机程序包括但不限于GCG程序包(Devereux,et al.,Nucleic Acids Research,12,387(1984、BLASTP、BLASTN和FASTA(Atschul et al.,J.Molec.Biol.215,403(1990))。
可以使用程序(例如CLUSTAL程序)来比较氨基酸序列。该程序比较氨基酸序列,并通过视情况而定在任一序列中插入空格来找到最优比对。可以针对最优比对来计算氨基酸同一性或相似性(同一性加上氨基酸类型的保守性)。像BLASTx这样的程序会比对相似序列的最长延伸(longest stretch),并为该拟合赋值。因此,可以在发现若干相似区,每个区具有不同的分数的情况下获得比较。本发明中考虑了两种类型的同一性分析。
通过出于最优比较目的对序列进行比对(例如,可以在第一序列中引入空位以与序列进行最佳比对)并且比较相应位置处的氨基酸残基或核苷酸,来确定两个氨基酸序列或两个核酸序列的百分比同一性。“最佳比对”是获得最高的百分比同一性的两个序列的比对。百分比同一性由所比较序列中的相同氨基酸残基或核苷酸的数量来确定的(即,%同一性=相同位置数/位置总数×100)。
可以使用本领域技术人员已知的数学算法来完成两个序列之间的百分比同一性的确定。用于比较两个序列的数学算法的例子是Karlin and Altschul(1990)Proc.Natl.Acad.Sci.USA87:2264-2268的算法,该算法在Karlin and Altschul(1993)Proc.Natl.Acad.Sci.USA 90:5873-5877中进行了改进。Altschul,et al.(1990)J.Mol.Biol.215:403-410的BLASTn和BLASTp程序已经合并了这种算法。可以用BLASTn程序来进行两个核苷酸序列之间的同一性百分比的确定。可以用BLASTp程序来进行两个蛋白质序列之间的同一性百分比的确定。为了获得出于比较目的的空位比对,可以如Altschul etal.(1997)Nucleic Acids Res.25:3389-3402所述使用Gapped BLAST。可替代地,可以使用PSI-Blast来执行迭代搜索,检测分子之间的远距离关系(Id.)。当使用BLAST、GappedBLAST和PSI-Blast程序时,可以使用各个程序(例如,BLASTp和BLASTp)的默认参数。参见http://www.ncbi.nlm.nih.gov。默认的常规参数可以包括,例如,字体大小=3,期望阈值=10。可以选择参数以自动调整为输入短序列。用于序列比较的数学算法的另一例子是Myers and Miller,CABIOS(1989)的算法。作为CGC序列比对软件包的一部分的ALIGN程序(版本2.0)已经合并了这种算法。本领域已知的用于序列分析的其他算法包括如Torellisand Robotti(1994)Comput.Appl.Biosci.,10:3-5中所述的ADVANCE和ADAM;以及Pearsonand Lipman(1988)Proc.Natl.Acad.Sci.85:2444-8中所述的FASTA。在FASTA中,ktup是设置搜索的灵敏度和速度的控制选项。出于评估本发明中的百分比同一性的目的,使用BLASTp以及默认参数作为比较方法。另外,当所述同一性百分比提供氨基酸的非整数值(即,具有90%序列同一性的25个氨基酸的序列提供的值为“22.5”)时,则将所得值下舍入到下一个整数,即“22”。因此,在提供的例子中,在25个氨基酸中具有22个匹配的序列在90%序列同一性内。
对于本领域技术人员来说显而易见的是,在基本不影响分子(例如TCR部分)的功能特性的情况下,有可能将在其C末端和/或N末端所提供的序列截短或延伸1、2、3、4、5或更多个残基。在其C末端和/或N末端所提供的序列可以被截短或延伸1、2、3、4或5个残基。所有这些变体都涵盖在本发明中。
可以使用任何适当的方法将突变(包括保守和无害的替换、插入和缺失)引入所提供的序列中,所述方法包括但不限于基于聚合酶链式反应(PCR)、基于限制酶的克隆或不依赖于连接的克隆(Ligation independent cloning,LIC)步骤的方法。这些方法在许多标准分子生物学文本中都有详细描述。有关聚合酶链式反应(PCR)和基于限制酶的克隆的更多细节,参见Sambrook&Russell,(2001)Molecular Cloning–A Laboratory Manual(3rd Ed.)CSHL Press。有关不依赖于连接的克隆(LIC)步骤的更多信息可以在Rashtchian,(1995)Curr Opin Biotechnol 6(1):30-6中找到。本发明提供的TCR序列可以从固态合成或本领域已知的任何其他合适的方法获得。
本发明的分子可具有用作治疗剂的理想的安全性特征。理想的安全性特征意味着除了显示良好的特异性外,本发明的分子还可以通过进一步的临床前安全性测试。这种测试的例子包括:全血测定,以确认在存在全血的情况下细胞因子释放最少,并因此使在体内引起潜在细胞因子释放综合征的风险低;以及同种异体反应性测试,以确认识别替代性HLA类型的可能性低。
本发明的分子可以适于高产率纯化。可以基于纯化过程期间保留的物质量来确定产率(即,在纯化过程结束时获得的正确折叠物质的量相对于重折叠前获得的水溶性物质的量),和/或产率可以基于在纯化过程结束时获得的正确折叠物质的量相对于原始培养物体积。高产率意指大于1%,或更优选大于5%,或更高的产率。高产率意指大于1mg/ml,或更优选大于3mg/ml,或大于5mg/ml,或更高的产率。
确定结合亲和力(与平衡常数KD成反比)和结合半衰期(表示为T1/2)的方法是本领域技术人员已知的。在优选的实施方式中,结合亲和力和结合半衰期分别使用表面等离子体共振(Surface Plasmon Resonance,SPR)或生物膜层干涉(Bio-LayerInterferometry,BLI)来确定,例如分别使用BIAcore仪器或Octet仪器来确定。应当理解,亲和力加倍导致KD减半。根据ln2除以解离率(koff)计算T1/2。因此,T1/2加倍导致koff减半。TCR的KD和koff值通常是对TCR的可溶形式(即被截短以去除细胞质和跨膜结构域残基的形式)进行测量的。为了考虑独立测量之间的变化,尤其是对超过20小时解离时间时的相互作用的测量之间的变化,可以使用相同的测定方案测量给定TCR的结合亲和力和/或结合半衰期数次(例如3次或更多次),并取结果的平均值。为了比较两个样品(即两个不同的TCR和/或同一TCR的两种制剂)之间的结合数据,优选使用相同的测定条件(例如温度)进行测量。描述的与TCR相关的测量方法也可以应用于本文描述的多结构域抗原结合多肽。
本发明的某些优选的多结构域结合分子能够在体外产生针对抗原阳性细胞的高效T细胞应答,所述抗原阳性细胞特别是那些呈递低水平的癌细胞典型抗原的细胞(即每个细胞大约5-100个抗原,例如50个抗原(Bossi et al.,(2013)Oncoimmunol.1;2(11):e26840;Purbhoo et al.,(2006).J Immunol 176(12):7308-7316.))。此类TCR可能适合并入本文所述的多结构域抗原结合多肽。测量的T细胞应答可以是T细胞活化标志物(比如干扰素γ或颗粒酶B)的释放、或靶细胞杀伤、或T细胞活化(比如T细胞增殖)的其他量度。优选地,高效应答是EC50值在nM-pM范围内的应答,所述EC50值优选地为500nM或更低,或最优选为1nM或更低,或500pM或更低。
本发明的分子的TCR部分可以是αβ异二聚体。本发明的分子的α-β异二聚体TCR部分通常包含α链TRAC恒定结构域序列和/或β链TRBC1或TRBC2恒定结构域序列。恒定结构域可以是可溶形式(即不具有跨膜结构域或胞质结构域)。相对于天然TRAC和/或TRBC1/2序列,恒定结构域中的一个或两个可包含突变、替换或缺失。术语TRAC和TRBC1/2也涵盖天然多态性变体,例如TRAC第4位处的N变为K(Bragado et al Internationalimmunology.1994 Feb;6(2):223-30)。
可通过截短或替换使TRAC的外显子2的Cys4与TRBC1或TRBC2的外显子2的Cys2之间的天然二硫键缺失来修饰α和β链恒定结构域序列。α和/或β链恒定结构域序列可以在各恒定结构域的残基之间具有引入的二硫键,例如WO 03/020763和WO06000830中所描述。可以通过用半胱氨酸残基替换TRAC的Thr48位和TRBC1或TRBC2的Ser57位来修饰α和β恒定结构域,所述半胱氨酸在TCR的α和β恒定结构域之间形成二硫键。TRBC1或TRBC2可另外包括恒定结构域第75位的半胱氨酸至丙氨酸突变和恒定结构域的第89位的天冬酰胺至天冬氨酸突变。在αβ异二聚体中存在的胞外恒定结构域中的一个或两个可以在C末端或C端截短,例如截短至多15个、或至多10个、或至多8个或更少的氨基酸。α链胞外恒定结构域的C末端可以截短8个氨基酸。
本发明的分子的TCR部分可以是单链形式。单链形式包括但不限于Vα-L-Vβ、Vβ-L-Vα、Vα-Cα-L-Vβ、Vα-L-Vβ-Cβ、或Vα-Cα-L-Vβ-Cβ型的αβTCR多肽,其中Vα和Vβ分别为TCRα和TCRβ可变区,Cα和Cβ分别为TCRα和TCRβ恒定区,并且L为接头序列(Weidanz et al.,(1998)J Immunol Methods.Dec 1;221(1-2):59-76;Epel et al.,(2002),Cancer ImmunolImmunother.Nov;51(10):565-73;WO 2004/033685;WO9918129)。单链TCR可以在各恒定结构域的残基之间具有引入的二硫键,如WO 2004/033685中所描述的。WO2004/033685;WO98/39482;WO01/62908;Weidanz et al.(1998)J Immunol Methods 221(1-2):59-76;Hoo etal.(1992)Proc Natl Acad Sci U S A89(10):4759-4763;Schodin(1996)Mol Immunol 33(9):819-829中进一步描述了单链TCR。
可以与本发明的分子相关联的治疗剂包括免疫调节剂和效应因子、放射性化合物、酶(例如穿孔素)或化疗剂(例如顺铂)。为了确保在所需位置发挥毒性作用,毒素可以在与本文所述的多结构域抗原结合多肽连接的脂质体内,以使得化合物缓慢释放。这将防止在体内转运过程中的损伤作用,并确保毒素在本文所述的多结构域抗原结合多肽与相关抗原呈递细胞结合后具有最大效应。
合适的治疗剂的实例包括但不限于:
·小分子细胞毒性剂,即具有杀死哺乳动物细胞的能力的分子量小于700道尔顿的化合物。这种化合物还可以含有能够具有细胞毒性作用的有毒金属。此外,应当理解,这些小分子细胞毒性剂还包括前药,即在生理条件下衰变或转化以释放细胞毒性剂的化合物。此类药剂的实例包括顺铂、美登素(maytansine)衍生物、雷卡霉素(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)、卟吩姆钠光敏素II(sorfimer sodiumphotofrin II)、替莫唑胺(temozolomide)、拓扑替康(topotecan)、trimetreate arbourate、奥瑞斯他汀E(auristatin E)、长春新碱(vincristine)和多柔比星(doxorubicin);
·肽细胞毒素,即具有杀死哺乳动物细胞能力的蛋白质或其片段。例如,蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、脱氧核糖核酸酶和核糖核酸酶;
·放射性核素,即随着α或β粒子或γ射线中的一种或多种的同时发射而衰变的元素的不稳定同位素。例如,碘131、铼186、铟111、钇90、铋210和213、锕225和砹213;可以使用螯合剂来促进这些放射性核素与高亲和力TCR或其多聚体的缔合;
·免疫刺激剂,即刺激免疫应答的免疫效应子分子。例如,细胞因子,比如IL-2和IFN-γ;
·超级抗原及其突变体;
· TCR-HLA融合体,例如与肽-HLA复合物的融合体,其中,所述肽衍生自常见的人病原体,例如埃伯斯坦巴尔病毒(Epstein Barr Virus,EBV);
·趋化因子,比如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,包括抗T细胞或NK细胞决定簇抗体(例如抗CD3、抗CD28或抗CD16);
·与位于免疫突触的分子结合的抗体或其片段;
·具有抗体样结合特征的替代蛋白质支架;
·补体活化剂;
·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、病毒/细菌肽。
特别优选的免疫效应子是抗CD3抗体、或所述抗CD3抗体的功能片段或变体。如本文所用,术语“抗体”涵盖此类片段和变体。抗CD3抗体的实例包括但不限于OKT3、UCHT-1、BMA-031和12F6。适用于本文所述的组合物和方法的抗体片段和变体/类似物包括微型抗体、Fab片段、F(ab’)2片段、dsFv和scFv片段、NanobodiesTM(这些构建体由Ablynx(比利时)销售,包含:衍生自骆驼科动物(例如骆驼或美洲驼)抗体和域抗体(Domantis(比利时)的合成的单一免疫球蛋白可变重结构域,包括亲和力成熟的单一免疫球蛋白可变重结构域或免疫球蛋白可变轻结构域)或表现出抗体样结合特性的替代蛋白质支架,例如Affibody(Affibody(瑞典),其包含工程化蛋白A支架)或Anticalins(Pieris(德国)),其包括工程化的anticalins),略举数例。免疫效应子与多结构域抗原结合多肽的TCR部分连接,其中优选地,免疫效应子是抗CD3抗体。
多结构域结合分子的各个组分的连接可以通过共价或非共价连接。共价连接可以是直接的,或通过接头序列间接的。接头序列通常是柔性的,因为它们主要由氨基酸(比如不具有可能限制柔性的庞大侧链的甘氨酸、丙氨酸和丝氨酸)组成。可替代地,具有更大刚性的接头可能是可取的。可以容易地确定可用的或最佳长度的接头序列。通常接头序列的长度小于约12个氨基酸,例如小于10个或为2-10个氨基酸。可用于本发明的分子的合适接头的实例包括但不限于:GGGSGGGG、GGGGS、GGGSG、GGSGG、GSGGG、GSGGGP、GGEPS、GGEGGGP和GGEGGGSEGGGS(如WO2010/133828中所述的)。
在进一步的方面,本发明提供了编码本发明的多结构域结合分子的核酸。在一些实施方式中,该核酸是cDNA。在一些实施方式中,该核酸可以是mRNA。核酸可以是非天然存在的和/或纯化的和/或工程化的。核酸序列可以根据所用的表达系统进行密码子优化。如本领域技术人员已知的,表达系统可以包括细菌细胞(例如大肠杆菌),或酵母细胞,或哺乳动物细胞,或昆虫细胞,或者该表达系统可以是无细胞表达系统。
本发明还提供含有至少一种上述核酸的质粒、载体、转录或表达组件形式的构建体。本发明还提供包括含有一种或多种上述构建体的重组宿主细胞。如上所述,编码本发明的特异性结合分子的核酸构成本发明的一个方面;产生该特异性结合分子的方法也构成本发明的一个方面,该方法包括表达该特异性结合分子的编码核酸。通过在适当条件下培养含有所述核酸的重组宿主细胞,可以便利地实现表达。通过表达而产生后,可以视情况而定用任何合适的技术来分离和/或纯化特异性结合分子然后使用。
用于多肽在各种不同宿主细胞中克隆和表达的体系是众所周知的。合适的宿主细胞包括细菌、哺乳动物细胞、酵母和杆状病毒系统。本领域可用于表达异源多肽的哺乳动物细胞系包括中国仓鼠卵巢细胞、HeLa细胞、幼仓鼠肾细胞、NSO小鼠黑色素瘤细胞和许多其他细胞。常见的优选细菌宿主为E.coli。在原核细胞(例如E.coli)中的表达抗体和抗体片段为本领域完备建立的。综述参见例如Plückthun,Bio/Technology 9:545-551(1991)。在培养物中的真核细胞中表达也是本领域技术人员可用的产生特异性结合分子的选项,近期综述参见例如Reff,Curr.Opinion Biotech.4:573-576(1993);Trill et al.,Curr.Opinion Biotech.6:553-560(1995)。
可以选择或构建含有适当调控序列的合适载体,该调控序列视情况而定包括启动子序列、终止子序列、多聚腺苷酸化序列、增强子序列、标记基因和其他序列。载体视情况而定可以是质粒,病毒例如噬菌体或噬菌粒。进一步的细节参见,例如,Sambrook et al.,Molecular Cloning:A Laboratory Manual:2nd Edition,Cold Spring HarborLaboratory Press(1989)。Ausubel et al.eds.,Short Protocols in MolecularBiology,2nd Edition,John Wiley&Sons(1992)中详细记载了许多核酸操作的已知技术和方案,例如核酸构建体的制备、诱变、测序、DNA引入细胞和基因表达以及蛋白分析。
因此,本发明的又一方面提供了一种含有本文所公开的核酸的宿主细胞。在再一个方面中,提供一种方法,该方法包括将这种核酸引入宿主细胞。可以使用任何可用技术进行引入。对于真核细胞,合适的技术可以包括磷酸钙转染、DEAE-葡聚糖、电穿孔、脂质体介导的转染,和使用反转录病毒或其他病毒(例如痘苗病毒,或对昆虫细胞而言,使用杆状病毒)的转导。对于细菌细胞,合适的技术可以包括氯化钙转化、电穿孔和使用噬菌体进行转染。引入之后可以引发或允许由该核酸表达,例如通过在该基因的表达条件下培养宿主细胞来进行。
本发明的核酸可以整合入宿主细胞的基因组(例如染色体)中。可以根据标准技术,通过包含促进与该基因组重组的序列来促进整合。
如本领域所熟知的,可以对分子进行翻译后修饰。糖基化就是这样一种修饰,其包括寡糖部分与TCR链中限定的氨基酸的共价连接。例如,天冬酰胺残基或丝氨酸/苏氨酸残基是熟知的寡糖连接位置。特定蛋白质的糖基化状态取决于许多因素,包括蛋白质序列、蛋白质构象和某些酶的可用性。此外,糖基化状态(即寡糖类型、共价键和连接总数)会影响蛋白质功能。因此,当生产重组蛋白时,控制糖基化通常是可取的。受控糖基化已被用于改进基于抗体的治疗剂(Jefferis et al.,(2009)Nat Rev Drug Discov Mar;8(3):226-34.)。对于本发明的分子的TCR部分,可以通过例如使用特定细胞系(包括但不限于哺乳动物细胞系,比如中国仓鼠卵巢(Chinese hamster ovary,CHO)细胞或人胚肾(Human embryonickidney,HEK)细胞)或通过化学修饰来控制糖基化。这种修饰可能是可取的,因为糖基化可以改善药代动力学、降低免疫原性并且更接近地模拟天然人蛋白质(Sinclair andElliott,(2005)Pharm Sci.Aug;94(8):1626-35)。
为了向患者给药,本发明的分子(优选与可检测标记或治疗剂相关联)、核酸、表达载体或细胞可以作为无菌药物组合物的一部分与一种或多种药学上可接受的运载体或赋形剂一起提供。该药物组合物可以是任何合适的形式(取决于将其给药于患者的所需方法)。其可以以单位剂型提供,通常在密封容器中提供,并且可以作为试剂盒的一部分提供。这种试剂盒会通常(但并非必然)包括使用说明书。它可以包括多个所述单位剂型。
药物组合物可以适于通过任何适当途径的给药,例如肠胃外(包括皮下、肌内、囊内或静脉内)、肠内(包括口服或直肠)、吸入或鼻内途径。此类组合物可以通过药学领域已知的任何方法制备,例如通过在无菌条件下将活性成分与运载体或赋形剂混合来制备。
本发明的分子的剂量可以在宽限度内变化,这取决于待治疗的疾病或病症、待治疗个体的年龄和状况等,本发明的分子的合适剂量范围可以在25ng/kg至50μg/kg或1μg至1g的范围内。医师将最终确定所使用的适当剂量。
本发明的多结构域抗原结合多肽、药物组合物、载体、核酸和细胞可以以基本纯的形式提供,例如纯度为至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%。
本发明还提供:
·用于医学,优选用于的治疗癌症或肿瘤的方法中的本发明的多结构域抗原结合多肽、核酸、药物组合物或细胞;
·本发明的多结构域抗原结合多肽、核酸、药物组合物或细胞在制造用于治疗癌症或肿瘤的药物中的用途;
·治疗患者的癌症或肿瘤的方法,该方法包括将本发明的多结构域抗原结合多肽、核酸、药物组合物或细胞给药至患者。
·用于向人对象给药的可注射制剂,该可注射制剂包含本发明的多结构域抗原结合多肽、核酸、药物组合物或细胞。
治疗方法可进一步包括分开、联合或依次给药另外的抗肿瘤剂。此类药剂的实例是本领域已知的,并且可以包括免疫活化剂和/或T细胞调节剂。
本发明的每个方面的优选特征在细节上作必要修改后用于每个其他方面。本文提到的现有技术文件在法律允许的最大范围内并入本文。
附图说明
图1:A)TCR-抗CD3-Fc融合蛋白的设计;B)本发明的TCR-抗CD3-Fc融合蛋白的示例序列;
图2示出了在抗原阳性靶细胞存在的情况下,合并Fc结构域的TCR-抗CD3融合体能够介导T细胞活化。示出了了三种IgG1-Fc融合体的数据;
图3:A)示出了在抗原阳性靶细胞存在的情况下,合并白蛋白结合肽的TCR-抗CD3融合体能够介导T细胞活化。示出了三种形式,其中白蛋白结合肽与C-α(F1)、N-α(F2)或C-β(F3)连接;B)示出了在抗原阳性靶细胞存在的情况下,合并白蛋白结合纳米抗体的TCR-抗CD3融合体能够介导T细胞活化。示出了两种形式,其中白蛋白结合肽与C-α(R)或C-β(Y)连接;C)示出了在抗原阳性靶细胞存在的情况下,合并白蛋白结合结构域抗体的TCR-抗CD3融合体能够介导T细胞活化。示出了了一种形式,其中与TCR-抗CD3融合体的C-α连接;
具体实施方式
实施例
以下实施例描述了本发明的多结构域结合分子,该多结构域结合分子可以称为TCR-抗CD3-Fc融合蛋白或TCR-抗CD3-白蛋白结合融合蛋白。
实施例1(Fc融合)
a)TCR-抗CD3-Fc融合蛋白的设计
在该实施例中,使用了TCR-抗CD3融合蛋白,该TCR-抗CD3融合蛋白包含与来自PRAME的HLA-A*02限制性肽结合的高亲和力TCR。WO2018234319中提供了这种分子的实例。
将人IgG1 Fc结构域通过接头与TCR-抗CD3的C末端融合(参见图1A作为示意)。制备另外两种构建体,该构建体包含本领域已知的人IgG1 Fc的功能变体。变体1不与Fcγ受体(Fcγreceptor,FcγR)或补体蛋白C1q结合,因此是功能沉默的。变体2显示与FcRn的结合增加,这可能导致体内半衰期延长。在每种情况下,Fc结构域包含已知的杵臼结构突变Y86T和T22Y以促进异源二聚化。
图1B示出了包含功能沉默的人IgG1 Fc的TCR-抗CD3-Fc融合体(变体1)的序列。
b)TCR-抗CD3-Fc融合蛋白的表达与纯化
使用基于悬浮适应中国仓鼠卵巢(CHO)细胞的瞬时表达系统(ExpiCHO表达系统,Thermo Fisher)进行Fc融合体的表达。根据制造商的说明,使用含有与各种Ig Fc结构域融合的相关TCR链的哺乳动物表达质粒来转染细胞。收获后,通过在冷冻离心机中以4000xg至5000xg离心细胞30分钟来使细胞培养上清液澄清。上清液通过0.22μm过滤器过滤并收集用于进一步纯化。
对于纯化,首先用缓冲液对Fc融合体进行调节,然后根据制造商的指南使用mAbselect Sure预装柱(GE Healthcare或等效树脂)进行纯化。汇集含有特定蛋白质的级分,并使用合适的柱(GE Healthcare)在生理相关缓冲液中通过尺寸排阻色谱进一步纯化。汇集含有特定蛋白质的级分并进行浓缩用于后续的测试和储存。
c)TCR-抗CD3-Fc融合蛋白有效活化T细胞
评估了TCR-抗CD3-Fc融合蛋白介导CD3+T细胞对抗原呈递T2细胞的有效重定向的能力。干扰素-γ(IFN-γ)释放被用作T细胞活化的读数。
根据制造商的说明,使用人IFN-γELISPOT试剂盒(BD Biosciences)进行检测。简而言之,T2细胞用作靶细胞并用5nM PRAME肽刺激。在测定培养基(含有10%热灭活的FBS和1%青霉素-链霉素-L-谷氨酰胺的RPMI 1640)中以1×106/ml的密度制备靶细胞,并以50μl体积每孔50000个细胞铺板。将从新鲜供体血液中分离的外周血单核细胞(Peripheralblood mononuclear cell,PBMC)用作效应细胞,并以50μl体积每孔35000个细胞铺板。将TCR-抗CD3-Fc融合蛋白滴定至10nM至0.0001nM的最终浓度,并以50μl体积加入孔中。
根据制造商的说明书准备板。用测定培养基将含有靶细胞、效应细胞和融合蛋白的孔补足至终体积为200μl。所有反应以一式三份进行。还制备了对照孔,其中省去了融合蛋白、效应细胞或靶细胞。将板孵育过夜(37℃/5%CO2)。第二天,用洗涤缓冲液(1×PBS小袋,含有0.05%吐温-20,在去离子水中配制)将板洗涤三次。然后将检测一抗以50μl的体积加入到每个孔中。将板在室温下孵育2小时,然后再次洗涤三次。通过向各孔中添加50μl稀释的链霉亲和素-HRP,在室温下孵育1小时,并重复洗涤步骤,来进行二抗检测。在使用前不超过15分钟,每1ml AEC底物添加一滴(20μl)AEC发色团并混合,并向每个孔中添加50μl。定期监测点显色,并将板在自来水中洗涤以终止显色反应。接着将板在室温下干燥至少2小时,然后使用CTL分析仪(Cellular Technology Limited)通过免疫印迹软件来对点计数。使用PRISM软件准备和分析数据。
图2中显示的结果表明,在抗原阳性靶细胞存在的情况下,TCR-抗CD3-Fc融合蛋白介导有效的T细胞活化。Ec50值在pM范围内(对于与IgG1-Fc的融合体、与IgG1-Fc-变体1的融合体和与IgG1-Fc-变体2的融合体,分别为238pM、257pM和25pM)。使用抗原阴性靶细胞的对照实验表明,功能沉默的IgG1变体2的背景活性可忽略不计。因此,功能沉默的Fc结构域被认为最适合用于治疗用途。
实施例2(白蛋白结合)
a)TCR-抗CD3-白蛋白结合融合蛋白的设计
在第一种设计中,TCR-抗CD3融合蛋白包含与来自gp100的HLA-A*02限制性肽结合的高亲和力TCR。这种分子的氨基酸序列在WO2011001152中公开。具体地,TCR-抗CD3融合体包含:WO2011001152的SEQ ID No:45的α链,其中氨基酸1-109替换为WO2011001152的SEQID No.8,并且基于SEQ ID No:45的编号,1位的氨基酸为A;和WO2011001152的SEQ ID No:36的β链,其中残基259-370对应于WO2011001152的SEQ ID No.27,1位和2位的氨基酸分别为A和I。具有氨基酸序列QRLMEDICLPRWGCLWEDDF的白蛋白结合肽(如Dennis et al.,JBiol Chem.2002Sep 20;277(38):35035-43中所述)通过接头与TCR-抗CD3融合体连接。合适的接头是GGGGS。制备了三种变体,其中白蛋白结合肽在三个不同的连接位点融合:C-α(F1)、N-α(F2)或C-β(F3)。
在第二种设计中,将白蛋白结合纳米抗体连接到与第一种设计中使用的相同的TCR-抗CD3融合体上。具有WO2006122787中的SEQ ID No:52的序列的白蛋白结合纳米抗体通过接头与TCR-抗CD3融合体连接。合适的接头是GGGGS。制备了两种变体,其中白蛋白结合纳米抗体在两个不同的连接位点融合:C-α(R)或C-β(Y)。
在第三种设计中,白蛋白结合结构域抗体与TCR-抗CD3融合体α链的C末端连接。该抗体属于平台。使用了结构域抗体的两种变体;即分别由WO201010893中的SEQID No:26和27提供的DOM 7h-10-14dAb和DOM 7h-11-15dAb。抗体通过接头连接或直接连接(即没有接头)。合适的接头是GGGGS。TCR-抗CD3融合蛋白包含与来自MAGEA3的HLA-A*01限制性肽结合的高亲和力TCR。这种分子的氨基酸序列在WO2013041865中提供。
b)TCR-抗CD3-白蛋白结合融合蛋白的表达与纯化
使用本领域已知的与TCR-抗CD3融合蛋白相同的方法(例如,参见WO2011001152,实施例2),TCR-抗CD3-白蛋白结合融合蛋白在E.coli中作为包涵体表达,随后进行重折叠和纯化。
c)TCR-抗CD3-白蛋白结合融合蛋白有效活化T细胞
评估了TCR-抗CD3-白蛋白结合融合蛋白介导CD3+T细胞对抗原阳性癌细胞的有效重定向的能力。干扰素-γ(IFN-γ)释放被用作T细胞活化的读数。
根据制造商的说明,使用人IFN-γELISPOT试剂盒(BD Biosciences)进行检测。简而言之,对于包含白蛋白结合肽的融合体,使用黑色素瘤Mel526细胞作为靶细胞。在测定培养基(添加150μM人血清白蛋白(HSA)和1%青霉素-链霉素-L-谷氨酰胺的RPMI 1640)中以1×106/ml的密度制备靶细胞,并以50μl体积每孔50000个细胞铺板。将从新鲜供体血液中分离的外周血单核细胞(PBMC)用作效应细胞,并以50μl体积每孔30000个细胞铺板。将TCR-抗CD3-Fc融合蛋白滴定至10nM至0.0001nM的最终浓度,并以50μl体积加入孔中。
对于包含的融合体,使用骨髓瘤EJM细胞作为靶细胞。在测定培养基(添加45μM HSA和1%青霉素-链霉素-L-谷氨酰胺的RPMI 1640)中以1×106/ml的密度制备靶细胞,并以50μl体积每孔50000个细胞铺板。将从新鲜供体血液中分离的外周血单核细胞(PBMC)用作效应细胞,并以50μl体积每孔30000个细胞铺板。将TCR-抗CD3-Fc融合蛋白滴定至10nM至0.0001nM的最终浓度,并以50μl体积加入孔中。
如实施例1c中所述准备板和显影。
图3A-图3C显示,在抗原阳性靶细胞存在的情况下,与白蛋白结合部分融合的TCR-抗CD3融合蛋白介导了有效的T细胞活化。Ec50值在pM范围内(137.4/178.0/137.1)。
实施例3(延长的半衰期)
a)TCR-抗CD3-白蛋白结合融合蛋白的PK评估
在小鼠血清中研究了TCR-抗CD3-AlbudAb融合体的PK特征。
通过静脉推注向小鼠给药0.1mg/kg融合蛋白,并在120小时时间段内定期采集血清样品。通过使用基于ELISA的测定进行PK评估。简而言之,将生物素化的pHLA复合物连接到链霉亲和素包被的板上,然后添加血清样品。使用山羊抗抗CD3 scFv一抗和HRP缀合的抗山羊IgG(活化以用于在450nm处用TMB进行比色检测)进行检测步骤。产生的结果用于通过使用稀释系列和针对标准曲线的分析来确认TCR-抗CD3-Albudab融合体的存在和结合活性。结果报告为%活性,并用于生成Cmax随时间变化的图。
得到的PK数据如图4A所示。请注意,表示为“TCR-Alb(10-14)”和“TCR-Alb(11-15)”的样品是指实施例2a中描述的TCR-抗CD3融合体。“TCR-Alb(D)”是与非白蛋白结合Albudab融合的对照样品,以及“TCR”是指不含Albudab的TCR-抗CD3。
使用图4A中的PK数据来计算人中TCR-抗CD3-AlbudAb融合体的理论PK曲线(图4B)。预计与Albudab融合将体内半衰期从7小时延长至264小时。
序列表
<110> 英美偌科有限公司
<120> 结合CD3和HLA-A*02限制性肽的半衰期延长的IMMTAC
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Claims (17)
1.一种多结构域结合分子,包含:
i)与T细胞接合免疫效应子相连的肽-主要组织相容性复合物(pMHC)结合部分;和
ii)半衰期延长结构域,所述半衰期延长结构域包含免疫球蛋白Fc或白蛋白结合结构域。
2.根据权利要求1所述的多结构域结合分子,其中,所述pMHC结合部分是T细胞受体(TCR)或TCR样抗体,所述T细胞受体(TCR)或TCR样抗体包含TCR和/或抗体可变结构域和至少一个恒定结构域。
3.根据权利要求2所述的多结构域结合分子,其中,所述TCR是异二聚体α/βTCR多肽对。
4.根据权利要求2所述的多结构域结合分子,其中,所述TCR是单链α/βTCR多肽。
5.根据权利要求1至4中任一项所述的多结构域结合分子,其中,T细胞接合免疫效应子结构域是CD3效应子结构域,所述CD3效应子结构域通过与CD3和/或TCR/CD3复合物相互作用来活化T细胞。
6.根据权利要求5所述的多结构域结合分子,其中,所述CD3效应结构域包含抗体scFv或抗体样支架。
7.根据权利要求1至6中任一项所述的多结构域结合分子,其中,所述半衰期延长结构域是免疫球蛋白Fc结构域。
8.根据权利要求1至6中任一项所述的多结构域结合分子,其中,所述半衰期延长结构域包含白蛋白结合结构域。
9.根据权利要求1至8中任一项所述的多结构域结合分子,其中,所述半衰期延长结构域与所述pMHC结合部分的C末端或N末端连接,或与所述T细胞接合免疫效应子的C末端或N末端连接。
10.根据权利要求1至8中任一项所述的多结构域结合分子,其中,所述半衰期延长结构域通过接头与所述pMHC结合部分连接,或与所述T细胞接合免疫效应子连接。
11.根据前述权利要求中任一项所述的多结构域结合分子,所述多结构域结合分子用作药物。
12.一种药物组合物,所述药物组合物包含根据权利要求1至10中任一项所述的多结构域结合分子。
13.核酸,所述核酸编码根据权利要求1至10中任一项所述的多结构域结合分子。
14.一种表达载体,所述表达载体包含权利要求13所述的核酸。
15.一种宿主细胞,所述宿主细胞包含权利要求13所述的核酸或权利要求14所述的载体,其中,编码多结构域结合分子的核酸作为单个开放阅读框或分别编码α链和β链的两个不同的开放阅读框存在。
16.一种制备根据权利要求1所述的多结构域结合分子的方法,所述方法包括将权利要求15所述的宿主细胞维持在可选的用于核酸表达的条件下以及分离多结构域抗原结合多肽。
17.一种治疗方法,所述方法包括向有需要的患者给药根据权利要求1至10中任一项所述的多结构域结合分子或权利要求12所述的药物组合物。
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2020
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- 2020-01-30 AU AU2020213907A patent/AU2020213907A1/en active Pending
- 2020-01-30 US US17/427,581 patent/US20220119479A1/en active Pending
- 2020-01-30 CN CN202080012052.4A patent/CN113474367A/zh active Pending
- 2020-01-30 EP EP20703193.1A patent/EP3917955A1/en active Pending
- 2020-01-30 WO PCT/EP2020/052316 patent/WO2020157211A1/en unknown
- 2020-01-30 MX MX2021009274A patent/MX2021009274A/es unknown
- 2020-01-30 JP JP2021544405A patent/JP2022523722A/ja active Pending
- 2020-01-30 KR KR1020217026912A patent/KR20210121120A/ko unknown
- 2020-01-30 CA CA3126628A patent/CA3126628A1/en active Pending
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2021
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US20220119479A1 (en) | 2022-04-21 |
GB201901306D0 (en) | 2019-03-20 |
EP3917955A1 (en) | 2021-12-08 |
WO2020157211A1 (en) | 2020-08-06 |
CA3126628A1 (en) | 2020-08-06 |
MX2021009274A (es) | 2021-08-24 |
KR20210121120A (ko) | 2021-10-07 |
JP2022523722A (ja) | 2022-04-26 |
AU2020213907A1 (en) | 2021-09-09 |
BR112021014962A2 (pt) | 2021-09-28 |
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