CN114805587A - Car-nk细胞及其在脏器和组织老化与纤维化治疗中的用途 - Google Patents
Car-nk细胞及其在脏器和组织老化与纤维化治疗中的用途 Download PDFInfo
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Abstract
本发明涉及一种CAR‑NK细胞及其用途。CAR‑NK细胞表达的抗DPP4嵌合抗原受体包括:胞外区、跨膜区和胞内区,胞外区包括特异性识别抗原人DPP4的单链抗体,单链抗体具有分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列或具有分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。CAR‑NK细胞的CAR可特异性地与DPP4结合,使CAR‑NK细胞可特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,可有效治疗和预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
Description
技术领域
本发明属于生物医药领域,具体地,本发明涉及一种CAR-NK细胞及其在脏器和组织老化与纤维化治疗中的用途,更具体地,本发明涉及一种能够特异识别DPP4的抗体或其抗原结合片段、抗DPP4嵌合抗原受体、核酸分子、表达载体、转基因淋巴细胞、药物组合物及其用途、以及试剂在制备药物中的用途。
背景技术
机体组织和脏器的纤维化是一种普遍存在的、自我修复的结果,受到衰老、炎症反应、遗传或病原微生物等因素的影响。纤维化是由于损伤和重建部位过度分泌细胞外基质(ECM),导致胶原蛋白和纤连蛋白积累而形成的。
纤维化不属于疾病范畴,但纤维化会导致组织结构的破坏、器官功能障碍并最终导致器官衰竭,目前已有研究证明纤维化是一种动态过程,存在被逆转的可能性,但目前尚无纤维化的有效治疗方式。因此,亟需开发出一种新型的治疗纤维化的有效方法。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。为此,本发明提供了一种CAR-NK细胞及其在脏器和组织老化与纤维化治疗中的用途,该CAR-NK细胞可有效缓解肝脏纤维化程度并清除肝内衰老细胞。
本发明是基于发明人的下列发现而完成的:
研究表明,随着年龄增加,机体整体衰老,老年个体的组织和脏器内存在的衰老细胞逐渐增多,衰老细胞会通过自身生长的停滞产生炎症反应或以分泌衰老相关分泌表型(SASP)的方式将衰老表型扩散至临近的健康细胞,发生诱导衰老。且老年个体多伴随免疫系统的衰老,对体内衰老细胞的清除能力下降,进一步加剧衰老细胞的积累程度,对组织和脏器产生持续性的损伤,导致过度分泌的细胞外基质发生堆积,最终加重机体组织和脏器内的纤维化程度。
还有研究表明,肝纤维化过程中处于静态的肝星形细胞(HSC)会被激活,产生过量的细胞外基质,同时还会出现细胞衰老。衰老的肝星形细胞不仅会招募免疫细胞将其清除,还会通过分泌衰老相关分泌表型(SASP)诱导邻近的细胞出现衰老,造成免疫细胞的清除能力下降,导致衰老细胞积累,进一步加重肝脏纤维化程度。
因此,纤维化与细胞衰老之间存在密切相关性。但目前对于肝脏纤维化的治疗多集中在阻止HSC的活化、消融ECM或减轻炎症反应。
二肽基肽酶4(Dipeptidyl peptidase-4,简称DPP4)作为一个完整的II型糖蛋白,由DPPP4基因编码,通过其信号肽锚定在细胞膜上。
然而,发明人经过实验发现,在纤维化的肝脏中,DPP4与衰老表型具有同时高表达的,且肝内特异性敲除DPP4可以有效防止CCl4诱导的纤维化以及降低肝内衰老细胞沉积。发明人经过实验还发现,以DPP4为靶点制备的CAR-NK细胞能够特异识别DPP4,将其注射到纤维化小鼠模型体内,可以有效降低四氯化碳(CCl4)诱导的纤维化程度;并且,还可以清除小鼠体内的衰老细胞。因此,本发明的CAR-NK细胞可有效地治疗肝纤维化和清除衰老及衰老相关分泌表型。
在本发明的一个方面,本发明提出了一种能够特异识别DPP4的抗体或其抗原结合片段。根据本发明的实施例,所述抗体或其抗原结合片段包含:选自下列至少之一的CDR序列:轻链可变区CDR序列:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;重链可变区CDR序列:SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6。根据本发明实施例的抗体或其抗原结合片段能够特异性的靶向结合DPP4。
在本发明的另一方面,本发明提出了一种抗DPP4嵌合抗原受体。根据本发明的实施例,所述抗DPP4嵌合抗原受体包括:胞外区,所述胞外区包括单链抗体和铰链区,所述单链抗体包括单链抗体的重链可变区和轻链可变区,所述单链抗体特异性识别抗原人DPP4,所述单链抗体的C端与所述铰链区的N端相连,所述轻链可变区具有分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列或所述重链可变区具有分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;跨膜区,所述跨膜区的N端与所述胞外区的铰链区的C端相连,并且嵌入到所述淋巴细胞的细胞膜中;胞内区,所述胞内区的N端与所述跨膜区的C端相连。根据本发明实施例的抗DPP4嵌合抗原受体(简称嵌合抗原受体或CAR)可特异性地与DPP4结合,从而使表达该嵌合抗原受体的淋巴细胞可特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,具有缓解和治疗机体组织和脏器的纤维化、降低衰老细胞沉积和清除衰老细胞等作用,可有效治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
在本发明的又一方面,本发明提出了一种核酸分子。根据本发明的实施例,所述核酸分子编码前述的抗DPP4嵌合抗原受体。根据本发明实施例的核酸分子可有效编码前述的抗DPP4嵌合抗原受体。
在本发明的又一方面,本发明提出了一种表达载体。根据本发明的实施例,所述表达载体携带前述的核酸分子。根据本发明实施例的表达载体可有效表达前述的抗DPP4嵌合抗原受体,尤其是在原核生物或者低等真核生物表达体系中可以有效地表达前述抗DPP4嵌合抗原受体。
在本发明的又一方面,本发明提出了一种转基因淋巴细胞。根据本发明的实施例,所述淋巴细胞表达携带前述的核酸分子、前述的表达载体;或表达前述的抗DPP4嵌合抗原受体。根据本发明实施例的转基因淋巴细胞可有效表达抗DPP4嵌合抗原受体,该抗DPP4嵌合抗原受体可特异性地与DPP4结合,使转基因淋巴细胞可特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,具有缓解和治疗机体组织和脏器的纤维化、降低衰老细胞沉积和清除衰老细胞等作用,可有效治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
在本发明的又一方面,本发明提出了一种药物组合物。根据本发明的实施例,所述药物组合物包括:前述的抗DPP4嵌合抗原受体、前述的核酸分子、前述的表达载体或前述的转基因淋巴细胞。根据本发明实施例的药物组合物可特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,具有缓解和治疗机体组织和脏器的纤维化、降低衰老细胞沉积和清除衰老细胞等作用,可有效治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
在本发明的又一方面,本发明提出了一种前述的转基因淋巴细胞或前述的药物组合物在制备药物中的用途,所述药物用于治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
在本发明的又一方面,本发明提出了一种试剂在制备药物中的用途,所述试剂用于抑制DPP4的表达或活性,所述药物用于治疗和/或预防衰老相关疾病和/或抗衰老。发明人经过实验发现,采用上述药物可有效治疗和/或预防衰老相关疾病和/或抗衰老。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1为本发明实施例1中小鼠肝脏的病理学切片图,腺相关病毒敲除DPP4小鼠肝脏的衰老相关的α平滑肌肌动蛋白(αSMA)、p16以及DPP4免疫组化图及其含量统计图;
图2为本发明实施例2中获得RFP阳性CAR NK细胞的检测结果;
图3为本发明实施例2中CAR NK细胞和NK92细胞的CD107a表达的检测结果;
图4为本发明实施例2中CAR NK细胞和NK92细胞的杀伤率的检测结果;
图5为本发明实施例3中注射CAR-NK细胞后的小鼠肝脏的衰老相关的αSMA、p16以及DPP4免疫组化图及其含量统计图。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。
需要说明的是,术语“第一”、“第二”仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此,限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地,在本发明的描述中,除非另有说明,“多个”的含义是两个或两个以上。
在本文中,术语“包含”或“包括”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
在本文中,术语“任选地”、“任选的”或“任选”通常是指随后所述的事件或状况可以但未必发生,并且该描述包括其中发生该事件或状况的情况,以及其中未发生该事件或状况的情况。
在本文中,术语“嵌合抗原受体(CAR)”是一种融合蛋白,其包含能够结合抗原的胞外结构域,与胞外结构域衍生自不同多肽的跨膜结构域,以及至少一个胞内结构域。“嵌合抗原受体(CAR)”也称为“嵌合受体”、“T-体”或“嵌合免疫受体(CIR)”。所述的“能够结合抗原的胞外结构域”是指能够结合某一抗原的任何寡肽或多肽。“胞内结构域”是指已知的作为传递信号以激活或抑制细胞内生物过程的结构域起作用的任何寡肽或多肽。
在本文中,“核酸分子”或“核酸”可交换使用,其是指任何长度的核苷酸链,并且包括DNA或RNA。核苷酸可以是脱氧核糖核苷酸、核糖核苷酸、修饰的核苷酸或碱基、和/或它们的类似物、或者能够通过DNA或RNA聚合酶掺入链的任何底物。
在本文中,术语“表达载体”和“构建体”可交换使用,其能够将一种或多种所关注的基因或序列递送入宿主细胞,并且优选在宿主细胞中表达所述基因或序列。载体的实例包括但不限于病毒载体、质粒、粘粒或噬菌体载体。
在本文中,“药物组合物”可指用于疾病的治疗,也可用于细胞的体外培养实验。用于疾病的治疗时,术语“药物组合物”通常是指单位剂量形式,并且可以通过制药领域中熟知的方法的任何一种进行制备。所有的方法包括使活性成分与构成一种或多种附属成分的辅料相结合的步骤。通常,通过均匀并充分地使活性化合物与液体辅料、细碎固体辅料或这两者相结合,制备组合物。
在本文中,术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地,本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
在本文中,术语“药学上可接受的辅料”或者“药学上可接受的载体”均可包括任何溶剂、固体赋形剂、稀释剂或其他液体赋形剂等等,适合于特有的目标剂型。除了任何常规的辅料与本发明的化合物不相容的范围,例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用,它们的用途也是本发明所考虑的范围。
在本文中,术语“治疗”是指用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的,和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病,包括:(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生;(b)抑制疾病,例如阻滞疾病发展;或(c)缓解疾病,例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药,包括但不限于将含本文所述化合物的药物给予有需要的个体。
在本文中,术语“预防和/或治疗组织和脏器的纤维化”是指预防和/或治疗组织和脏器的纤维化及其组织和脏器的纤维化引起的相关疾病。
在本文中,术语“细胞衰老(cell aging)”是指细胞在执行生命活动过程中,随着时间的推移,细胞增殖与分化能力和生理功能逐渐发生衰退的变化过程的细胞。细胞的生命历程都要经过未分化、分化、生长、成熟、衰老和死亡几个阶段。衰老死亡的细胞被机体的免疫系统清除,同时新生的细胞也不断从相应的组织器官生成,以弥补衰老死亡的细胞。细胞衰老死亡与新生细胞生长的动态平衡是维持机体正常生命活动的基础。
本发明提出了一种能够特异识别DPP4的抗体或其抗原结合片段、抗DPP4嵌合抗原受体、核酸分子、表达载体、转基因淋巴细胞、药物组合物及其用途、以及试剂在制备药物中的用途,下面将分别对其进行详细描述。
抗体
本文中,术语“抗体”是能够与特异性抗原结合的免疫球蛋白分子。包括两条分子量较轻的轻链和两条分子量较重的重链,重链(H链)和轻链(L链)由二硫键连接形成一个四肽链分子。其中,肽链的氨基端(N端)氨基酸序列变化很大,称为可变区(V区),羧基端(C端)相对稳定,变化很小,称为恒定区(C区)。L链和H链的V区分别称为VL和VH。
在可变区中某些区域氨基酸组成和排列顺序具有更高的变化程度,称为高变区(Hypervariable region,HVR),高变区为抗原和抗体结合的位置,因此也称为互补决定区(complementarity-determining region,CDR)。重链可变区和轻链可变区上均有三个CDR。
在本发明的一个方面,本发明提出了一种能够特异识别DPP4的抗体或其抗原结合片段。根据本发明的实施例,所述抗体或其抗原结合片段包含:选自下列至少之一的CDR序列:轻链可变区CDR序列:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;重链可变区CDR序列:SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6。根据本发明实施例的抗体或其抗原结合片段能够特异性的靶向结合DPP4。“抗原结合片段”是指保持特异性结合抗原(DPP4)能力的抗体片段,抗原结合片段的实施例包括但不限于Fv片段、二硫键稳定的Fv片段(dsFv)、Fab片段、(Fab)2、scFv-Fc融合蛋白、scFv-Fv融合蛋白、Fv-Fc融合蛋白、由抗原结合片段形成的多特异性抗体、单结构域抗体、VHH纳米抗体、结构域抗体、二价结构域抗体或最小识别单位的至少之一。
QSSKSLLYSDGKTYLN(SEQ ID NO:1)。
WMSTRAS(SEQ ID NO:2)。
QQFLEFPDT(SEQ ID NO:3)。
SNYWG(SEQ ID NO:4)。
YISYSDNTNYNPSLKS(SEQ ID NO:5)。
QNSGIED(SEQ ID NO:6)。
根据本发明的实施例,所述抗体或其抗原结合片段包括:分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例,所述轻链可变区具有如SEQ ID NO:7所示的氨基酸序列。
DIVMTQGALPNPVPSGESASITCQSSKSLLYSDGKTYLNWYLKRPGQSPQLLIYWMSTRASGVSDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEFPDTFGAGTKLELK(SEQ ID NO:7)。
根据本发明的实施例,所述重链可变区具有如SEQ ID NO:8所示的氨基酸序列。
VQLQESGPGLVKPSQSLSLTCSVTGYSLISNYWGWIRKFPGNKMEWMGYISYSDNTNYNPSLKSRISLTRDTSKNQFFLQLNSVTTEDTATYYCARQNSGIEDWGQGVMVTVSS(SEQ ID NO:8)。
根据本发明的实施例,所述抗体或其抗原结合片段特异性识别DPP4的胞外区。
根据本发明的实施例,所述抗体含有重链恒定区和轻链恒定区中的至少之一,所述重链恒定区和轻链恒定区的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体中的至少之一,优选为鼠源抗体。
根据本发明的实施例,所述轻链恒定区和重链恒定区均来自于鼠源IgG抗体或其突变体。
根据本发明的实施例,所述轻链具有如SEQ ID NO:9所示的氨基酸序列。
DIVMTQGALPNPVPSGESASITCQSSKSLLYSDGKTYLNWYLKRPGQSPQLLIYWMSTRASGVSDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEFPDTFGAGTKLELKRADAAPTVSIFPPSTEQLATGGASVVCLMNNFYPRDISVKWKIDGTERRDGVLDSVTDQDSKDSTYSMSSTLSLTKADYESHNLYTCEVVHKTSSSPVVKSFNRNEC(SEQ ID NO:9)。
根据本发明的实施例,所述重链具有如SEQ ID NO:10所示的氨基酸序列。
VQLQESGPGLVKPSQSLSLTCSVTGYSLISNYWGWIRKFPGNKMEWMGYISYSDNTNYNPSLKSRISLTRDTSKNQFFLQLNSVTTEDTATYYCARQNSGIEDWGQGVMVTVSSAETTAPSVYPLAPGTALKSDSMVTLGCLVKGYFPEPVTVTWNSGALSSGVHTFPAVLQSGLYTLTSSVTVPSSTWSSQAVTCNVAHPASSTKVDKKIVPRECNPCGCTGSEVSSVFIFPPKTKDVFTITLTPKVTCVVVDISQNDPEVRFSWFIDDVEVHTAQTHAPEKQSNSTLRSVSELPIVHRDWLDGKTFKCKVNSGAFPAPIEKSISKPEGTPRGPQVYTMAPPKEEMTQSQVSLTCMVKGFYPPDIYTEWKMNGQPQENYKNTPPTMDTDGSYFLYSKLNVKKETWQQGNTFTCSVLHEGLHNHHTEKSLSHSPGK(SEQ ID NO:10)。
根据本发明的实施例,所述抗体为单链抗体、多聚体抗体、CDR移植抗体或小分子抗体。
核酸分子、表达载体、重组细胞
在制备或者获取这些抗体或其抗原结合片段的过程中,可以利用表达这些抗体或其抗原结合片段的核酸分子,与不同的载体连接,然后在不同细胞中表达,来获得相应抗体或其抗原结合片段。
为此,在本发明的另一方面,本发明提出了一种分离的核酸分子。根据本发明的实施例,所述核酸分子编码上述所述的抗体或其抗原结合片段。
根据本发明的实施例,所述核酸分子为DNA。
在本发明的又一方面,本发明还提供了一种表达载体,所述表达载体包含上述分离的核酸分子。在将上述分离的多核苷酸连接到载体上时,可以将多核苷酸与载体上的控制元件直接或者间接相连,只要这些控制元件能够控制多核苷酸的翻译和表达等即可。当然这些控制元件可以直接来自于载体本身,也可以是外源性的,即并非来自于载体本身。当然,多核苷酸与控制元件进行可操作地连接即可。
本文中“可操作地连接”是指将外源基因连接到载体上,使得载体内的控制元件,例如转录控制序列和翻译控制序列等等,能够发挥其预期的调节外源基因的转录和翻译的功能。当然用来编码抗体重链和轻链的多核苷酸,可以分别独立的插入到不同的载体上,常见的是插入到同一载体上。常用的载体例如可以为质粒、噬菌体等等。
根据本发明的实施例,所述表达载体为非致病性病毒载体;
根据本发明的实施例,所述表达载体为腺病毒载体、慢病毒载体或逆转录病毒载体。
在本发明的又一方面,本发明还提供了一种重组细胞,该重组细胞中包含有该表达载体。可以将表达载体导入到哺乳动物细胞中,构建获得重组细胞,然后利用这些重组细胞表达本发明提供的抗体或者抗原结合片段。通过该重组细胞进行培养,即可以获得相应抗体。这些可用的哺乳动物细胞例如可以为CHO细胞等。
根据本发明的实施例,所述重组细胞为真核细胞。
根据本发明的实施例,所述重组细胞为哺乳动物细胞。
本领域技术人员能够理解的是,前面针对抗体或其抗原结合片段所描述的特征和优点,同样适用于该核酸分子、表达载体和重组细胞,在此不再赘述。
抗DPP4嵌合抗原受体
在本发明的另一方面,本发明提出了一种抗DPP4嵌合抗原受体。根据本发明的实施例,所述抗DPP4嵌合抗原受体包括:胞外区,所述胞外区包括单链抗体和铰链区,所述单链抗体包括单链抗体的重链可变区和轻链可变区,所述单链抗体特异性识别抗原人DPP4,所述单链抗体的C端与所述铰链区的N端相连,所述轻链可变区具有分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列或所述重链可变区具有分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;跨膜区,所述跨膜区的N端与所述胞外区的铰链区的C端相连,并且嵌入到所述淋巴细胞的细胞膜中;胞内区,所述胞内区的N端与所述跨膜区的C端相连。根据本发明实施例的抗DPP4嵌合抗原受体(简称嵌合抗原受体或CAR)可特异性地与DPP4结合,从而使表达该嵌合抗原受体的淋巴细胞可特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,具有缓解和治疗机体组织和脏器的纤维化、降低衰老细胞沉积和清除衰老细胞等作用,可有效治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
根据本发明的实施例,所述轻链可变区具有分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者所述重链可变区具有分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例,所述轻链可变区具有如SEQ ID NO:7所示的氨基酸序列;或所述重链可变区具有如SEQ ID NO:8所示的氨基酸序列。
根据本发明的实施例,所述单链抗体进一步包括连接肽。
根据本发明的实施例,所述连接肽的氨基酸序列为(GGGGS)n,其中n为大于或等于1的整数,优选为1、2、3、4或5。
根据本发明的实施例,所述所述连接肽的氨基酸序列选自GGGGS。
编码GGGGS的核苷酸序列如下所示:
GGTGGCGGAGGCTCCGGTGGAGGTGGTAGCGGAGGCGGAGGTTCT(SEQ ID NO:11)。
根据本发明的实施例,所述重链可变区的C端与所述连接肽的N端相连,所述连接肽的C端与所述轻链可变区的N端相连。
根据本发明的实施例,所述铰链区选自CD8的铰链区。根据本发明的实施例,所述跨膜区选自CD8分子跨膜段。
根据本发明的实施例,所述胞内结构域区包括共刺激结构域和胞内信号传导结构域。
根据本发明的实施例,所述共刺激结构域包括41BB分子胞内段。
根据本发明的实施例,所述胞内信号传导结构域选自CD8分子胞内段。
根据本发明的实施例,所述抗DPP4嵌合抗原受体具有如SEQ ID NO:12所示的核苷酸序列。
GACATCGTGATGACCCAGGGCGCCCTGCCCAACCCCGTGCCCAGCGGCGAGAGCGCCAGCATCACCTGCCAGAGCAGCAAGAGCCTGCTGTACAGCGACGGCAAGACCTACCTGAACTGGTACCTGAAGAGGCCCGGCCAGAGCCCCCAGCTGCTGATCTACTGGATGAGCACCAGGGCCAGCGGCGTGAGCGACAGGTTCAGCGGCAGCGGCAGCGGCACCGACTTCACCCTGAAGATCAGCAGGGTGGAGGCCGAGGACGTGGGCGTGTACTACTGCCAGCAGTTCCTGGAGTTCCCCGACACCTTCGGCGCCGGCACCAAGCTGGAGCTGGGTGGCGGAGGCTCCGGTGGAGGTGGTAGCGGAGGCGGAGGTTCTGAGGTGCAGCTGCAGGAGAGCGGCCCCGGCCTGGTGAAGCCCAGCCAGAGCCTGAGCCTGACCTGCAGCGTGACCGGCTACAGCCTGATCAGCAACTACTGGGGCTGGATCAGGAAGTTCCCCGGCAACAAGATGGAGTGGATGGGCTACATCAGCTACAGCGACAACACCAACTACAACCCCAGCCTGAAGAGCAGGATCAGCCTGACCAGGGACACCAGCAAGAACCAGTTCTTCCTGCAGCTGAACAGCGTGACCACCGAGGACACCGCCACCTACTACTGCGCCAGGCAGAACAGCGGCATCGAGGACTGGGGCCAGGGCGTGATGGTGAGCCACTTCGTGCCGGTCTTCCTGCCAGCGAAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC(SEQ ID NO:12)。
核酸分子和表达载体
在本发明的又一方面,本发明提出了一种核酸分子。根据本发明的实施例,所述核酸分子编码前述的抗DPP4嵌合抗原受体。根据本发明实施例的核酸分子可有效编码前述的抗DPP4嵌合抗原受体。
根据本发明的实施例,所述核酸分子为DNA。
在本发明的又一方面,本发明提出了一种表达载体。根据本发明的实施例,所述表达载体携带前述的核酸分子。根据本发明实施例的表达载体可有效表达前述的抗DPP4嵌合抗原受体,尤其是在原核生物或者低等真核生物表达体系中可以有效地表达前述抗DPP4嵌合抗原受体。
根据本发明的实施例,所述表达载体为非致病性病毒载体;
根据本发明的实施例,所述表达载体为腺病毒载体、慢病毒载体或逆转录病毒载体。
本领域技术人员能够理解的是,前面针对抗DPP4嵌合抗原受体所描述的特征和优点,同样适用于该核酸分子和表达载体,在此不再赘述。
转基因淋巴细胞
在本发明的又一方面,本发明提出了一种转基因淋巴细胞。根据本发明的实施例,所述淋巴细胞表达携带前述的核酸分子、前述的表达载体;或表达前述的抗DPP4嵌合抗原受体。根据本发明实施例的转基因淋巴细胞可有效表达抗DPP4嵌合抗原受体,该抗DPP4嵌合抗原受体可特异性地与DPP4结合,使转基因淋巴细胞可特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,具有缓解和治疗机体组织和脏器的纤维化、降低衰老细胞沉积和清除衰老细胞等作用,可有效治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
根据本发明的实施例,所述转基因淋巴细胞包括选自NK细胞、NKT细胞和巨噬细胞中的至少之一。
本领域技术人员能够理解的是,前面针对抗DPP4嵌合抗原受体、核酸分子和表达载体所描述的特征和优点,同样适用于该转基因淋巴细胞,在此不再赘述。
药物组合物
在本发明的又一方面,本发明提出了一种药物组合物。根据本发明的实施例,所述药物组合物包括:前述的抗DPP4嵌合抗原受体、前述的核酸分子、前述的表达载体或前述的转基因淋巴细胞。根据本发明实施例的药物组合物可以靶向表面表达DPP4蛋白的细胞,从而特异性地清除表达有DPP4结合的衰老细胞或纤维化细胞,减轻肝内纤维化程度和衰老相关表型,具有缓解和治疗机体组织和脏器的纤维化、降低衰老细胞沉积和清除衰老细胞等作用,可有效治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
根据本发明的实施例,进一步包括:药学上可接受的辅料。
本领域技术人员能够理解的是,前面针对抗DPP4嵌合抗原受体、核酸分子、表达载体和转基因淋巴细胞所描述的特征和优点,同样适用于该药物组合物,在此不再赘述。
用途
在本发明的又一方面,本发明提出了一种前述的转基因淋巴细胞或前述的药物组合物在制备药物中的用途,所述药物用于治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老。
根据本发明的实施例,所述组织和脏器的纤维化包括肝纤维化、肺纤维化、肾纤维化、骨髓纤维化和/或肌肉纤维化。
本领域技术人员能够理解的是,前面针对抗DPP4嵌合抗原受体、核酸分子、表达载体、转基因淋巴细胞和药物组合物所描述的特征和优点,同样适用于该用途,在此不再赘述。
在本发明的又一方面,本发明提出了一种试剂在制备药物中的用途,所述试剂用于抑制DPP4的表达或活性,所述药物用于治疗和/或预防衰老相关疾病和/或抗衰老。发明人经过实验发现,采用上述药物可消除或减轻了衰老相关分泌表型,以及抑制DPP4的表达或活性,具有抑制细胞衰老的作用,可有效治疗和/或预防衰老相关疾病和/或抗衰老。
根据本发明的实施例,所述药物用于清除衰老细胞。
根据本发明的实施例,所述试剂包括敲低所述DPP4的siRNA或前述的转基因淋巴细胞。
根据本发明的实施例,所述siRNA具有如SEQ ID NO:13所示的核苷酸序列。
ACCGCTAGCTAACTGGAGGCTTGCTGAAGGCTGTATGCTGTATAGAAGCTGCTTCCATCAGGTTTTGGCCACTGACTGACCTGATGGACAGCTTCTATACAGGACACAAGGCCTGTTACTAGCACTCACATGGAACAAATGGCCCAAGCTTGGT(SEQ ID NO:13)。
本领域技术人员能够理解的是,前面针对药物组合物所描述的特征和优点,同样适用于该用途,在此不再赘述。
方法
在本发明的又一方面,本发明提出了一种治疗和/或预防组织和脏器的纤维化。根据本发明的实施例,所述方法包括:向受试者施用药学上可接受量的前述的药物组合物。根据本发明的实施例,该方法可有效预防和/或治疗组织和脏器的纤维化。
根据本发明的实施例,所述方法的给药途径采用静脉注射或腹腔注射。
在本发明的又一方面,本发明提出了一种治疗和/或预防衰老相关疾病和/或抗衰老。根据本发明的实施例,所述方法包括:向受试者施用药学上可接受量的药物,所述药物包含用于抑制DPP4的表达或活性的试剂。根据本发明的实施例,该方法可消除或减轻了衰老相关分泌表型,以及抑制DPP4的表达或活性,具有抑制细胞衰老的作用,可有效预防和/或治疗组织和脏器的纤维化。
根据本发明的实施例,所述方法的给药途径采用静脉注射或腹腔注射。
根据本发明的实施例,所述药物用于清除衰老细胞。
根据本发明的实施例,所述试剂包括敲低所述DPP4的siRNA或前述的转基因淋巴细胞。
根据本发明的实施例,所述siRNA具有如SEQ ID NO:13所示的核苷酸序列。
本领域技术人员能够理解的是,前面针对药物组合物所描述的特征和优点,同样适用于该用途,在此不再赘述。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:
由生工生物工程(上海)股份有限公司合成DPP4抗体,DPP4抗体具有如SEQ ID NO:9所示的轻链和具有如SEQ ID NO:10所示的重链。发明人采用ELISA实验被用于检测上述获得的抗体与DPP4的结合特性,结果表明本发明的抗体能够结合DPP4。
实施例2:
本实施例选用遗传背景为C57BL/6J的5-6周龄野生型小鼠,通过腹腔注射8周、每周2次的CCl4橄榄油试剂(1:7),构建肝纤维化小鼠模型。
将小鼠随机分为4组,每组6只。其中,第一组(WT-Wild Type),正常饲养;第二组(CCl4)小鼠进行腹腔注射8周、每周2次的CCl4橄榄油试剂(1:7),制造肝纤维化小鼠模型;第三组(AAV-Ctrl)注射空病毒(上海吉凯基因医学科技股份有限公司),再腹腔注射8周、每周2次的CCl4橄榄油试剂(1:7);第四组(AAV-DPP4)注射肝内特异性敲低DPP4的腺相关病毒(siRNA:ACCGCTAGCTAACTGGAGGCTTGCTGAAGGCTGTATGCTGTATAGAAGCTGCTTCCATCAGGTTTTGGCCACTGACTGACCTGATGGACAGCTTCTATACAGGACACAAGGCCTGTTACTAGCACTCACATGGAACAAATGGCCCAAGCTTGGT(SEQ ID NO:13))(上海吉凯基因医学科技股份有限公司),再腹腔注射8周、每周2次的CCl4橄榄油试剂(1:7)。8周后,对各组小鼠肝脏进行病理学切片,采用免疫荧光技术观察肝脏纤维化程度和衰老标志物(P16)的表达情况,具体参见图1。
由图1可知,低DPP4水平的小鼠肝脏内纤维沉积和衰老相关标志物的水平明显降低,表明DPP4与肝脏纤维化和纤维化的肝脏中衰老细胞的积累水平相关。因此,通过降低DPP4水平或许可以成为缓解肝脏纤维化,降低肝内衰老细胞沉积的治疗方法。
实施例3:
发明人将编码抗DPP4嵌合抗原受体(抗DPP4的单链抗体的序列、CD8α序列、4-1BB胞内段序列和CD3ζ-链序列)的核苷酸序列(SEQ ID NO:12)进行人工合成,然后克隆至慢病毒载体质粒pUC57上,然后包装慢病毒载体质粒,得到病毒感染液。将得到的病毒感染液感染NK92细胞,采用流式细胞术对感染后的NK92细胞进行分选,获得RFP阳性CAR-NK细胞(又称CAR NK细胞),具体参见图2,其中,图2左图为分选前的结果,图2右图为分选后的结果。并将获得的CAR NK细胞送至生工生物工程(上海)股份有限公司测序,结果显示所测序列与SEQ ID NO:12的序列相同。
通过流式细胞术分选,获得RFP全阳性的CAR NK细胞,获得靶向人源DPP4的CAR NK细胞(又称anti-DPP4 CAR-NK细胞)后,将野生型NK92和CAR NK分别与表达DPP4的HepG2细胞系共培养24h,检测CAR NK细胞的激活和靶向杀伤率,如图3所示.结果表明,相比于野生型NK92细胞,CAR NK细胞有更高的CD107a表达,代表有更高比例的NK细胞被激活。同时,通过LDH实验显示,具体参见图4,CAR NK有更高的靶细胞杀伤率,而且随着效靶比的提高,靶细胞杀伤率也提高。
实施例4:
本实施例选用遗传背景为C57BL/6J的5-6周龄野生型小鼠,将小鼠分为4组,每组6只。其中,第一组小鼠为健康的空白对照组(WT-Wild Type),第二组小鼠进行腹腔注射8周、每周2次的CCl4橄榄油试剂(1:7),制造肝纤维化小鼠模型,尾静脉注射0.1ml PBS,每周一次,即为PBS组;第三组肝纤维化小鼠,注射等量的0.1ml 106个NK92细胞(购于武汉普诺赛生命科技有限公司,货号:CL-0530),每周一次,即为NK92组;第四组肝纤维化小鼠,注射等量的0.1ml 106个实施例2制备的anti-DPP4 CAR-NK细胞,每周一次,即为CAR-NK组;连续处理四周,对各组小鼠肝脏进行病理学切片,观察肝脏纤维化程度和衰老标志物的表达情况,具体参见图5。
由图2可以明显的看到,注射四周anti-DPP4 CAR-NK细胞的肝纤维化小鼠,肝脏内纤维化程度显著降低,并且衰老相关标志物明显减少。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
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Trp Met Ser Thr Arg Ala Ser
1 5
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<211> 9
<212> PRT
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<220>
<223> 3
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Gln Gln Phe Leu Glu Phe Pro Asp Thr
1 5
<210> 4
<211> 5
<212> PRT
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<220>
<223> 4
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Ser Asn Tyr Trp Gly
1 5
<210> 5
<211> 16
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<220>
<223> 5
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Tyr Ile Ser Tyr Ser Asp Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 6
<211> 7
<212> PRT
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Gln Asn Ser Gly Ile Glu Asp
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<210> 7
<211> 112
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Glu Ser Ala Ser Ile Thr Cys Gln Ser Ser Lys Ser Leu Leu Tyr Ser
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Pro Gln Leu Leu Ile Tyr Trp Met Ser Thr Arg Ala Ser Gly Val Ser
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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
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Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Phe
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Leu Glu Phe Pro Asp Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
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<210> 8
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<212> PRT
<213> Artificial
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Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Leu Ile Ser Asn Tyr
20 25 30
Trp Gly Trp Ile Arg Lys Phe Pro Gly Asn Lys Met Glu Trp Met Gly
35 40 45
Tyr Ile Ser Tyr Ser Asp Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
50 55 60
Arg Ile Ser Leu Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Gln
65 70 75 80
Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
85 90 95
Gln Asn Ser Gly Ile Glu Asp Trp Gly Gln Gly Val Met Val Thr Val
100 105 110
Ser Ser
<210> 9
<211> 219
<212> PRT
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<220>
<223> 9
<400> 9
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1 5 10 15
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20 25 30
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35 40 45
Pro Gln Leu Leu Ile Tyr Trp Met Ser Thr Arg Ala Ser Gly Val Ser
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
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85 90 95
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100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Thr Glu
115 120 125
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130 135 140
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145 150 155 160
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165 170 175
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180 185 190
Ser His Asn Leu Tyr Thr Cys Glu Val Val His Lys Thr Ser Ser Ser
195 200 205
Pro Val Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 10
<211> 436
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<400> 10
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1 5 10 15
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20 25 30
Trp Gly Trp Ile Arg Lys Phe Pro Gly Asn Lys Met Glu Trp Met Gly
35 40 45
Tyr Ile Ser Tyr Ser Asp Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
50 55 60
Arg Ile Ser Leu Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Gln
65 70 75 80
Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
85 90 95
Gln Asn Ser Gly Ile Glu Asp Trp Gly Gln Gly Val Met Val Thr Val
100 105 110
Ser Ser Ala Glu Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Gly
115 120 125
Thr Ala Leu Lys Ser Asp Ser Met Val Thr Leu Gly Cys Leu Val Lys
130 135 140
Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ala Leu
145 150 155 160
Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Gly Leu Tyr
165 170 175
Thr Leu Thr Ser Ser Val Thr Val Pro Ser Ser Thr Trp Ser Ser Gln
180 185 190
Ala Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp
195 200 205
Lys Lys Ile Val Pro Arg Glu Cys Asn Pro Cys Gly Cys Thr Gly Ser
210 215 220
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Thr Lys Asp Val Phe
225 230 235 240
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245 250 255
Gln Asn Asp Pro Glu Val Arg Phe Ser Trp Phe Ile Asp Asp Val Glu
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Val His Thr Ala Gln Thr His Ala Pro Glu Lys Gln Ser Asn Ser Thr
275 280 285
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290 295 300
Gly Lys Thr Phe Lys Cys Lys Val Asn Ser Gly Ala Phe Pro Ala Pro
305 310 315 320
Ile Glu Lys Ser Ile Ser Lys Pro Glu Gly Thr Pro Arg Gly Pro Gln
325 330 335
Val Tyr Thr Met Ala Pro Pro Lys Glu Glu Met Thr Gln Ser Gln Val
340 345 350
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355 360 365
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370 375 380
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385 390 395 400
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Ser Pro Gly Lys
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<210> 11
<211> 45
<212> DNA
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<220>
<223> 11
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ggtggcggag gctccggtgg aggtggtagc ggaggcggag gttct 45
<210> 12
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<212> DNA
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<220>
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<400> 12
gacatcgtga tgacccaggg cgccctgccc aaccccgtgc ccagcggcga gagcgccagc 60
atcacctgcc agagcagcaa gagcctgctg tacagcgacg gcaagaccta cctgaactgg 120
tacctgaaga ggcccggcca gagcccccag ctgctgatct actggatgag caccagggcc 180
agcggcgtga gcgacaggtt cagcggcagc ggcagcggca ccgacttcac cctgaagatc 240
agcagggtgg aggccgagga cgtgggcgtg tactactgcc agcagttcct ggagttcccc 300
gacaccttcg gcgccggcac caagctggag ctgggtggcg gaggctccgg tggaggtggt 360
agcggaggcg gaggttctga ggtgcagctg caggagagcg gccccggcct ggtgaagccc 420
agccagagcc tgagcctgac ctgcagcgtg accggctaca gcctgatcag caactactgg 480
ggctggatca ggaagttccc cggcaacaag atggagtgga tgggctacat cagctacagc 540
gacaacacca actacaaccc cagcctgaag agcaggatca gcctgaccag ggacaccagc 600
aagaaccagt tcttcctgca gctgaacagc gtgaccaccg aggacaccgc cacctactac 660
tgcgccaggc agaacagcgg catcgaggac tggggccagg gcgtgatggt gagccacttc 720
gtgccggtct tcctgccagc gaagcccacc acgacgccag cgccgcgacc accaacaccg 780
gcgcccacca tcgcgtcgca gcccctgtcc ctgcgcccag aggcgtgccg gccagcggcg 840
gggggcgcag tgcacacgag ggggctggac ttcgcctgtg atatctacat ctgggcgccc 900
ttggccggga cttgtggggt ccttctcctg tcactggtta tcaccaaacg gggcagaaag 960
aaactcctgt atatattcaa acaaccattt atgagaccag tacaaactac tcaagaggaa 1020
gatggctgta gctgccgatt tccagaagaa gaagaaggag gatgtgaact gagagtgaag 1080
ttcagcagga gcgcagacgc ccccgcgtac cagcagggcc agaaccagct ctataacgag 1140
ctcaatctag gacgaagaga ggagtacgat gttttggaca agagacgtgg ccgggaccct 1200
gagatggggg gaaagccgag aaggaagaac cctcaggaag gcctgtacaa tgaactgcag 1260
aaagataaga tggcggaggc ctacagtgag attgggatga aaggcgagcg ccggaggggc 1320
aaggggcacg atggccttta ccagggtctc agtacagcca ccaaggacac ctacgacgcc 1380
cttcacatgc aggccctgcc ccctcgc 1407
<210> 13
<211> 154
<212> DNA
<213> Artificial
<220>
<223> 13
<400> 13
accgctagct aactggaggc ttgctgaagg ctgtatgctg tatagaagct gcttccatca 60
ggttttggcc actgactgac ctgatggaca gcttctatac aggacacaag gcctgttact 120
agcactcaca tggaacaaat ggcccaagct tggt 154
<210> 14
<211> 5
<212> PRT
<213> Artificial
<220>
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Gly Gly Gly Gly Ser
1 5
Claims (10)
1.一种能够特异识别DPP4的抗体或其抗原结合片段,其特征在于,包含:
选自下列至少之一的CDR序列:
轻链可变区CDR序列:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;
重链可变区CDR序列:SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6。
2.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包括:
分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者
分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;
任选地,所述轻链可变区具有如SEQ ID NO:7所示的氨基酸序列;
任选地,所述重链可变区具有如SEQ ID NO:8所示的氨基酸序列;
任选地,所述抗体或其抗原结合片段特异性识别DPP4的胞外区;
任选地,所述抗体含有重链恒定区和轻链恒定区中的至少之一,所述重链恒定区和轻链恒定区的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体中的至少之一;
任选地,所述轻链恒定区和重链恒定区均来自于鼠源IgG抗体或其突变体;
任选地,所述轻链具有如SEQ ID NO:9所示的氨基酸序列;
任选地,所述重链具有如SEQ ID NO:10所示的氨基酸序列;
任选地,所述抗体为单链抗体、多聚体抗体、CDR移植抗体或小分子抗体。
3.一种抗DPP4嵌合抗原受体,其特征在于,包括:
胞外区,所述胞外区包括单链抗体和铰链区,所述单链抗体的C端与所述铰链区的N端相连,所述单链抗体特异性识别抗原人DPP4,所述单链抗体包括单链抗体的重链可变区和轻链可变区,所述轻链可变区具有分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列或所述重链可变区具有分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;
跨膜区,所述跨膜区的N端与所述胞外区的铰链区的C端相连,并且嵌入到所述淋巴细胞的细胞膜中;
胞内区,所述胞内区的N端与所述跨膜区的C端相连。
4.根据权利要求1所述的抗DPP4嵌合抗原受体,其特征在于,所述轻链可变区具有分别如SEQ ID NO:1、2和3的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列;或者
所述重链可变区具有分别如SEQ ID NO:4、5和6的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列;
任选地,所述轻链可变区具有如SEQ ID NO:7所示的氨基酸序列;或
所述重链可变区具有如SEQ ID NO:8所示的氨基酸序列;
任选地,所述单链抗体进一步包括连接肽;
任选地,所述连接肽的氨基酸序列为(GGGGS)n,其中n为大于或等于1的整数,优选为1、2、3、4或5,优选为GGGGS;
任选地,所述重链可变区的C端与所述连接肽的N端相连,所述连接肽的C端与所述轻链可变区的N端相连;
任选地,所述铰链区选自CD8a分子的铰链区;
任选地,所述跨膜区选自CD8分子跨膜段;
任选地,所述胞内结构域区包括共刺激结构域和胞内信号传导结构域;
任选地,所述共刺激结构域选自41BB分子胞内段;
任选地,所述胞内信号传导结构域选自CD3ζ分子胞内段;
任选地,所述抗DPP4嵌合抗原受体具有如SEQ ID NO:12所示的核苷酸序列。
5.一种核酸分子,其特征在于,编码权利要求3或4所述的抗DPP4嵌合抗原受体;
任选地,所述核酸分子为DNA。
6.一种表达载体,其特征在于,携带权利要求5所述的核酸分子;
任选地,所述表达载体为非致病性病毒载体;
任选地,所述表达载体为腺病毒载体、慢病毒载体或逆转录病毒载体。
7.一种转基因淋巴细胞,其特征在于,所述淋巴细胞表达携带权利要求5所述的核酸分子、权利要求6所述的表达载体;或
表达权利要求3或4所述的抗DPP4嵌合抗原受体;
任选地,所述转基因淋巴细胞包括选自NK细胞、NKT细胞和巨噬细胞中的至少之一。
8.一种药物组合物,其特征在于,包括:
权利要求3或4所述的抗DPP4嵌合抗原受体、权利要求5所述的核酸分子、权利要求6所述的表达载体或权利要求7所述的转基因淋巴细胞;
任选地,进一步包括:药学上可接受的辅料。
9.权利要求7所述的转基因淋巴细胞或权利要求8所述的药物组合物在制备药物中的用途,所述药物用于治疗和/或预防组织和脏器的纤维化、衰老相关疾病和/或抗衰老;
任选地,所述组织和脏器的纤维化包括肝纤维化、肺纤维化、肾纤维化、骨髓纤维化和肌肉纤维化。
10.试剂在制备药物中的用途,所述试剂用于抑制DPP4的表达或活性,所述药物用于治疗和/或预防衰老相关疾病和/或抗衰老;
任选地,所述药物用于抑制细胞衰老和/或清除衰老细胞;
任选地,所述试剂包括敲低所述DPP4的siRNA或权利要求7所述的转基因淋巴细胞;
任选地,所述siRNA具有如SEQ ID NO:13所示的核苷酸序列。
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US20210093665A1 (en) * | 2019-09-27 | 2021-04-01 | Stark Labs | Chimeric antigen receptors against senescent cells and uses thereof |
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US20210093665A1 (en) * | 2019-09-27 | 2021-04-01 | Stark Labs | Chimeric antigen receptors against senescent cells and uses thereof |
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