CN117209588A - 乙肝表面抗原特异性t细胞受体及其用途 - Google Patents
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Abstract
本发明提供了一种能够特异性靶向HBV表面抗原的T细胞受体(TCR),本发明还提供了编码所述TCR的核酸分子、包含所述核酸分子的载体、包含上述TCR、核酸分子或载体的TCR‑T细胞及其在预防或治疗HBV感染及其相关疾病的药物中的应用。
Description
技术领域
本申请涉及免疫治疗技术领域,具体涉及一种T细胞抗原受体、T细胞、药物组合物及其用途。
背景技术
1.1 HBV在世界范围内的流行
HBV是一种非细胞病变的双链DNA病毒,主要通过血液传播,母婴传播或性传播。虽然HBV有可用的疫苗和直接作用的高效抗病毒药,但HBV在全世界人群中仍造成很大的疾病负担。2015年全球携带HBV的人数为2.57亿,因慢性HBV感染并发症导致的死亡人数超过88.4万。流行病学研究估算表明,与美洲或欧洲比较,亚洲和非洲国家的HBV感染比例更高。此外,因为HBV逆转录酶缺乏校正功能,导致HBV易突变并产生不同的基因型。当前有10种不同HBV基因型分布于不同地理区域。
1.2亚洲人感染最常见的HBV基因型
而在亚洲国家中,HBV的基因型主要为B和C亚型。研究人员重点关注不同区域中不同基因型的流行,因为越来越多证据表明HBV基因型会影响临床预后。例如,与其他基因型比较,肝硬化和向HCC发展在基因型C和D中最为常见。
1.3 HCC及其致癌通路
HCC(Hepatocellular Carcinoma)是一种原发性肝细胞癌,是亚洲人最常见的,也是致命性的肝癌。2017年,由于慢性肝炎感染的长期并发症,HCC导致约47万人死亡。HCC发生的分子病理是一个复杂过程,涉及多种分子畸变以及基因突变,最终导致恶性疾病发生和HCC发展。
HBV-DNA整合见于80-90%的HBV相关HCC。在分子层面上,HBV病毒会引发感染的肝细胞基因表达的变化,从而赋予细胞肿瘤的特征。HBV-DNA的整合通过对插入位点基因表达的影响,增加了基因组的不稳定性,从而激活某些致癌途径,如磷酸肌醇-3-激酶/Akt、myc、Wnt/β-联蛋白、c-Met和hedgehog等。研究认为Akt信号传导的活化可以抑制转化生长因子(TGF)-β诱导的凋亡,促进肿瘤形成,同时也与β-联蛋白信号传导有关联,从而引发肝细胞癌变。HBV-DNA整合所致的分子改变也会影响DNA损伤检控点,并导致硬化肝脏中肿瘤的形成。这些分子改变包括p53肿瘤抑制基因功能丧失、p27细胞周期调节因子失活、胰岛素样生长抑制2受体位点杂合性缺失以及p16细胞周期抑制蛋白表达的缺失。
同时,病毒也可以抑制或阻断先天免疫,从而影响获得性免疫反应的发展。这种慢性、持续性的免疫反应,在病理层面上表现为肝炎和长期的纤维化反应,最终导致肝硬化和肝癌。
1.4 HCC的治疗现状
当前,外科手术切除和肝移植是最有效的HCC治疗方法,但符合进行这些手术标准的HCC患者不足30%,且符合条件的患者5年内术后复发率高达80%。而等待供体肝脏的时间很长,等待移植的人数持续增加,导致将近25%的患者因肿瘤进展而无法进行移植。
最常用的保守治疗是经导管的肝动脉化疗栓塞(TACE),但是这种疗法禁用于晚期肝硬化和肝脏功能代偿不全。因为与栓塞相关的缺血性损伤会导致腹水增加,甚至可能导致死亡。
目前(美国)食品药品管理局(FDA)批准用于治疗HCC的靶向药为索拉非尼和瑞格非尼,均为酪氨酸激酶抑制剂。然而晚期HCC患者的临床试验数据提示,这些药品可能导致出血风险增高以及动静脉血栓。且其在适应症人群中生存期优势只有2-3个月,随着时间延长,发生疾病进展十分常见。
化疗一般对HCC患者不产生显著的生存优势,虽然目前仍在开发几种与化疗药物的联合疗法,如PIAF(顺铂、干扰素、多柔比星和5-氟尿嘧啶)、GEMOX(吉西他滨和奥沙利铂)和FOLFOX4(氟尿嘧啶、亚叶酸钙和奥沙利铂),但与之相关的临床试验尚未成功,结果也不完整。
近年来,HCC的免疫治疗研究取得了重大突破。根据一项免疫联合疗法一线治疗III期研究IMbrave150,其研究结果显示,与标准疗法索拉非尼单药治疗相比,采用阿替利珠单抗和贝伐珠单抗(T+A)联合用药能够大幅降低患者死亡风险和疾病进展风险,但ORR(RECIST v1.1)仅达到27.3%,其mPFS仅为6.8个月。在晚期HCC预后更差的中国患者中,其mPFS仅为5.7个月。以上数据表明HCC的免疫治疗与以往相比有了很大进步,但其疗效仍差强人意,有待进一步研究。
HBV相关HCC患者需要抗病毒治疗以抑制病毒复制、降低血清病毒负荷、缓解肝内炎症反应,改善肝硬化相关预后。值得注意的是,抗病毒疗法虽然可以高效抑制HBV复制,减轻肝炎症状,却不能清除病毒或在治疗停止后持续控制住病毒。在抗病毒疗法的临床实践中常常使用核苷和核苷类似物以及干扰素来预防和治疗HBV相关的HCC,但这些产品的实际治疗效果很不确定,在总生存期和疾病复发方面的临床结果仍有争议。而且,长期的抗病毒药物应用与耐药性发生有关,持续应用可导致这些药物无效。由于化疗有可能再次激活HBV,因此在应用化疗的患者中,推荐用恩替卡韦或替诺福韦进行预防性抗病毒治疗。
综上,由于上述当前可用治疗方式与药物的局限性和高风险性,需要新的治疗策略为慢性乙肝和HBV相关HCC患者提供更多治疗选择。
1.5 T细胞在HBV相关HCC免疫治疗中的作用以及使用TCR T细胞的基本原理
T细胞是来源于骨髓、淋巴,并在胸腺(Thymus)中分化成熟的免疫细胞,其表面表达有T细胞抗原受体(TCR),在细胞介导的免疫中起到清除感染和癌细胞的重要作用。TCR能够识别由主要组织相容性复合物(MHC)分子呈递的靶抗原表位并与之特异性结合。一旦T细胞识别其靶点,即可通过大量增殖、释放细胞因子和细胞毒性等作用杀伤靶细胞。
人们尝试使用T细胞过继免疫疗法,治疗人类恶性肿瘤(例如白血病)和病毒类疾病(例如巨细胞病毒(CMV)和爱泼斯坦-巴尔病毒(EB病毒,EBV)。然而,从患者的血液中分离和扩增病毒或肿瘤特异性的T细胞非常困难且耗时。因此,研究人员采用了新的治疗策略,通过导入靶向特定抗原的T细胞受体(TCR)或TCRα/β异二聚体,使得这些基因编辑过的T淋巴细胞作用于特定的病毒或肿瘤抗原,赋予T细胞明确的抗原特异性。
乙肝病毒在被感染的肝细胞中合成HBsAg蛋白,并在内质网中合并组装,形成(亚)病毒颗粒后分泌,或通过膜的生理交换到达细胞表面。HBV-DNA整合的HCC细胞通常也会有HBsAg的表达。
临床证据表明,HBV特异性T细胞的过继免疫疗法对于HBV复制或肿瘤生长能起到控制作用。接受了对HBV有特异性免疫(来自接种HBV疫苗或依靠自身免疫达到HBV感染痊愈)的供者的骨髓,白血病患者甚至可以在骨髓移植后获得对HBV的免疫能力。同样,给对HBV有特异性免疫的受试者移植HBV阳性的肝脏,也能够清除移植肝脏的HBV感染。
然而,在许多慢性乙型肝炎和HBV相关的HCC患者中,针对HBV的特异性T细胞免疫受到严重抑制。在这些患者中HBV特异性T细胞存在功能缺陷,数量稀少且易衰竭(exhaustion)。由于这些功能缺陷,患者血液的离体分析几乎检测不到HBV特异性的T细胞。
因此,利用基因工程等生物学手段开发靶向HBV表面抗原的特异性TCR,转染体外分离病人T细胞,构建高亲和力的TCR-T细胞进行回输治疗成为一种新的选择。然而目前,并没有一种验证安全有效的TCR-T细胞用于治疗HBV相关疾病,尤其是HBV诱发的肝癌。
发明内容
申请人通过广泛而深入的研究,提供了一种全新的HBV表面抗原特异性的TCR或其片段、TCRT细胞,其能够特异性杀灭由HBV感染所诱发的肝癌细胞。
本申请采用了以下技术方案:
本申请的第一方面提供了一种全新的特异性结合乙肝表面抗原FLLTRILTI-HLA-A*02复合物的TCR分子或其片段。所述的TCR或其片段包含TCRα链可变域和TCRβ链可变域,所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:3所示;和/或所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:6所示。在另一些实施方案中,所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:15所示;和/或所述TCRβ链可变域的βCDR3的氨基酸序列如SEQID NO:18所示。在另一些实施方案中,所述TCRα链可变域的αCDR3的氨基酸序列如SEQ IDNO:26所示;和/或所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:29所示。
在一些实施方案中,所述TCRα链可变域的αCDR1、αCDR2和αCDR3分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示,所述TCRβ链可变域的βCDR1、βCDR2和βCDR3分别如SEQID NO:4、SEQ ID NO:5和SEQ ID NO:6所示。
在一些实施方案中,所述TCRα链可变域的αCDR1、αCDR2和αCDR3分别如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示,所述TCRβ链可变域的βCDR1、βCDR2和βCDR3分别如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示。
在一些实施方案中,所述TCRα链可变域的αCDR1、αCDR2和αCDR3分别如SEQ ID NO:24、SEQ ID NO:25和SEQ ID NO:26所示,所述TCRβ链可变域的βCDR1、βCDR2和βCDR3分别如SEQ ID NO:27、SEQ ID NO:28和SEQ ID NO:29所示。
在一些实施方案中,本申请的TCR、其片段和多肽可包含一个或多个CDR,其是本文所述CDR的变体CDR。变体可以在所述CDR序列中具有一个或两个氨基酸取代。在一些实施方案中,变体可以在所述CDR序列中具有三个或四个氨基酸取代。
在一些实施方案中,所述TCRα链可变域为与SEQ ID NO:7具有至少90%序列相同性的氨基酸序列。在一些实施方案中,所述TCRβ链可变域为与SEQ ID NO:8具有至少90%序列相同性的氨基酸序列。
在一些实施方案中,所述TCRα链可变域为与SEQ ID NO:19具有至少90%序列相同性的氨基酸序列。在一些实施方案中,所述TCRβ链可变域为与SEQ ID NO:20具有至少90%序列相同性的氨基酸序列。
在一些实施方案中,所述TCRα链可变域为与SEQ ID NO:30具有至少90%序列相同性的氨基酸序列。在一些实施方案中,所述TCRβ链可变域为与SEQ ID NO:31具有至少90%序列相同性的氨基酸序列。
在一些实施方案中,所述TCRα链可变域氨基酸序列如SEQ ID NO:7所示。在一些实施方案中,所述TCRβ链可变域氨基酸序列如SEQ ID NO:8所示。在一些实施方案中,所述TCRα链可变域氨基酸序列如SEQ ID NO:19所示。在一些实施方案中,所述TCRβ链可变域氨基酸序列如SEQ ID NO:20所示。在一些实施方案中,所述TCRα链可变域氨基酸序列如SEQ IDNO:30所示。在一些实施方案中,所述TCRβ链可变域氨基酸序列如SEQ ID NO:31所示。
在一些实施方案中,所述TCR为αβ异质二聚体,其包含TCRα链恒定区TRAC*01和TCRβ链恒定区TRBC1*01或TRBC2*01。恒定区可以选自人TCR恒定区序列,也可以选自鼠源恒定区序列。在一些实施方案中,在恒定区引入一个额外的人工二硫键提高稳定性并降低与内源链错配率。
在一些实施方案中,所述TCR的α链氨基酸序列如SEQ ID NO:10所示。在一些实施方案中,所述TCR的β链氨基酸序列如SEQ ID NO:11所示。在一些实施方案中,所述TCR的α链氨基酸序列如SEQ ID NO:21所示。在一些实施方案中,所述TCR的β链氨基酸序列如SEQ IDNO:22所示。在一些实施方案中,所述TCR的α链氨基酸序列如SEQ ID NO:32所示。在一些实施方案中,所述TCR的β链氨基酸序列如SEQ ID NO:33所示。
在一些实施方案中,所述TCR为单链。
在一些实施方案中,所述单链TCR通过P2A将TCRβ链和TCRα链连接而成。
在一些实施方案中,T细胞抗原受体多肽包括:依次相连的T细胞受体β链可变域(TRBV)、T细胞受体β链恒定区(TRBC)、P2A自剪切肽、T细胞受体α链可变域(TRAV)和T细胞受体α链恒定区(TRAC)。在一些实施方案中,所述P2A自剪切肽的氨基酸序列如SEQ ID NO:9所示。在一些实施方案中,所述单链TCR的氨基酸序列如SEQ ID NO:12所示。在一些实施方案中,所述单链TCR的氨基酸序列如SEQ ID NO:23所示。在另一些实施方案中,所述单链TCR的氨基酸序列如SEQ ID NO:34所示。
在一些实施方案中,半胱氨酸残基在所述TCR的α和β链恒定域之间形成人工二硫键。
在一些实施方案中,所述TCR是可溶的。
在一些实施方案中,所述TCR包括(a)除跨膜结构域以外的全部或部分TCRα链;以及(b)除跨膜结构域以外的全部或部分TCRβ链;并且(a)和(b)各自包含功能性可变结构域,或包含功能性可变结构域和所述TCR链恒定结构域的至少一部分。
在一些实施方案中,所述TCR的α链和/或β链的C-或N-末端结合有偶联物,与所述T细胞受体结合的偶联物为可检测标记物、治疗剂、PK修饰部分或任何这些物质的组合。
在一些实施方案中,所述的TCR或其片段,能够结合由HLA-A*02呈递的HBV表面抗原多肽。在一些实施方案中,所述多肽包含氨基酸序列FLLTRILTI(SEQ ID NO:35)或FLLTKILTI(SEQ ID NO:36)或由其组成。
本申请的第二方面,提供了一种核酸分子,所述核酸分子包含编码本申请第一方面的TCR分子或其片段的核酸序列或其互补序列。
本申请的核苷酸序列是经密码子优化的。
在一些实施方案中,所述TCRα链可变域的编码序列如SEQ ID NO:37所示。在一些实施方案中,所述TCRβ链可变域的编码序列如SEQ ID NO:38所示。在一些实施方案中,所述TCRα链可变域的编码序列如SEQ ID NO:42所示。在一些实施方案中,所述TCRβ链可变域的编码序列如SEQ ID NO:43所示。在一些实施方案中,所述TCRα链可变域的编码序列如SEQID NO:47所示。在一些实施方案中,所述TCRβ链可变域的编码序列如SEQ ID NO:48所示。
在一些实施方案中,所述TCRα链的编码序列如SEQ ID NO:39所示。在一些实施方案中,所述TCRβ链的编码序列如SEQ ID NO:40所示。在一些实施方案中,所述TCRα链的编码序列如SEQ ID NO:44所示。在一些实施方案中,所述TCRβ链的编码序列如SEQ ID NO:45所示。在一些实施方案中,所述TCRα链的编码序列如SEQ ID NO:49所示。在一些实施方案中,所述TCRβ链的编码序列如SEQ ID NO:50所示。
在一些实施方案中,所述TCR的编码序列为单链,通过P2A编码序列将TCRβ链编码序列和TCRα链编码序列连接而成。在一些实施方案中,所述TCR的单链编码序列如SEQ IDNO:41、SEQ ID NO:46或SEQ ID NO:51所示。
本申请的第三方面提供了一种载体,所述的载体包含本申请第二方面所述的核酸分子;在一些实施方案中,所述载体选自质粒、二元载体、DNA载体、mRNA载体、逆转录病毒载体、慢病毒载体、基于转座子的载体和人工染色体。在一些实施方案中,所述的载体为病毒载体;在一些实施方案中,所述的载体为慢病毒载体。
本申请的第四方面,提供了一种多肽,所述多肽由本申请第二方面所述的核酸或第三方面所述的载体编码。
本申请的第五方面,提供了一种细胞,所述细胞中包含本申请第一方面所述的TCR或其片段、第二方面所述的核酸分子、本申请第三方面所述的载体或本申请第四方面所述的多肽;在一些实施方案中,所述细胞为干细胞;在一些实施方案中,所述细胞为NK细胞;在一些实施方案中,所述细胞为T细胞;在一些实施方案中,所述细胞为CD4+ T细胞,在一些实施方案中,所述细胞为CD8+ T细胞。
本申请的第六方面,提供了一种药物组合物,所述组合物含有药学上可接受的载体以及本申请第一方面所述的TCR或其片段、第二方面所述的核酸分子、第三方面所述的载体、第四方面所述的多肽或第五方面所述的细胞。
本申请的第七方面,提供了本申请第一方面所述的TCR或其片段、第二方面所述的核酸分子、第三方面所述的载体、第四方面所述的多肽、第五方面所述的细胞或第六方面所述的药物组合物的用途,用于制备治疗HBV感染相关疾病的药物。在一些实施方案中,所述HBV相关疾病为肝炎、肝纤维化、肝硬化或肝癌的一种或其组合。
本申请的第八方面,提供了一种治疗疾病的方法,包括给需要治疗的对象施用适量的本申请第一方面所述的TCR或其片段、本申请第二方面所述的核酸分子、本申请第三方面所述的载体、本申请第四方面所述的多肽、本申请第五方面所述的细胞或本申请第六方面所述的药物组合物;在一些实施方案中,所述的疾病为HBV相关疾病;在一些实施方案中,所述HBV相关疾病为肝炎、肝纤维化、肝硬化或肝癌的一种或其组合。
本申请的第九方面,提供了一种HBV TCR-T细胞的制备方法,其包括如下步骤:
获得编码T细胞抗原受体多肽的核酸分子;
在核酸分子的两个末端分别添加含有不同的双酶切位点的引物,获得合成基因;
采用与双酶切位点对应的外切酶酶切合成基因的对应双酶切位点,并插入pCDH质粒载体中,获得重组质粒;
使用重组质粒转染慢病毒包装载体,获得慢病毒颗粒;
采用慢病毒感染T细胞,获得对乙型肝炎病毒表面抗原具有亲和力的HBV TCR-T细胞。
应理解,在本申请范围内中,本申请的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本申请的有益效果:
本申请提供了全新的靶向HBV表面抗原的特异性TCR或其片段,令人惊奇的发现本申请的TCR对乙肝表面抗原FLLTRILTI-HLA-A*02复合物具备极强的亲合力,能够靶向识别A、B、C和D四种基因型的HBV表面抗原S20-28,且能够识别在HBV流行人群中最常见的HLA等位基因亚型;因此本申请的TCR具有广泛的适用人群范围。本申请的TCRT细胞在体内外具有极强的抗病毒能力,能够特异性靶向杀灭HBV感染的细胞;在体内针对性地对肝癌细胞进行定向清除,从而用于治疗HBV诱发的肝癌;且不会产生脱靶效应,因此,不会损害肝脏之外的其它组织,降低了免疫治疗时的不良反应。
另一方面,本申请对恒定区序列进行改造,通过引入半胱氨酸增加恒定区的链间二硫键,提高转导的TCRα/β异源二聚体的稳定性,并减少与内源TCR链的错配。另外,本申请对TCR的表达密码子进行优化,提高表达效率。
附图说明
为了更清楚地说明本申请实施例中的技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本申请的一些实施例,对于本领域技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为一种单链HBV S20 TCR结构示意图。
图2为HBV S20 TCR-T表达结构及原理示意图。
图3为A01/B01/C01 TCR慢病毒滴度检测结果。
图4为HBV S20 TCR-T生产工艺流程图。
图5为A01/B01/C01 TCR慢病毒感染活化T细胞MOI检测。
图6为A01/B01/C01 TCR-T制备后TCR特异表达检测。
图7为构建的HepG2-LMS-LG靶细胞检测表达。
图8为A01 TCR-T对靶细胞不同效靶比杀伤作用。
图9为B01 TCR-T对靶细胞不同效靶比RTCA活性及细胞因子功能检测。
图10为C01 TCR-T对靶细胞不同效靶比RTCA活性及细胞因子功能检测。
图11为A01/B01/C01 TCR-T对靶细胞杀伤功能比较检测。
图12为HBV S20 TCR-T不同T细胞亚群对靶细胞功能。
图13为A01/B01/C01 TCR-T识别S20多肽关键氨基酸确定。
图14为A01/B01/C01 TCR-T对人源多肽数据库交叉反应检测。
图15为A01/B01/C01 TCR-T不同基因型S20结合能力检测。
图16为A01/B01/C01 TCR-T识别HLA-A02不同亚型检测。
图17为免疫缺陷小鼠HepG2-LMS-LG移植瘤模型A01 TCR-T体内药效及药代实验结果。
图18为免疫缺陷小鼠HepG2-LMS-LG移植瘤模型B01 TCR-T体内药效实验结果。
图19为免疫缺陷小鼠HepG2-LMS-LG移植瘤模型C01 TCR-T体内药效实验结果。
具体实施方式
为了更容易理解本发明,描述实施例之前,先对本发明某些技术和科学术语做说明。除显而易见在本发明申请文件中的它处另有明确定义,本发明使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
术语“乙肝表面抗原T细胞受体(TCR)”在本文中被定义为这样的TCR,其在主要组织相容性复合体(MHC)分子环境下与HBV表面抗原结合从而在表达重组TCR的细胞中诱导产生辅助子或细胞毒性应答。具体而言,所述HBV表面抗原可为HBs20-28,其可在本申请中以HBs20、HBs20-28、S20-28和S20互换使用,如无特殊说明则指基因型A和D的S20-28抗原即FLLTRILTI多肽。在一些实施例中所述HBV表面抗原为HBV基因型A和D;在一些实施例中,所述HBV表面抗原为HBV基因型B和C。在一些实施例中,所述HBV表面抗原包含FLLTRILTI(SEQID NO:35)氨基酸序列;在一些实施例中,所述HBV表面抗原包含FLLTKILTI(SEQ ID NO:36)氨基酸序列。在一些实施例中,所述HBV表面抗原为FLLTRILTI(SEQ ID NO:35)氨基酸序列;在一些实施例中,所述HBV表面抗原为FLLTKILTI(SEQ ID NO:36)氨基酸序列。
术语“MHC分子”是免疫球蛋白超家族的蛋白质,可以是Ⅰ类或Ⅱ类MHC分子。因此,其对于抗原的呈递具有特异性,不同的个体有不同的MHC,能呈递一种蛋白抗原中不同的短肽到各自的APC细胞表面。人类的MHC通常称为HLA基因或HLA复合体。
TCR是由α链/β链或者γ链/δ链以异质二聚体形式存在的细胞膜表面的糖蛋白。在95%的T细胞中TCR异质二聚体由α和β链组成,而5%的T细胞具有由γ和δ链组成的TCR。天然αβ异质二聚TCR具有α链和β链,α链和β链构成αβ异源二聚TCR的亚单位。广义上讲,α和β各链包含可变区、连接区和恒定区,β链通常还在可变区和连接区之间含有短的多变区,但该多变区常视作连接区的一部分。各可变区包含嵌合在框架结构(framework regions)中的3个CDR(互补决定区),CDR1、CDR2和CDR3,本申请TCR的α链和β链的CDR区划定采用IMGT编号规则。CDR区决定了TCR与pMHC复合物的结合,其中CDR3由可变区和连接区重组而成,被称为超变区。TCR的α和β链一般看作各有两个“结构域”即可变域和恒定域,可变域由连接的可变区和连接区构成。TCR恒定域的序列可以在国际免疫遗传学信息系统(IMGT)的公开数据库中找到,如TCR分子α链的恒定域序列为“TRAC*01”,TCR分子β链的恒定域序列为“TRBC1*01”或“TRBC2*01”。此外,TCR的α和β链还包含跨膜区和胞质区,胞质区很短。
在本申请中,术语“T细胞受体”、“TCR”、“TCR分子”可互换使用。
TCR分子
本申请的TCR或其片段识别HLA-A2限制性的HBV表面抗原。大约总人口的50%表达MHC I类分子HLA-A*02,因此,HLA-A*02限制性TCR可具有普遍的治疗用途。具体而言,本申请的TCR可以识别许多HLA-A*02等位基因的产物,包括HLA-A*0201、*0202、*0203、*0206和*0207等。尽管,白种人和亚洲人的HLA基因亚型可存在明显的差异;然而,超过95%的HLA-A2阳性的白种人是HLA-A0201;而HLA-A2阳性的中国人由如下HLA-A2亚型组成:23%HLA-A0201;45%HLA-A0207;8%HLA-A0206;23%HLA-A0203。
在一些实施例中,所述TCR包含TCRα链可变域和TCRβ链可变域,并且TCRα和β链各具有3个互补决定区(CDR)。
在一些实施例中,所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:3所示;和/或所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:6所示。在一些实施例中,所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:15所示;和/或所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:18所示。在一些实施例中,所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:26所示;和/或所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ IDNO:29所示。
在一些实施例中,αCDR1、αCDR2和αCDR3分别如SEQ ID NO:1、SEQ ID NO:2和SEQID NO:3所示;和/或βCDR1、βCDR2和βCDR3分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示。
在一些实施例中,αCDR1、αCDR2和αCDR3分别如SEQ ID NO:13、SEQ ID NO:14和SEQID NO:15所示;和/或βCDR1、βCDR2和βCDR3分别如SEQ ID NO:16、SEQ ID NO:17和SEQ IDNO:18所示。
在一些实施例中,αCDR1、αCDR2和αCDR3分别如SEQ ID NO:24、SEQ ID NO:25和SEQID NO:26所示;和/或βCDR1、βCDR2和βCDR3分别如SEQ ID NO:27、SEQ ID NO:28和SEQ IDNO:29所示。
在一些实施例中,本申请的TCR、其片段和多肽可包含一个或多个CDR,其是本文所述CDR的变体CDR。变体可以在所述CDR序列中具有一个或两个氨基酸取代。在一些实施方案中,变体可以在所述CDR序列中具有三个或四个氨基酸取代。
可以将上述本申请的CDR区氨基酸序列嵌入到任何适合的框架结构中来制备嵌合TCR。只要框架结构与本申请的TCR的CDR区兼容,本领域技术人员根据本申请公开的CDR区就能够设计或合成出具有相应功能的TCR分子。因此,本申请TCR分子是指包含上述α和/或β链CDR区序列及任何适合的框架结构的TCR分子。本申请TCRα链可变域为与SEQ ID NO:7、SEQ ID NO:19或SEQ ID NO:30具有至少90%,优选地95%,更优选地98%序列相同性的氨基酸序列;和/或本申请TCRβ链可变域为与SEQ ID NO:8、SEQ ID NO:20或SEQ ID NO:31具有至少90%,优选地95%,更优选地98%序列相同性的氨基酸序列。
在一些实施例中,所述TCRα链可变域氨基酸序列如SEQ ID NO:7所示。在一些实施例中,所述TCRβ链可变域氨基酸序列如SEQ ID NO:8所示。在一些实施例中,所述TCRα链可变域氨基酸序列如SEQ ID NO:19所示。在一些实施例中,所述TCRβ链可变域氨基酸序列如SEQ ID NO:20所示。在一些实施例中,所述TCRα链可变域氨基酸序列如SEQ ID NO:30所示。在一些实施例中,所述TCRβ链可变域氨基酸序列如SEQ ID NO:31所示。
在一些实施例中,所述TCRα链可变域氨基酸序列如SEQ ID NO:7所示,所述TCRβ链可变域氨基酸序列如SEQ ID NO:8所示。在一些实施例中,所述TCRα链可变域氨基酸序列如SEQ ID NO:19所示,所述TCRβ链可变域氨基酸序列如SEQ ID NO:20所示。在一些实施例中,所述TCRα链可变域氨基酸序列如SEQ ID NO:30所示,所述TCRβ链可变域氨基酸序列如SEQID NO:31所示。
在一些实施例中,所述TCR为αβ异质二聚体,其包含TCRα链恒定域和TCRβ链恒定域。在一些实施例中,本申请的TCR分子的恒定域是人的恒定域。本领域技术人员知晓或可以通过查阅相关书籍或IMGT(国际免疫遗传学信息系统)的公开数据库来获得人的恒定域氨基酸序列。例如,本发明TCR分子α链的恒定域序列可以为“TRAC*01”,TCR分子β链的恒定域序列可以为“TRBC1*01”或“TRBC2*01”。在一些实施例中,恒定域引入一个额外的二硫键提高稳定性并减少外源转入的TCR分子与内源的TCR分子错配。本申请的TCR分子的恒定域也可以是小鼠的恒定域。将TRAC和TRBC同时换成小鼠来源的恒定域可以避免外源转入的TCR分子与内源的TCR分子错配,造成TCR靶向错误。此效用与外源导入人工二硫键目的类似。
在一些实施例中,所述TCR的α链氨基酸序列如SEQ ID NO:10所示,和/或所述TCR的β链氨基酸序列如SEQ ID NO:11所示。在一些实施例中,所述TCR的α链氨基酸序列如SEQID NO:21所示,和/或所述TCR的β链氨基酸序列如SEQ ID NO:22所示。在一些实施例中,所述TCR的α链氨基酸序列如SEQ ID NO:32所示,和/或所述TCR的β链氨基酸序列如SEQ IDNO:33所示。
在一些实施例中,本申请的TCR分子是由α链的部分或全部和/或β链的部分或全部组成的单链TCR分子。在一些实施例中,所述单链TCR为通过P2A将TCRβ链氨基酸序列和TCRα链氨基酸序列连接而成。在本申请的一个优选例中,T细胞抗原受体多肽包括:依次相连的TRBV、TRBC、P2A自剪切肽、TRAV和TRAC。在本申请的另一个优选例中,T细胞抗原受体多肽包括:依次相连的TRAV、TRAC、P2A自剪切肽、TRBV、TRBC。
在一些实施例中,所述单链TCR分子的α链可变域氨基酸序列包含CDR1(SEQ IDNO:1)、CDR2(SEQ ID NO:2)和CDR3(SEQ ID NO:3)。优选地,所述单链TCR分子包含α链可变域氨基酸序列SEQ ID NO:7。更优选地,所述单链TCR分子的α链可变域氨基酸序列为SEQ IDNO:7。所述单链TCR分子的β链可变域氨基酸序列包含CDR1(SEQ ID NO:4)、CDR2(SEQ IDNO:5)和CDR3(SEQ ID NO:6)。优选地,所述单链TCR分子包含β链可变域氨基酸序列SEQ IDNO:8。更优选地,所述单链TCR分子的β链可变域氨基酸序列为SEQ ID NO:8。
在一些实施例中,所述单链TCR分子的α链可变域氨基酸序列包含CDR1(SEQ IDNO:13)、CDR2(SEQ ID NO:14)和CDR3(SEQ ID NO:15)。优选地,所述单链TCR分子包含α链可变域氨基酸序列SEQ ID NO:19。更优选地,所述单链TCR分子的α链可变域氨基酸序列为SEQID NO:19。所述单链TCR分子的β链可变域氨基酸序列包含CDR1(SEQ ID NO:16)、CDR2(SEQID NO:17)和CDR3(SEQ ID NO:18)。优选地,所述单链TCR分子包含β链可变域氨基酸序列SEQ ID NO:20。更优选地,所述单链TCR分子的β链可变域氨基酸序列为SEQ ID NO:20。
在一些实施例中,所述单链TCR分子的α链可变域氨基酸序列包含CDR1(SEQ IDNO:24)、CDR2(SEQ ID NO:25)和CDR3(SEQ ID NO:26)。优选地,所述单链TCR分子包含α链可变域氨基酸序列SEQ ID NO:30。更优选地,所述单链TCR分子的α链可变域氨基酸序列为SEQID NO:30。所述单链TCR分子的β链可变域氨基酸序列包含CDR1(SEQ ID NO:27)、CDR2(SEQID NO:28)和CDR3(SEQ ID NO:29)。优选地,所述单链TCR分子包含β链可变域氨基酸序列SEQ ID NO:31。更优选地,所述单链TCR分子的β链可变域氨基酸序列为SEQ ID NO:31。
在一些实施例中,所述单链TCR的氨基酸序列如SEQ ID NO:12所示。在一些实施例中,所述单链TCR的氨基酸序列如SEQ ID NO:23所示。在一些实施例中,所述单链TCR的氨基酸序列如SEQ ID NO:34所示。
天然存在的TCR是一种膜蛋白,通过其跨膜区得以稳定。如同免疫球蛋白(抗体)作为抗原识别分子一样,TCR也可以被开发应用于诊断和治疗,这时需要获得可溶性的TCR分子。可溶性的TCR分子不包括其跨膜区。可溶性TCR有很广泛的用途,它不仅可用于研究TCR与pMHC的相互作用,也可用作检测感染的诊断工具或作为自身免疫病的标志物。类似地,可溶性TCR可以被用来将治疗剂(如细胞毒素化合物或免疫刺激性化合物)输送到呈递特异性抗原的细胞,另外,可溶性TCR还可与其他分子(如,抗CD3抗体)结合来重新定向T细胞,从而使其靶向呈递特定抗原的细胞。
在一些实施例中,所述TCR是可溶的。
在一些实施例中,所述TCR包括(a)除跨膜结构域以外的全部或部分TCRα链;以及(b)除跨膜结构域以外的全部或部分TCRβ链;并且(a)和(b)各自包含功能性可变结构域,或包含功能性可变结构域和所述TCR链恒定结构域的至少一部分。
在一些实施例中,半胱氨酸残基在所述TCR的α和β链恒定域之间形成人工二硫键。
所述可溶性TCR可以通过本领域中已知的任何方法制备。可用于制备可溶性TCR的方法的实例包括但不限于:构建聚合受体链,其中,可以用TCRα和β可变区置换来自至少一种磷酸胆碱特异性抗体的免疫球蛋白重链可变区;在TCR跨膜区域的上游引入翻译终止密码子或者用来自GPI连接蛋白Thy-1的羧基末端的糖基磷脂酰肌醇(GPI)连接的信号替代TCRα和β链cDNA的跨膜区。
本申请的可溶性TCR可以单独使用,也可与偶联物以共价或其他方式结合,优选以共价方式结合。所述偶联物包括可检测标记物、治疗剂、PK修饰部分或任何以上这些物质的组合结合或偶联。
用于诊断目的的可检测标记物包括但不限于:荧光或发光标记物、放射性标记物、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶。
可与本申请TCR结合或偶联的治疗剂包括但不限于:化疗剂(例如,顺铂)、前药激活酶、细胞因子、毒素(例如,PE38、卡西霉素(calcimycin)或白喉毒素)、免疫调节抗体片段(例如抗-CD3或抗-CD16、抗体Fc片段、抗体scFv片段)、放射性核素、病毒颗粒、脂质体、金纳米颗粒、纳米磁粒或任何形式的纳米颗粒等。
在一些实施例中,所述可溶性TCR可与至少一种抗病毒药连接。所述抗病毒药可为HBV靶向性药物。例如,抗病毒药可以包括但不限于,阿德福韦二匹伏酯、干扰素α-2b、聚乙二醇干扰素α-2a、拉米夫定、恩替卡韦、替比夫定(telbivudine)等。
本申请的TCR也可以多价复合体的形式提供。本申请的多价TCR复合体包含两个、三个、四个或更多个本申请TCR相结合而形成的多聚物,如可以用p53的四聚结构域来产生四聚体,或多个本申请TCR与另一分子结合而形成的复合物。与非多聚野生型或本申请的T细胞受体异源二聚体相比,本申请的多价TCR复合物对FLLTRILTI-HLA-A*02复合物的结合能力可增强。因此,本申请TCR的多价复合物也属于本申请。本申请的TCR复合物可用于体外或体内追踪或靶向呈递特定抗原的细胞,也可用于产生具有此类应用的其他多价TCR复合物的中间体。
核酸分子
本申请提供了编码本文上述TCR分子或其片段的核酸分子,所述片段可以是一个或多个CDR,α和/或β链的可变域,以及α链和/或β链。
编码本申请TCR分子TCRα链可变域的核苷酸序列如SEQ ID NO:37、SEQ ID NO:42或SEQ ID NO:47所示。和/或编码TCRβ链可变域的核苷酸序列如SEQ ID NO:38、SEQ ID NO:43或SEQ ID NO:48所示。
编码本申请TCRα链的核苷酸序列如SEQ ID NO:39、SEQ ID NO:44或SEQ ID NO:49所示。和/或编码TCRβ链可变域的核苷酸序列如SEQ ID NO:40、SEQ ID NO:45或SEQ ID NO:50所示。
在一些实施例中,所述TCR的编码序列为单链,通过P2A编码序列将TCRβ链编码序列和TCRα链编码序列连接而成,且所述单链编码核苷酸在同一阅读框中。在一些实施例中,所述TCR的单链编码序列如SEQ ID NO:41、SEQ ID NO:46或SEQ ID NO:51所示。
在一些实施例中,所述核酸编码一种或多种结构特征,用于增加和/或稳定所表达的TCRα和β链之间的缔合。在一些实施例中,所述特征可以是特定的氨基酸或氨基酸序列。在一些实施方式中,所述核酸可编码一个或多个非天然半胱氨酸残基,用于在所述TCRα和β链之间形成一个或多个二硫键。在一些实施方式中,所述核酸可编码所述TCRα和β链的恒定域中的一个或多个非天然半胱氨酸残基。
在一些实施例中,本申请提供了至少一种构建体,其包含与至少一种启动子可操作地连接的本申请的多核苷酸。TCR的α链和β链的编码序列可与至少一种在细胞中有功能的启动子可操作地连接。适合的启动子可为组成型和诱导型启动子,并且本领域技术人员可很好地选择合适的启动子。例如,适合的启动子可包括但不限于,逆转录病毒的LTR、SV40启动子、CMV启动子和细胞启动子(例如,β-肌动蛋白启动子)。
本申请核酸分子的核苷酸序列可以是单链或双链的,该核酸分子可以是RNA或DNA,并且可以包含或不包含内含子。优选地,本申请核酸分子的核苷酸序列不包含内含子但能够编码本申请TCR或其片段。
核苷酸序列可以是经密码子优化的。不同的细胞在具体密码子的利用上是不同的,可以根据细胞的类型,改变序列中的密码子来增加表达量。哺乳动物细胞以及多种其他生物的密码子选择表是本领域技术人员公知的。
载体
本申请提供了至少一种“载体”用于将外源性核酸转移到细胞中的介质(DNA或RNA)。所述载体可以是用于在所述细胞中表达核酸的表达载体。这样的载体可包含与编码待表达序列的核酸可操作地连接的启动子序列。载体也可包含终止密码子和表达增强子。
本领域已知的任何合适的载体、启动子、增强子和终止密码子可用于从本申请的载体表达多肽。合适的载体包括质粒、二元载体、DNA载体、mRNA载体、病毒载体(例如γ逆转录病毒载体、慢病毒载体、腺病毒载体)、基于转座子的载体和人工染色体(例如酵母人工染色体),例如,如Maus等人,Annu Rev Immunol(2014)32:189-225中所述,其通过引用以其整体引入本文作为参考。
在一些实施例中,根据本发明,所述病毒载体可以是慢病毒、逆转录病毒、腺病毒或单纯疱疹病毒载体。
细胞
本申请还包括表达本申请的TCR和/或其片段的分离的细胞,其中所述细胞可以是干细胞或免疫细胞。所述免疫细胞可以是T细胞、天然杀伤细胞、树突细胞或巨噬细胞。在一些实施例中所述免疫细胞是T细胞。该T细胞可衍生自从受试者分离的T细胞,或者可以是从受试者中分离的混合细胞群,诸如外周血淋巴细胞(PBL)群的一部分。如,该细胞可以分离自外周血单核细胞(PBMC),可以是CD4+辅助T细胞或CD8+细胞毒性T细胞。该细胞可在CD4+辅助T细胞/CD8+细胞毒性T细胞的混合群中。一般地,该细胞可以用抗体(如,抗-CD3抗体)活化,以便使它们能够更容易接受转染,例如用包含编码本申请TCR分子的核苷酸序列的载体进行转染。在一些实施例中,本申请的细胞还可以是干细胞,如造血干细胞(HSC)。将TCR基因转移至HSC不会导致在细胞表面表达TCR,因为干细胞表面不表达CD3分子。然而,当HSC分化为迁移至胸腺的淋巴前体(lymphoid precursor)时,CD3分子的表达将启动TCR分子的表达。表达本申请的TCR和/或其片段的细胞可适用于过继转移方案从而提供特别有效的治疗模式。本申请的分离细胞可以克服HBV特异性CD8+和CD4+细胞在患者体内缺失和功能欠佳的问题。
有许多方法适合用于编码本申请TCR或其片段的DNA或RNA进行T细胞转染(如,Robbins等,(2008)J.Immunol.180:6116-6131)。将多核苷酸分子或载体引入细胞的方法在本领域中是已知的。载体可通过在本领域中的任何方法容易地引入宿主细胞,例如,哺乳动物、细菌、酵母或昆虫细胞。例如,表达载体可通过物理、化学或生物学手段转移入宿主细胞。
将多核苷酸引入宿主细胞的物理方法包括磷酸钙沉淀、脂质转染法、粒子轰击、微注射、电穿孔等等。将感兴趣的多核苷酸引入宿主细胞的生物学方法包括使用DNA和RNA载体。将多核苷酸引入宿主细胞的化学手段包括胶体分散系统,诸如大分子复合物、纳米胶囊、微球;和基于脂质的系统,包括水包油乳剂、胶束、混合胶束和脂质体。
本申请的一些实施例提供了上述的T细胞的制备方法,其包括如下步骤:
获得编码上述实施例中的T细胞抗原受体多肽的核酸分子;
在核酸分子的两个末端分别添加含有不同的双酶切位点的引物,获得合成基因;
采用与双酶切位点对应的外切酶酶切合成基因的对应双酶切位点,并插入pCDH质粒载体中,获得重组质粒;
使用重组质粒转染慢病毒包装载体,获得慢病毒颗粒;
采用慢病毒感染T细胞,获得对乙型肝炎病毒表面抗原具有亲和力的HBV TCR-T细胞。
本申请还提供了产生可溶性TCR、其片段或多肽的方法,所述方法包括将本申请的载体引入细胞中,并在适合所述细胞表达所述载体的条件下培养所述细胞。
适合于表达多肽的任何细胞均可用于产生本申请的TCR、其片段和多肽。所述细胞可以是原核生物或真核生物。合适的原核细胞包括大肠杆菌(E.coli)。真核细胞的例子包括酵母细胞、植物细胞、昆虫细胞或哺乳动物细胞。在一些情况下,所述细胞不是原核细胞,因为有些原核细胞不允许与真核生物相同的翻译后修饰。另外,在真核生物中很高的表达水平是可能的,并且可以使用适当的标签更容易地从真核生物中纯化蛋白质。也可以利用提高所述TCR、片段或多肽分泌到培养基中的特定质粒。
组合物
本申请还提供了包含本发明的TCR、其片段、核酸、载体、多肽或细胞的组合物。在一些实施例中,所述组合物是药物组合物。在一些实施方式中,所述组合物是适合用于研究、治疗、预防和/或诊断的组合物。
在一些实施例中,本申请的TCR、片段、核酸、载体、多肽或细胞优选与本领域技术人员公知的一种或多种其它可药用成分一起配制成药剂或药物,所述可药用成分包括但不限于可药用载体、佐剂、赋形剂、稀释剂、填充剂、缓冲剂、防腐剂、抗氧化剂、润滑剂、稳定剂、增溶剂、表面活性剂、掩蔽剂、着色剂、调味剂和甜味剂。术语“可药用”用于本文中时涉及化合物、成分、材料、组合物、剂型等,它们在合理的医学判断范围内、适合用于接触所讨论的对象(例如人类)的组织而没有过度的毒性、刺激、变态反应或者其它问题或并发症、与合理的效益/风险比相称。每种载体、佐剂、赋形剂等在与制剂的其它成分相容的意义上,也必须是“可接受的”。合适的载体、佐剂,赋形剂等可以在标准的药物教科书中找到,例如,《雷氏药物科学》(Remington's Pharmaceutical Sciences);以及《药用赋形剂手册》(Handbook of Pharmaceutical Excipients)。
医药用途
在另一方面,提供了本申请的TCR或其片段、核酸、载体、多肽、细胞或药物组合物在制备用于治疗或预防疾病或病症的药物中的应用。
在一些实施例中,本发明的TCR或其片段、核酸、载体、多肽、细胞或药物组合物可用于预防或治疗由HBV感染所引发的相关疾病。由HBV感染所引发的相关疾病包括急性肝炎(包括暴发性肝衰竭)、慢性肝炎、肝纤维化、肝硬化、肝癌如肝细胞癌(HCC)、或胰腺癌。
治疗方法
可以通过分离患有与HBV相关疾病的病人或志愿者的T细胞,并将本申请的TCR导入上述T细胞中,随后将这些基因工程修饰的细胞回输到病人体内来进行治疗。因此,本申请提供了一种治疗HBV相关疾病的方法,包括将分离的表达本申请TCR的T细胞,优选地,该T细胞来源于病人本身,输入到病人体内。一般地,包括(1)分离病人的T细胞,(2)用本申请核酸分子或能够编码本申请TCR分子的载体,体外转导T细胞,(3)将基因工程修饰的T细胞输入到病人体内。分离、转染及回输的细胞的数量可以由医师决定。
下面将结合具体实施例,对本申请的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。需说明的是,以下实施例的描述顺序不作为对实施例优选顺序的限定。
下面实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人在分子克隆:实验室手册(Molecular cloning-A Laboratory manual.第三版.2001)中的条件,或按照制造厂商所建议的条件。除非另有说明,否则百分比和份数按重量计算。除非另有说明,文中涉及的试剂与材料均可商购获得,或本领域技术人员可依据公知常识自行制备。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本申请中。文中的较佳实施方法与材料仅作示范之用,但不能限制本申请的内容。
实施例1:克隆HBV表面抗原S20-28特异性T细胞并构建TCR基因载体
主要包括两个阶段:(1)克隆HBV表面抗原S20-28特异性T细胞获得其TCR序列(2)克隆目的基因到骨架质粒。具体描述如下:
克隆HBV表面抗原S20-28特异性T细胞获得其TCR序列:
分离HBV感染康复志愿者(HLA-A*02+亚型)的新鲜血液中的外周血单个核细胞(Peripheral blood mononuclear cell,PBMC);将1nM S20-28:FLLTRILTI和T2细胞胞(美国典型菌种收藏所(罗克福德,马里兰州))在37℃下共孵育2小时,然后使用负载S20-28的1x105T2刺激1x106PBMC共培养14天,并在培养基中添加终浓度为10ng/ml的IL-7(Peprotech,Hamburg,Germany)和终浓度为10ng/ml的IL-15(Peprotech,Hamburg,Germany),以及终浓度为50U/ml的阿地白介素(Novartis Pharmaceuticals)。用HLA-A*02-S20-28多聚体染色T细胞,再以流式细胞术分离和富集结合了HLA-A*02-S20-28多聚体的CD8阳性T细胞,培养扩增分选出的T细胞并进一步筛选出S20-28表位特异性的克隆。提取S20-28表位特异性的克隆的RNA测序确定TCR两条链序列,构建HBV S20-28特异性TCR库。挑选其中A01/B01/C01三个克隆,其TCR具有高亲和力,不需要对可变域进行修饰(例如亲和力成熟)。A01/B01/C01对应的α、β链的CDR1、CDR2、CDR3、TCRα可变域和TCRβ可变域的氨基酸序列如表1。
表1.A01/B01/C01的CDR、TCRα可变域和TCRβ可变域的氨基酸序列
TCR片段 | A01 | B01 | C01 |
αCDR1 | SEQ ID NO:1 | SEQ ID NO:13 | SEQ ID NO:24 |
αCDR2 | SEQ ID NO:2 | SEQ ID NO:14 | SEQ ID NO:25 |
αCDR3 | SEQ ID NO:3 | SEQ ID NO:15 | SEQ ID NO:26 |
βCDR1 | SEQ ID NO:4 | SEQ ID NO:16 | SEQ ID NO:27 |
βCDR2 | SEQ ID NO:5 | SEQ ID NO:17 | SEQ ID NO:28 |
βCDR3 | SEQ ID NO:6 | SEQ ID NO:18 | SEQ ID NO:29 |
TCRα可变域 | SEQ ID NO:7 | SEQ ID NO:19 | SEQ ID NO:30 |
TCRβ可变域 | SEQ ID NO:8 | SEQ ID NO:20 | SEQ ID NO:31 |
进一步地,在TCR恒定区引入一个额外的二硫键提高稳定性并减少内外源TCR链错配;另外,对TCR编码序列进行了密码子优化以提高表达量。改造后的A01、B01和C01的TCRα链和TCRβ链的氨基酸序列以及改造后的TCRα可变域、TCRβ可变域、TCRα链和TCRβ链编码序列如表2所示。TCRα和β链之间通过P2A自剪切肽元件连接,以确保每个转导细胞都表达相同水平的α和β链,A01、B01和C01对应的单链TCR分子的氨基酸序列分别如SEQ ID NO:12、SEQID NO:23和SEQ ID NO:34所示;编码序列分别如SEQ ID NO:41、SEQ ID NO:46和SEQ IDNO:51所示。
表2.改造后的A01/B01/C01 TCR及其片段的氨基酸序列和编码序列
克隆目的基因到骨架质粒:
为了提高TCR基因的表达效率,选择合适的骨架质粒至关重要。我们以公开的pCDH-EF1-MCS-T2A-copGFP质粒原始序列为基础(慢病毒骨架质粒酶切位点信息如表3),将其氨苄青霉素抗性基因替换为卡那霉素抗性基因后进行了骨架质粒的全基因合成。再分别设计目的基因序列两端引物引入EcoRI和SalI酶切位点,对目的基因(A01/B01/C01单链TCR编码序列)片段进行PCR扩增获得长度1800bp左右的扩增产物,根据PCR产物电泳结果选择目的基因条带进行纯化回收。同时将回收的PCR产物和pCDH-EF1-MCS-T2A-copGFP骨架质粒用EcoRI和SalI双酶切回收,2个片段利用T4 DNA连接酶连接,连接产物利用Stbl3感受态细胞进行转化,挑单克隆培养,提取质粒后通过双酶切、电泳和测序对目的质粒进行鉴定。构建完成的目的质粒包括5'LTR(长末端重复序列)、HIV-1(包装整合信号)、RRE(Rev反应元件)、cPPT/CTS(中心多嘌呤管道/中心终止序列)、EF-1αcore promoter(人类EF-1α的核心启动子)、WPRE(土拨鼠肝炎病毒转录后调控元件)、3'LTR-SIN(自灭活型的长末端重复序列)等主要功能元件(慢病毒骨架质粒关键功能元件及位置如表4所示),以及S20-TCR基因。
表3.慢病毒骨架质粒酶切位点信息汇总表
酶切位置 | 限制性酶 | 识别位点 |
3,090 | NheI | GCTAGC |
3,096 | EcoRI | GAATTC |
4,920 | SalI | GTCGAC |
KpnI | GGTACC |
表4.慢病毒骨架质粒关键功能元件及位置表
实施例2:慢病毒包装
A01/B01/C01 TCR-T细胞产品生产使用的慢病毒载体是来自于HIV-1的第三代“自灭活(self-inactivating,SIN)”具有VSV-G假性包膜的慢病毒载体,携带编码靶向HBsAg特异性T细胞受体(HBsAg TCR)的核酸。该慢病毒载体仅具有感染活性,无复制能力,其颗粒直径约为80-120nm,形状大致呈球体或者20面体对称结构。病毒外膜是类脂包膜,并嵌有VSV-G包膜蛋白,向内是由蛋白p17形成的球形基质(Matrix),以及蛋白p24形成的半锥形衣壳(Capsid),衣壳内含有携带TCR的RNA核酸信息。
第三代自灭活的慢病毒载体的核酸分子各元件功能描述如下:
在TCR基因两端分别是截短型/嵌合长末端重复序列,分别为△5’LTR和△3’LTR。其中△5’LTR为缺失U3,更换为上呼吸道合胞病毒(respiratory syncytial viruspneumonia,RSV)的增强子和启动子,使载体的复制不再依赖tat;△3’LTR为删除U3,使其不再有启动/增强活性,使其成为自灭活载体。
RRE元件功能:Rev的顺式作用元件,促使未经拼接的大mRNA分子从细胞核向胞浆转运。
cPPT元件功能:提高载体转导效率。
EF-1a启动子功能:调控基因表达(转录)的起始时间和表达程度。
WPRE元件功能:可上调转录物的多聚腺苷化及促进转录物出核,提高目的基因的表达效率。
慢病毒载体由第三代四质粒系统瞬时转染293T细胞并经纯化获得,其中四质粒系统由三个包装质粒(又称“辅助质粒”)和一个目的质粒组成。
包装质粒pGagPol-KanR编码病毒结构蛋白Gag及逆转录酶Pol,前者形成病毒核心结构,后者为RNA逆转录及整合所必需。
包装质粒pRev-KanR编码Rev蛋白,与RNA结合促进mRNA转运及蛋白表达。
包装质粒pVSV-G-KanR编码水疱性口炎病毒包膜蛋白VSV-G,替换HIV病毒包膜蛋白,使慢病毒载体几乎可感染所有组织来源的细胞,并提升了慢病毒颗粒的稳定性。
D10细胞完全培养配制:DMEM、10%FBS、1%Sodium Pyruvate、置于4℃冰箱中备用。
Day 0:293T细胞小于20代,不过分长满;以2×107铺150mm皿,20mL D10培养基,充分混匀细胞,37℃培养过夜。
Day 1:293T细胞融合度达到60-80%时进行转染,铺板到转染的时间不大于24h。
慢病毒包装按表5准备质粒复合物。
表5.质粒复合物所需材料
主质粒 | RRE | REV | VSVG | PEIpro | OptiMEM |
18ug | 10ug | 7ug | 7ug | 70uL | 1mL+1mL |
一边轻轻涡旋质粒,一边将PEIpro滴加进去,充分混匀并在室温下静置15min,形成质粒-PEI复合物;将复合物缓缓加入到150mm皿293T细胞中,充分混匀,置二氧化碳培养箱37℃培养6h。
Day 1:将转染6h的293T细胞,轻轻换液成20mL新鲜D10培养基。
Day 3:收集转染48h的病毒上清,暂存于4℃冰箱中,继续添加D10培养基20mL。
Day 4:收集转染72h的病毒上清,与收集转染48h的病毒上清混合;4度,3000g离心10min,过0.45um滤器去除碎片保留上清,使用100K的超滤杯进行病毒浓缩。
4℃,3000g离心至所需病毒浓缩的体积,离心结束后,取出离心装置,将过滤杯和下面的过滤液收集杯分开,将过滤杯倒扣在样品收集杯上;4℃,1000g离心2min,样品收集杯中的即为病毒浓缩液,收集浓缩液,分装,-70℃以下保存。
病毒液滴度检测:准备24孔板,Jurkat按1*105/孔,500ul,加入一定量病毒浓缩液,梯度稀释,培养72H后,流式检测病毒滴度。
病毒滴度检测:
流式缓冲液配制:DPBS、2%FBS,置于4℃冰箱中备用
取Jurkat细胞,每组1×106细胞,400g 5min离心弃上清,用流式缓冲液洗涤2次;
PE Dextramer HBV-S20按1:100比例用流式缓冲液稀释,每个样本加入100ul抗体稀释液,4℃避光孵育30分钟,加入流式缓冲液洗涤细胞,400g 5min离心弃上清,重复2次;
用100ul流式缓冲液重悬细胞,上样流式检测;
载体感染滴度(TU/mL)=每孔细胞铺板数×阳性率(%)×稀释倍数/滴定体积(mL)
结果如图3所示,A01 TCR、B01 TCR、C01 TCR慢病毒滴度都在1E8 TU/ml以上,说明3个HBV S20 TCR都可以成功包装病毒且滴度较高。
实施例3:制备HBV S20 TCR-T
T细胞培养基配制:PRIME-XV-T cell CDM、400IU/mlIL-2。
T细胞冻存液配制:75%CS10+25%HSA。
Day0:从单采血中分离获得较纯的CD3+T细胞,用T细胞培养基调整细胞浓度至1×106/mL,按Transact(CD3/CD28微球):细胞悬液=1:30加入激活剂,轻轻充分混匀,再加入终浓度为400IU/mL的白细胞介素2,刺激培养24h后病毒感染;
Day1:计数细胞,调整T细胞的密度在5×105/mL,加入病毒液;
Day2-11:细胞感染后,每天观察细胞状态,适时补加含IL-2 400IU/mL的T细胞培养液,使T细胞的密度维持在5×105/mL,使细胞扩增;
Day12:300g离心5分钟收获细胞,用含5%人血白蛋白的生理盐水溶液清洗细胞,用T细胞专用冻存液按照适当的密度进行冻存,经程序降温仪冷冻后保存于液氮中(图4)。
实施例4:流式细胞仪检测HBV S20 TCR-T的MOI检测及TCR特异表达
HBV S20 TCR-T MOI检测
流式缓冲液配制:DPBS、2%FBS,置于4℃冰箱中备用。
取A01 TCR-T、B01 TCR-T、C01 TCR-T各MOI组细胞和NT细胞(对照组),PBS洗涤1次后弃上清,加入PE Dextramer HBV-S20,4℃避光30min后PBS洗涤,重悬,最后流式细胞仪检测。
结果如图5所示,A01 TCR-T、B01 TCR-T、C01 TCR-T表达趋势一致,同时各组HBVS20TCR-T MOI=1.2时,TCR阳性率都在60%以上,说明三个单克隆号的HBV S20 TCR-T MOI梯度检测都稳定表达。
HBV S20 TCR-T特异表达检测
流式缓冲液配制:DPBS、2%FBS,置于4℃冰箱中备用。
取A01 TCR-T、B01 TCR-T、C01 TCR-T各组制备好的细胞和NT细胞(对照组),PBS洗涤1次后弃上清,加入PE Dextramer HBV-S20和APC TCR vβ5.1,4℃避光30min后PBS洗涤,重悬,最后流式细胞仪检测。
结果如图6所示,A01 TCR-T、B01 TCR-T、C01 TCR-T表达的错配率均较低,特异表达都达到50%以上,说明三个单克隆号的HBV S20 TCR-T都可以特异表达,且错配率较低。
实施例5:HBV S20 TCR-T对HBsAg+肝癌细胞的杀伤及细胞因子检测
M10细胞完全培养配制:DMEM、10%FBS、1%Sodium Pyruvate、1%HEPES、1%NEAA置于4℃冰箱中备用。
制备HepG2-LMS-LG靶细胞
取生长状态良好的HepG2(HLA-A02型),在一个Collagen包被好的24孔板中分别1E5/孔、共3孔的HepG2,再按照25ul、5ul、1ul加入LMS-LG慢病毒载体(表达HBsAg全长蛋白(包含FLLTRILTI序列)、luciferase荧光素酶以及GFP荧光蛋白)进行靶细胞构建,待细胞汇合度90%转板至6孔板扩大培养各孔细胞,细胞汇合度再次达到90%左右进行流式检测,取GFP阳性率大于95%且细胞生长状态最好的细胞进行扩大培养,并建立靶细胞种子细胞库,
结果见图7,靶细胞HepG2-LMS-LG阳性率大于99%且表达均一,表明靶细胞构建完成。
A01 TCR-T对HepG2-LMS-LG靶细胞的杀伤(化学发光法)
D0:取生长状态良好的HepG2-LMS-LG细胞,按照1E4/孔、100ul/孔种一块Cllagen包被好的96孔平地板,再按照8:1、4:1、2:1、1:1、1:2、1:4、1:8加入100ul A01 TCR-T细胞,未加A01 TCR-T细胞的孔补加100ul T细胞培养基,37℃培养箱共培养24h。
D1:取出共孵育的孔板,各实验孔加入50ul ONE-GloTM Luciferase AssaySystem,充分震荡混匀,使用酶标仪进行检测,计算方法:杀伤效率=(1-目的孔平均值/单独Target cells孔平均值)x100%
实验结果见图8,效靶比8:1和4:1时,A01 TCR-T杀伤靶细胞效率都达到80%以上,随着效靶比降低,杀伤效率下降,直到效靶比1:4时还可以检测到,而对阴性细胞以及UT对靶细胞都没有检测到杀伤功能,说明A01 TCR-T可以特异杀伤HBsAg阳性靶细胞。
B01/C01 TCR-T对HepG2-LMS-LG靶细胞的杀伤(RTCA)
D0:取生长状态良好的HepG2-LMS-LG细胞,消化后调整细胞密度至4×105/ml备用,取一块Collagen包被好的RTCA用96孔板,加入50ul/孔M10培养基进行仪器基线测定,再每孔加入密度为4×105/ml对应的细胞50ul,静置约5min后上机约16h连续检测生长曲线;
D1:取已测好TCR%和细胞活率的B01/C01 TCR-T、UT,按照阳性活细胞数8×105/ml、2.0×105/ml、0.5×105/ml进行效应细胞准备,按照效靶比2:1、1:2、1:8,加入效应细胞50ul/孔,上机连续检测杀伤曲线。
D3:拷贝RTCA的生长和杀伤曲线,停机,收集共培养上清进行细胞因子检测。
细胞因子检测:
取CBA试剂盒(Human Th1/Th2 Cytokine Cytometric Bead Array Kit II,BD,551809)平衡至室温。
吸取2ml Assay Diluent复溶标准品至浓度5000pg/ml,室温平衡30min。
标准品配制:取标准品,标记为S1,依次2倍稀释标准品S2-S9,S10为空白。
配置Human Th1/Th2 Cytokine Capture Beads混合液:取微球溶液A1-A6,震荡混匀后按相同体积混合。
取96孔U形底板,加入50ul的Human Th1/Th2 Cytokine Capture Beads混合液,再加入50ul的Human Th1/Th2 PE Detection Reagent。
细胞因子检测样本400g 5min离心,按每个样本50ul加入样本检测孔,标曲孔加入50ul配制S10-S1。
室温避光孵育180min,加入100ul Wash buffer,300g 5min离心,弃上清。
用100ul流Wash buffer重悬,上样流式检测,进行流式结果分析。
结果显示:B01 TCR-T效靶比2:1,1:2,1:8 48H对靶细胞杀伤比例都达到60%以上,且UT对靶细胞功能不明显(图9A、图9B),B01 TCR-T对靶细胞IFN-γ细胞因子分泌明显而UT则较低(图9C)。C01 TCR-T效靶比2:1,1:2,1:8 48H对靶细胞杀伤比例也都达到60%以上,同时UT对靶细胞功能不明显且C01 TCR-T对阴性细胞也几乎没有功能(图10A),C01TCR-T对靶细胞IFN-γ细胞因子分泌明显,对阴性细胞分泌较低,而UT则没有明显细胞因子分泌(图10B)。
A01/B01/C01 TCR-T同时对靶细胞杀伤功能检测
D0:取生长状态良好的HepG2-LMS-LG细胞,按照1E4/孔、100ul/孔种一块Cllagen包被好的96孔平地板,再按照1:1、1:2、1:4加入100ul A01/B01/C01 TCR-T细胞,未加TCR-T细胞的孔补加100ul T细胞培养基,37℃培养箱共培养24h。
D1:取出共孵育的孔板,各实验孔加入50ul ONE-GloTM Luciferase AssaySystem,充分震荡混匀,使用酶标仪进行检测,计算方法:杀伤效率=(1-目的孔平均值/单独Target cells孔平均值)x100%
结果显示:A01 TCR-T、B01 TCR-T、C01 TCR-T均表现出对HepG2-LMS-LG显著的特异性杀伤作用,并且表现出明显的剂量依赖效应,而对HBsAg阴性的靶细胞几乎没有杀伤作用(图11)。
实施例6:HBV S20 TCR-T不同T细胞亚群对靶细胞功能
CD4+T细胞是辅助性T淋巴细胞,其主要功能是增强吞噬细胞介导的抗感染作用和增强B细胞介导的体液免疫应答。CD8+T细胞是抑制/杀伤性T淋巴细胞,主要功能是特异性直接杀伤靶细胞。我们通过分离HBV S20 TCR-T的CD4/CD8细胞亚群,研究其抗肿瘤的功能。
细胞分选
吹匀HBV S20 TCR-T,取2份1×106细胞,分别加入25μl CD4和CD8阳选磁珠,混匀后转入分离柱置2-8℃孵育20分钟;
将分离柱放入磁力架2分钟,待附着磁珠的细胞吸附在管壁上后,小心弃去管内的上清。将分离柱从磁力架取下,加入1ml洗液(Buffer1),吹洗2-3次后,再次置于磁力架上2分钟。重复上述步骤5次;
用100μl的Buffer2重悬细胞;
加入10μl的,室温孵育45分钟一边温和混匀;
将分离柱放入磁力架1分钟,将上清中的T细胞转入新的试管中;
将细胞用4ml Buffer2彻底洗涤,400g 5min离心弃上清;
获取的高纯度无磁珠的CD4+和CD8+活细胞用流式检测亚群及后续功能实验
细胞亚群检测:
流式缓冲液配制:DPBS、2%FBS,置于4℃冰箱中备用。
吹匀分选完的CD4+和CD8+细胞,,400g 5min离心弃上清,用流式缓冲液洗涤2次。
PE-Cy7-CD4(BIOLEGEND,300512)/PerCP-Cy5.5-CD8(BIOLEGEND,301032)/
PE Dextramer抗体按1:100比例用流式缓冲液稀释,每个样本加入100ul抗体稀释液,4℃避光孵育30分钟,加入流式缓冲液洗涤细胞,400g 5min离心弃上清,重复2次。
用100ul流式缓冲液重悬细胞,上样流式检测。
结果显示分选后的CD4+和CD8+细胞纯度均达到95%以上,CD4+细胞的阳性率略高于CD8+细胞(图12A)。
HBV S20 TCR-T亚群对HepG2-LMS-LG靶细胞的杀伤(RTCA)
靶细胞完全培养基(M10):DMEM、10%FBS、1%Sodium Pyruvate、1%HEPES、1%NEAA置于4℃冰箱中备用;
T细胞完全培养基(TCM):取适量PRIME-XV培养基于50mL离心管中,加入400IU/mLIL-2,充分混匀,保存在2-8℃冰箱中,配制后有效期为6个月。
D0:取生长状态良好的HepG2-LMS-LG细胞,消化后调整细胞密度至4×105/ml备用,取一块Collagen包被好的RTCA用96孔板,加入50ul/孔M10培养基进行仪器基线测定,再每孔加入密度为4×105/ml HepG2-LMS-LG细胞50ul,静置约5min后上机约16h连续检测生长曲线;
D1:取已测好阳性率和细胞活率的CD4+和CD8+分选T细胞和未分选的HBV S20 TCR-T作为对照组,按照效靶比4:1、1:1、1:4,加入效应细胞50ul/孔,上机连续检测杀伤曲线。
D3:拷贝RTCA的生长和杀伤曲线,停机,收集共培养上清进行细胞因子检测。
细胞因子检测按照实施例5细胞因子的检测步骤进行。
结果显示,3种效靶比条件下,CD8+细胞表现出卓越的肿瘤细胞杀伤能力,其靶细胞半数杀伤时间仅为对照组的一半,高效靶比条件下,CD4+细胞也对靶细胞有不俗的杀伤效果(图12B)。在效靶比1:1情况下CD8+细胞的细胞因子释放水平与对照组持平,高于CD4+细胞组(图12C、图12D)。
综合以上结果,我们发现了CD8+ TCR-T细胞比CD4+对肿瘤细胞有更强的杀伤和细胞因子释放能力。
实施例7:A01/B01/C01 TCR-T对人源多肽数据库交叉反应检测
由于TCR和抗原表位以及MHC/HLA分子的序列多样性,使得TCR存在可能的交叉反应活性,从而引起潜在的脱靶毒性。丙氨酸筛查库(Alanine Scanning Peptide Library)是用来鉴别与多肽功能、稳定性和构象密切相关的特定氨基酸位点。我们将HBV S20表位肽中每个氨基酸残基分别单独突变为丙氨酸,测试HBV S20 TCR-T对突变后的抗原表位的交叉识别能力。
鉴定HBV S20 TCR-T识别的关键氨基酸实验
靶细胞完全培养基(R10):按RPMI 1640:FBS=10:1比例配制,充分混匀,保存在2-8℃冰箱中,配制后有效期为6个月。
T细胞完全培养基(TCM):取适量PRIME-XV培养基于50mL离心管中,加入400IU/mLIL-2,充分混匀,保存在2-8℃冰箱中,配制后有效期为6个月。
多肽准备:阳性对照S20-A/D(1号,氨基酸序列为FLLTRILTI)、阴性对照C18-A/D(2号,氨基酸序列为FLLTKILTI)、S20突变多肽(3-11号,相比S20-A/D氨基酸序列FLLTRILTI分别突变F1A、L2A、L3A、T4A、R5A、I6A、L7A、T8A和I9A)各取1管2mg,用170μl DMSO溶解,终浓度为10mM,10mM取3μl使用297μl TCM稀释至100μM,再进行10倍梯度稀释至10uM。
靶细胞准备:取传代数次后生长状态良好的T2细胞,500g/5min离心后去上清,使用R10培养基重悬细胞,检测细胞活率和密度,根据计数结果取1.8E+06的T2细胞用6ml TCM培养基重悬,取96孔U底板,按100μl/孔加入T2细胞,3E4/孔;加入对应多肽溶液,使其终浓度为:1uM;将96孔U底板放入37度培养箱孵育,2小时后加入效应细胞。
效应细胞准备:吹匀HBV S20 TCR-T,检测细胞活率和密度,根据计数结果取2.6E+06的HBV S20 TCR-T细胞用3ml TCM培养基重悬,调整阳性细胞密度至6E+05/ml,按50μl/孔加入效应细胞,吹匀后放入37℃培养箱。共孵育24h后取细胞流式检测细胞因子产生水平。
细胞因子检测按照实施例5细胞因子的检测步骤进行。结果显示,HBV S20 TCR-T对3/4/5/6号位氨基酸突变的多肽识别功能显著降低,细胞因子分泌检测不到或远远低于S20原多肽(图13,柱状图从左至右依次代表1-11号多肽结果),确定了HBV S20 TCR-T识别表位肽的关键氨基酸基序(3/4/5/6,LTRI)。该4个氨基酸残基在与TCR的结合中被认为在直接结合或控制空间结构中起到关键作用,为计算机预测分析评估人自身抗原肽交叉反应性提供依据,进一步评估HBV S20 TCR-T表位识别的特异性和安全性。
我们通过计算机预测结合数据库比对,并对人源多肽库进行BLAST序列比对,获取了与S20表位肽肽存在6个氨基酸一致的14条多肽序列,且未发现与S20有超过6个氨基酸一致的人源多肽;同样采用T2分别负载不同浓度多肽后与HBV S20 TCR-T共孵育检测细胞因子。
多肽准备:阳性对照S20-A/D(1号)、阴性对照C18-A/D(2号)、S20表位肽肽存在6个氨基酸一致的14条多肽序列(14-27号)各取1管2mg,用200ul DMSO溶解,终浓度为10mg/ml,10mg/ml取10ul使用90ul TCM稀释至1mg/ml,再依次进行10倍梯度稀释至100ng/ml
靶细胞准备:取传代数次后生长状态良好的T2细胞,500g/5min离心后去上清,使用R10培养基重悬细胞,检测细胞活率和密度,根据计数结果取1.8E+06的T2细胞用9ml TCM培养基重悬,取96孔U底板,按100μl/孔加入T2细胞,2E4/孔;按照浓度梯度加入对应得1,2,14-27号多肽溶液,使其终浓度为:0.1μg/ml和1ug/ml;将96孔U底板放入37度培养箱孵育2小时后加入效应细胞。
效应细胞准备:吹匀HBV S20 TCR-T,检测细胞活率和密度,根据计数结果取4.4E+06的HBV S20 TCR-T细胞用4.5ml TCM培养基重悬,调整阳性细胞密度至1.0E+06/ml,按50μl/孔加入效应细胞,吹匀后放入37℃培养箱。共孵育24h后取细胞流式检测细胞因子产生水平。
细胞因子检测按照实施例5细胞因子的检测步骤进行。
结果显示,A01/B01/C01 TCR-T对全部14条多肽都不存在交叉反应性(图14)。
综合以上结果,我们确定了HBV S20 TCR-T识别的关键氨基酸基序为3~6位(LTRI),改变该区域氨基酸残基,TCR对突变多肽的识别功能显著降低。通过生物信息学预测算法,对人源多肽库进行比对,得到14条与S20表位肽保持6个氨基酸一致的人源多肽库,通过T2细胞负载的方式检测,确定HBV S20 TCR-T对这些人自身抗原肽都不存在交叉反应,表明HBV S20 TCR-T针对人体自身内源性抗原的潜在脱靶毒性风险很低。
实施例8:A01/B01/C01 TCR-T不同基因型S20结合能力检测
T细胞识别肿瘤抗原,主要是通过TCR识别肿瘤细胞表面的HLA-肽复合物。TCR-T通过与肿瘤抗原的特异性结合来激活活化信号,从而对肿瘤细胞产生靶向杀伤功能。通过T2细胞负载不同浓度的S20-gt A/D(基因型A或D,氨基酸序列FLLTRILTI)或S20-gt B/C(基因型B或C氨基酸序列FLLTKILTI)多肽,研究HBV S20 TCR-T对不同基因型的HBV功能。
靶细胞完全培养基(R10):按RPMI 1640:FBS=10:1比例配制,充分混匀,保存在2-8℃冰箱中,配制后有效期为6个月。
T细胞完全培养基(TCM):取适量PRIME-XV培养基于50mL离心管中,加入400IU/mLIL-2,充分混匀,保存在2-8℃冰箱中,配制后有效期为6个月。
多肽准备:S20-AD、S20-BC、C18-AD多肽取1管2mg,用170ul DMSO溶解,终浓度为10mM,10mM取3ul使用297ul TCM稀释至100uM,再依次进行10倍梯度稀释至10nM;
靶细胞准备:取传代数次后生长状态良好的T2细胞,500g/5min离心后去上清,使用R10培养基重悬细胞,检测细胞活率和密度,根据计数结果取2.5E+06的T2细胞用5ml TCM培养基重悬,取96孔U底板,按100μl/孔加入T2细胞,5E4/孔,阴性对照组各孔加入100ulTCM;按照浓度梯度加入对应得S20-AD、S20-BC或C18-AD多肽溶液,使其终浓度为:10-5M-10-9M。
效应细胞准备:吹匀HBV S20 TCR-T,检测细胞活率和密度,根据计数结果取3.6E+06的HBV S20 TCR-T细胞用2.5ml TCM培养基重悬,调整阳性细胞细胞密度至1.0E+06/ml,按50μl/孔加入效应细胞,吹匀后放入37℃培养箱。共孵育24h后取细胞上清流式检测细胞因子产生水平。
细胞因子检测按照实施例5细胞因子的检测步骤进行。结果显示,A01/B01/C01TCR-T对负载HBV S20 gt A/D多肽或S20 gt B/C多肽的T2细胞均有明显的细胞因子分泌,当负载多肽浓度达到10-5M时,IFN-γ的分泌都达到5ng/ml以上,对C18-27 gt A/D则没有功能。且A01/B01/C01 TCR-T细胞因子分泌与S20多肽负载浓度呈剂量关系(图15)。
综合以上结果,HBV S20 TCR-T对HBV不同基因型均有明显功能,HBV S20 TCR-T可以覆盖绝大多数HBV病毒分型,对几个常见的基因型都有很好的功能。
实施例9:A01/B01/C01 TCR-T识别HLA-A02不同亚型检测
TCR特异性识别靶细胞上MHC分子递呈的抗原肽时受HLA亚型限制,我们选取4种靶细胞:HepG2细胞是HLA-A*02:01/24:02型的人肝癌细胞系;SW403细胞是HLA-A*02:05/03:01型的人肝癌细胞系;KATO III细胞是HLA-A*02:01/02:07型的人胃癌细胞系;SNU-1细胞是HLA-A*02:07/30:04型的人胃癌细胞系;使其负载S20-28表位肽后,刺激HBV S20 TCR-T细胞杀伤和分泌细胞因子的能力,以评价HBV S20 TCR-T体外与HLA-A02不同亚型的靶细胞所呈递的S20-28表位肽-MHC复合物的结合功能活性。
悬浮细胞完全培养基(R10):按RPMI 1640:FBS=10:1比例配制,保存在2-8℃冰箱中,配制后有效期为6个月。
T细胞完全培养基(TCM):取适量PRIME-XV培养基于50mL离心管中,加入400IU/mLIL-2,充分混匀,保存在2-8℃冰箱中,配制后有效期为6个月。
多肽准备:S20多肽取1管2mg,用200ul DMSO溶解,终浓度为10mg/ml,取10ul使用90ul TCM稀释至1mg/ml,再依次进行10倍梯度稀释至10μg/ml;
靶细胞准备:取传代数次后生长状态良好的靶细胞HepG2、SW403、KATO III和SNU-1,500g/5min离心后去上清,使用R10培养基重悬细胞,检测细胞活率和密度,根据计数结果取8.0E+05的细胞分别用4ml的TCM培养基重悬,取96孔U底板,按100μl/孔加入细胞悬液,2E4/孔,T only组加入100ulTCM培养基,靶细胞负载组按照实验设计,在对应孔加入S20多肽溶液,使其终浓度为:1μg/ml,混匀后后放入37℃培养箱孵育2小时。
效应细胞准备:吹匀HBV S20 TCR-T效应细胞(A01 TCR-T、B01 TCR-T、C01 TCR-T),吹匀后检测细胞活率和密度,根据计数结果和阳性率用TCM培养基调整细胞密度,按效靶比2:1,50μl/孔加入效应细胞,混匀后放入37℃培养箱。共孵育24h后500g/5min离心取细胞上清,收集共培养上清检测细胞因子水平。
试验结果显示,以HLA-A*02:01(HepG2)为参照,A01 TCR-T、B01 TCR-T和C01 TCR-T在HLA-A*02:07限制性下与负载S20多肽的KATO III和SNU-1共孵育后均可检测到明显的细胞因子分泌,而与无S20多肽负载的靶细胞共孵育则无法检测到相关细胞因子分泌。HLA-A*02:05型靶细胞SW403无论在有无S20多肽负载的情况下均无法检测到相关细胞因子分泌(图16)。
综合以上结果表明,负载S20表位肽的HLA-A*02:01和/或HLA-A*02:07靶细胞HepG2、KATO III和SNU-1细胞可有效激活HBV S20 TCR-T分泌相关细胞因子,显示其显著的特异性结合功能活性。而因HLA亚型限制,HLA-A*02:05型靶细胞SW403,即使其负载S20表位肽,也无法激活HBV S20 TCR-T的杀伤功能。HBV S20 TCR-T针对多种HLA-A*02:01和HLA-A*02:07等位基因递呈的S20表位肽的交叉识别活性意味着HBV S20 TCR-T有着更广泛的适用人群和病人覆盖率。
实施例10:免疫缺陷小鼠HepG2-LMS-LG移植瘤模型A01 TCR-T体内药效及药代实验
为了了解A01 TCR-T在体内环境中对肿瘤细胞的杀伤作用,我们使用了免疫缺陷小鼠(上海南方模式生物科技股份有限公司)和HBsAg+肝癌细胞(HepG2-LMS-LG)进行建模,构建了小鼠的CDX模型(肿瘤细胞系移植模型),以模拟临床肝癌病人在清淋化疗状态下接受A01 TCR-T细胞后对体内肝癌细胞的杀伤清除效果。
我们使用了NPG小鼠,于Day-6在小鼠右侧腋部皮下接种1×107个肿瘤细胞。Day 0时,肿瘤大小达到约100mm3,我们将小鼠分为6组,每组10只。其中4组接受不同剂量的A01TCR-T细胞注射,分别为高剂量组(2×107个细胞/只)、中剂量组(1×107个细胞/只)、低剂量组(0.5×107个细胞/只)和极低剂量组(0.2×107个细胞/只),剩余两组作为对照组,分别接受细胞冻存液(Vehicle)和未转染的T细胞(UT)(1.5×107个细胞/只)进行试验。此后按每周2次对肿瘤大小进行测量,收集肿瘤和药代相关数据。
试验结果显示:与对照组相比,各剂量的A01 TCR-T细胞均对肿瘤的生长有显著的抑制作用,4个剂量组小鼠的肿瘤体积均有明显减小(图17a),且小鼠静脉注射后耐受性良好,体重未发生减轻(图17b)。用药后1天各组织均可检测到A01 TCR-T拷贝数,然后呈现逐渐降低的趋势,用药后7天降至最低水平;但给药后14天和21天,多数小鼠血液、肝、脾、肺、心等血流丰富的组织出现了细胞重新扩增的现象,并在药后21天达到峰值(图17c)。
综合以上结果,A01 TCR-T在体内环境中对肿瘤细胞有明显的杀伤作用,除可见本动物模型导致而与研究药物无关的移植物抗宿主反应(GvHD)引起的多脏器/组织单个核细胞浸润、抗肿瘤作用,未见供试品相关的其它系统毒性,未观察到临床不良反应的剂量水平(NOAEL)为1×108TCR阳性T cells/kg,由于HBV S20 TCR-T临床研究均使用患者自体T细胞制备,因此不会产生GvHD。
实施例11:免疫缺陷小鼠HepG2-LMS-LG移植瘤模型B01 TCR-T体内药效实验
我们使用免疫缺陷小鼠和HBsAg+肝癌细胞(HepG2-LMS-LG)进行建模,构建了小鼠的CDX模型(肿瘤细胞系移植模型),模拟临床肝癌病人在清淋化疗状态下接受B01 TCR-T细胞后对体内肝癌细胞的杀伤清除效果。
我们使用了NPG小鼠,于Day-6在小鼠右侧腋部皮下接种1×107个肿瘤细胞。Day 0时,我们将小鼠分为6组,每组10只。其中4组接受不同剂量的B01 TCR-T细胞注射,分别为高剂量组(2×107个细胞/只)、中剂量组(1×107个细胞/只)、低剂量组(0.5×107个细胞/只)和极低剂量组(0.2×107个细胞/只),剩余2组作为对照组,分别接受细胞冻存液(Vehicle)(雌雄两组)和未转染的T细胞(Mock-T)(4.3×107个细胞/只)进行试验。此后按每周2次对肿瘤大小进行测量,并收集数据。
试验结果显示:与对照组相比,各剂量的B01 TCR-T细胞均对肿瘤的生长有显著的抑制作用,4个剂量组小鼠的肿瘤体积均有明显减小(图18a),动物瘤体积抑制率均超过90%,且小鼠静脉注射后耐受性良好,体重未发生减轻(图18b)。
综合以上结果,B01 TCR-T在体内环境中对肿瘤细胞有明显的杀伤作用,且未见明显不良反应。
实施例12:免疫缺陷小鼠HepG2-LMS-LG移植瘤模型C01 TCR-T体内药效实验
我们使用免疫缺陷小鼠和HBsAg+肝癌细胞(HepG2-LMS-LG)进行建模,构建了小鼠的CDX模型(肿瘤细胞系移植模型),模拟临床肝癌病人在清淋化疗状态下接受C01 TCR-T细胞后对体内肝癌细胞的杀伤清除效果。
我们使用了NPG小鼠,于Day-6在小鼠右侧腋部皮下接种1×107个肿瘤细胞。Day 0时,我们将小鼠分为4组,每组5只。其中2组接受不同剂量的C01 TCR-T细胞注射,分别为高剂量组(2×107个细胞/只)和低剂量组(5×106个细胞/只),剩余两组作为对照组,分别接受细胞冻存液(Vehicle)和未转染的T细胞(Mock-T)(2.9×107个细胞/只)进行试验。此后持续监测肿瘤大小,并收集数据。
qPCR检测拷贝数方法
试验结果显示:与对照组相比,高剂量的C01 TCR-T细胞相对于低剂量组对肿瘤的生长有更显著的抑制作用,小鼠的肿瘤体积有明显减小(图19a)。各剂量组小鼠静脉注射后耐受性良好,体重未发生减轻(图19b)。相较于对照组,高剂量组动物组织中可检测到较高的C01 TCR-T拷贝数(qPCR法),提示细胞在动物体内的存续和扩增,且小鼠体内的扩增程度与肿瘤大小呈现出明显的负相关性,表明C01 TCR-T在小鼠体内扩增越明显,对肿瘤的杀伤抑制作用越强(图19c)。
综合以上结果,C01 TCR-T在体内环境中对肿瘤细胞有明显的杀伤作用,且未见明显不良反应,且检测到较高TCR-T拷贝数。
以上对本申请进行了详细介绍,本文中应用了具体个例对本申请的原理及实施方式进行了阐述,以上实施例的说明只是用于帮助理解本申请的方法及其核心思想;同时,对于本领域的技术人员,依据本申请的思想,在具体实施方式及应用范围上均会有改变之处,综上,本说明书内容不应理解为对本申请的限制。
SEQUENCE LISTING
<110> 新加坡星汉德生物医药有限公司
<120> 乙肝表面抗原特异性T细胞受体及其用途
<130> SCG20220523
<160> 51
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Met Glu Thr Leu Leu Gly Val Ser Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp Pro Gln Ala Leu Ser
20 25 30
Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys Ser Tyr Lys Thr Ser
35 40 45
Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser Gly Arg Gly Leu Val
50 55 60
His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu Lys His Ser Gly Arg
65 70 75 80
Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser Ser Ser Leu Leu Ile
85 90 95
Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr Phe Cys Ala Thr Asp
100 105 110
Glu Arg Asp Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys
115 120 125
Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro
130 135 140
Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys
165 170 175
Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile
180 185 190
Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu
195 200 205
Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu
210 215 220
Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu
225 230 235 240
Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
245 250 255
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 11
<211> 303
<212> PRT
<213> Artificial Sequence
<400> 11
Met Asp Ser Trp Thr Leu Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asp Tyr Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Ser Leu Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr
115 120 125
Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser
290 295 300
<210> 12
<211> 591
<212> PRT
<213> Artificial Sequence
<400> 12
Met Asp Ser Trp Thr Leu Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asp Tyr Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Ser Leu Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr
115 120 125
Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser Gly
290 295 300
Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu
305 310 315 320
Glu Asn Pro Gly Pro Met Glu Thr Leu Leu Gly Val Ser Leu Val Ile
325 330 335
Leu Trp Leu Gln Leu Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp
340 345 350
Pro Gln Ala Leu Ser Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys
355 360 365
Ser Tyr Lys Thr Ser Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser
370 375 380
Gly Arg Gly Leu Val His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu
385 390 395 400
Lys His Ser Gly Arg Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser
405 410 415
Ser Ser Leu Leu Ile Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr
420 425 430
Phe Cys Ala Thr Asp Glu Arg Asp Asp Met Arg Phe Gly Ala Gly Thr
435 440 445
Arg Leu Thr Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
450 455 460
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
465 470 475 480
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
485 490 495
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
500 505 510
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
515 520 525
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
530 535 540
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
545 550 555 560
Asn Phe Gln Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys
565 570 575
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
580 585 590
<210> 13
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 13
Lys Thr Leu Tyr Gly
1 5
<210> 14
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 14
Leu Gln Lys Gly Gly Glu Glu
1 5
<210> 15
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 15
Gly Ala Asp Thr Ser Thr Asp Lys Leu Ile
1 5 10
<210> 16
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 16
Ser Gly His Arg Ser
1 5
<210> 17
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 17
Tyr Phe Ser Glu Thr Gln
1 5
<210> 18
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 18
Ala Ser Ser His Gly Gly Ala Tyr Glu Gln Tyr
1 5 10
<210> 19
<211> 110
<212> PRT
<213> Artificial Sequence
<400> 19
Gln Glu Leu Glu Gln Ser Pro Gln Ser Leu Ile Val Gln Glu Gly Lys
1 5 10 15
Asn Leu Thr Ile Asn Cys Thr Ser Ser Lys Thr Leu Tyr Gly Leu Tyr
20 25 30
Trp Tyr Lys Gln Lys Tyr Gly Glu Gly Leu Ile Phe Leu Met Met Leu
35 40 45
Gln Lys Gly Gly Glu Glu Lys Ser His Glu Lys Ile Thr Ala Lys Leu
50 55 60
Asp Glu Lys Lys Gln Gln Ser Ser Leu His Ile Thr Ala Ser Gln Pro
65 70 75 80
Ser His Ala Gly Ile Tyr Leu Cys Gly Ala Asp Thr Ser Thr Asp Lys
85 90 95
Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln Val Phe Pro Asn
100 105 110
<210> 20
<211> 110
<212> PRT
<213> Artificial Sequence
<400> 20
Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr Arg Gly Gln Gln
1 5 10 15
Val Thr Leu Ser Cys Ser Pro Ile Ser Gly His Arg Ser Val Ser Trp
20 25 30
Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu Phe Glu Tyr Phe
35 40 45
Ser Glu Thr Gln Arg Asn Lys Gly Asn Phe Pro Gly Arg Phe Ser Gly
50 55 60
Arg Gln Phe Ser Asn Ser Arg Ser Glu Met Asn Val Ser Thr Leu Glu
65 70 75 80
Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser His Gly Gly Ala
85 90 95
Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr
100 105 110
<210> 21
<211> 271
<212> PRT
<213> Artificial Sequence
<400> 21
Met Glu Thr Val Leu Gln Val Leu Leu Gly Ile Leu Gly Phe Gln Ala
1 5 10 15
Ala Trp Val Ser Ser Gln Glu Leu Glu Gln Ser Pro Gln Ser Leu Ile
20 25 30
Val Gln Glu Gly Lys Asn Leu Thr Ile Asn Cys Thr Ser Ser Lys Thr
35 40 45
Leu Tyr Gly Leu Tyr Trp Tyr Lys Gln Lys Tyr Gly Glu Gly Leu Ile
50 55 60
Phe Leu Met Met Leu Gln Lys Gly Gly Glu Glu Lys Ser His Glu Lys
65 70 75 80
Ile Thr Ala Lys Leu Asp Glu Lys Lys Gln Gln Ser Ser Leu His Ile
85 90 95
Thr Ala Ser Gln Pro Ser His Ala Gly Ile Tyr Leu Cys Gly Ala Asp
100 105 110
Thr Ser Thr Asp Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln Val
115 120 125
Phe Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
130 135 140
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
180 185 190
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
195 200 205
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 22
<211> 307
<212> PRT
<213> Artificial Sequence
<400> 22
Met Gly Ser Arg Leu Leu Cys Trp Val Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Lys Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Ser Cys Ser Pro Ile Ser Gly His
35 40 45
Arg Ser Val Ser Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe
50 55 60
Leu Phe Glu Tyr Phe Ser Glu Thr Gln Arg Asn Lys Gly Asn Phe Pro
65 70 75 80
Gly Arg Phe Ser Gly Arg Gln Phe Ser Asn Ser Arg Ser Glu Met Asn
85 90 95
Val Ser Thr Leu Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser His Gly Gly Ala Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp
305
<210> 23
<211> 603
<212> PRT
<213> Artificial Sequence
<400> 23
Met Gly Ser Arg Leu Leu Cys Trp Val Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Lys Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Ser Cys Ser Pro Ile Ser Gly His
35 40 45
Arg Ser Val Ser Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe
50 55 60
Leu Phe Glu Tyr Phe Ser Glu Thr Gln Arg Asn Lys Gly Asn Phe Pro
65 70 75 80
Gly Arg Phe Ser Gly Arg Gln Phe Ser Asn Ser Arg Ser Glu Met Asn
85 90 95
Val Ser Thr Leu Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser His Gly Gly Ala Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Ser Arg Gly Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
305 310 315 320
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Thr Val
325 330 335
Leu Gln Val Leu Leu Gly Ile Leu Gly Phe Gln Ala Ala Trp Val Ser
340 345 350
Ser Gln Glu Leu Glu Gln Ser Pro Gln Ser Leu Ile Val Gln Glu Gly
355 360 365
Lys Asn Leu Thr Ile Asn Cys Thr Ser Ser Lys Thr Leu Tyr Gly Leu
370 375 380
Tyr Trp Tyr Lys Gln Lys Tyr Gly Glu Gly Leu Ile Phe Leu Met Met
385 390 395 400
Leu Gln Lys Gly Gly Glu Glu Lys Ser His Glu Lys Ile Thr Ala Lys
405 410 415
Leu Asp Glu Lys Lys Gln Gln Ser Ser Leu His Ile Thr Ala Ser Gln
420 425 430
Pro Ser His Ala Gly Ile Tyr Leu Cys Gly Ala Asp Thr Ser Thr Asp
435 440 445
Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln Val Phe Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Ser Asp Val Pro Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 24
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 24
Thr Ser Ile Asn Asn
1 5
<210> 25
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 25
Ile Arg Ser Asn Glu Arg Glu
1 5
<210> 26
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 26
Ala Thr Asp Ala Tyr Gly Gln Asn Phe Val
1 5 10
<210> 27
<211> 5
<212> PRT
<213> Artificial Sequence
<400> 27
Ser Gly His Asp Tyr
1 5
<210> 28
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 28
Phe Asn Asn Asn Val Pro
1 5
<210> 29
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 29
Ala Ser Gly Ser Asn Thr Glu Ala Phe
1 5
<210> 30
<211> 110
<212> PRT
<213> Artificial Sequence
<400> 30
Gln Gln Gly Glu Glu Asp Pro Gln Ala Leu Ser Ile Gln Glu Gly Glu
1 5 10 15
Asn Ala Thr Met Asn Cys Ser Tyr Lys Thr Ser Ile Asn Asn Leu Gln
20 25 30
Trp Tyr Arg Gln Asn Ser Gly Arg Gly Leu Val His Leu Ile Leu Ile
35 40 45
Arg Ser Asn Glu Arg Glu Lys His Ser Gly Arg Leu Arg Val Thr Leu
50 55 60
Asp Thr Ser Lys Lys Ser Ser Ser Leu Leu Ile Thr Ala Ser Arg Ala
65 70 75 80
Ala Asp Thr Ala Ser Tyr Phe Cys Ala Thr Asp Ala Tyr Gly Gln Asn
85 90 95
Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro Tyr
100 105 110
<210> 31
<211> 109
<212> PRT
<213> Artificial Sequence
<400> 31
Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu
1 5 10 15
Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asp Tyr Leu Phe Trp
20 25 30
Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr Phe Asn
35 40 45
Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser
50 55 60
Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser
65 70 75 80
Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Gly Ser Asn Thr
85 90 95
Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val
100 105
<210> 32
<211> 267
<212> PRT
<213> Artificial Sequence
<400> 32
Met Glu Thr Leu Leu Gly Val Ser Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp Pro Gln Ala Leu Ser
20 25 30
Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys Ser Tyr Lys Thr Ser
35 40 45
Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser Gly Arg Gly Leu Val
50 55 60
His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu Lys His Ser Gly Arg
65 70 75 80
Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser Ser Ser Leu Leu Ile
85 90 95
Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr Phe Cys Ala Thr Asp
100 105 110
Ala Tyr Gly Gln Asn Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val
115 120 125
Leu Pro Tyr Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 33
<211> 303
<212> PRT
<213> Artificial Sequence
<400> 33
Met Asp Ser Trp Thr Leu Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asp Tyr Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Gly Ser Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr
115 120 125
Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser
290 295 300
<210> 34
<211> 592
<212> PRT
<213> Artificial Sequence
<400> 34
Met Asp Ser Trp Thr Leu Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asp Tyr Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Gly Ser Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr
115 120 125
Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser Gly
290 295 300
Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu
305 310 315 320
Glu Asn Pro Gly Pro Met Glu Thr Leu Leu Gly Val Ser Leu Val Ile
325 330 335
Leu Trp Leu Gln Leu Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp
340 345 350
Pro Gln Ala Leu Ser Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys
355 360 365
Ser Tyr Lys Thr Ser Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser
370 375 380
Gly Arg Gly Leu Val His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu
385 390 395 400
Lys His Ser Gly Arg Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser
405 410 415
Ser Ser Leu Leu Ile Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr
420 425 430
Phe Cys Ala Thr Asp Ala Tyr Gly Gln Asn Phe Val Phe Gly Pro Gly
435 440 445
Thr Arg Leu Ser Val Leu Pro Tyr Ile Gln Asn Pro Glu Pro Ala Val
450 455 460
Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe
465 470 475 480
Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly
485 490 495
Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser
500 505 510
Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys
515 520 525
Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val
530 535 540
Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn
545 550 555 560
Leu Asn Phe Gln Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu
565 570 575
Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
580 585 590
<210> 35
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 35
Phe Leu Leu Thr Arg Ile Leu Thr Ile
1 5
<210> 36
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 36
Phe Leu Leu Thr Lys Ile Leu Thr Ile
1 5
<210> 37
<211> 327
<212> DNA
<213> Artificial Sequence
<400> 37
cagcagggcg aagaggatcc ccaggccctg agcattcagg aaggcgagaa cgccaccatg 60
aactgcagct acaagaccag catcaacaac ctgcagtggt acagacagaa cagcggcaga 120
ggcctggtgc acctgatcct gatcagaagc aacgagagag agaagcactc cggcagactg 180
agagtgaccc tggacaccag caagaagtcc agcagcctgc tgatcaccgc cagcagagcc 240
gccgataccg ccagctactt ctgcgccacc gacgagcggg acgacatgag atttggcgcc 300
ggaacccggc tgaccgtgaa gcccaat 327
<210> 38
<211> 327
<212> DNA
<213> Artificial Sequence
<400> 38
ggcgtgatcc agagccccag acacgaagtg accgagatgg gccaggaagt gaccctgcgc 60
tgcaagccta tcagcggcca cgactacctg ttctggtaca gacagaccat gatgcggggc 120
ctggaactgc tgatctactt caacaacaac gtgcccatcg acgacagcgg catgcccgag 180
gatagattca gcgccaagat gcccaacgcc agcttcagca ccctgaagat ccagcccagc 240
gagcccagag acagcgccgt gtacttttgc gccagcagcc tgaacaccga ggcattcttt 300
gggcagggca cccggctgac agtggtg 327
<210> 39
<211> 801
<212> DNA
<213> Artificial Sequence
<400> 39
atggaaacac tgctgggagt gtccctcgtg atcctgtggc tgcagctggc cagagtgaac 60
agccagcagg gcgaagagga tccccaggcc ctgagcattc aggaaggcga gaacgccacc 120
atgaactgca gctacaagac cagcatcaac aacctgcagt ggtacagaca gaacagcggc 180
agaggcctgg tgcacctgat cctgatcaga agcaacgaga gagagaagca ctccggcaga 240
ctgagagtga ccctggacac cagcaagaag tccagcagcc tgctgatcac cgccagcaga 300
gccgccgata ccgccagcta cttctgcgcc accgacgagc gggacgacat gagatttggc 360
gccggaaccc ggctgaccgt gaagcccaat atccagaacc ccgagcccgc cgtgtaccag 420
ctgaaggacc ccagaagcca ggacagcacc ctgtgtctgt tcaccgactt cgacagccag 480
atcaacgtgc ccaagaccat ggaaagcggc accttcatca ccgataagtg cgtgctggac 540
atgaaggcca tggacagcaa gagcaacggc gccattgcct ggtccaacca gaccagcttc 600
acatgccagg acatcttcaa agagacaaac gccacctacc cttccagcga cgtgccctgt 660
gacgccaccc tgaccgagaa gtccttcgag acagacatga atctgaattt ccagaacctg 720
agcgtgatgg gcctgcggat cctgctgctg aaagtggccg gcttcaacct gctgatgacc 780
ctgcggctgt ggtccagctg a 801
<210> 40
<211> 909
<212> DNA
<213> Artificial Sequence
<400> 40
atggacagct ggaccctgtg ttgcgtgtcc ctgtgcatcc tggtggccaa gcacacagat 60
gccggcgtga tccagagccc cagacacgaa gtgaccgaga tgggccagga agtgaccctg 120
cgctgcaagc ctatcagcgg ccacgactac ctgttctggt acagacagac catgatgcgg 180
ggcctggaac tgctgatcta cttcaacaac aacgtgccca tcgacgacag cggcatgccc 240
gaggatagat tcagcgccaa gatgcccaac gccagcttca gcaccctgaa gatccagccc 300
agcgagccca gagacagcgc cgtgtacttt tgcgccagca gcctgaacac cgaggcattc 360
tttgggcagg gcacccggct gacagtggtg gaagatctga ggaacgtgac cccccccaag 420
gtgtccctgt tcgagcccag caaggccgag atcgccaaca agcagaaagc caccctcgtg 480
tgcctggcca gaggcttctt ccccgaccac gtggaactgt cctggtgggt caacggcaaa 540
gaggtgcaca gcggagtctg caccgacccc caggcttaca aagagagcaa ctacagctac 600
tgcctgtcca gcagactgcg ggtgtccgct accttctggc acaacccccg gaaccacttc 660
agatgccagg tgcagttcca cggcctgagc gaagaggaca agtggcccga gggcagcccc 720
aagcccgtga cccagaatat cagcgccgag gcctggggca gagccgattg tggcatcacc 780
agcgccagct accaccaggg ggtgctgagc gccaccatcc tgtacgagat cctgctgggc 840
aaggccaccc tgtacgccgt gctggtgtcc ggactggtgc tgatggccat ggtcaagaag 900
aagaacagc 909
<210> 41
<211> 1776
<212> DNA
<213> Artificial Sequence
<400> 41
atggacagct ggaccctgtg ttgcgtgtcc ctgtgcatcc tggtggccaa gcacacagat 60
gccggcgtga tccagagccc cagacacgaa gtgaccgaga tgggccagga agtgaccctg 120
cgctgcaagc ctatcagcgg ccacgactac ctgttctggt acagacagac catgatgcgg 180
ggcctggaac tgctgatcta cttcaacaac aacgtgccca tcgacgacag cggcatgccc 240
gaggatagat tcagcgccaa gatgcccaac gccagcttca gcaccctgaa gatccagccc 300
agcgagccca gagacagcgc cgtgtacttt tgcgccagca gcctgaacac cgaggcattc 360
tttgggcagg gcacccggct gacagtggtg gaagatctga ggaacgtgac cccccccaag 420
gtgtccctgt tcgagcccag caaggccgag atcgccaaca agcagaaagc caccctcgtg 480
tgcctggcca gaggcttctt ccccgaccac gtggaactgt cctggtgggt caacggcaaa 540
gaggtgcaca gcggagtctg caccgacccc caggcttaca aagagagcaa ctacagctac 600
tgcctgtcca gcagactgcg ggtgtccgct accttctggc acaacccccg gaaccacttc 660
agatgccagg tgcagttcca cggcctgagc gaagaggaca agtggcccga gggcagcccc 720
aagcccgtga cccagaatat cagcgccgag gcctggggca gagccgattg tggcatcacc 780
agcgccagct accaccaggg ggtgctgagc gccaccatcc tgtacgagat cctgctgggc 840
aaggccaccc tgtacgccgt gctggtgtcc ggactggtgc tgatggccat ggtcaagaag 900
aagaacagcg gcagcggcgc caccaacttc agcctgctga agcaggccgg cgacgtggag 960
gagaaccccg gccccatgga aacactgctg ggagtgtccc tcgtgatcct gtggctgcag 1020
ctggccagag tgaacagcca gcagggcgaa gaggatcccc aggccctgag cattcaggaa 1080
ggcgagaacg ccaccatgaa ctgcagctac aagaccagca tcaacaacct gcagtggtac 1140
agacagaaca gcggcagagg cctggtgcac ctgatcctga tcagaagcaa cgagagagag 1200
aagcactccg gcagactgag agtgaccctg gacaccagca agaagtccag cagcctgctg 1260
atcaccgcca gcagagccgc cgataccgcc agctacttct gcgccaccga cgagcgggac 1320
gacatgagat ttggcgccgg aacccggctg accgtgaagc ccaatatcca gaaccccgag 1380
cccgccgtgt accagctgaa ggaccccaga agccaggaca gcaccctgtg tctgttcacc 1440
gacttcgaca gccagatcaa cgtgcccaag accatggaaa gcggcacctt catcaccgat 1500
aagtgcgtgc tggacatgaa ggccatggac agcaagagca acggcgccat tgcctggtcc 1560
aaccagacca gcttcacatg ccaggacatc ttcaaagaga caaacgccac ctacccttcc 1620
agcgacgtgc cctgtgacgc caccctgacc gagaagtcct tcgagacaga catgaatctg 1680
aatttccaga acctgagcgt gatgggcctg cggatcctgc tgctgaaagt ggccggcttc 1740
aacctgctga tgaccctgcg gctgtggtcc agctga 1776
<210> 42
<211> 330
<212> DNA
<213> Artificial Sequence
<400> 42
caagagctgg aacagtctcc ccagagcctg atcgtgcaag agggcaagaa cctgaccatc 60
aactgcacca gcagcaagac cctgtacggc ctgtactggt acaagcagaa gtacggcgag 120
ggcctgatct tcctgatgat gctgcagaaa ggcggcgagg aaaagagcca cgagaagatc 180
accgccaagc tggacgagaa gaagcagcag agcagcctgc acatcacagc cagccagcct 240
tctcacgccg gcatctattt gtgcggagcc gacaccagca ccgacaagct gatctttggc 300
accggcacac ggctccaggt gttccccaat 330
<210> 43
<211> 330
<212> DNA
<213> Artificial Sequence
<400> 43
ggcgtgaccc agacacctag atacctgatc aagaccagag gccagcaagt gaccctgagc 60
tgctctccta tcagcggcca cagaagcgtg tcctggtatc agcagacacc tggacagggc 120
ctgcagttcc tgttcgagta cttcagcgag acacagcgga acaagggcaa cttccccggc 180
agattttccg gcagacagtt cagcaacagc cgcagcgaga tgaacgtgtc cacactggaa 240
ctgggcgaca gcgccctgta tctgtgtgct agttctcacg gcggagccta cgagcagtat 300
ttcggccctg gcaccagact gaccgtgacc 330
<210> 44
<211> 813
<212> DNA
<213> Artificial Sequence
<400> 44
atggaaaccg tgctgcaggt tctgctggga atcctgggat ttcaggccgc ctgggtgtcc 60
agccaagagc tggaacagtc tccccagagc ctgatcgtgc aagagggcaa gaacctgacc 120
atcaactgca ccagcagcaa gaccctgtac ggcctgtact ggtacaagca gaagtacggc 180
gagggcctga tcttcctgat gatgctgcag aaaggcggcg aggaaaagag ccacgagaag 240
atcaccgcca agctggacga gaagaagcag cagagcagcc tgcacatcac agccagccag 300
ccttctcacg ccggcatcta tttgtgcgga gccgacacca gcaccgacaa gctgatcttt 360
ggcaccggca cacggctcca ggtgttcccc aatattcaga accccgatcc tgccgtgtac 420
cagctgagag acagcaagag cagcgacaag agcgtgtgcc tgttcaccga cttcgacagc 480
cagaccaacg tgtcccagag caaggacagc gacgtgtaca tcaccgataa gtgcgtgctg 540
gacatgcgga gcatggactt caagagcaac agcgccgtgg cctggtccaa caagagcgat 600
ttcgcctgcg ccaacgcctt caacaatagc attatccccg aggacacatt cttccccagc 660
tccgatgtgc cctgcgacgt gaagctggtg gaaaagtcct tcgagacaga caccaacctg 720
aacttccaga acctgagcgt gatcggcttc agaatcctgc tgctgaaggt ggccggcttc 780
aacctgctga tgacactgag actgtggtcc agc 813
<210> 45
<211> 921
<212> DNA
<213> Artificial Sequence
<400> 45
atgggatcta gactgctttg ttgggtgctg ctgtgcctgc ttggagccgg acctgtgaaa 60
gctggcgtga cccagacacc tagatacctg atcaagacca gaggccagca agtgaccctg 120
agctgctctc ctatcagcgg ccacagaagc gtgtcctggt atcagcagac acctggacag 180
ggcctgcagt tcctgttcga gtacttcagc gagacacagc ggaacaaggg caacttcccc 240
ggcagatttt ccggcagaca gttcagcaac agccgcagcg agatgaacgt gtccacactg 300
gaactgggcg acagcgccct gtatctgtgt gctagttctc acggcggagc ctacgagcag 360
tatttcggcc ctggcaccag actgaccgtg accgaggatc tgaagaacgt gttcccacct 420
gaggtggccg tgttcgagcc ttctaaggcc gagattgccc acacacagaa agccacactc 480
gtgtgtctgg ccaccggctt ctatcccgat cacgtggaac tgtcttggtg ggtcaacggc 540
aaagaggtgc acagcggcgt ctgcacagat ccccagcctc tgaaagaaca gcccgctctg 600
aacgacagcc ggtactgtct gagcagcaga ctgagagtgt ccgccacctt ctggcagaac 660
cccagaaacc acttcagatg ccaggtgcag ttctacggcc tgagcgagaa cgatgagtgg 720
acccaggata gagccaagcc tgtgacacag atcgtgtctg ccgaagcctg gggcagagcc 780
gattgtggaa ttaccagcgc cagctaccat cagggcgtgc tgtctgccac aatcctgtac 840
gagatcctgc tgggcaaagc cactctgtac gccgtgctgg tttctgccct ggtgctgatg 900
gccatggtca agcggaagga t 921
<210> 46
<211> 1809
<212> DNA
<213> Artificial Sequence
<400> 46
atgggatcta gactgctttg ttgggtgctg ctgtgcctgc ttggagccgg acctgtgaaa 60
gctggcgtga cccagacacc tagatacctg atcaagacca gaggccagca agtgaccctg 120
agctgctctc ctatcagcgg ccacagaagc gtgtcctggt atcagcagac acctggacag 180
ggcctgcagt tcctgttcga gtacttcagc gagacacagc ggaacaaggg caacttcccc 240
ggcagatttt ccggcagaca gttcagcaac agccgcagcg agatgaacgt gtccacactg 300
gaactgggcg acagcgccct gtatctgtgt gctagttctc acggcggagc ctacgagcag 360
tatttcggcc ctggcaccag actgaccgtg accgaggatc tgaagaacgt gttcccacct 420
gaggtggccg tgttcgagcc ttctaaggcc gagattgccc acacacagaa agccacactc 480
gtgtgtctgg ccaccggctt ctatcccgat cacgtggaac tgtcttggtg ggtcaacggc 540
aaagaggtgc acagcggcgt ctgcacagat ccccagcctc tgaaagaaca gcccgctctg 600
aacgacagcc ggtactgtct gagcagcaga ctgagagtgt ccgccacctt ctggcagaac 660
cccagaaacc acttcagatg ccaggtgcag ttctacggcc tgagcgagaa cgatgagtgg 720
acccaggata gagccaagcc tgtgacacag atcgtgtctg ccgaagcctg gggcagagcc 780
gattgtggaa ttaccagcgc cagctaccat cagggcgtgc tgtctgccac aatcctgtac 840
gagatcctgc tgggcaaagc cactctgtac gccgtgctgg tttctgccct ggtgctgatg 900
gccatggtca agcggaagga tagcagaggc ggaagcggcg ccacaaactt cagcctgctt 960
aaacaggccg gcgacgtgga agagaacccc ggacctatgg aaaccgtgct gcaggttctg 1020
ctgggaatcc tgggatttca ggccgcctgg gtgtccagcc aagagctgga acagtctccc 1080
cagagcctga tcgtgcaaga gggcaagaac ctgaccatca actgcaccag cagcaagacc 1140
ctgtacggcc tgtactggta caagcagaag tacggcgagg gcctgatctt cctgatgatg 1200
ctgcagaaag gcggcgagga aaagagccac gagaagatca ccgccaagct ggacgagaag 1260
aagcagcaga gcagcctgca catcacagcc agccagcctt ctcacgccgg catctatttg 1320
tgcggagccg acaccagcac cgacaagctg atctttggca ccggcacacg gctccaggtg 1380
ttccccaata ttcagaaccc cgatcctgcc gtgtaccagc tgagagacag caagagcagc 1440
gacaagagcg tgtgcctgtt caccgacttc gacagccaga ccaacgtgtc ccagagcaag 1500
gacagcgacg tgtacatcac cgataagtgc gtgctggaca tgcggagcat ggacttcaag 1560
agcaacagcg ccgtggcctg gtccaacaag agcgatttcg cctgcgccaa cgccttcaac 1620
aatagcatta tccccgagga cacattcttc cccagctccg atgtgccctg cgacgtgaag 1680
ctggtggaaa agtccttcga gacagacacc aacctgaact tccagaacct gagcgtgatc 1740
ggcttcagaa tcctgctgct gaaggtggcc ggcttcaacc tgctgatgac actgagactg 1800
tggtccagc 1809
<210> 47
<211> 330
<212> DNA
<213> Artificial Sequence
<400> 47
cagcagggcg aagaggatcc ccaggccctg agcattcagg aaggcgagaa cgccaccatg 60
aactgcagct acaagaccag catcaacaac ctgcagtggt acagacagaa cagcggcaga 120
ggcctggtgc acctgatcct gatcagaagc aacgagagag agaagcactc cggcagactg 180
agagtgaccc tggacaccag caagaagtcc agcagcctgc tgatcaccgc cagcagagcc 240
gccgataccg ccagctactt ctgtgccaca gacgcctacg gccagaactt cgtgtttggc 300
cctggcacca gactgagcgt gctgccctat 330
<210> 48
<211> 327
<212> DNA
<213> Artificial Sequence
<400> 48
ggcgtgatcc agagccccag acacgaagtg accgagatgg gccaggaagt gaccctgcgc 60
tgcaagccta tcagcggcca cgactacctg ttctggtaca gacagaccat gatgcggggc 120
ctggaactgc tgatctactt caacaacaac gtgcccatcg acgacagcgg catgcccgag 180
gatagattca gcgccaagat gcccaacgcc agcttcagca ccctgaagat ccagcccagc 240
gagcccagag acagcgccgt gtacttttgt gccagcggca gcaacaccga ggcattcttt 300
gggcagggca cccggctgac agtggtg 327
<210> 49
<211> 804
<212> DNA
<213> Artificial Sequence
<400> 49
atggaaacac tgctgggagt gtccctcgtg atcctgtggc tgcagctggc cagagtgaac 60
agccagcagg gcgaagagga tccccaggcc ctgagcattc aggaaggcga gaacgccacc 120
atgaactgca gctacaagac cagcatcaac aacctgcagt ggtacagaca gaacagcggc 180
agaggcctgg tgcacctgat cctgatcaga agcaacgaga gagagaagca ctccggcaga 240
ctgagagtga ccctggacac cagcaagaag tccagcagcc tgctgatcac cgccagcaga 300
gccgccgata ccgccagcta cttctgtgcc acagacgcct acggccagaa cttcgtgttt 360
ggccctggca ccagactgag cgtgctgccc tatatccaga accccgagcc cgccgtgtac 420
cagctgaagg accccagaag ccaggacagc accctgtgtc tgttcaccga cttcgacagc 480
cagatcaacg tgcccaagac catggaaagc ggcaccttca tcaccgataa gtgcgtgctg 540
gacatgaagg ccatggacag caagagcaac ggcgccattg cctggtccaa ccagaccagc 600
ttcacatgcc aggacatctt caaagagaca aacgccacct acccttccag cgacgtgccc 660
tgtgacgcca ccctgaccga gaagtccttc gagacagaca tgaatctgaa tttccagaac 720
ctgagcgtga tgggcctgcg gatcctgctg ctgaaagtgg ccggcttcaa cctgctgatg 780
accctgcggc tgtggtccag ctga 804
<210> 50
<211> 909
<212> DNA
<213> Artificial Sequence
<400> 50
atggacagct ggaccctgtg ttgcgtgtcc ctgtgcatcc tggtggccaa gcacacagat 60
gccggcgtga tccagagccc cagacacgaa gtgaccgaga tgggccagga agtgaccctg 120
cgctgcaagc ctatcagcgg ccacgactac ctgttctggt acagacagac catgatgcgg 180
ggcctggaac tgctgatcta cttcaacaac aacgtgccca tcgacgacag cggcatgccc 240
gaggatagat tcagcgccaa gatgcccaac gccagcttca gcaccctgaa gatccagccc 300
agcgagccca gagacagcgc cgtgtacttt tgtgccagcg gcagcaacac cgaggcattc 360
tttgggcagg gcacccggct gacagtggtg gaagatctga ggaacgtgac cccccccaag 420
gtgtccctgt tcgagcccag caaggccgag atcgccaaca agcagaaagc caccctcgtg 480
tgcctggcca gaggcttctt ccccgaccac gtggaactgt cctggtgggt caacggcaaa 540
gaggtgcaca gcggagtctg caccgacccc caggcttaca aagagagcaa ctacagctac 600
tgcctgtcca gcagactgcg ggtgtccgct accttctggc acaacccccg gaaccacttc 660
agatgccagg tgcagttcca cggcctgagc gaagaggaca agtggcccga gggcagcccc 720
aagcccgtga cccagaatat cagcgccgag gcctggggca gagccgattg tggcatcacc 780
agcgccagct accaccaggg ggtgctgagc gccaccatcc tgtacgagat cctgctgggc 840
aaggccaccc tgtacgccgt gctggtgtcc ggactggtgc tgatggccat ggtcaagaag 900
aagaacagc 909
<210> 51
<211> 1779
<212> DNA
<213> Artificial Sequence
<400> 51
atggacagct ggaccctgtg ttgcgtgtcc ctgtgcatcc tggtggccaa gcacacagat 60
gccggcgtga tccagagccc cagacacgaa gtgaccgaga tgggccagga agtgaccctg 120
cgctgcaagc ctatcagcgg ccacgactac ctgttctggt acagacagac catgatgcgg 180
ggcctggaac tgctgatcta cttcaacaac aacgtgccca tcgacgacag cggcatgccc 240
gaggatagat tcagcgccaa gatgcccaac gccagcttca gcaccctgaa gatccagccc 300
agcgagccca gagacagcgc cgtgtacttt tgtgccagcg gcagcaacac cgaggcattc 360
tttgggcagg gcacccggct gacagtggtg gaagatctga ggaacgtgac cccccccaag 420
gtgtccctgt tcgagcccag caaggccgag atcgccaaca agcagaaagc caccctcgtg 480
tgcctggcca gaggcttctt ccccgaccac gtggaactgt cctggtgggt caacggcaaa 540
gaggtgcaca gcggagtctg caccgacccc caggcttaca aagagagcaa ctacagctac 600
tgcctgtcca gcagactgcg ggtgtccgct accttctggc acaacccccg gaaccacttc 660
agatgccagg tgcagttcca cggcctgagc gaagaggaca agtggcccga gggcagcccc 720
aagcccgtga cccagaatat cagcgccgag gcctggggca gagccgattg tggcatcacc 780
agcgccagct accaccaggg ggtgctgagc gccaccatcc tgtacgagat cctgctgggc 840
aaggccaccc tgtacgccgt gctggtgtcc ggactggtgc tgatggccat ggtcaagaag 900
aagaacagcg gcagcggcgc caccaacttc agcctgctga agcaggccgg cgacgtggag 960
gagaaccccg gccccatgga aacactgctg ggagtgtccc tcgtgatcct gtggctgcag 1020
ctggccagag tgaacagcca gcagggcgaa gaggatcccc aggccctgag cattcaggaa 1080
ggcgagaacg ccaccatgaa ctgcagctac aagaccagca tcaacaacct gcagtggtac 1140
agacagaaca gcggcagagg cctggtgcac ctgatcctga tcagaagcaa cgagagagag 1200
aagcactccg gcagactgag agtgaccctg gacaccagca agaagtccag cagcctgctg 1260
atcaccgcca gcagagccgc cgataccgcc agctacttct gtgccacaga cgcctacggc 1320
cagaacttcg tgtttggccc tggcaccaga ctgagcgtgc tgccctatat ccagaacccc 1380
gagcccgccg tgtaccagct gaaggacccc agaagccagg acagcaccct gtgtctgttc 1440
accgacttcg acagccagat caacgtgccc aagaccatgg aaagcggcac cttcatcacc 1500
gataagtgcg tgctggacat gaaggccatg gacagcaaga gcaacggcgc cattgcctgg 1560
tccaaccaga ccagcttcac atgccaggac atcttcaaag agacaaacgc cacctaccct 1620
tccagcgacg tgccctgtga cgccaccctg accgagaagt ccttcgagac agacatgaat 1680
ctgaatttcc agaacctgag cgtgatgggc ctgcggatcc tgctgctgaa agtggccggc 1740
ttcaacctgc tgatgaccct gcggctgtgg tccagctga 1779
Claims (17)
1.一种T细胞受体(TCR)或其片段,其包含TCRα链可变域和TCRβ链可变域;其中,
所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:3所示,且所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:6所示;或
所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:15所示,且所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:18所示;或
所述TCRα链可变域的αCDR3的氨基酸序列如SEQ ID NO:26所示,且所述TCRβ链可变域的βCDR3的氨基酸序列如SEQ ID NO:29所示。
2.如权利要求1所述的TCR或其片段,其特征在于,所述TCRα链可变域包含互补决定区αCDR1、αCDR2和αCDR3,且所述TCRβ链可变域包含互补决定区βCDR1、βCDR2和βCDR3,其中:
αCDR1、αCDR2和αCDR3分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示,βCDR1、βCDR2和βCDR3分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示;或
αCDR1、αCDR2和αCDR3分别如SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:15所示,βCDR1、βCDR2和βCDR3分别如SEQ ID NO:16、SEQ ID NO:17和SEQ ID NO:18所示;或
αCDR1、αCDR2和αCDR3分别如SEQ ID NO:24、SEQ ID NO:25和SEQ ID NO:26所示,βCDR1、βCDR2和βCDR3分别如SEQ ID NO:27、SEQ ID NO:28和SEQ ID NO:29所示。
3.如权利要求1所述的TCR或其片段,其特征在于,所述TCRα链可变域氨基酸序列如SEQID NO:7、SEQ ID NO:19或SEQ ID NO:30所示或于其具有至少90%序列相同性的氨基酸序列;和/或
所述TCRβ链可变域氨基酸序列如SEQ ID NO:8、SEQ ID NO:20或SEQ ID NO:31所示或于其具有至少90%序列相同性的氨基酸序列。
4.如权利要求1所述的TCR或其片段,其特征在于,所述TCRα链和TCRβ链分别包含恒定域;所述TCRα链氨基酸序列如SEQ ID NO:10、SEQ ID NO:21或SEQ ID NO:32所示;和/或
所述TCRβ链氨基酸序列如SEQ ID NO:11、SEQ ID NO:22或SEQ ID NO:33所示。
5.如权利要求1所述的TCR或其片段,其特征在于,所述TCR的α链和/或β链的C-或N-末端结合有偶联物,所述偶联物为可检测标记物、治疗剂、PK修饰部分或任何这些物质的组合。
6.如权利要求1-5任一项所述的TCR或其片段,其能够结合由HLA-A*02呈递的HBV表面抗原多肽。
7.如权利要求6所述的TCR或其片段,其中所述多肽包含氨基酸序列FLLTRILTI(SEQ IDNO:35)或FLLTKILTI(SEQ ID NO:36)或由其组成。
8.一种核酸分子,其特征在于,所述核酸分子包含编码权利要求1-7任一项所述的TCR分子或其片段的核酸序列或其互补序列。
9.如权利要求8所述的核酸分子,其特征在于,所述TCRα链可变域的编码序列如SEQ IDNO:37、SEQ ID NO:42或SEQ ID NO:47所示;和/或
所述TCRβ链可变域的编码序列如SEQ ID NO:38、SEQ ID NO:43或SEQ ID NO:48所示。
10.如权利要求8所述的核酸分子,其特征在于,所述TCRα链的编码序列如SEQ ID NO:39、SEQ ID NO:44或SEQ ID NO:49所示;和/或
所述TCRβ链的编码序列如SEQ ID NO:40、SEQ ID NO:45或SEQ ID NO:50所示。
11.如权利要求8所述的核酸分子,其特征在于,所述核酸分子为单链,通过P2A编码序列将TCRβ链编码序列和TCRα链编码序列连接而成;优选地,所述TCR的单链编码序列如SEQID NO:41、SEQ ID NO:46或SEQ ID NO:51所示。
12.一种载体,其特征在于,所述的载体包含权利要求8-11任一项所述的核酸分子;其中所述载体选自质粒、二元载体、DNA载体、mRNA载体、逆转录病毒载体、慢病毒载体、基于转座子的载体和人工染色体。
13.一种分离的多肽,其由根据权利要求8至11中任一项所述的核酸分子或根据权利要求12所述的载体编码。
14.一种分离的细胞,其特征在于,所述细胞中包含权利要求1-4任一项所述的TCR或其片段、权利要求8-11任一项所述的核酸分子、权利要求12所述的载体或权利要求13所述的多肽。
15.一种药物组合物,其特征在于,所述组合物含有药学上可接受的载体以及权利要求1-7任一项所述的TCR或其片段、权利要求8-11任一项所述的核酸分子、权利要求12所述载体、权利要求13所述的多肽、或权利要求14所述的细胞。
16.权利要求1-7任一项所述的TCR或其片段、权利要求8-11任一项所述的核酸分子、权利要求12所述载体、权利要求13所述的多肽、权利要求14所述的细胞或权利要求15所述的药物组合物在制备用于预防或治疗由HBV感染所引发的相关疾病的药物中的用途。
17.如权利要求16所述的用途,其特征在于,所述HBV感染相关疾病包含肝炎、肝纤维化、肝硬化、肝癌所组成的一种或多种。
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