CN112585162A - Ha-1特异性t细胞受体及其用途 - Google Patents
Ha-1特异性t细胞受体及其用途 Download PDFInfo
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- CN112585162A CN112585162A CN201980052682.1A CN201980052682A CN112585162A CN 112585162 A CN112585162 A CN 112585162A CN 201980052682 A CN201980052682 A CN 201980052682A CN 112585162 A CN112585162 A CN 112585162A
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- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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- C—CHEMISTRY; METALLURGY
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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Abstract
本发明涵盖对次要组织相容性抗原1(HA‑1)的一种等位基因变体、特别是等位基因变体HA‑1H具有特异性的分离的T细胞受体(TCR)。还描述了包含TCR的功能部分的分离的多肽。此外,限定了与TCR相关的多价TCR复合物、核酸分子、载体、细胞、抗体以及医学用途。
Description
技术领域
本发明涉及与次要组织相容性抗原1(HA-1)的一种等位基因形式特异性结合的分离的T细胞受体(TCR),以及包含该TCR的功能部分的多肽。还涉及多价TCR复合物、编码TCR的核酸、表达TCR的细胞和包含TCR的药物组合物。本发明还涉及TCR用于作为药物,特别是涉及TCR用于在治疗癌症中使用。
背景技术
在过去的50年中,骨髓移植(BMT)和造血干细胞移植(HSCT)已成功地用作许多恶性和非恶性疾病(例如严重的再生障碍性贫血和白血病)的一线治疗。在BMT或HSCT期间,在患者自身的造血细胞系统已被亚致死全身辐射或高剂量细胞毒性药物破坏后,患者接受来自健康供体的造血细胞(即造血干细胞)。供体的干细胞可以源自供体的骨髓,或者是供体动员的造血干细胞的干细胞移植的一部分。这种方法被称为同种异体,因为移植的细胞源自非自体来源,即健康的遗传上不相同的供体。
同种异体BMT或HSCT的一种失败模式是由于宿主对移植物的排斥,也称为宿主抗移植物病(HvGD),其中在亚致死辐射或细胞毒性药物的移植前方案中逃脱破坏的患者残留免疫细胞将移植的供体细胞鉴定为“外源”并且随后引发免疫反应,导致对移植的骨髓或造血干细胞的排斥。
BMT/HSCT的另一种甚至更为严重的失败形式是所谓的“移植物抗宿主病”(GvHD),其实际上是源自从供体移植的骨髓或造血干细胞的移植免疫细胞对患者(受体)体细胞的反应。GvHD主要归因于所有有核体细胞和血小板表达的MHC分子的差异。MHC代表主要组织相容性复合物分子,其中已知两个主要类别。呈递或展示胞质蛋白质的肽片段的MHC I类分子在GvHD中起主要作用。在人中,MHC也称为HLA复合物(人白细胞抗原复合物),并且位于6号染色体上。
HLA复合物是多基因的并且基于高度多态的基因,这意味着在群体的不同个体中存在许多不同的等位基因(同一基因的替代形式)。每个人细胞表达六种不同的MHC I类等位基因(来自每个亲本的一个HLA-A、HLA-B和HLA-C等位基因)和另外六至八个MHC II类等位基因。在BMT和HSCT的情况下,MHC分子本身可能充当抗原,即,其可能被供体的免疫细胞鉴定为“外源”。因此,GvHD反应主要基于供体和受体的HLA/MHC分子表达不匹配。因此,最重要的是选择供体以在MHC I类和II类表型方面具有最少量的不匹配,以使GvHD的风险最小。
即使供体和患者在其MHC I/II基因型方面尽可能匹配,但仍有超过50%的所有患者患有GvHD。预防患者发展GvHD的一种可能方法是使用例如抗CD3单克隆抗体或其它对成熟T细胞具有特异性的抗体从移植物去除T细胞,因为供体的T细胞通过识别不同于供体库的患者HLA分子而诱导GvHD。尽管目前BMT和HSCT是在HLA匹配的环境中进行的,但是在大量患者中仍发生GvHD,产生克服这一问题的需求。
这很可能是由于所谓的次要组织相容性抗原(MiHA)中的不匹配所致,而后者独立于HLA基因而遗传。在过去的几年中,已经鉴定出大量的MiHA(Frontiers in Immunology,第7卷,第100章,2016年3月),其可以由雄性特异性Y染色体(H-Y抗原)或其它染色体(常染色体MiHA)编码。在常染色体MiHA中,被称为HA-1、HA-2、HA-3、HA-4和HA-5的抗原是最早发现的抗原,并且所有这些抗原均在HLA-A1(HA-3)的背景下或在HLA-A2(HA-1、HA-2、HA-4和HA-5)的背景下呈递。还已知限定HA-1的MiHA的SNP变体(单核苷酸多态性)在69%的表达HLA-A2的患者中表达,而HA-2可以在95%、HA-4在16%以及HA-5在约7%的群体中检测到。相比之下,在88%的表达HLA-A1的患者中发现了在HLA-A1的背景下呈递的HA-3(N Engl JMed.1996年2月1日;334(5):281-5)。
因为HA-1几乎仅在造血细胞和癌细胞上表达,所以其代表了用于过继T细胞疗法(ACT)的有希望的肿瘤特异性靶标。以前,已经成功地分离或产生了HLA-A2限制的HA-1特异性细胞毒性T淋巴细胞(T细胞)(Haematologica.2005年10月;90(10):1415-21)。HA-1包含具有氨基酸序列VLHDDLLEA(SEQ ID NO:2)的九肽形式的表位(Science.1998年2月13日;279(5353):1054-7),并且源自HMHA1(KIAA0223)基因(rs号:rs1801284)的等位基因(SNP变体)。HMHA1基因座包含两个等位基因HA-1H和HA-1R,其在两个核苷酸处不同,导致单个氨基酸替换。第二种九肽表位,即VLRDDLLEA(SEQ ID NO:4;Science1998年2月13日:第279卷,第5353期,第1054-1057页)由HLA-A*02:01低效呈递。由于等位基因多态性和孟德尔分离模式,个体可以是纯合子HA-1H/H、杂合子HA-1H/R或纯合子HA-1R/R。
发明内容
本发明的一个目的是提供与MiHA HA-1的仅一种等位基因变体特异性结合的T细胞受体。
本发明涉及对HA-1的仅一种等位基因形式(即HA-1H)具有特异性的T细胞受体(TCR)。在本发明的一个具体实施方案中,公开了对由HLA-A2分子或在HLA-A2分子的背景下呈递的HA-1H具有结合特异性的T细胞受体。本发明还涉及用于作为药物或用于在恶性肿瘤治疗中使用的的TCR。TCR可以用于例如其中BMT/HSCT患者的HA-1H等位基因(在合适的MHC/HLA分子上呈递肽VLHDDLLEA)是纯合的(即患者为HA-1H/H)或者是杂合的(即HA-1H/R)并且其中供体的R等位基因是纯合的(即HA-1R/R)的情况,并且一部分供体T细胞已经被分离并用本发明的TCR之一转导而因此表达对HA-1H等位基因具有特异性的TCR,并且其中将经转导的供体T细胞输注到患者体内,并且其中患者和供体是其他HLA相同或HLA匹配的。输注的表达HA-1H特异性TCR的重组供体T细胞检测并消除(通过细胞毒性活性)在合适的MHC/HLA分子的背景下表达HA-1H的患者任何残留造血肿瘤细胞。还设想了保存这样的HA-1H特异性供体T细胞以用于将来输注以能够耗竭在肿瘤复发期间再次出现的患者肿瘤细胞。本发明的另一方面是本发明TCR或表达本发明TCR的重组T细胞用于在计划进行BMT/HSCT的患者中进行预处理治疗的用途。通过这样使用本发明TCR或表达这种HA-1H特异性TCR的重组T细胞,可以通过输注这种重组T细胞来代替或支持亚致死辐射,由于本发明TCR的重组表达,该重组T细胞对患者的造血细胞具有同种异体反应性,并且因此可以根除在HLA-A2背景下呈递HA-1H的免疫细胞。T细胞可以源自BMT/HSCT的供体。
根据本发明的TCR是分离和/或纯化的,并且可以是可溶性的或膜结合的。
在一些实施方案中,TCR的氨基酸序列可以包含一个或多个表型沉默替换。另外,可以标记本发明的TCR。有用的标记是本领域已知的,并且可以使用常规方法任选地经由各种长度的接头与TCR或TCR变体偶联。术语“标记”或“标记基团”是指任何可检测标记。另外地或可替代地,可以对氨基酸序列进行修饰以包含治疗剂或药代动力学修饰部分。治疗剂可以选自由免疫效应分子、细胞毒剂和放射性核素组成的组。免疫效应分子可以例如是细胞因子。药代动力学修饰部分可以是至少一个聚乙二醇重复单元、至少一个二醇基团、至少一个唾液酸基团或其组合。
根据本发明的TCR,特别是可溶形式的TCR,可以通过连接另外的功能部分来进行修饰,例如用于降低免疫原性、增加流体动力学尺寸(溶液中的尺寸)、溶解度和/或稳定性(例如通过增强的对蛋白水解降解的保护)和/或延长血清半衰期。其它有用的功能部分和修饰包括“自杀”或“安全开关”,其可用于关闭或打开患者体内携带本发明TCR的效应宿主细胞。
本文还设想了具有改变的糖基化模式的TCR。
也可以考虑将药物或治疗实体(例如小分子化合物)添加至TCR,特别是可溶形式的本发明TCR。
TCR,特别是可溶形式的本发明TCR,可以另外被修饰以引入有助于鉴定、追踪、纯化和/或分离各个分子(标签)的另外的结构域。
在一些实施方案中,TCR是单链类型的,其中TCRα链和TCRβ链通过接头序列连接。
本发明的另一方面涉及包含如本文所述的TCR的功能部分的多肽,其中所述功能部分包含选自由以下SEQ ID NO组成的组的氨基酸序列中的至少一个:SEQ ID NO:7、SEQID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47、SEQ ID NO:57、SEQ ID NO:10、SEQID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50和SEQ ID NO:60。
在具体实施方案中,功能部分包含TCRα可变链和/或TCRβ可变链。
具体实施方案涉及包含至少两个如本文所述的TCR的多价TCR复合物。在一个更具体的实施方案中,所述TCR中至少一个与治疗剂缔合。
一些实施方案涉及在效应细胞上、特别是在免疫效应细胞上表达为功能性多肽或功能性多价多肽的本发明TCR,其中在与由HLA-A*02:01编码分子呈递的氨基酸序列SEQ IDNO:2结合之后,在上述表达TCR的效应细胞中诱导IFN-γ分泌。
其中由HLA-A*02:01编码分子呈递是指肽、特别是表位与MHC分子的结合沟结合。
呈递表位的MHC分子可以由HLA-A*02等位基因之一,例如由HLA-A*02:01或HLA-A*02:06等位基因,优选由HLA-A*02:01等位基因编码。
在10-7[M]的HA-1肽浓度下,通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的氨基酸序列SEQ ID NO:2结合而诱导的IFN-γ分泌可以是与由HLA-A*02:01编码分子呈递的SEQ ID NO:4结合而诱导的IFN-γ分泌的至少3倍高,例如10倍高、20倍高、100倍高。
因此,对于所有HA-1H-TCR转基因T细胞,为了识别HA-1R变体,需要与HA-1H相比至少1,000倍、优选至少5,000倍高、更优选至少8000倍高、最优选至少10,0000倍高的肽浓度。
在具体实施方案中,例如当TCR转基因T细胞与T2细胞的比例为2:1时,在10-7[M]的HA-1肽浓度下,通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的氨基酸序列SEQ ID NO:2结合而诱导的IFN-γ分泌可以大于500pg/ml,例如大于1000pg/ml、更优选大于2000pg/ml、最优选大于3000pg/ml。
细胞因子和趋化因子释放(例如IFN-γ分泌)可以如下测量:通过体外测定使用固定有T细胞抗体的磁珠,其中将经转导以分别表达SEQ ID NO:2或SEQ ID NO:4的氨基酸序列的K562细胞(Greiner等人.2006,Blood.2006Dec 15;108(13):4109-17)与表达待研究的TCR的CD8+富集和/或非CD8+富集PBMC一起孵育,或者在体外测定中使用在外部负载有VLHDDLLEA肽(SEQ ID NO:2)或肽VLRDDLLEA(例如肽SEQ ID NO:4)的T2细胞并且随后与表达待研究的TCR的CD8+富集和/或非CD8+富集PBMC共孵育。
本发明的另一方面涉及编码如本文所述的TCR或编码如上所述的多肽的核酸。
本发明的另一方面涉及包含如上所述的本申请核酸的质粒或载体。优选地,载体是表达载体或适合于细胞特别是真核细胞的转导或转染的载体。载体可以是例如逆转录病毒载体(例如γ-逆转录病毒)或慢病毒载体。
本发明的另一方面涉及表达如本文所述的TCR的细胞。细胞可以是分离的或非天然存在的。
本发明的另一方面涉及包含如上所述的核酸或如上所述的质粒或载体的细胞。更具体地,细胞可以包含:
a)包含至少一种如上所述的核酸的表达载体,或
b)包含编码如本文所述的TCR的α链的核酸的第一表达载体,和包含编码如本文所述的TCR的β链的核酸的第二表达载体。
细胞可以是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。通常,细胞是免疫效应细胞,尤其是T细胞。其它合适的细胞类型包括γ-δT细胞、NK细胞和NK样T细胞。
另一方面涉及与如本文所述的TCR的一部分特异性结合的抗体或其抗原结合片段,所述部分介导对HA-1H的特异性。在一个具体实施方案中,TCR的介导HA-1H特异性的部分包含SEQ ID NO:7、SEQ ID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47、SEQ IDNO:57的α链CDR3,和/或SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQID NO:50和SEQ ID NO:60的β链CDR3。
本发明的另一方面涉及药物组合物,包含如本文所述的TCR、如本文所述的多肽、如本文所述的多价TCR复合物、如本文所述的核酸、如本文所述的载体、如本文所述的细胞、或如本文所述的抗体。
通常,药物组合物包含至少一种药学上可接受的载体。
本发明的另一方面涉及如本文所述的TCR、如本文所述的多肽、如本文所述的多价TCR复合物、如本文所述的核酸、如本文所述的载体、如本文所述的细胞、或如本文所述的用于作为药物的抗体,特别是用于在治疗癌症(特别是在治疗HLA匹配的骨髓和/或干细胞移植的情况下的血液学癌症)中使用的抗体,其中患者先前已接受了来自HLA匹配的供体的同种异体骨髓和/或干细胞移植,其中供体为HA-1H阴性(并且因此为HA-1R纯合和/或HLA-A2阴性),并且其中患者(是纯合HA-1H或杂合HA-1H/R并且HLA-A2阳性)患有血液学癌细胞的复发或再现,或者作为预防措施(在移植后没有复发/再现的迹象的情况下治疗患者)。通过从患者或供体在移植后分离CD8+T细胞并且用根据本发明的TCR离体转导这种分离的CD8+T细胞来治疗患有血液学癌细胞的复发的患者。血液学癌症可以选自由以下组成的组:非霍奇金淋巴瘤(NHL)、霍奇金淋巴瘤(HL)、多发性骨髓瘤、急性髓细胞性白血病(AML)和急性淋巴母细胞性白血病(ALL)、混合表型急性白血病(MPAL)、慢性髓细胞性白血病(CML)、B细胞多形性淋巴瘤、毛细胞白血病、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、中枢神经系统淋巴瘤、CD37+树突状细胞淋巴瘤、淋巴母细胞性淋巴瘤、脾边缘区淋巴瘤、浆细胞骨髓瘤、骨外浆细胞瘤、黏膜相关淋巴组织(MALT组织)的结外边缘区B细胞淋巴瘤、结边缘区B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、前体B淋巴母细胞性淋巴瘤、免疫母细胞性大细胞淋巴瘤、血管内大B细胞淋巴瘤、原发渗出性淋巴瘤、伯基特淋巴瘤/白血病、恶性潜能不明的B细胞增殖、淋巴瘤样肉芽肿病、移植后淋巴组织增生性疾病。其它血液学癌症或疾病包括骨髓增生异常。
附图说明
图1示出了用不同的HA-1H-反应性TCR转导的CD8+T细胞的HA-1H-MHC-多聚体结合。从健康供体的PBMC中分离CD8 T细胞,并且用六种不同的HA-1H-TCR和一种不能识别HA-1H的对照TCR进行转导。使用鼠源恒定β区作为转导标志物,通过FACS富集转导的CD8 T细胞。在这些细胞扩增后,将其用HA-1H-MHC多聚体和针对CD8和鼠源恒定β区(mCb)的抗体染色,并且通过流式细胞术进行分析。在活CD8+/mCb+细胞上对群体进行门控,并且示出了多聚体/CD8的染色。
图2表明HA-1H-TCR-转基因T细胞识别HLA-A2上呈递的HA-1H-肽。将转基因T细胞与外部负载有HA-1H-肽的T2细胞或已经用编码HA-1H-表位的HMHA1基因的部分转导的K562/HLA-A2细胞共培养。作为阴性对照,分别使用负载有对照肽的T2细胞和未转导的K562/HLA-A2细胞。通过用标准ELISA测量共培养物上清液中的IFN-γ浓度来分析靶细胞的识别。
图3A和3B示出了HA-1H-TCR-转基因T细胞的功能性亲合力。(A)将转基因T细胞与外部负载有分级浓度的HA-1H-肽(10-11M-10-5M)或HA-1R-肽(10-8M-10-5M)的T2细胞共培养。(B)将HA-1H-TCR转基因T细胞针对HA-1R-肽的功能性亲合力与如WO2018058002A1中所述用HA-1特异性TCR(TCR2)转导的T细胞进行比较。根据本发明的TCR 1-6(TCR_1、TCR_2、TCR_3、TCR_4、TCR_5、TCR_6)的数据在图3A和3B中相同。
图4A和4B示出了HA-1H-TCR转基因T细胞识别未修饰的靶细胞上生理水平的HA-1H的能力。将转基因T细胞与不同的淋巴母细胞系(LCL)共培养,所述细胞系是HA-1H阳性(LCL1-5)或HA-1H阴性(LCL 6-7)。(A)通过用标准ELISA测量共培养物上清液中的IFN-γ浓度来分析细胞因子释放。表达对照TCR的T细胞用作阴性对照。(B)通过每两小时对共培养物拍照来以ZOOM(Essen BioScience)测量针对用荧光标志物稳定转导的LCL的细胞毒性。未转导的CD8 T细胞用作阴性对照。
图5A和5B示出了HA-1H-TCR转基因T细胞识别肿瘤细胞系上存在的HA-1H的能力。将转基因T细胞与不同的HA-1H阳性肿瘤细胞系共培养。(A)通过用标准ELISA测量共培养物上清液中的IFN-γ浓度来分析细胞因子释放。(B)通过每两个小时拍照来利用ZOOM测量针对用荧光标志物稳定转导的肿瘤细胞系的细胞毒性。
图6A和6B示出了与如WO2018058002A1中所述的TCR2相比,表达TCR_3或TCR_4的T细胞识别和裂解(杀伤)HA-1H阳性肿瘤细胞系的能力。(A)将转基因T细胞与不同的HA-1H阳性肿瘤细胞系共培养。通过用标准ELISA测量共培养物上清液中的IFN-γ浓度来分析细胞因子释放。(B)通过流式细胞术分析针对HA-1H阳性肿瘤细胞系的细胞毒性。将HA-1H阴性/GFP阳性K562细胞与肿瘤细胞系的HA-1H阳性/mCherry阳性细胞以1:1的比率混合,并且与TCR转基因T细胞共培养。45小时之后计算mCherry阳性(HA-1H阳性)与GFP阳性(HA-1H阴性)细胞的比率,并且相对于对照TCR测量的比率进行归一化。较小的数字表明由于T细胞的细胞毒性的HA-1H阳性肿瘤细胞裂解。
图7示出了与如WO2018058002A1中所述的TCR2相比,TCR_3和TCR_4的识别基序的分析。将转基因T细胞与外部负载有HA-1H肽的T2细胞共培养,转基因T细胞具有每个单独的氨基酸残基被丝氨酸相继替换的肽或对照肽。
图8A和8B示出了不同恒定TCR区的比较。利用鼠源、最小鼠源化或人的恒定TCR区克隆TCR_3。(A)将转基因T细胞与不同的HA-1H阳性肿瘤细胞系共培养。通过使用标准ELISA测量共培养物上清液中的IFN-γ浓度来分析细胞因子释放。通过流式细胞术分析针对HA-1H阳性肿瘤细胞系的细胞毒性。将HA-1H阴性/GFP阳性K562细胞与肿瘤细胞系的HA-1H阳性/mCherry阳性细胞以1:1的比率混合,并且与TCR转基因T细胞共培养。45小时后,计算mCherry阳性(HA-1H阳性)细胞与GFP阳性(HA-1H阴性)细胞的比率,并且相对于对照TCR测量的比率进行归一化。较小的数字表示HA-1H阳性肿瘤细胞的裂解。(B)将转基因T细胞与不同的HA-1H阴性(OMW、BER)和HA-1H阳性(FH22、SLE005、SPO-010、BM16、BSM)LCL(淋巴母细胞系)共培养。通过用标准ELISA测量共培养物上清液中的IFN-γ浓度来分析细胞因子释放。
具体实施方式
在关于一些优选实施方案详细描述本发明之前,提供以下一般定义。
如以下说明性地描述的本发明可以在不存在本文未具体公开的任何一个或多个元素、一个或多个限制的情况下适当地实践。
将针对特定实施方案并参考某些附图来描述本发明,但是本发明不限于此,而是仅由权利要求书限定。
在本说明书和权利要求书中使用术语“包含/包括”时,其不排除其它元素。为了本发明的目的,术语““由...组成”被认为是术语“包含/包括”的优选实施方案。如果在下文中将组限定为包含至少一定数量的实施方案,则还应理解公开了优选仅由这些实施方案组成的组。
为了本发明的目的,术语“获得”被认为是术语“可获得”的优选实施方案。如果在下文中例如将抗体定义为从特定来源可获得,则也应理解为公开了从该来源获得的抗体。
当提及单数名词使用不定冠词或定冠词(例如“a”、“an”或“the”)时,除非特别说明,否则该词包括该名词的复数形式。在本发明的上下文中,术语“约”或“大约”表示本领域技术人员将理解为仍确保所讨论特征的技术效果的精度范围。该术语通常表示与所示数值的偏差为±10%,优选±5%。
技术术语以其对于本领域技术人员的常识或含义使用。如果将特定含义传达给某些术语,则将在以下使用术语的上下文中给出术语的定义。
TCR背景
TCR由两条不同且分开的蛋白质链(即TCR alpha(α)和TCR beta(β)链)构成。TCRα链包含可变区(V)、连接区(J)和恒定区(C)。TCRβ链包含可变区(V)、多变区(D)、连接区(J)和恒定区(C)。TCRα链和TCRβ链二者的重排V(D)J区包含高变区(CDR,互补决定区),其中CDR3区决定了特异性表位识别。在C末端区域,TCRα链和TCRβ链均包含疏水性跨膜结构域,并且在短的胞质尾区终止。
通常,TCR是一个α链和一个β链的异二聚体。该异二聚体可以与呈递肽的MHC分子结合。
在本发明的上下文中,术语“可变TCRα区”或“TCRα可变链”或“可变结构域”是指TCRα链的可变区。在本发明的上下文中,术语“可变TCRβ区”或“TCRβ可变链”是指TCRβ链的可变区。
使用国际免疫遗传学(IMGT)TCR命名法(IMGT数据库,www.IMGT.org;Giudicelli,V.,等人,IMGT/LIGM-DB,免疫球蛋白和T细胞受体核苷酸序列的综合数据库,Nucl.Acids Res.,34,D781-D784(2006).PMID:16381979;T cell Receptor Factsbook,LeFranc and LeFranc,Academic Press ISBN 0-12-441352-8)对TCR基因座和基因进行命名。
靶标
本发明的第一方面涉及对HA-1的一种等位基因变体具有特异性的分离的TCR。该等位基因变体是单核苷酸多态性类型。
特别地,TCR特异性识别SEQ ID NO:2的氨基酸序列(VLHDDLLEA)。
通常,TCR识别被主要组织相容性复合物(MHC)分子呈递的抗原的肽片段。
人白细胞抗原(HLA)系统或复合物是人体中编码主要组织相容性复合物(MHC)蛋白的基因复合物。HLA-A*02是HLA-A基因座处的一个具体的I类主要组织相容性复合物(MHC)等位基因组。HLA-A*02:01是特定的HLA-A*02亚等位基因。
因此,在具体实施方案中,TCR特异性识别SEQ ID NO:2的氨基酸序列,该氨基酸序列由HLA-A*02等位基因编码的MHC分子、优选由HLA-A*02:01编码的分子或HLA-A*02:06编码的分子、更优选由HLA-A02:01编码的分子呈递。
TCR对HA-1H具有高度特异性,并且对其它肽特别是等位基因变异HA-1R基本上没有交叉反应。这意味着其不识别HA-1等位基因变异。换句话说,其不识别SEQ ID NO:4的氨基酸序列。交叉反应性可以通过如本文所述的IFN-γ分泌来测量。
在本发明的上下文中,术语“特异性(specific for)”是指TCR与靶标特异性结合。
本文使用的术语“等位基因变异”和“等位基因形式”是相同的。
在优选的实施方案中,TCR的识别基序至少包含SEQ ID NO:127所示的序列。在具体实施方案中,TCR的识别基序由SEQ ID NO:127所示的序列组成。其中识别基序可以通过丝氨酸替换来确定。
识别基序限定影响TCR活化的表位的氨基酸,例如在IFN-γ分泌测定中确定的。特别地,结合表位中氨基酸残基的影响可以通过氨基酸替换扫描,例如丝氨酸扫描来确定。
在丝氨酸扫描中,使用每个单独氨基酸残基被丝氨酸相继替换的表位肽。如果肽导致TCR活化显著降低,例如通过IFN-γ分泌确定的,则表明被替换的位置属于识别基序。显著降低可以是与未替换的肽序列(即未替换的表位)相比的至少3倍、优选至少5倍、更优选至少10倍的IFN-γ分泌降低。
TCR特异性序列
TCR的TCRα链CDR3可具有选自由以下组成的组的氨基酸序列:SEQ ID NO:7、SEQID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47和SEQ ID NO:57。
TCR的TCRβ链CDR3可具有选自由以下组成的组的氨基酸序列:SEQ ID NO:10、SEQID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50和SEQ ID NO:60。
一些实施方案涉及包含TCRα链和TCRβ链的分离的TCR,其中
a)-TCRα链包含具有SEQ ID NO:7的序列的互补决定区3(CDR3),
-TCRβ链包含具有SEQ ID NO:10的氨基酸序列的CDR3;或
b)-TCRα链包含具有SEQ ID NO:17的序列的CDR3,
-TCRβ链包含具有SEQ ID NO:20的氨基酸序列的CDR3;或
c)-TCRα链包含具有SEQ ID NO:27的序列的CDR3,
-TCRβ链包含具有SEQ ID NO:30的氨基酸序列的CDR3;或
d)-TCRα链包含具有SEQ ID NO:37的序列的CDR3,
-TCRβ链包含具有SEQ ID NO:40的氨基酸序列的CDR3;或
e)-TCRα链包含具有SEQ ID NO:47的序列的CDR3,
-TCRβ链包含具有SEQ ID NO:50的氨基酸序列的CDR3;或
f)-TCRα链包含具有SEQ ID NO:57的序列的CDR3,
-TCRβ链包含具有SEQ ID NO:60的氨基酸序列的CDR3。
更具体的实施方案涉及分离的TCR,其中TCR包含:
a)-TCRα链,包含具有SEQ ID NO:5的氨基酸序列的CDR1,具有SEQ ID NO:6的氨基酸序列的CDR 2和具有SEQ ID NO:7的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:8的氨基酸序列的CDR1,具有SEQ ID NO:9的氨基酸序列的CDR 2和具有SEQ ID NO:10的序列的CDR 3;或
b)-TCRα链,包含具有SEQ ID NO:15的氨基酸序列的CDR1,具有SEQ ID NO:16的氨基酸序列的CDR 2和具有SEQ ID NO:17的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:18的氨基酸序列的CDR1,具有SEQ ID NO:19的氨基酸序列的CDR 2和具有SEQ ID NO:20的序列的CDR 3;或
c)-TCRα链,包含具有SEQ ID NO:25的氨基酸序列的CDR1,具有SEQ ID NO:26的氨基酸序列的CDR 2和具有SEQ ID NO:27的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:28的氨基酸序列的CDR1,具有SEQ ID NO:29的氨基酸序列的CDR 2和具有SEQ ID NO:30的序列的CDR 3;
d)-TCRα链,包含具有SEQ ID NO:35的氨基酸序列的CDR1,具有SEQ ID NO:36的氨基酸序列的CDR 2和具有SEQ ID NO:37的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:38的氨基酸序列的CDR1,具有SEQ ID NO:39的氨基酸序列的CDR 2和具有SEQ ID NO:40的序列的CDR 3;或
e)-TCRα链,包含具有SEQ ID NO:45的氨基酸序列的CDR1,具有SEQ ID NO:46的氨基酸序列的CDR 2和具有SEQ ID NO:47的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:48的氨基酸序列的CDR1,具有SEQ ID NO:49的氨基酸序列的CDR 2和具有SEQ ID NO:50的序列的CDR 3;或
f)-TCRα链,包含具有SEQ ID NO:55的氨基酸序列的CDR1,具有SEQ ID NO:56的氨基酸序列的CDR 2和具有SEQ ID NO:57的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:58的氨基酸序列的CDR1,具有SEQ ID NO:59的氨基酸序列的CDR 2和具有SEQ ID NO:60的序列的CDR 3。
优选的实施方案涉及由CDR、特别是由如上所述的TCRα链和TCRβ链的CDR 3限定的分离的TCR,其中重组TCR序列被修饰为包含鼠源化Cα区和Cβ区。
一些实施方案涉及分离的TCR,其中所述TCR包含
a)具有与SEQ ID NO:11至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:12至少80%相同的氨基酸序列的可变TCRβ区;或
b)具有与SEQ ID NO:21至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:22至少80%相同的氨基酸序列的可变TCRβ区;或
c)具有与SEQ ID NO:31至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:32至少80%相同的氨基酸序列的可变TCRβ区;或
d)具有与SEQ ID NO:41至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:42至少80%相同的氨基酸序列的可变TCRβ区;或
e)具有与SEQ ID NO:51至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:52至少80%相同的氨基酸序列的可变TCRβ区;或
f)具有与SEQ ID NO:61至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:62至少80%相同的氨基酸序列的可变TCRβ区。
如本文所用,“至少80%相同”,特别是“具有至少80%相同的氨基酸序列”包括氨基酸序列与示出的氨基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。
在一些实施方案中,TCR包含TCRα链和TCRβ链,其中
a)-可变TCRα区具有与SEQ ID NO:11至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:7所示氨基酸序列的CDR3区,
-可变TCRβ区具有与SEQ ID NO:12至少80%相同的氨基酸序列,并且包含具有SEQID NO:10所示氨基酸序列的CDR3区;或
b)-可变TCRα区具有与SEQ ID NO:21至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:17所示氨基酸序列的CDR3区,
-可变TCRβ区具有与SEQ ID NO:22至少80%相同的氨基酸序列,并且包含具有SEQID NO:20所示的氨基酸序列的CDR3区;或
c)-可变TCRα区具有与SEQ ID NO:31至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:27所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:32至少80%相同的氨基酸序列,并且包含具有SEQID NO:30所示氨基酸序列的CDR3区;或
d)-可变TCRα区具有与SEQ ID NO:41至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:37所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:42至少80%相同的氨基酸序列,并且包含具有SEQID NO:40所示氨基酸序列的CDR3区;或
e)-可变TCRα区具有与SEQ ID NO:51至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:47所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:52至少80%相同的氨基酸序列,并且包含具有SEQID NO:50所示氨基酸序列的CDR3区;或
f)-可变TCRα区具有与SEQ ID NO:61至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:57所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:62至少80%相同的氨基酸序列,并且包含具有SEQID NO:60所示氨基酸序列的CDR3区。
示例性实施方案涉及分离的TCR,其中所述TCR包含
a)具有SEQ ID NO:11的氨基酸序列的可变TCRα区和具有SEQ ID NO:12的氨基酸序列的可变TCRβ区;或
b)具有SEQ ID NO:21的氨基酸序列的可变TCRα区和具有SEQ ID NO:22的氨基酸序列的可变TCRβ区;或
c)具有SEQ ID NO:31的氨基酸序列的可变TCRα区和具有SEQ ID NO:32的氨基酸序列的可变TCRβ区;或
d)具有SEQ ID NO:41的氨基酸序列的可变TCRα区和具有SEQ ID NO:42的氨基酸序列的可变TCRβ区;或
e)具有SEQ ID NO:51的氨基酸序列的可变TCRα区和具有SEQ ID NO:52的氨基酸序列的可变TCRβ区;或
f)具有SEQ ID NO:61的氨基酸序列的可变TCRα区和具有SEQ ID NO:62的氨基酸序列的可变TCRβ区。
下表示出本发明的示例性TCR的概述。
表1:本发明的示例性TCR的概述
TCR | CDR1_α | CDR2_α | CDR3_α | TRAV | TRAJ | CDR1_β | CDR2_β | CDR3_β | TRBV | TRBJ |
1 | DSASNY | IRSNVGE | CAASDLNF | 13-1 | 41 | SEHNR | FQNEAQ | CASSLVSRVDGYTF | 7-9 | 1-2 |
2 | DSASNY | IRSNVGE | CAAHTPGYSTLTF | 13-1 | 11 | SEHNR | FQNEAQ | CASSPRAGGETQYF | 7-9 | 2-5 |
3 | TSINN | IRSNERE | CATGDQTGANNLFF | 17 | 36 | SEHNR | FQNEAQ | CASSLTRTEKLFF | 7-9 | 1-4 |
4 | DSASNY | IRSNVGE | CAGRGKLTF | 13-1 | 48 | SEHNR | FQNEAQ | CASSLVRDEKLFF | 7-9 | 1-4 |
5 | SVFSS | VVTGGEV | CAGAGNNDMRF | 27 | 43 | SEHNR | FQNEAQ | CASSLVRGIEAFF | 7-9 | 1-1 |
6 | DSSSTY | IFSNMDM | CAEKWIIF | 5 | 30 | SEHNR | FQNEAQ | CASSLTTPDGYTF | 7-9 | 1-2 |
从实例中可以看出,根据本发明的TCR对HA-1H具有特异性,并且对其它表位或抗原仅表现出非常低的交叉反应性。
优选使用Vector NTI AdvanceTM 10程序(Invitrogen Corporation,CarlsbadCA,USA)的AlignX应用完成多个序列之间同一性百分比的确定。该程序使用改进的ClustalW算法(Thompson等人,1994.Nucl Acids Res.22:第4673-4680页;InvitrogenCorporation;Vector NTI AdvanceTM 10 DNA and protein sequence analysissoftware.User’s Manual,2004,第389-662页)。同一性百分比的确定是使用AlignX应用的标准参数执行的。
根据本发明的TCR是分离的或纯化的。在本发明的上下文中,“分离的”是指TCR不存在于其在自然界中天然存在的环境中。在本发明的上下文中,“纯化的”是指例如TCR不含或基本上不含其最初来源的细胞的其它蛋白质和非蛋白质部分。
在一些实施方案中,TCR的氨基酸序列可以包含一个或多个表型沉默替换。
“表型沉默替换”也称为“保守氨基酸替换”。“保守氨基酸替换”的概念是本领域技术人员理解的,并且优选地是指编码带正电残基(H、K和R)的密码子被替换为编码带正电残基的密码子,编码带负电残基(D和E)的密码子被替换为编码带负电残基的密码子,编码中性极性残基(C、G、N、Q、S、T和Y)的密码子被替换为编码中性极性残基的密码子,并且编码中性非极性残基(A、F、I、L、M、P、V和W)的密码子被替换为编码中性非极性残基的密码子。这些变异可以自发发生,通过随机诱变引入,或可以通过定向诱变引入。可以进行这些变化而不破坏这些多肽的本质特征。普通技术人员可以通过本领域已知的方法容易且常规地筛选氨基酸变体和/或编码它们的核酸,以确定这些变体是否实质上降低或破坏配体结合能力。
技术人员理解,也可以对编码TCR的核酸进行修饰。整个核酸序列的有用修饰包括序列的密码子优化。可以进行导致表达的氨基酸序列内的保守替换的改变。可以在TCR链氨基酸序列的互补决定区和非互补决定区中做出不影响功能的这些改变。通常,不应在CDR3区中进行添加和缺失。
根据本发明的一些实施方案,对TCR的氨基酸序列进行修饰以包含可检测标记、治疗剂或药代动力学修饰部分。
可检测的标记的非限制性实例是放射性标记、荧光标记、核酸探针、酶和造影剂。可以与TCR缔合的治疗剂包括放射性化合物、免疫调节剂、酶或化学治疗剂。治疗剂可以用与TCR连接的脂质体包裹,使得化合物可以在靶部位缓慢释放。这将避免在体内运输过程中的损坏,并且确保在TCR与相关抗原呈递细胞结合后治疗剂(例如毒素)具有最大效果。治疗剂的其它实例是:
肽细胞毒素,即具有杀伤哺乳动物细胞的能力的蛋白质或肽,例如蓖麻毒蛋白、白喉毒素、假单胞菌细菌外毒素A、DNase和RNase。小分子细胞毒剂(即具有杀伤哺乳动物细胞的能力的化合物)的分子量小于700道尔顿。这样的化合物可以包含能够具有细胞毒性作用的有毒金属。此外,应当理解,这些小分子细胞毒剂还包括前药,即在生理条件下降解或转化以释放细胞毒剂的化合物。这样的药剂可以例如包括多西他赛、吉西他滨、顺铂、美登素衍生物、rachelmycin、加利车霉素(calicheamicin)、依托泊苷、异环磷酰胺、伊立替康、卟吩姆钠光敏素II(porfimer sodium photofrin II)、替莫唑胺、托泊替康、葡糖醛酸三甲曲沙(trimetrexate glucoronate)、米托蒽醌、澳瑞他汀E(auristatin E)、长春新碱和多柔比星;放射性核素,例如碘131、铼186、铟111、钇90、铋210和213、锕225和砹213。放射性核素与TCR或其衍生物的缔合可以例如通过螯合剂来进行;免疫刺激剂(immunostimulator),也称为免疫刺激剂(immunostimulant),即刺激免疫反应的免疫效应分子。示例性的免疫刺激剂是细胞因子如IL-2和IFN-γ,抗体或其片段,包括抗T细胞或NK细胞决定簇抗体(例如抗CD3、抗CD28或抗CD16);具有抗体样结合特性的替代蛋白支架;超抗原,即引起T细胞非特异性活化从而导致多克隆T细胞活化和大量细胞因子释放的抗原,及其突变体;趋化因子,如IL-8、血小板因子4、黑色素瘤生长刺激蛋白等;补体激活剂;异种蛋白结构域、同种异体蛋白结构域、病毒/细菌蛋白结构域、病毒/细菌肽。
人T淋巴细胞上的抗原受体分子(T细胞受体分子)与细胞表面的CD3(T3)分子复合物非共价缔合。这种复合物与抗CD3单克隆抗体的扰乱会诱导T细胞活化。因此,一些实施方案涉及与抗CD3抗体或所述抗CD3抗体的功能片段或变体缔合(通常通过与α或β链的N或C末端融合)的如本文所述的TCR。适用于本文所述的组合物和方法的抗体片段和变体/类似物包括微型抗体(minibody)、Fab片段,F(ab<'>)2片段、dsFv和scFv片段,纳米抗体TM(Ablynx(Belgium),包含源自骆驼科(例如骆驼或大羊驼)抗体的合成单免疫球蛋白可变重链结构域的分子)和结构域抗体(Domain Antibodies)(包含亲合力成熟的单个免疫球蛋白可变重链结构域或免疫球蛋白可变轻链结构域(Domantis(Belgium))或表现出抗体样结合特性的替代蛋白支架,例如Affibodies(包含工程化的蛋白A支架Affibody(瑞典))或Anticalins(包含工程化的anticalins Pieris(德国))。
治疗剂可优选地选自由免疫效应分子、细胞毒剂和放射性核素组成的组。优选地,免疫效应分子是细胞因子。
药代动力学修饰部分可以是例如至少一个聚乙二醇重复单元、至少一个二醇基团、至少一个唾液酸基团或其组合。至少一个聚乙二醇重复单元、至少一个二醇基、至少一个唾液酸基团的缔合可以通过本领域技术人员已知的多种方式来引起。在一个优选的实施方案中,这些单元与TCR共价连接。可以通过一个或数个药代动力学修饰部分来修饰根据本发明的TCR。特别地,通过一个或数个药代动力学修饰部分来修饰TCR的可溶形式。药代动力学修饰部分可以实现治疗剂的药代动力学特性的有益变化,例如改善的血浆半衰期、降低或增强的免疫原性和改善的溶解度。
根据本发明的TCR可以是可溶性的或膜结合的。术语“可溶性”是指呈可溶形式(即不具有跨膜结构域或胞质结构域)的TCR,例如用作将治疗剂递送至抗原呈递细胞的靶向剂。为了稳定,可溶性αβ异二聚体TCR优选在相应恒定结构域的残基之间具有引入的二硫键,例如在WO 03/020763中所述。本发明的αβ异二聚体中存在的恒定结构域的一者或二者可以在C末端或C端截短,例如至多15个、至多10个或至多8个或更少的氨基酸。为了用于过继疗法中,αβ异二聚体TCR可以例如被转染为具有胞质结构域和跨膜结构域二者的全长链。TCR可包含对应于在自然界中发现的相应的α和β恒定结构域之间的二硫键,另外或可替代地,可存在非天然二硫键。
因此,TCR,特别是可溶形式的根据本发明的TCR,可以通过连接另外的功能部分来修饰,例如用于降低免疫原性,增加流体动力学尺寸(溶液中的尺寸)、溶解度和/或稳定性(例如通过增强的对蛋白水解降解的保护)和/或延长血清半衰期。
其它有用的功能部分和修饰包括“自杀”或“安全开关”,其可用于关闭在患者体内携带本发明TCR的效应宿主细胞。一个实例是Gargett和Brown Front Pharmacol.2014;5:235描述的诱导型Caspase 9(iCasp9)“安全开关”。简单地说,通过周知的方法对效应宿主细胞进行修饰以表达Caspase 9结构域,其二聚作用依赖于小分子二聚剂药物,例如AP1903/CIP,并且导致在修饰的效应细胞中快速诱导凋亡。该系统例如在EP2173869(A2)中描述。其它“自杀”“安全开关”的实例在本领域中是已知的,例如单纯疱疹病毒胸苷激酶(HSV-TK)、CD20的表达以及随后使用抗CD20抗体的耗竭、截短EGFR的表达以及随后使用抗EGFR抗体的耗竭(Wang等人,Blood,2011年8月4日;118(5):1255-63),或myc标签(Kieback等人,Proc Natl Acad Sci USA.2008年1月15日;105(2):623-8)。
本文还设想了糖基化模式改变的TCR。如本领域中已知的,糖基化模式可以取决于氨基酸序列(例如,以下讨论的具体糖基化氨基酸残基的存在或不存在)和/或产生蛋白质的宿主细胞或生物体。多肽的糖基化通常是N-连接或O-连接的。N-连接是指碳水化合物部分连接至天冬酰胺残基的侧链。通过改变氨基酸序列以使其包含一个或多个选自天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X为除脯氨酸外的任何氨基)的三肽序列,方便地实现了将N-连接的糖基化位点添加至结合分子。可以通过在起始序列添加或替换为一个或多个丝氨酸或苏氨酸残基来引入O-连接的糖基化位点。
TCR的糖基化的另一种方法是通过将糖苷与蛋白质化学或酶促偶联。取决于所使用的偶联方式,一个或多个糖可以连接至:(a)精氨酸和组氨酸,(b)游离羧基,(c)游离巯基,例如半胱氨酸的那些,(d)游离羟基,例如丝氨酸、苏氨酸或羟脯氨酸的那些,(e)芳香族残基,例如苯丙氨酸、酪氨酸或色氨酸的那些,或(f)谷氨酰胺的酰胺基。类似地,去糖基化(即,去除结合分子上存在的碳水化合物部分)可以化学地实现,例如通过将TCR暴露于三氟甲磺酸,或者通过采用内切糖苷酶和外切糖苷酶酶促地实现。
也可以考虑向TCR、特别是可溶形式的本发明TCR添加药物,例如小分子化合物。可以通过共价键或非共价相互作用(例如通过静电力)实现连接。为了形成药物缀合物,可以使用本领域已知的各种接头。
TCR,特别是可溶形式的本发明TCR,可以另外被修饰以引入有助于鉴定、追踪、纯化和/或分离各个分子(标签)的另外的结构域。因此,在一些实施方案中,可以对TCRα链或TCRβ链进行修饰以包含表位标签。
表位标签是可以合并至本发明TCR的标签的有用实例。表位标签是短的氨基酸片段,其允许结合特异性抗体并且因此能够鉴定和追踪患者体内可溶性TCR或宿主细胞的结合和运动或培养的(宿主)细胞。可以使用多种不同的技术来实现表位标签并且因此标签化的TCR的检测。
通过在存在对所述标签具有特异性的结合分子(抗体)的情况下培养细胞,可以进一步将标签用于刺激和扩增携带本发明TCR的宿主细胞。
通常,在一些情况下,可以将TCR修饰为具有多种突变,这些突变改变TCR与靶标抗原的亲合力和解离速率。特别地,突变可以增加亲合力和/或降低解离速率。因此,TCR可以在至少一个CDR及其可变结构域框架区中突变。
然而,在一个优选实施方案中,没有对TCR的CDR区进行修饰或体外亲合力成熟,例如对于实施例中的TCR受体。这意味着CDR区具有天然存在的序列。这可能是有利的,因为体外亲合力成熟可能导致对TCR分子的免疫原性。这可能导致使疗效和治疗降低或失活的抗药抗体产生和/或引起不良反应。
突变可以是一个或多个替换、缺失或插入。这些突变可以通过本领域已知的任何合适的方法来引入,例如聚合酶链式反应、基于限制性酶的克隆、不依赖连接的克隆程序,其在例如Sambrook,Molecular Cloning–第4版(2012)Cold Spring Harbor LaboratoryPress中描述。
从理论上讲,由于内源TCR链和外源TCR链之间的错配,可能发生具有交叉反应风险的不可预测的TCR特异性。为避免TCR序列错配,可对重组TCR序列进行修饰以包含鼠源化Cα区和Cβ区,该技术已被表明有效增强多种不同转导的TCR链的正确配对。TCR的鼠源化(即通过其鼠源对应物交换α链和β链中的人恒定区)是一种普遍使用的技术,用于改善TCR在宿主细胞中的细胞表面表达。不希望受特定理论的束缚,认为鼠源化TCR更有效地与CD3共受体缔合;和/或优先彼此配对并且更不易在离体遗传修饰的人T细胞上形成混合的TCR,以表达具有期望抗原特异性的TCR,但仍保留并表达其“原始”(即内源)TCR。已经鉴定了负责改善鼠源化TCR表达的九个氨基酸(Sommermeyer和Uckert,J Immunol.2010年6月1日;184(11):6223-31),并且设想了将TCRα和/或β链恒定区中氨基酸残基的至少一个或全部替换为其鼠源对应物残基。该技术也称为“最小鼠源化”,并且提供了增强细胞表面表达而同时降低氨基酸序列中“外来”氨基酸残基的数量并且因此降低免疫原性的风险的优点。因此,在一些实施方案中,可以对TCR序列进行修饰以包含最小鼠源化Cα区和Cβ区。
一些实施方案涉及如本文所述的分离的TCR,其中TCR是单链类型,其中TCRα链和TCRβ链通过接头序列连接。
合适的单链TCR形式包含由对应于可变TCRα区的氨基酸序列构成的第一区段,由对应于可变TCRβ区的氨基酸序列构成的第二区段,可变TCRβ区与对应于TCRβ链恒定区胞外序列的氨基酸序列的N末端融合,以及将第一区段的C末端连接至第二区段的N末端的接头序列。或者,第一区段可以由对应于TCRβ链可变区的氨基酸序列构成,第二区段可以由应于TCRα链可变区序列的氨基酸序列构成,TCRα链可变区序列与对应于TCRα链恒定区胞外序列的氨基酸序列的N末端融合。上述单链TCR可进一步在第一链和第二链之间包含二硫键,并且其中接头序列的长度和二硫键的位置使得第一区段和第二区段的可变结构域序列基本上如天然TCR中那样相互取向。更具体地,第一区段可以由对应于TCRα链可变区序列的氨基酸序列构成,TCRα链可变区序列与对应于TCRα链恒定区胞外序列的氨基酸序列的N末端融合,第二区段可以由对应于TCRβ可变区的氨基酸序列构成,TCRβ可变区与对应于TCRβ链恒定区胞外序列的氨基酸序列的N末端融合,并且可以在第一链和第二链之间提供二硫键。接头序列可以是不损害TCR功能的任何序列。
在本发明的上下文中,“功能性”TCRα和/或β链融合蛋白应指至少保持基本生物学活性的TCR或TCR变体,例如通过氨基酸的添加、缺失或替换进行修饰。对于TCR的α和/或β链,这意味着两条链都仍然能够形成T细胞受体(具有未经修饰的α链和/或β链或者具有另一种本发明的融合蛋白α链和/或β链),其发挥它的生物学功能,特别是与所述TCR的特定肽-MHC复合物结合,和/或在特定肽:MHC相互作用后的功能性信号转导。
在具体实施方案中,可以将TCR修饰为功能性TCRα和/或β链融合蛋白,其中所述表位标签的长度为6至15个氨基酸,优选9至11个氨基酸。在另一个实施方案中,可以将TCR修饰为功能性TCRα和/或β链融合蛋白,其中所述TCRα和/或β链融合蛋白包含两个或更多个间隔或直接串联的表位标签。融合蛋白的实施方案可以包含2个、3个、4个、5个或甚至更多个表位标签,只要融合蛋白保持其生物学活性/多种活性(“功能性”)。
优选的是根据本发明的功能性TCRα和/或β链融合蛋白,其中所述表位标签选自但不限于CD20或Her2/neu标签或其它常规标签例如myc标签、FLAG标签、T7标签、HA(血凝素)标签、His标签、S标签、GST标签或GFP标签。Myc、T7、GST、GFP标签是源自现有分子的表位。相比之下,FLAG是设计用于高抗原性的合成表位标签(参见,例如,美国专利号4,703,004和4,851,341)。可以优选使用myc标签,因为高质量的试剂可用于其检测。除了被抗体识别外,表位标签当然可以具有一种或多种另外的功能。这些标签的序列在文献中描述并且是本领域技术人员众所周知的。
TCR片段和变体
本发明的另一方面涉及包含如本文所述的TCR的功能部分的多肽。所述功能部分可以包含选自由以下SEQ ID NO组成的组的氨基酸序列中的至少一个:SEQ ID NO:7、SEQID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47、SEQ ID NO:57、SEQ ID NO:10、SEQID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50和SEQ ID NO:60。
在具体的实施方案中,多肽可以是单独的TCR的功能部分,例如以可溶形式。或者,多肽可以与其它结构域结合。
功能部分可以介导TCR与抗原、特别是与抗原-MHC复合物的结合。
在一个实施方案中,功能部分包含如本文所述的TCRα可变链和/或TCRβ可变链。
TCR变体分子(即组合了包含TCR的功能部分的多肽和其它结构域的分子)可以具有TCR受体的结合特性,但是可以与效应细胞(除了T细胞)的信号传导结构域组合,特别是与NK细胞的信号传导结构域组合。因此,一些实施方案涉及包含如本文所述的TCR的功能部分与效应细胞(例如NK细胞)的信号传导结构域的组合的蛋白质。
“结合”是指与靶标特异性和非共价缔合、联合或结合的能力。
本发明的另一方面涉及包含至少两个如本文所述的TCR的多价TCR复合物。在该方面的一个实施方案中,至少两个TCR分子通过接头部分连接以形成多价复合物。优选地,复合物是水溶性的,因此应当相应地选择接头部分。优选地,接头部分能够连接至TCR分子上的限定位置,从而使形成的复合物的结构多样性最小化。本方面的一个实施方案由本发明的TCR复合物提供,其中聚合物链或肽接头序列在每个TCR的不位于TCR的可变区序列中的氨基酸残基之间延伸。由于本发明的复合物可用于医学,因此接头部分的选择应适当基于其药物适用性,例如其免疫原性。满足上述期望标准的接头部分的实例是本领域例如连接抗体片段的领域中已知的。
接头的实例是亲水聚合物和肽接头。亲水聚合物的实例是聚亚烷基二醇。此类中最常用的是基于聚乙二醇或PEG。然而,其它是基于其它合适的任选替换的聚亚烷基二醇,包括聚丙二醇,以及乙二醇和丙二醇的共聚物。肽接头包含氨基酸链,并且作用于产生可在其上连接TCR分子的简单接头或多聚结构域。
一个实施方案涉及多价TCR复合物,其中所述TCR中的至少一个与治疗剂缔合。
细胞因子和趋化因子释放
一些实施方案涉及如本文所述的分离的TCR,如本文所述的多肽,如本文所述的多价TCR复合物,其中通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的SEQID NO:2的氨基酸序列的结合诱导IFN-γ分泌。
在10-7[M]的HA-1肽浓度下,当将与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列的结合同与由HLA-A*02:01编码分子呈递的SEQ ID NO:4的结合相比时,通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列的结合而诱导的IFN-γ分泌可以是至少3倍高,优选至少10倍高,更优选至少20倍高,甚至更优选至少50倍高,最优选至少100倍高。
在10-6[M]的HA-1肽浓度下,当将与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列的结合同与由HLA-A*02:01编码分子呈递的SEQ ID NO:4的结合相比时,通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列的结合而诱导的IFN-γ分泌可以是至少3倍高,优选至少10倍高,更优选至少20倍高,甚至更优选至少50倍高,最优选至少100倍高。
在10-5[M]的HA-1肽浓度下,当将与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列的结合同与由HLA-A*02:01编码分子呈递的SEQ ID NO:4的结合相比时,通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列的结合而诱导的IFN-γ分泌可以是至少3倍高,例如至少10倍高,优选至少10倍高,例如至少20倍高,至少50倍高,至少100倍高。
因此,对于所有HA-1H-TCR转基因T细胞,为了识别HA-1R变体,需要与HA-1H相比的至少1,000倍、优选至少5,000倍、更优选至少8000倍、最优选至少10,0000倍高的肽浓度。
在具体实施方案中,例如当TCR转基因T细胞与T2细胞的比率为2:1时,在10-7[M]的HA-1肽浓度下,通过效应细胞上表达的本发明TCR与由HLA-A*02:01编码分子呈递的SEQ IDNO:2的氨基酸序列结合而诱导的IFN-γ分泌可以是大于500pg/ml,例如大于1000
pg/ml,更优选大于2000pg/ml,最优选大于3000pg/ml。
“效应细胞”可以是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。通常,效应细胞是免疫效应细胞,特别是T细胞。其它合适的细胞类型包括γ-δT细胞和NK样T细胞。
本发明还涉及用于鉴定与靶标氨基酸序列SEQ ID NO:2或其HLA-A2结合形式,优选由HLA-A*02:01编码分子或HLA-A*02:06编码分子呈递、优选由HLA-A*02:01编码分子或HLA-A*02:06编码分子呈递的SEQ ID NO:2结合的TCR或其片段的方法,其中所述方法包括使候选TCR或其片段与氨基酸序列SEQ ID NO:2或其HLA-A02结合形式、优选由HLA-A*02:01编码分子或HLA-A*02:06编码分子、优选由HLA-A*02:01编码分子呈递的SEQ ID NO:2接触,以及确定候选TCR或其片段是否与靶标结合和/或介导免疫应答。
候选TCR或其片段是否介导免疫应答可以例如通过测量细胞因子分泌(例如IFN-γ分泌)来确定。如上所述,可以通过体外测定来测量细胞因子的分泌,其中将用编码氨基酸序列SEQ ID NO:2的ivtRNA转染的K562细胞(或其它APC)与表达TCR的CD8+富集的PBMC或包含待研究的TCR片段的分子一起孵育。
核酸、载体
本发明的另一方面涉及编码如本文所述的TCR或编码编码如本文所述的TCR的多核苷酸的核酸。
下表列出了编码各个肽序列的核苷酸序列:
“核酸分子”通常是指DNA或RNA的聚合物,其可以是单链或双链的,合成的或从天然来源获得的(例如,分离和/或纯化的),其可以包含天然的、非天然或改变的核苷酸,并且其可以包含天然、非天然或改变的核苷酸间连接,例如氨基磷酸酯连接或硫代磷酸酯连接,而不是未修饰的寡核苷酸的核苷酸之间的磷酸二酯。优选地,本文所述的核酸是重组的。如本文所用,术语“重组”是指(i)通过将天然或合成核酸片段连接至可在活细胞中复制的核酸分子而在活细胞外部构建的分子,或(ii)由以上(i)中所述的那些的复制获得的分子。为了本文的目的,复制可以是体外复制或体内复制。可以使用本领域已知的方法或可商购的方法(例如来自Genscript、Thermo Fisher等类似公司)基于化学合成和/或酶促连接反应来构建核酸。参见,例如Sambrook等人,可以使用天然存在的核苷酸或各种修饰的核苷酸来以化学方式合成核酸,所述修饰的核苷酸被设计成提高分子的生物稳定性或提高杂交后形成的双链体的物理稳定性(例如,硫代磷酸酯衍生物和吖啶取代的核苷酸)。核酸可包含编码任何的重组TCR、多肽、或蛋白质、或其功能部分或功能变体的任何核苷酸序列。
本公开内容还提供分离或纯化的核酸的变体,其中所述核酸变体包含与编码本文所述TCR的核苷酸序列至少75%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核苷酸序列。这样的变体核苷酸序列编码特异性识别HA-1H抗原的功能性TCR。
本公开内容还提供分离的或纯化的核酸,其包含与本文所述的任何核酸的核苷酸序列互补的核苷酸序列或在严格条件下与本文所述的任何核酸的核苷酸序列杂交的核苷酸序列。
在严格条件下杂交的核苷酸序列优选在高严格条件下杂交。“高严格条件”是指核苷酸序列与靶序列(本文所述的任何核酸的核苷酸序列)以比非特异性杂交更强可检测的量特异性杂交。高严格条件包括将具有精确互补序列的多核苷酸或仅包含很少的分散错配的多核苷酸与碰巧具有很少的与核苷酸序列匹配的小区域(例如3-10个碱基)的随机序列区分开的条件。这样的互补小区域比14-17个或更多个碱基的全长互补更容易解链,并且高严格杂交使其易于区分。相对高严格性条件包括,例如,低盐和/或高温条件,例如在约50-70℃的温度下由约0.02-0.1M NaCl或等效物提供的条件。这样的高严格条件容许核苷酸序列与模板链或靶标链之间的极少(如果有的话)错配,并且特别适合于检测本文所述的任何TCR的表达。一般认为,通过添加增加量的甲酰胺可以使条件更加严格。
如本文其它地方已经描述的,可以对编码TCR的核酸进行修饰。整个核酸序列中的有用修饰可以是密码子优化。可以进行导致表达的氨基酸序列内的保守替换的改变。可以在TCR链氨基酸序列的互补决定区和非互补决定区中做出不影响功能的这些变化。通常,不应在CDR3区中进行添加和缺失。
另一个实施方案涉及包含编码如本文所述的TCR的核酸的载体。
载体优选是质粒、穿梭载体、噬菌粒、粘粒、表达载体、逆转录病毒载体、腺病毒载体或用于基因治疗的颗粒和/或载体。
“载体”是具有将核酸序列携带到合适的宿主细胞中的能力的任何分子或组合物,在该宿主细胞中可以发生编码的多肽的合成。通常并且优选地,载体是使用本领域已知的重组DNA技术已经工程化以引入期望的核酸序列(例如本发明的核酸)的核酸。载体可包含DNA或RNA和/或包含脂质体。载体可以是质粒、穿梭载体、噬菌粒、粘粒、表达载体、逆转录病毒载体、慢病毒载体、腺病毒载体或用于基因治疗的颗粒和/或载体。载体可以包含允许其在宿主细胞中复制的核酸序列,例如复制起点。载体还可以包含一个或多个选择性标志物基因和本领域普通技术人员已知的其它遗传元件。载体优选是包含根据本发明的核酸的表达载体,所述核酸可操作地连接至允许所述核酸表达的序列。
优选地,载体是表达载体。更优选地,载体是逆转录病毒,更具体地γ-逆转录病毒或慢病毒载体。
细胞、细胞系
本发明的另一方面涉及表达如本文所述的TCR的细胞。
在一些实施方案中,细胞是分离的或非天然存在的。
在具体实施方案中,细胞可以包含编码如本文所述的TCR的核酸或包含所述核酸的载体。
在细胞中,可以引入包含编码上述TCR的核酸序列的上述载体,或者可以引入编码所述TCR的ivtRNA。细胞可以是外周血淋巴细胞,例如T细胞。TCR的克隆和外源表达方法例如在Engels等人(Relapse or eradication of cancer is predicted by peptide-majorhistocompatibility complex affinity.Cancer Cell,23(4),516–26.2013)中描述。用慢病毒载体对原代人T细胞的转导例如在Cribbs“simplified production andconcentration of lentiviral vectors to achieve high transduction in primaryhuman T cells”BMC Biotechnol.2013;13:98中描述。
术语“转染”和“转导”是可互换的,并且是指将外源核酸序列引入宿主细胞(例如真核宿主细胞)中的过程。注意,核酸序列的引入或转移不限于所提及的方法,而是可以通过任何数量的手段来实现,包括电穿孔、显微注射、基因枪递送、脂转染、重复转染(superfection)和提到的通过逆转录病毒或其它适合转导或转染的病毒的感染。
一些实施方案涉及细胞,所述细胞包含:
a)包含至少一种本文所述的核酸的表达载体,或
b)包含编码如本文所述的TCR的α链的核酸的第一表达载体,和包含编码如本文所述的TCR的β链的核酸的第二表达载体。
在一些实施方案中,细胞是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。细胞可以是自然杀伤细胞或T细胞。优选地,细胞是T细胞。T细胞可以是CD4+或CD8+T细胞。
在一些实施方案中,细胞是干细胞样记忆T细胞。
干细胞样记忆T细胞(TSCM)是CD8+T细胞的分化程度较低的亚群,具有自我更新的能力并且长期持续的特征。一旦这些细胞在体内遇到其抗原,其进一步分化为中央记忆T细胞(TCM)、效应记忆T细胞(TEM)和终末分化的效应记忆T细胞(TEMRA),同时一些TSCM保持静止(Flynn等人.,Clinical&Translational Immunology(2014))。这些剩余的TSCM细胞显示出在体内建立持久免疫记忆的能力,并且因此被认为是用于过继T细胞疗法的重要T细胞亚群(Lugli等人,Nature Protocols 8,33–42(2013)Gattinoni等人,Nat.Med.2011年10月;17(10):1290–1297)。可以使用免疫-磁选择来将T细胞库限制为干细胞记忆T细胞亚型参见(Riddell等人.2014,Cancer Journal 20(2):141–44)。
靶向TCR的抗体
本发明的另一方面涉及与本文所述的TCR的一部分特异性结合的抗体或其抗原结合片段,所述部分介导对HA-1H的特异性。在一个实施方案中,TCR的介导HA-1H特异性的部分包含SEQ ID NO:7、SEQ ID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47和SEQ IDNO:57的α链CDR3,和/或SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQID NO:50和SEQ ID NO:60的β链CDR3。
抗体或其抗原结合片段可以调节TCR的活性。其可以阻断或可以不阻断TCR与HA-1H的结合。其可用于调节TCR的治疗活性或用于诊断目的。
药物组合物、药物治疗和试剂盒
本发明的另一方面涉及药物组合物,其包含:如本文所述的TCR,包含所述TCR的功能部分的多肽,如本文所述的多价TCR复合物,编码TCR的核酸,包含所述核酸的载体,包含所述TCR的细胞,或与本文所述的TCR的一部分特异性结合的抗体。
本发明的那些活性成分优选以与可接受的载体或载体材料混合的剂量用于这样的药物组合物中,从而可以治疗或至少减轻疾病。这样的组合物可以(除了活性成分和载体之外)包含填充材料、盐、缓冲剂、稳定剂、增溶剂和其它材料,它们是现有技术中已知的。
术语“药学上可接受的”定义不干扰活性成分的生物活性的有效性的无毒材料。载体的选择取决于应用。
药物组合物可以包含增强活性成分的活性或补充治疗的另外的成分。这样的另外的成分和/或因子可以是药物组合物的一部分,以实现协同作用或使不利或不希望的作用最小化。
用于本发明活性成分的配制或制备以及施用/给药的技术在最新版的“Remington's Pharmaceutical Sciences",Mack Publishing Co.,Easton,PA中公开。合适的施用是肠胃外施用,例如肌内、皮下、髓内注射以及鞘内、直接心室内、静脉内、结节内、腹膜内或肿瘤内注射。静脉内注射是患者的优选治疗。
根据一个优选实施方案,药物组合物是输注剂或注射剂。
可注射组合物是药学上可接受的流体组合物,其包含至少一种活性成分,例如表达TCR的扩增的T细胞群(例如对于待治疗患者是自体或同种异体)。活性成分通常溶解或悬浮在生理上可接受的载体中,并且该组合物可以另外包含少量的一种或多种无毒辅助物质,例如乳化剂、防腐剂和pH缓冲剂等。可用于与本公开内容的融合蛋白一起使用的这样的可注射组合物是常规的;合适的制剂是本领域普通技术人员众所周知的。
通常,药物组合物包含至少一种药学上可接受的载体。
因此,本发明的另一方面涉及如本文所述的TCR、包含所述TCR的功能部分的多肽、根据如本文所述的多价TCR复合物、编码所述TCR的核酸、包含所述核酸的载体、包含所述TCR的细胞或与如本文所述的TCR的一部分特异性结合的抗体,用于作为药物。
一些实施方案涉及如本文所述的TCR、包含所述TCR的功能部分的多肽、根据如本文所述的多价TCR复合物、编码所述TCR的核酸、包含所述核酸的载体、包含所述TCR的细胞,用于在治疗癌症中使用。
在一个实施方案中,癌症是血液学癌症。
血液学癌症也称为血癌,其不形成实体瘤,并且因此主要分散在体内。
血液学癌症可以选自由以下组成的组:非霍奇金淋巴瘤(NHL)、霍奇金淋巴瘤(HL)、多发性骨髓瘤、急性髓细胞性白血病(AML)和急性淋巴母细胞性白血病(ALL)、混合表型急性白血病(MPAL)、慢性髓细胞性白血病(CML)、B细胞多形性淋巴瘤、毛细胞白血病、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、中枢神经系统淋巴瘤、CD37+树突状细胞淋巴瘤、淋巴母细胞性淋巴瘤、脾边缘区淋巴瘤、浆细胞骨髓瘤、骨外浆细胞瘤、黏膜相关淋巴组织(MALT组织)的结外边缘区B细胞淋巴瘤、结边缘区B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、前体B淋巴母细胞性淋巴瘤、免疫母细胞性大细胞淋巴瘤、血管内大B细胞淋巴瘤、原发渗出性淋巴瘤、伯基特淋巴瘤/白血病、恶性潜能不明的B细胞增殖、淋巴瘤样肉芽肿病、移植后淋巴组织增生性疾病。其它血液学癌症或疾病包括骨髓增生异常。
本文还考虑了包含以下一种或多种的药物组合物和试剂盒:(i)如本文所述的分离的TCR;(ii)包含编码重组TCR的核酸的病毒颗粒;(iii)经修饰以表达如本文所述的重组TCR的免疫细胞,例如T细胞或NK细胞;(iv)编码如本文所述的重组TCR的核酸。在一些实施方案中,本公开内容提供了包含含有编码本文所述的重组TCR的核苷酸序列的慢病毒载体颗粒(或已经使用本文所述的载体颗粒进行修饰以表达重组TCR的T细胞)的组合物。这样的组合物可以如本文进一步描述的以本公开内容的方法施用给受试者。
包含本文所述的经修饰T细胞的组合物可以根据已知技术或基于本公开内容对本领域技术人员显而易见的其变化用在用于过继免疫疗法的方法和组合物中。
在一些实施方案中,如下配制细胞:首先从其培养基中收获细胞,然后以治疗有效量在适于施用的介质或容器系统(“药学上可接受的”载体)中洗涤并浓缩细胞。合适的输注介质可以是任何等渗介质制剂,通常是生理盐水、Normosol R(Abbott)或Plasma-Lyte A(Baxter),但也可以使用在水中或林格氏乳酸中的5%右旋葡萄糖。输注介质可以补充人血清白蛋白。
在组合物中用于有效治疗的细胞数目通常大于10个细胞,并且高至106个,高至并包括108或109个细胞,并且可以大于1010个细胞。细胞的数目将取决于组合物所预期的最终用途,以及其中所含细胞的类型。例如,如果期望对特定抗原具有特异性的细胞,则该群体将包含大于70%,通常大于80%、85%和90-95%的这样的细胞。对于本文提供的用途,细胞通常为一升或更少的体积,可以为500ml或更少,甚至250ml或100ml或更少。因此,期望的细胞的密度通常大于106个细胞/ml,并且通常大于107个细胞/ml,通常大于108个细胞/ml或更大。临床相关数目的免疫细胞可以分配至多次输注,其累积等于或大于109、1010或1011个细胞。本文提供的药物组合物可以呈多种形式,例如固体、液体、粉末、含水或冻干形式。合适的药物载体的实例是本领域已知的。这样的载体和/或添加剂可以通过常规方法配制并且可以以合适的剂量施用于受试者。稳定剂如脂质、核酸酶抑制剂、聚合物和螯合剂可以保护组合物免于在体内降解。在旨在通过注射施用的组合物中,可以包含表面活性剂、防腐剂、湿润剂、分散剂、助悬剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
本文所述的重组TCR或包含编码本文提供的重组TCR的核苷酸序列的病毒载体颗粒可以包装成试剂盒。试剂盒可以任选地包括一种或多种组分,例如使用说明书、装置和其它试剂,以及组件,例如用于实施方法的管、容器和注射器。示例性试剂盒可包含本文提供的编码重组TCR的核酸、重组TCR多肽或病毒,并且可任选地包含使用说明书、用于检测受试者中病毒的装置,用于将组合物施用于受试者的装置,以及用于将组合物施用于受试者的装置。
本文还设想了包含编码目的基因(例如重组TCR)的多核苷酸的试剂盒。本文还设想了包含编码目的序列(例如重组TCR)的病毒载体和任选地编码免疫检查点抑制剂的多核苷酸序列的试剂盒。
本文设想的试剂盒还包括用于实施检测编码本文公开的任一种或多种TCR的多核苷酸的存在的方法的试剂盒。具体地,这样的诊断试剂盒可包含用于进行深度测序以检测编码本文公开的TCR的多核苷酸的合适扩增和检测引物组和其它相关试剂。在另一些实施方案中,本文的试剂盒可包含用于检测本文公开的TCR的试剂,例如抗体或其它结合分子。诊断试剂盒还可包含用于确定编码本文公开的TCR的多核苷酸的存在或用于确定本文公开的TCR的存在的说明书。试剂盒还可包含说明书。说明书通常包含描述以下的有形表达:试剂盒中包含的组分,以及施用方法,包括用于确定受试者的适当状态、合适的剂量和合适的施用方法的方法。说明书还可以包括用于在治疗期间内监测受试者的指导。
本文提供的试剂盒还可以包括用于向受试者施用本文所述的组合物的装置。在本文提供的试剂盒中可以包括本领域已知的用于施用药物或疫苗的多种装置中的任一种。示例性装置包括但不限于皮下注射针、静脉内针、导管、无针注射装置、吸入器和液体分配器,例如滴管(eyedropper)。通常,用于施用试剂盒的病毒的装置将与试剂盒的病毒兼容;例如,无针注射装置如高压注射装置可包括在含有不会被高压注射破坏的病毒的试剂盒中,但是通常不包括在含有会被高压注射破坏的病毒的试剂盒中。
本文提供的试剂盒还可以包括用于向受试者施用化合物(例如T细胞活化剂或刺激剂,或TLR激动剂如TLR4激动剂)的装置。本领域已知的用于向受试者施用药物的多种装置中的任何装置都可以包括在本文提供的试剂盒中。示例性装置包括皮下注射针、静脉内针、导管、无针注射,但不限于皮下注射针、静脉内针、导管、无针注射装置、吸入器和液体分配器,例如滴管。通常,用于施用试剂盒的化合物的装置将与施用化合物的期望方法兼容。
实验
实施例:
实施例1:HA-1H-TCR转基因T细胞结合HA-1H多聚体
使用了体外引发方法来分离HA-1H反应性T细胞克隆。引发系统使用HLA-A*02:01阳性供体的成熟树突状细胞(mDC)作为抗原呈递细胞和自体CD8+富集的T细胞作为应答细胞。将编码人HMHA1基因的31个氨基酸(ARFAEGLEKLKECVLHDDLLEARRPRAHECL;SEQ ID NO:126)的体外转录RNA(ivtRNA)用作特异性抗原的来源。在电穿孔到mDC中后,HMHA1编码ivtRNA被翻译成蛋白质,随后被加工并由mDC上的HLA-A*02:01分子作为肽被呈递。T细胞与来自同一供体的ivtRNA转染的mDC的体外共培养导致从头诱导抗原特异性T细胞,其充当相应TCR的来源。抗原特异性T细胞可以通过多种方法富集,并且通过有限稀释或基于FACS的单细胞分选来克隆。通过下一代测序对HA-1H反应性T细胞克隆的TCRα链和TCRβ链的序列进行鉴定,并且在恒定TCR区被其鼠对应物交换之后将其克隆到逆转录病毒载体pES.12-6中。通过ficoll梯度离心分离出健康供体的PBMC。通过阴性磁性选择(Miltenyi)富集CD8 T细胞,并在非组织培养24孔板中用抗CD3和抗CD28mAh(BD Pharmingen,Heidelberg,Germany)进行刺激。通过用相应的TCR编码逆转录病毒质粒和两种表达质粒转染HEK293T细胞来产生双嗜性逆转录病毒颗粒。刺激后第二天,转导CD8 T细胞,并且在第十二天使用鼠恒定β区作为转导标志物通过FACS富集经转导的CD8+细胞,然后通过快速扩增方案(Riddell SR,Science,1992Jul 10;257(5067):238-41)进行扩增。
结果:
用从HA-1H反应性T细胞克隆分离出的六种不同的TCR和一种不能识别HA-1H的对照TCR来转导CD8 T细胞。使用GeneOptimizerTM算法(ThermoFisher)对分离的TCR的核苷酸序列进行密码子优化,并且将恒定区鼠源化。将密码子优化且鼠源化的TCR用于本文所述的所有其它实验。将其用HA-1H-MHC多聚体(immunAware)和针对CD8和鼠恒定β区的抗体染色。除了一个外的所有HA-1H-TCR转基因T细胞群均非常有效地结合HA-1H-MHC多聚体(>90%);仅TCR_6显示出较低百分比的HA-1H-MHC多聚体阳性细胞(37%)。对照TCR未观察到HA-1H-MHC多聚体染色。这些结果表明,从HA-1H反应性T细胞克隆分离出的TCR可以在健康供体的T细胞中以转基因方式被表达。(图1)
实施例2:HA-1H-TCR转基因T细胞识别HA-1H阳性靶细胞
根据以下方案确认TCR转基因T细胞的HA-1H特异性:
向作为靶细胞的T2细胞(HLA-A*02:01阳)负载饱和量(10-5M)的HA-1H肽(SEQ IDNO:2)或对照肽Astn1 P1268L(KLYGLDWAEL)。另外,用HLA-A*02:01和编码HA-1H表位的HMHA1基因的部分转导K562细胞。将仅用HLA-A*02:01转导的K562细胞用作对照。使用20,000个T细胞和10,000个靶细胞以2:1的比例共培养每个靶细胞系和TCR转基因T细胞。20-24小时后,通过标准夹心ELISA(BD人IFN-γELISA装置)分析共培养物上清液中的IFN-γ浓度。
结果:
HA-1H-TCR转基因T细胞识别负载有HA-1H的T2和HMHA1转导的K562细胞,但是没有识别对照靶细胞。表达对照TCR的T细胞仅识别负载有对照肽的T2细胞。这些结果表明,从HA-1H反应性T细胞克隆分离出的TCR在转移至健康供体的T细胞后具有功能。(图2)
实施例3:HA-1H-TCR转基因T细胞不能识别负载有HA-1R-肽的靶细胞
为了分析在识别两种变体HA-1H和HA-1R中的差异,分析了HA-1H-TCR转基因T细胞对负载在HLA-A*02:01上的两种变体的功能亲合力:
使T2细胞以外部方式负载有不同浓度(10-11M-10-5M)的HA-1H-肽和(10-8M-10-5M)的HA-1R-肽并且使用20,000个T细胞和10,000个T2细胞以2:1的比例与TCR转基因T细胞共培养。20-24小时后,通过标准夹心ELISA(BD人IFN-γELISA装置)分析共培养物上清液中的IFN-γ浓度。
结果:
TCR_3和TCR_4显示出对HLA-A*02:01编码分子上负载的HA-1H-肽的最高功能亲合力,并且TCR_2显示出最低功能亲合力。在非生理的高肽浓度(10-5M)下观察到了一些HA-1H-TCR转基因T细胞对HA-1R的仅非常少的识别,并且对于所有HA-1H-TCR转基因T细胞,为了识别HA-1R-变体,需要相对于HA-1H至少10,0000倍高的肽浓度。这些结果表明,HA-1H-TCR对于HA-1H-变体是高度特异性的。另外,将对于HLA-A*02:01编码分子上负载的HA-1R-肽的功能亲合力与WO2018058002A1中所述的TCR(TCR2)进行了比较。与本文所述的TCR相反,该TCR也在10-6M浓度下识别HA-1R-肽,并且在10-5M的浓度下释放显著更多的IFN-γ,表明本文所述的所有TCR比WO2018058002A1中所述的TCR具有显著更高的特异性。(图3A和3B)
实施例4:HA-1H-TCR转基因T细胞识别HA-1H阳性LCL
为了分析HA-1H-TCR转基因T细胞识别未修饰的靶细胞上生理水平的HA-1H的能力,将T细胞与不同的淋巴母细胞系(LCL)共培养,并且分析TCR转基因T细胞的细胞因子释放和细胞毒性:
分离出七种LCL的DNA(Quick Extract DNAExtract Solution,Illumina),并且通过PCR扩增了编码HA-1的HMHA1基因的部分。从琼脂糖凝胶分离出PCR产物以送去测序(Eurofins Genomics)。基于测序结果,将LCL分配至HA-1H阳性(HA-1H/H和HA-1H/R)或HA-1H阴性(HA-1R/R)组。为了分析细胞因子的释放,使用20,000个T细胞和10,000个T2细胞以2:1的比例共培养TCR转基因T细胞和LCL。20-24小时后,通过标准夹心ELISA(BD人IFN-γELISA装置)分析共培养物上清液中的IFN-γ浓度。对于细胞毒性测定,利用已经用荧光标志物基因转导的100,000个TCR转基因T细胞和20,000个LCL以5:1的效应物与靶标比例建立共培养物。使用活细胞监测(ZOOM)在总共20小时的时间期间内每两小时测量荧光靶细胞的减少(RCU中的总积分强度×μm2/图像,RCU=红色校准单位)。
结果:
所有HA-1H-TCR转基因T细胞在与HA-1H阳性LCL(LCL 1-5)共培养时释放IFN-γ,但是在与HA-1H阴性LCL(LCL 6-7)共培养之后没有。表达对照TCR的T细胞不识别任何LCL。另外,HA-1H阳性LCL被HA-1H-TCR转基因T细胞裂解。未转导的CD8 T细胞用作阴性对照,并且未裂解LCL。这些结果表明,HA-1H-TCR可以识别生理水平的HLA-A*02:01编码分子上负载的HA-1H。(图4A和4B)
实施例5:HA-1H-TCR转基因T细胞识别HA-1H阳性肿瘤细胞系
为了分析HA-1H-TCR转基因T细胞识别肿瘤细胞系上呈递的HA-1H的能力,将T细胞与不同的HA-1H阳性肿瘤细胞系共培养。
分离出肿瘤细胞系的DNA(Quick Extract DNA Extract Solution,Illumina),并且通过PCR扩增了编码HA-1的HMHA1基因的部分。从琼脂糖凝胶分离出PCR产物,并从凝胶提取以用于后续测序(Eurofins Genomics)。将HA-1H阳性(HA-1H/H和HA-1H/R)肿瘤细胞系用于实验。为了分析细胞因子释放,使用20,000个T细胞和10,000个T2细胞以2:1的比例共培养TCR转基因T细胞和肿瘤细胞系。20-24小时后,通过标准夹心ELISA(BD人IFN-γELISA装置)分析共培养物上清液中的IFN-γ浓度。对于细胞毒性测定,利用已经用荧光标志物基因转导的100,000个TCR转基因T细胞和20,000个肿瘤细胞以约5:1的效应物与靶标比例建立共培养物。使用活细胞监测(ZOOM)在总共20小时的时间期间内每两小时测量荧光靶细胞的减少(RCU中的总积分强度xμm2/图像,RCU=红色校准单位)。
结果:
当与肿瘤细胞系共培养时,除了TCR_2之外的所有HA-1H-TCR转基因T细胞都释放IFN-γ。表达对照TCR的T细胞不识别肿瘤细胞系。HA-1H-TCR转基因T细胞也显示出对肿瘤细胞系的细胞毒性活性。与细胞因子释放数据一致,TCR_2以较低效率裂解靶细胞。未转导的CD8 T细胞用作阴性对照。(图5A和5B)
实施例6:表达TCR_3和TCR_4的T细胞以与先前描述的TCR相当的水平识别HA-1H阳性肿瘤细胞系
为了将HA-1H-TCR转基因T细胞对HA-1H阳性肿瘤细胞系的识别与WO2018058002A1中描述的表达TCR2的T细胞进行比较,共培养20,000个T细胞和10,000个肿瘤细胞。20小时后,通过标准夹心ELISA(BD人IFN-γELISA装置)分析共培养物上清液中的IFN-γ浓度。对于细胞毒性测定,将10,000个HA-1H阴性/GFP阳性K562细胞和表达mCherry的肿瘤细胞系的10,000个细胞与20,000个TCR转基因T细胞共培养。45小时后,通过流式细胞术分析样品,并计算mCherry阳性(HA-1H阳性)与GFP阳性(HA-1H阴性)细胞的比例并且相对于对对照TCR测量的比例进行归一化。
结果:
在与HA-1H阳性肿瘤细胞系共培养后,表达TCR_3和TCR_4的T细胞释放出与WO2018058002A1中描述的表达TCR2的T细胞相似的量的IFN-γ(图6A)。表达TCR_3和TCR_4的T细胞还显示出与TCR2可比较的针对不同肿瘤细胞系的细胞毒性活性(图6B)。
实施例7:TCR识别基序
为了分析TCR的特异性识别基序,进行丝氨酸替换扫描。通过用丝氨酸对表位的原始氨基酸进行单替换,可以鉴定肽内对TCR介导的识别必不可少的位置。为了定义识别基序,将表达不同HA-1TCR(TCR_3、TCR_4和WO2018058002A1中所描述的TCR2)的效应T细胞与T2细胞共培养,所述T2细胞负载有每个单独氨基酸残基被丝氨酸相继替换的HA-1H肽(SEQID NO:2),或者负载有对照肽。使T2细胞分别负载饱和浓度(10-5M)的肽,洗涤,并且以1:1的E:T与效应细胞共培养。共培养约20小时后收获上清液,并且通过ELISA分析分泌的IFN-γ。表达对照TCR的T细胞用作阴性对照。
结果:
与TCR2(WO2018058002A1)相比,TCR_3和TCR_4显示出在丝氨酸更特异性的识别模式,如识别较少的肽。
不同的恒定TCR区的比较
为了比较不同的恒定TCR区的作用,将TCR_3与鼠、最小鼠源化(Sommermeyer和Uckert,2010,J.Immunol.)和人恒定区克隆。通过共培养20,000个T细胞和10,000个肿瘤细胞来测试具有不同恒定TCR区的HA-1H-TCR转基因T细胞对HA-1H-TCR阳性肿瘤细胞系或LCL的识别。20-24小时后,通过标准夹心ELISA(BD人IFN-γELISA装置)分析共培养物上清液中的IFN-γ浓度。对于细胞毒性测定,将10,000个HA-1H阴性/GFP阳性K562细胞和表达mCherry的肿瘤细胞系的10,000个细胞与20,000个TCR转基因T细胞共培养。45小时后,通过流式细胞术分析样品,并计算mCherry阳性(HA-1H阳性)与GFP阳性(HA-1H阴性)细胞的比例并且相对于对对照TCR测量的比例进行归一化。
结果:
如所预期的,当使用最小鼠源化或人恒定TCR区代替鼠源化恒定区时,HA-1H-TCR转基因T细胞的反应性稍微降低(图8A和B)。然而,即使具有人恒定TCR区,在与HA-1H阳性靶细胞共培养后,T细胞仍特异性释放IFN-γ并显示出细胞毒性作用。
该描述还包括以下实施方案:
实施方案1.对次要组织相容性抗原1(HA-1)的一种等位基因变体具有特异性的分离的T细胞受体(TCR)。
实施方案2.根据实施方案1所述的分离的TCR,其中HA-1的所述等位基因变体是HA-1H。
实施方案3.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR特异性识别氨基酸序列SEQ ID NO:2或其片段。
实施方案4.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR不识别氨基酸序列SEQ ID NO:4或其片段。
实施方案5.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR的识别基序至少包含SEQ ID NO:127所示的序列。
实施方案6.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR特异性识别HLA-A2结合形式的SEQ ID NO:2的氨基酸序列。
实施方案7.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR特异性识别由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列。
实施方案8.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含TCRα链,所述TCRα链包含互补决定区3(CDR3),所述CDR3具有选自由以下组成的组的氨基酸序列:SEQ ID NO:7、SEQ ID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47和SEQ IDNO:57。
实施方案9.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含TCRβ链,所述TCRβ链包含CDR3,所述CDR3具有选自由以下组成的组的氨基酸序列:SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50和SEQ ID NO:60。
实施方案10.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含
a)-TCRα链,包含具有SEQ ID NO:5的氨基酸序列的CDR1、具有SEQ ID NO:6的氨基酸序列的CDR2和具有SEQ ID NO:7的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:8的氨基酸序列的CDR1、具有SEQ ID NO:9的氨基酸序列的CDR2和具有SEQ ID NO:10的序列的CDR3;或
b)-TCRα链,包含具有SEQ ID NO:15的氨基酸序列的CDR1、具有SEQ ID NO:16的氨基酸序列的CDR2和具有SEQ ID NO:17的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:18的氨基酸序列的CDR1、具有SEQ ID NO:19的氨基酸序列的CDR2和具有SEQ ID NO:20的序列的CDR3;或
c)-TCRα链,包含具有SEQ ID NO:25的氨基酸序列的CDR1、具有SEQ ID NO:26的氨基酸序列的CDR2和具有SEQ ID NO:27的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:28的氨基酸序列的CDR1、具有SEQ ID NO:29的氨基酸序列的CDR2和具有SEQ ID NO:30的序列的CDR3;
d)-TCRα链,包含具有SEQ ID NO:35的氨基酸序列的CDR1、具有SEQ ID NO:36的氨基酸序列的CDR2和具有SEQ ID NO:37的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:38的氨基酸序列的CDR1、具有SEQ ID NO:39的氨基酸序列的CDR2和具有SEQ ID NO:40的序列的CDR3;或
e)-TCRα链,包含具有SEQ ID NO:45的氨基酸序列的CDR1、具有SEQ ID NO:46的氨基酸序列的CDR2和具有SEQ ID NO:47的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:48的氨基酸序列的CDR1、具有SEQ ID NO:49的氨基酸序列的CDR2和具有SEQ ID NO:50的序列的CDR3;或
f)-TCRα链,包含具有SEQ ID NO:55的氨基酸序列的CDR1、具有SEQ ID NO:56的氨基酸序列的CDR2和具有SEQ ID NO:57的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:58的氨基酸序列的CDR1、具有SEQ ID NO:59的氨基酸序列的CDR2和具有SEQ ID NO:60的序列的CDR3。
实施方案11.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含TCRα链和TCRβ链,其中
a)-可变TCRα区具有与SEQ ID NO:11至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:7所示氨基酸序列的CDR3区,
-可变TCRβ区具有与SEQ ID NO:12至少80%相同的氨基酸序列,并且包含具有SEQID NO:10所示氨基酸序列的CDR3区;或
b)-可变TCRα区具有与SEQ ID NO:21至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:17所示氨基酸序列的CDR3区,
-可变TCRβ区具有与SEQ ID NO:22至少80%相同的氨基酸序列,并且包含具有SEQID NO:20所示的氨基酸序列的CDR3区;或
c)-可变TCRα区具有与SEQ ID NO:31至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:27所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:32至少80%相同的氨基酸序列,并且包含具有SEQID NO:30所示氨基酸序列的CDR3区;或
d)-可变TCRα区具有与SEQ ID NO:41至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:37所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:42至少80%相同的氨基酸序列,并且包含具有SEQID NO:40所示氨基酸序列的CDR3区;或
e)-可变TCRα区具有与SEQ ID NO:51至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:47所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:52至少80%相同的氨基酸序列,并且包含具有SEQID NO:50所示氨基酸序列的CDR3区;或
f)-可变TCRα区具有与SEQ ID NO:61至少80%相同的氨基酸序列,并且包含具有SEQ ID NO:57所示氨基酸序列的CDR3区;
-可变TCRβ区具有与SEQ ID NO:62至少80%相同的氨基酸序列,并且包含具有SEQID NO:60所示氨基酸序列的CDR3区。
实施方案12.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含
a)具有与SEQ ID NO:11至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:12至少80%相同的氨基酸序列的可变TCRβ区;或
b)具有与SEQ ID NO:21至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:22至少80%相同的氨基酸序列的可变TCRβ区;或
c)具有与SEQ ID NO:31至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:32至少80%相同的氨基酸序列的可变TCRβ区;或
d)具有与SEQ ID NO:41至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:42至少80%相同的氨基酸序列的可变TCRβ区;或
e)具有与SEQ ID NO:51至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:52至少80%相同的氨基酸序列的可变TCRβ区;或
f)具有与SEQ ID NO:61至少80%相同的氨基酸序列的可变TCRα区和具有与SEQID NO:62至少80%相同的氨基酸序列的可变TCRβ区。
实施方案13:根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含
a)具有SEQ ID NO:11的氨基酸序列的可变TCRα区和具有SEQ ID NO:12的氨基酸序列的可变TCRβ区;或
b)具有SEQ ID NO:21的氨基酸序列的可变TCRα区和具有SEQ ID NO:22的氨基酸序列的可变TCRβ区;或
c)具有SEQ ID NO:31的氨基酸序列的可变TCRα区和具有SEQ ID NO:32的氨基酸序列的可变TCRβ区;或
d)具有SEQ ID NO:41的氨基酸序列的可变TCRα区和具有SEQ ID NO:42的氨基酸序列的可变TCRβ区;或
e)具有SEQ ID NO:51的氨基酸序列的可变TCRα区和具有SEQ ID NO:52的氨基酸序列的可变TCRβ区;或
f)具有SEQ ID NO:61的氨基酸序列的可变TCRα区和具有SEQ ID NO:62的氨基酸序列的可变TCRβ区。
实施方案14.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR是纯化的。
实施方案15.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR的氨基酸序列包含一个或多个表型沉默替换。
实施方案16.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR的氨基酸序列被修饰以包含可检测标记、治疗剂或药代动力学修饰部分。
实施方案17.根据实施方案16所述的分离的TCR,其中所述治疗剂选自由免疫效应分子、细胞毒剂和放射性核素组成的组。
实施方案18.根据实施方案17所述的分离的TCR,其中所述免疫效应分子是细胞因子。
实施方案19.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR是可溶性的或膜结合的。
实施方案20:根据实施方案16所述的分离的TCR,其中所述药代动力学修饰部分是至少一个聚乙二醇重复单元、至少一个二醇基团、至少一个唾液酸基团或其组合。
实施方案21.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR是单链型的,其中所述TCRα链与所述TCRβ链通过接头序列连接。
实施方案22.根据前述实施方案中任一项所述的分离的TCR,其中所述TCRα链或所述TCRβ链被修饰以包含表位标签。
实施方案23.根据前述实施方案中任一项所述的分离的TCR,其中所述重组TCR序列可以被修饰以包含最小鼠源化Cα区和Cβ区。
实施方案24.分离的多肽,包含实施方案1至21中任一项所述的TCR的功能部分,其中所述功能部分包含以下氨基酸序列中的至少一个:SEQ ID NO:7、SEQ ID NO:17、SEQ IDNO:27、SEQ ID NO:37、SEQ ID NO:47、SEQ ID NO:57、SEQ ID NO:10、SEQ ID NO:20、SEQ IDNO:30、SEQ ID NO:40、SEQ ID NO:50和SEQ ID NO:60。
实施方案25.根据实施方案24所述的分离的多肽,其中所述功能部分包含TCRα可变链和/或TCRβ可变链。
实施方案26.多价TCR复合物,包含至少两个如实施方案1至23中任一项所体现的TCR。
实施方案27.多价TCR复合物,其中所述TCR中的至少一个与治疗剂缔合。
实施方案28.根据实施方案1至23所述的分离的TCR、根据实施方案24和25所述的多肽、根据实施方案25和26所述的多价TCR复合物,其中IFN-γ分泌是通过与由HLA-A*02:01编码分子呈递的SEQ ID NO:2的氨基酸序列结合而诱导的。
实施方案29.编码根据实施方案1至22中任一项所述的TCR或编码根据实施方案24至25所述的多肽的核酸。
实施方案30.根据实施方案29所述的核酸,其中所述核酸是密码子优化的。
实施方案31.包含实施方案29或30所述的核酸的载体。
实施方案32.根据实施方案31所述的载体,其中所述载体是表达载体。
实施方案33.根据实施方案31或32所述的载体,其中所述载体是逆转录病毒载体。
实施方案34.根据实施方案31或32所述的载体,其中所述载体是慢病毒载体。
实施方案35.表达根据实施方案1至23所述的TCR的细胞。
实施方案36.根据实施方案34所述的细胞,其中所述细胞是分离的或非天然存在的。
实施方案37.包含根据实施方案29或30所述的核酸或根据实施方案31至35所述的载体的细胞。
实施方案38.根据实施方案35至37所述的细胞,其中所述细胞包含:
a)包含至少一种如实施方案29或30所体现的核酸的表达载体,
b)包含编码如实施方案1至23中任一项所体现的TCR的α链的核酸的第一表达载体,和包含编码如实施方案1至23中任一项所体现的TCR的β链的核酸的第二表达载体。
实施方案39.根据实施方案35至38中任一项所述的细胞,其中所述细胞是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。
实施方案40.根据实施方案35至38中任一所述的细胞,其中所述细胞是T细胞。
实施方案41.与根据实施方案1至23所述的TCR的部分特异性结合的抗体或其抗原结合片段,所述部分介导对HA-1的一种等位基因变体的特异性。
实施方案42.根据实施方案40所述的抗体或其抗原结合片段,其中TCR的介导对HA-1的一种等位基因变体的特异性的部分包含SEQ ID NO:7、SEQ ID NO:17、SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:47、SEQ ID NO:57的α链CDR3,和/或SEQ ID NO:10、SEQ IDNO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50和SEQ ID NO:60的β链CDR3。
实施方案43.根据实施方案41或42所述的抗体或其抗原结合片段,其中HA-1的所述等位基因变体是HA-1H。
实施方案44.药物组合物,包含根据实施方案1至22所述的TCR、根据实施方案24至25所述的多肽、根据实施方案27至28中任一项所述的多价TCR复合物、根据实施方案29或30所述的核酸、根据实施方案31至34所述的载体、根据实施方案35至40中任一项所述的细胞、或根据实施方案41至42所述的抗体。
实施方案45:根据实施方案44所述的药物组合物,其中所述药物组合物包含至少一种药学上可接受的载体。
实施方案46:根据实施方案1至23所述的TCR、根据实施方案24至25所述的多肽、根据实施方案27至28中任一项所述的多价TCR复合物、根据实施方案29或30所述的核酸、根据实施方案31至34所述的载体、根据实施方案34至39中任一项所述的细胞、或根据实施方案41至43所述的抗体,用于作为药物。
实施方案47:根据实施方案1至23所述的TCR、根据实施方案24至25所述的多肽、根据实施方案26至27中任一项所述的多价TCR复合物、根据实施方案29或30所述的核酸、或根据实施方案35至40中任一项所述的细胞,用于在治疗癌症中使用。
实施方案48.根据实施方案45使用的所述TCR、所述多肽、所述多价TCR复合物、所述核酸或所述细胞,其中所述癌症是血液学癌症。
实施方案49:根据实施方案45使用的所述TCR、所述多肽、所述多价TCR复合物、所述核酸或所述细胞,其中所述血液学癌症选自由以下组成的组:非霍奇金淋巴瘤(NHL)、霍奇金淋巴瘤(HL)、多发性骨髓瘤、急性髓细胞性白血病(AML)和急性淋巴母细胞性白血病(ALL)、混合表型急性白血病(MPAL)、慢性髓细胞性白血病(CML)、B细胞多形性淋巴瘤、毛细胞白血病、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、中枢神经系统淋巴瘤、CD37+树突状细胞淋巴瘤、淋巴母细胞性淋巴瘤、脾边缘区淋巴瘤、浆细胞骨髓瘤、骨外浆细胞瘤、黏膜相关淋巴组织(MALT组织)的结外边缘区B细胞淋巴瘤、结边缘区B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、前体B淋巴母细胞性淋巴瘤、免疫母细胞性大细胞淋巴瘤、血管内大B细胞淋巴瘤、原发渗出性淋巴瘤、伯基特淋巴瘤/白血病、恶性潜能不明的B细胞增殖、淋巴瘤样肉芽肿病、移植后淋巴组织增生性疾病和骨髓增生异常。
序列表
<110> 基因医疗免疫疗法有限责任公司
<120> HA-1特异性T细胞受体及其用途
<130> M11350WO
<150> EP18187539.4
<151> 2018-08-06
<160> 127
<170> PatentIn版本3.5
<210> 1
<211> 1136
<212> PRT
<213> 智人
<400> 1
Met Phe Ser Arg Lys Lys Arg Glu Leu Met Lys Thr Pro Ser Ile Ser
1 5 10 15
Lys Lys Asn Arg Ala Gly Ser Pro Ser Pro Gln Pro Ser Gly Glu Leu
20 25 30
Pro Arg Lys Asp Gly Ala Asp Ala Val Phe Pro Gly Pro Ser Leu Glu
35 40 45
Pro Pro Ala Gly Ser Ser Gly Val Lys Ala Thr Gly Thr Leu Lys Arg
50 55 60
Pro Thr Ser Leu Ser Arg His Ala Ser Ala Ala Gly Phe Pro Leu Ser
65 70 75 80
Gly Ala Ala Ser Trp Thr Leu Gly Arg Ser His Arg Ser Pro Leu Thr
85 90 95
Ala Ala Ser Pro Gly Glu Leu Pro Thr Glu Gly Ala Gly Pro Asp Val
100 105 110
Val Glu Asp Ile Ser His Leu Leu Ala Asp Val Ala Arg Phe Ala Glu
115 120 125
Gly Leu Glu Lys Leu Lys Glu Cys Val Leu His Asp Asp Leu Leu Glu
130 135 140
Ala Arg Arg Pro Arg Ala His Glu Cys Leu Gly Glu Ala Leu Arg Val
145 150 155 160
Met His Gln Ile Ile Ser Lys Tyr Pro Leu Leu Asn Thr Val Glu Thr
165 170 175
Leu Thr Ala Ala Gly Thr Leu Ile Ala Lys Val Lys Ala Phe His Tyr
180 185 190
Glu Ser Asn Asn Asp Leu Glu Lys Gln Glu Phe Glu Lys Ala Leu Glu
195 200 205
Thr Ile Ala Val Ala Phe Ser Ser Thr Val Ser Glu Phe Leu Met Gly
210 215 220
Glu Val Asp Ser Ser Thr Leu Leu Ala Val Pro Pro Gly Asp Ser Ser
225 230 235 240
Gln Ser Met Glu Ser Leu Tyr Gly Pro Gly Ser Glu Gly Thr Pro Pro
245 250 255
Ser Leu Glu Asp Cys Asp Ala Gly Cys Leu Pro Ala Glu Glu Val Asp
260 265 270
Val Leu Leu Gln Arg Cys Glu Gly Gly Val Asp Ala Ala Leu Leu Tyr
275 280 285
Ala Lys Asn Met Ala Lys Tyr Met Lys Asp Leu Ile Ser Tyr Leu Glu
290 295 300
Lys Arg Thr Thr Leu Glu Met Glu Phe Ala Lys Gly Leu Gln Lys Ile
305 310 315 320
Ala His Asn Cys Arg Gln Ser Val Met Gln Glu Pro His Met Pro Leu
325 330 335
Leu Ser Ile Tyr Ser Leu Ala Leu Glu Gln Asp Leu Glu Phe Gly His
340 345 350
Ser Met Val Gln Ala Val Gly Thr Leu Gln Thr Gln Thr Phe Met Gln
355 360 365
Pro Leu Thr Leu Arg Arg Leu Glu His Glu Lys Arg Arg Lys Glu Ile
370 375 380
Lys Glu Ala Trp His Arg Ala Gln Arg Lys Leu Gln Glu Ala Glu Ser
385 390 395 400
Asn Leu Arg Lys Ala Lys Gln Gly Tyr Val Gln Arg Cys Glu Asp His
405 410 415
Asp Lys Ala Arg Phe Leu Val Ala Lys Ala Glu Glu Glu Gln Ala Gly
420 425 430
Ser Ala Pro Gly Ala Gly Ser Thr Ala Thr Lys Thr Leu Asp Lys Arg
435 440 445
Arg Arg Leu Glu Glu Glu Ala Lys Asn Lys Ala Glu Glu Ala Met Ala
450 455 460
Thr Tyr Arg Thr Cys Val Ala Asp Ala Lys Thr Gln Lys Gln Glu Leu
465 470 475 480
Glu Asp Thr Lys Val Thr Ala Leu Arg Gln Ile Gln Glu Val Ile Arg
485 490 495
Gln Ser Asp Gln Thr Ile Lys Ser Ala Thr Ile Ser Tyr Tyr Gln Met
500 505 510
Met His Met Gln Thr Ala Pro Leu Pro Val His Phe Gln Met Leu Cys
515 520 525
Glu Ser Ser Lys Leu Tyr Asp Pro Gly Gln Gln Tyr Ala Ser His Val
530 535 540
Arg Gln Leu Gln Arg Asp Gln Glu Pro Asp Val His Tyr Asp Phe Glu
545 550 555 560
Pro His Val Ser Ala Asn Ala Trp Ser Pro Val Met Arg Ala Arg Lys
565 570 575
Ser Ser Phe Asn Val Ser Asp Val Ala Arg Pro Glu Ala Ala Gly Ser
580 585 590
Pro Pro Glu Glu Gly Gly Cys Thr Glu Gly Thr Pro Ala Lys Asp His
595 600 605
Arg Ala Gly Arg Gly His Gln Val His Lys Ser Trp Pro Leu Ser Ile
610 615 620
Ser Asp Ser Asp Ser Gly Leu Asp Pro Gly Pro Gly Ala Gly Asp Phe
625 630 635 640
Lys Lys Phe Glu Arg Thr Ser Ser Ser Gly Thr Met Ser Ser Thr Glu
645 650 655
Glu Leu Val Asp Pro Asp Gly Gly Ala Gly Ala Ser Ala Phe Glu Gln
660 665 670
Ala Asp Leu Asn Gly Met Thr Pro Glu Leu Pro Val Ala Val Pro Ser
675 680 685
Gly Pro Phe Arg His Glu Gly Leu Ser Lys Ala Ala Arg Thr His Arg
690 695 700
Leu Arg Lys Leu Arg Thr Pro Ala Lys Cys Arg Glu Cys Asn Ser Tyr
705 710 715 720
Val Tyr Phe Gln Gly Ala Glu Cys Glu Glu Cys Cys Leu Ala Cys His
725 730 735
Lys Lys Cys Leu Glu Thr Leu Ala Ile Gln Cys Gly His Lys Lys Leu
740 745 750
Gln Gly Arg Leu Gln Leu Phe Gly Gln Asp Phe Ser His Ala Ala Arg
755 760 765
Ser Ala Pro Asp Gly Val Pro Phe Ile Val Lys Lys Cys Val Cys Glu
770 775 780
Ile Glu Arg Arg Ala Leu Arg Thr Lys Gly Ile Tyr Arg Val Asn Gly
785 790 795 800
Val Lys Thr Arg Val Glu Lys Leu Cys Gln Ala Phe Glu Asn Gly Lys
805 810 815
Glu Leu Val Glu Leu Ser Gln Ala Ser Pro His Asp Ile Ser Asn Val
820 825 830
Leu Lys Leu Tyr Leu Arg Gln Leu Pro Glu Pro Leu Ile Ser Phe Arg
835 840 845
Leu Tyr His Glu Leu Val Gly Leu Ala Lys Asp Ser Leu Lys Ala Glu
850 855 860
Ala Glu Ala Lys Ala Ala Ser Arg Gly Arg Gln Asp Gly Ser Glu Ser
865 870 875 880
Glu Ala Val Ala Val Ala Leu Ala Gly Arg Leu Arg Glu Leu Leu Arg
885 890 895
Asp Leu Pro Pro Glu Asn Arg Ala Ser Leu Gln Tyr Leu Leu Arg His
900 905 910
Leu Arg Arg Ile Val Glu Val Glu Gln Asp Asn Lys Met Thr Pro Gly
915 920 925
Asn Leu Gly Ile Val Phe Gly Pro Thr Leu Leu Arg Pro Arg Pro Thr
930 935 940
Glu Ala Thr Val Ser Leu Ser Ser Leu Val Asp Tyr Pro His Gln Ala
945 950 955 960
Arg Val Ile Glu Thr Leu Ile Val His Tyr Gly Leu Val Phe Glu Glu
965 970 975
Glu Pro Glu Glu Thr Pro Gly Gly Gln Asp Glu Ser Ser Asn Gln Arg
980 985 990
Ala Glu Val Val Val Gln Val Pro Tyr Leu Glu Ala Gly Glu Ala Val
995 1000 1005
Val Tyr Pro Leu Gln Glu Ala Ala Ala Asp Gly Cys Arg Glu Ser
1010 1015 1020
Arg Val Val Ser Asn Asp Ser Asp Ser Asp Leu Glu Glu Ala Ser
1025 1030 1035
Glu Leu Leu Ser Ser Ser Glu Ala Ser Ala Leu Gly His Leu Ser
1040 1045 1050
Phe Leu Glu Gln Gln Gln Ser Glu Ala Ser Leu Glu Val Ala Ser
1055 1060 1065
Gly Ser His Ser Gly Ser Glu Glu Gln Leu Glu Ala Thr Ala Arg
1070 1075 1080
Glu Asp Gly Asp Gly Asp Glu Asp Gly Pro Ala Gln Gln Leu Ser
1085 1090 1095
Gly Phe Asn Thr Asn Gln Ser Asn Asn Val Leu Gln Ala Pro Leu
1100 1105 1110
Pro Pro Met Arg Leu Arg Gly Gly Arg Met Thr Leu Gly Ser Cys
1115 1120 1125
Arg Glu Arg Gln Pro Glu Phe Val
1130 1135
<210> 2
<211> 9
<212> PRT
<213> 智人
<400> 2
Val Leu His Asp Asp Leu Leu Glu Ala
1 5
<210> 3
<211> 1136
<212> PRT
<213> 智人
<400> 3
Met Phe Ser Arg Lys Lys Arg Glu Leu Met Lys Thr Pro Ser Ile Ser
1 5 10 15
Lys Lys Asn Arg Ala Gly Ser Pro Ser Pro Gln Pro Ser Gly Glu Leu
20 25 30
Pro Arg Lys Asp Gly Ala Asp Ala Val Phe Pro Gly Pro Ser Leu Glu
35 40 45
Pro Pro Ala Gly Ser Ser Gly Val Lys Ala Thr Gly Thr Leu Lys Arg
50 55 60
Pro Thr Ser Leu Ser Arg His Ala Ser Ala Ala Gly Phe Pro Leu Ser
65 70 75 80
Gly Ala Ala Ser Trp Thr Leu Gly Arg Ser His Arg Ser Pro Leu Thr
85 90 95
Ala Ala Ser Pro Gly Glu Leu Pro Thr Glu Gly Ala Gly Pro Asp Val
100 105 110
Val Glu Asp Ile Ser His Leu Leu Ala Asp Val Ala Arg Phe Ala Glu
115 120 125
Gly Leu Glu Lys Leu Lys Glu Cys Val Leu Arg Asp Asp Leu Leu Glu
130 135 140
Ala Arg Arg Pro Arg Ala His Glu Cys Leu Gly Glu Ala Leu Arg Val
145 150 155 160
Met His Gln Ile Ile Ser Lys Tyr Pro Leu Leu Asn Thr Val Glu Thr
165 170 175
Leu Thr Ala Ala Gly Thr Leu Ile Ala Lys Val Lys Ala Phe His Tyr
180 185 190
Glu Ser Asn Asn Asp Leu Glu Lys Gln Glu Phe Glu Lys Ala Leu Glu
195 200 205
Thr Ile Ala Val Ala Phe Ser Ser Thr Val Ser Glu Phe Leu Met Gly
210 215 220
Glu Val Asp Ser Ser Thr Leu Leu Ala Val Pro Pro Gly Asp Ser Ser
225 230 235 240
Gln Ser Met Glu Ser Leu Tyr Gly Pro Gly Ser Glu Gly Thr Pro Pro
245 250 255
Ser Leu Glu Asp Cys Asp Ala Gly Cys Leu Pro Ala Glu Glu Val Asp
260 265 270
Val Leu Leu Gln Arg Cys Glu Gly Gly Val Asp Ala Ala Leu Leu Tyr
275 280 285
Ala Lys Asn Met Ala Lys Tyr Met Lys Asp Leu Ile Ser Tyr Leu Glu
290 295 300
Lys Arg Thr Thr Leu Glu Met Glu Phe Ala Lys Gly Leu Gln Lys Ile
305 310 315 320
Ala His Asn Cys Arg Gln Ser Val Met Gln Glu Pro His Met Pro Leu
325 330 335
Leu Ser Ile Tyr Ser Leu Ala Leu Glu Gln Asp Leu Glu Phe Gly His
340 345 350
Ser Met Val Gln Ala Val Gly Thr Leu Gln Thr Gln Thr Phe Met Gln
355 360 365
Pro Leu Thr Leu Arg Arg Leu Glu His Glu Lys Arg Arg Lys Glu Ile
370 375 380
Lys Glu Ala Trp His Arg Ala Gln Arg Lys Leu Gln Glu Ala Glu Ser
385 390 395 400
Asn Leu Arg Lys Ala Lys Gln Gly Tyr Val Gln Arg Cys Glu Asp His
405 410 415
Asp Lys Ala Arg Phe Leu Val Ala Lys Ala Glu Glu Glu Gln Ala Gly
420 425 430
Ser Ala Pro Gly Ala Gly Ser Thr Ala Thr Lys Thr Leu Asp Lys Arg
435 440 445
Arg Arg Leu Glu Glu Glu Ala Lys Asn Lys Ala Glu Glu Ala Met Ala
450 455 460
Thr Tyr Arg Thr Cys Val Ala Asp Ala Lys Thr Gln Lys Gln Glu Leu
465 470 475 480
Glu Asp Thr Lys Val Thr Ala Leu Arg Gln Ile Gln Glu Val Ile Arg
485 490 495
Gln Ser Asp Gln Thr Ile Lys Ser Ala Thr Ile Ser Tyr Tyr Gln Met
500 505 510
Met His Met Gln Thr Ala Pro Leu Pro Val His Phe Gln Met Leu Cys
515 520 525
Glu Ser Ser Lys Leu Tyr Asp Pro Gly Gln Gln Tyr Ala Ser His Val
530 535 540
Arg Gln Leu Gln Arg Asp Gln Glu Pro Asp Val His Tyr Asp Phe Glu
545 550 555 560
Pro His Val Ser Ala Asn Ala Trp Ser Pro Val Met Arg Ala Arg Lys
565 570 575
Ser Ser Phe Asn Val Ser Asp Val Ala Arg Pro Glu Ala Ala Gly Ser
580 585 590
Pro Pro Glu Glu Gly Gly Cys Thr Glu Gly Thr Pro Ala Lys Asp His
595 600 605
Arg Ala Gly Arg Gly His Gln Val His Lys Ser Trp Pro Leu Ser Ile
610 615 620
Ser Asp Ser Asp Ser Gly Leu Asp Pro Gly Pro Gly Ala Gly Asp Phe
625 630 635 640
Lys Lys Phe Glu Arg Thr Ser Ser Ser Gly Thr Met Ser Ser Thr Glu
645 650 655
Glu Leu Val Asp Pro Asp Gly Gly Ala Gly Ala Ser Ala Phe Glu Gln
660 665 670
Ala Asp Leu Asn Gly Met Thr Pro Glu Leu Pro Val Ala Val Pro Ser
675 680 685
Gly Pro Phe Arg His Glu Gly Leu Ser Lys Ala Ala Arg Thr His Arg
690 695 700
Leu Arg Lys Leu Arg Thr Pro Ala Lys Cys Arg Glu Cys Asn Ser Tyr
705 710 715 720
Val Tyr Phe Gln Gly Ala Glu Cys Glu Glu Cys Cys Leu Ala Cys His
725 730 735
Lys Lys Cys Leu Glu Thr Leu Ala Ile Gln Cys Gly His Lys Lys Leu
740 745 750
Gln Gly Arg Leu Gln Leu Phe Gly Gln Asp Phe Ser His Ala Ala Arg
755 760 765
Ser Ala Pro Asp Gly Val Pro Phe Ile Val Lys Lys Cys Val Cys Glu
770 775 780
Ile Glu Arg Arg Ala Leu Arg Thr Lys Gly Ile Tyr Arg Val Asn Gly
785 790 795 800
Val Lys Thr Arg Val Glu Lys Leu Cys Gln Ala Phe Glu Asn Gly Lys
805 810 815
Glu Leu Val Glu Leu Ser Gln Ala Ser Pro His Asp Ile Ser Asn Val
820 825 830
Leu Lys Leu Tyr Leu Arg Gln Leu Pro Glu Pro Leu Ile Ser Phe Arg
835 840 845
Leu Tyr His Glu Leu Val Gly Leu Ala Lys Asp Ser Leu Lys Ala Glu
850 855 860
Ala Glu Ala Lys Ala Ala Ser Arg Gly Arg Gln Asp Gly Ser Glu Ser
865 870 875 880
Glu Ala Val Ala Val Ala Leu Ala Gly Arg Leu Arg Glu Leu Leu Arg
885 890 895
Asp Leu Pro Pro Glu Asn Arg Ala Ser Leu Gln Tyr Leu Leu Arg His
900 905 910
Leu Arg Arg Ile Val Glu Val Glu Gln Asp Asn Lys Met Thr Pro Gly
915 920 925
Asn Leu Gly Ile Val Phe Gly Pro Thr Leu Leu Arg Pro Arg Pro Thr
930 935 940
Glu Ala Thr Val Ser Leu Ser Ser Leu Val Asp Tyr Pro His Gln Ala
945 950 955 960
Arg Val Ile Glu Thr Leu Ile Val His Tyr Gly Leu Val Phe Glu Glu
965 970 975
Glu Pro Glu Glu Thr Pro Gly Gly Gln Asp Glu Ser Ser Asn Gln Arg
980 985 990
Ala Glu Val Val Val Gln Val Pro Tyr Leu Glu Ala Gly Glu Ala Val
995 1000 1005
Val Tyr Pro Leu Gln Glu Ala Ala Ala Asp Gly Cys Arg Glu Ser
1010 1015 1020
Arg Val Val Ser Asn Asp Ser Asp Ser Asp Leu Glu Glu Ala Ser
1025 1030 1035
Glu Leu Leu Ser Ser Ser Glu Ala Ser Ala Leu Gly His Leu Ser
1040 1045 1050
Phe Leu Glu Gln Gln Gln Ser Glu Ala Ser Leu Glu Val Ala Ser
1055 1060 1065
Gly Ser His Ser Gly Ser Glu Glu Gln Leu Glu Ala Thr Ala Arg
1070 1075 1080
Glu Asp Gly Asp Gly Asp Glu Asp Gly Pro Ala Gln Gln Leu Ser
1085 1090 1095
Gly Phe Asn Thr Asn Gln Ser Asn Asn Val Leu Gln Ala Pro Leu
1100 1105 1110
Pro Pro Met Arg Leu Arg Gly Gly Arg Met Thr Leu Gly Ser Cys
1115 1120 1125
Arg Glu Arg Gln Pro Glu Phe Val
1130 1135
<210> 4
<211> 9
<212> PRT
<213> 智人
<400> 4
Val Leu Arg Asp Asp Leu Leu Glu Ala
1 5
<210> 5
<211> 6
<212> PRT
<213> 智人
<400> 5
Asp Ser Ala Ser Asn Tyr
1 5
<210> 6
<211> 7
<212> PRT
<213> 智人
<400> 6
Ile Arg Ser Asn Val Gly Glu
1 5
<210> 7
<211> 8
<212> PRT
<213> 智人
<400> 7
Cys Ala Ala Ser Asp Leu Asn Phe
1 5
<210> 8
<211> 5
<212> PRT
<213> 智人
<400> 8
Ser Glu His Asn Arg
1 5
<210> 9
<211> 6
<212> PRT
<213> 智人
<400> 9
Phe Gln Asn Glu Ala Gln
1 5
<210> 10
<211> 14
<212> PRT
<213> 智人
<400> 10
Cys Ala Ser Ser Leu Val Ser Arg Val Asp Gly Tyr Thr Phe
1 5 10
<210> 11
<211> 127
<212> PRT
<213> 智人
<400> 11
Met Thr Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala Ser
100 105 110
Asp Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His
115 120 125
<210> 12
<211> 134
<212> PRT
<213> 智人
<400> 12
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Ser Arg Val Asp Gly Tyr Thr Phe Gly Ser Gly Thr
115 120 125
Arg Leu Thr Val Val Glu
130
<210> 13
<211> 263
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 13
Met Thr Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala Ser
100 105 110
Asp Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val Thr Pro His Ile
115 120 125
Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln
130 135 140
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val
145 150 155 160
Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr Val Leu
165 170 175
Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser
180 185 190
Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala
195 200 205
Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys
210 215 220
Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser Val Met
225 230 235 240
Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
245 250 255
Thr Leu Arg Leu Trp Ser Ser
260
<210> 14
<211> 306
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 14
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Ser Arg Val Asp Gly Tyr Thr Phe Gly Ser Gly Thr
115 120 125
Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Thr Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys
290 295 300
Asn Ser
305
<210> 15
<211> 6
<212> PRT
<213> 智人
<400> 15
Asp Ser Ala Ser Asn Tyr
1 5
<210> 16
<211> 7
<212> PRT
<213> 智人
<400> 16
Ile Arg Ser Asn Val Gly Glu
1 5
<210> 17
<211> 13
<212> PRT
<213> 智人
<400> 17
Cys Ala Ala His Thr Pro Gly Tyr Ser Thr Leu Thr Phe
1 5 10
<210> 18
<211> 5
<212> PRT
<213> 智人
<400> 18
Ser Glu His Asn Arg
1 5
<210> 19
<211> 6
<212> PRT
<213> 智人
<400> 19
Phe Gln Asn Glu Ala Gln
1 5
<210> 20
<211> 14
<212> PRT
<213> 智人
<400> 20
Cys Ala Ser Ser Pro Arg Ala Gly Gly Glu Thr Gln Tyr Phe
1 5 10
<210> 21
<211> 132
<212> PRT
<213> 智人
<400> 21
Met Thr Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala His
100 105 110
Thr Pro Gly Tyr Ser Thr Leu Thr Phe Gly Lys Gly Thr Met Leu Leu
115 120 125
Val Ser Pro Asp
130
<210> 22
<211> 134
<212> PRT
<213> 智人
<400> 22
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Arg Ala Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu
130
<210> 23
<211> 268
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 23
Met Thr Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala His
100 105 110
Thr Pro Gly Tyr Ser Thr Leu Thr Phe Gly Lys Gly Thr Met Leu Leu
115 120 125
Val Ser Pro Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
130 135 140
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
165 170 175
Asp Lys Thr Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
180 185 190
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
195 200 205
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
210 215 220
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 24
<211> 306
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 24
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Arg Ala Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Thr Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys
290 295 300
Asn Ser
305
<210> 25
<211> 5
<212> PRT
<213> 智人
<400> 25
Thr Ser Ile Asn Asn
1 5
<210> 26
<211> 7
<212> PRT
<213> 智人
<400> 26
Ile Arg Ser Asn Glu Arg Glu
1 5
<210> 27
<211> 14
<212> PRT
<213> 智人
<400> 27
Cys Ala Thr Gly Asp Gln Thr Gly Ala Asn Asn Leu Phe Phe
1 5 10
<210> 28
<211> 5
<212> PRT
<213> 智人
<400> 28
Ser Glu His Asn Arg
1 5
<210> 29
<211> 6
<212> PRT
<213> 智人
<400> 29
Phe Gln Asn Glu Ala Gln
1 5
<210> 30
<211> 13
<212> PRT
<213> 智人
<400> 30
Cys Ala Ser Ser Leu Thr Arg Thr Glu Lys Leu Phe Phe
1 5 10
<210> 31
<211> 133
<212> PRT
<213> 智人
<400> 31
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 Gly
100 105 110
Asp Gln Thr Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu
115 120 125
Thr Val Ile Pro Tyr
130
<210> 32
<211> 133
<212> PRT
<213> 智人
<400> 32
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Thr Arg Thr Glu Lys Leu Phe Phe Gly Ser Gly Thr Gln
115 120 125
Leu Ser Val Leu Glu
130
<210> 33
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 33
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 Gly
100 105 110
Asp Gln Thr Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu
115 120 125
Thr Val Ile Pro Tyr Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu
130 135 140
Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn
180 185 190
Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile
195 200 205
Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp
210 215 220
Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe
225 230 235 240
Gln Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala
245 250 255
Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 34
<211> 305
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 34
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Thr Arg Thr Glu Lys Leu Phe Phe Gly Ser Gly Thr Gln
115 120 125
Leu Ser Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Thr
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn
290 295 300
Ser
305
<210> 35
<211> 6
<212> PRT
<213> 智人
<400> 35
Asp Ser Ala Ser Asn Tyr
1 5
<210> 36
<211> 7
<212> PRT
<213> 智人
<400> 36
Ile Arg Ser Asn Val Gly Glu
1 5
<210> 37
<211> 9
<212> PRT
<213> 智人
<400> 37
Cys Ala Gly Arg Gly Lys Leu Thr Phe
1 5
<210> 38
<211> 5
<212> PRT
<213> 智人
<400> 38
Ser Glu His Asn Arg
1 5
<210> 39
<211> 6
<212> PRT
<213> 智人
<400> 39
Phe Gln Asn Glu Ala Gln
1 5
<210> 40
<211> 13
<212> PRT
<213> 智人
<400> 40
Cys Ala Ser Ser Leu Val Arg Asp Glu Lys Leu Phe Phe
1 5 10
<210> 41
<211> 128
<212> PRT
<213> 智人
<400> 41
Met Thr Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Gly Arg
100 105 110
Gly Lys Leu Thr Phe Gly Thr Gly Thr Arg Leu Thr Ile Ile Pro Asn
115 120 125
<210> 42
<211> 133
<212> PRT
<213> 智人
<400> 42
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Arg Asp Glu Lys Leu Phe Phe Gly Ser Gly Thr Gln
115 120 125
Leu Ser Val Leu Glu
130
<210> 43
<211> 264
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 43
Met Thr Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Gly Arg
100 105 110
Gly Lys Leu Thr Phe Gly Thr Gly Thr Arg Leu Thr Ile Ile Pro Asn
115 120 125
Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser
130 135 140
Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn
145 150 155 160
Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp
180 185 190
Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn
195 200 205
Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu
210 215 220
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser Val
225 230 235 240
Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu
245 250 255
Met Thr Leu Arg Leu Trp Ser Ser
260
<210> 44
<211> 305
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 44
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Arg Asp Glu Lys Leu Phe Phe Gly Ser Gly Thr Gln
115 120 125
Leu Ser Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Thr
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn
290 295 300
Ser
305
<210> 45
<211> 5
<212> PRT
<213> 智人
<400> 45
Ser Val Phe Ser Ser
1 5
<210> 46
<211> 7
<212> PRT
<213> 智人
<400> 46
Val Val Thr Gly Gly Glu Val
1 5
<210> 47
<211> 11
<212> PRT
<213> 智人
<400> 47
Cys Ala Gly Ala Gly Asn Asn Asp Met Arg Phe
1 5 10
<210> 48
<211> 5
<212> PRT
<213> 智人
<400> 48
Ser Glu His Asn Arg
1 5
<210> 49
<211> 6
<212> PRT
<213> 智人
<400> 49
Phe Gln Asn Glu Ala Gln
1 5
<210> 50
<211> 13
<212> PRT
<213> 智人
<400> 50
Cys Ala Ser Ser Leu Val Arg Gly Ile Glu Ala Phe Phe
1 5 10
<210> 51
<211> 128
<212> PRT
<213> 智人
<400> 51
Met Val Leu Lys Phe Ser Val Ser Ile Leu Trp Ile Gln Leu Ala Trp
1 5 10 15
Val Ser Thr Gln Leu Leu Glu Gln Ser Pro Gln Phe Leu Ser Ile Gln
20 25 30
Glu Gly Glu Asn Leu Thr Val Tyr Cys Asn Ser Ser Ser Val Phe Ser
35 40 45
Ser Leu Gln Trp Tyr Arg Gln Glu Pro Gly Glu Gly Pro Val Leu Leu
50 55 60
Val Thr Val Val Thr Gly Gly Glu Val Lys Lys Leu Lys Arg Leu Thr
65 70 75 80
Phe Gln Phe Gly Asp Ala Arg Lys Asp Ser Ser Leu His Ile Thr Ala
85 90 95
Ala Gln Thr Gly Asp Thr Gly Leu Tyr Leu Cys Ala Gly Ala Gly Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
<210> 52
<211> 133
<212> PRT
<213> 智人
<400> 52
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Arg Gly Ile Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val Glu
130
<210> 53
<211> 264
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 53
Met Val Leu Lys Phe Ser Val Ser Ile Leu Trp Ile Gln Leu Ala Trp
1 5 10 15
Val Ser Thr Gln Leu Leu Glu Gln Ser Pro Gln Phe Leu Ser Ile Gln
20 25 30
Glu Gly Glu Asn Leu Thr Val Tyr Cys Asn Ser Ser Ser Val Phe Ser
35 40 45
Ser Leu Gln Trp Tyr Arg Gln Glu Pro Gly Glu Gly Pro Val Leu Leu
50 55 60
Val Thr Val Val Thr Gly Gly Glu Val Lys Lys Leu Lys Arg Leu Thr
65 70 75 80
Phe Gln Phe Gly Asp Ala Arg Lys Asp Ser Ser Leu His Ile Thr Ala
85 90 95
Ala Gln Thr Gly Asp Thr Gly Leu Tyr Leu Cys Ala Gly Ala Gly Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser
130 135 140
Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn
145 150 155 160
Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp
180 185 190
Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn
195 200 205
Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu
210 215 220
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser Val
225 230 235 240
Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu
245 250 255
Met Thr Leu Arg Leu Trp Ser Ser
260
<210> 54
<211> 305
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 54
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Arg Gly Ile Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Thr
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn
290 295 300
Ser
305
<210> 55
<211> 6
<212> PRT
<213> 智人
<400> 55
Asp Ser Ser Ser Thr Tyr
1 5
<210> 56
<211> 7
<212> PRT
<213> 智人
<400> 56
Ile Phe Ser Asn Met Asp Met
1 5
<210> 57
<211> 8
<212> PRT
<213> 智人
<400> 57
Cys Ala Glu Lys Trp Ile Ile Phe
1 5
<210> 58
<211> 5
<212> PRT
<213> 智人
<400> 58
Ser Glu His Asn Arg
1 5
<210> 59
<211> 6
<212> PRT
<213> 智人
<400> 59
Phe Gln Asn Glu Ala Gln
1 5
<210> 60
<211> 13
<212> PRT
<213> 智人
<400> 60
Cys Ala Ser Ser Leu Thr Thr Pro Asp Gly Tyr Thr Phe
1 5 10
<210> 61
<211> 128
<212> PRT
<213> 智人
<400> 61
Met Lys Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Lys Trp Ile Ile Phe Gly Lys Gly Thr Arg Leu His Ile Leu Pro Asn
115 120 125
<210> 62
<211> 133
<212> PRT
<213> 智人
<400> 62
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Thr Thr Pro Asp Gly Tyr Thr Phe Gly Ser Gly Thr Arg
115 120 125
Leu Thr Val Val Glu
130
<210> 63
<211> 264
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 63
Met Lys Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Lys Trp Ile Ile Phe Gly Lys Gly Thr Arg Leu His Ile Leu Pro Asn
115 120 125
Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser
130 135 140
Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn
145 150 155 160
Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp
180 185 190
Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn
195 200 205
Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu
210 215 220
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser Val
225 230 235 240
Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu
245 250 255
Met Thr Leu Arg Leu Trp Ser Ser
260
<210> 64
<211> 305
<212> PRT
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人
<400> 64
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Thr Gly Val Ser Gln Asn Pro Arg His Lys Ile Thr
20 25 30
Lys Arg Gly Gln Asn Val Thr Phe Arg Cys Asp Pro Ile Ser Glu His
35 40 45
Asn Arg Leu Tyr Trp Tyr Arg Gln Thr Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Glu Lys Ser Arg Leu Leu
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Pro Lys Gly Ser Phe Ser Thr Leu
85 90 95
Glu Ile Gln Arg Thr Glu Gln Gly Asp Ser Ala Met Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Thr Thr Pro Asp Gly Tyr Thr Phe Gly Ser Gly Thr Arg
115 120 125
Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Thr
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn
290 295 300
Ser
305
<210> 65
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 对照肽Astn1 P1268L
<400> 65
Lys Leu Tyr Gly Leu Asp Trp Ala Glu Leu
1 5 10
<210> 66
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 66
gacagcgcca gcaactac 18
<210> 67
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 67
atcagatcca acgtgggcga g 21
<210> 68
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 68
tgcgccgcca gcgacctgaa tttt 24
<210> 69
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 69
agcgagcaca accgg 15
<210> 70
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 70
ttccagaacg aggcccag 18
<210> 71
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 71
tgtgccagca gcctggtgtc cagagtggat ggctacacat tt 42
<210> 72
<211> 379
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 72
atgaccagca tccgggccgt gttcatcttc ctgtggctgc agctggacct ggtcaacggc 60
gagaatgtgg aacagcaccc cagcacactg agcgtgcaag agggcgattc tgccgtgatc 120
aagtgcacct acagcgacag cgccagcaac tacttcccct ggtacaagca agaactcggc 180
aagggccctc agctgatcat cgacatcaga tccaacgtgg gcgagaagaa ggaccagcgg 240
attgccgtga cactgaacaa gaccgccaag cacttcagcc tgcacatcac cgagacacag 300
cctgaggata gcgccgtgta cttttgcgcc gccagcgacc tgaattttgg caagggcaca 360
agcctgctgg tcacccctc 379
<210> 73
<211> 400
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 73
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagca gcctggtgtc cagagtggat 360
ggctacacat ttggcagcgg caccagactg acagtggtgg 400
<210> 74
<211> 792
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 74
atgaccagca tccgggccgt gttcatcttc ctgtggctgc agctggacct ggtcaacggc 60
gagaatgtgg aacagcaccc cagcacactg agcgtgcaag agggcgattc tgccgtgatc 120
aagtgcacct acagcgacag cgccagcaac tacttcccct ggtacaagca agaactcggc 180
aagggccctc agctgatcat cgacatcaga tccaacgtgg gcgagaagaa ggaccagcgg 240
attgccgtga cactgaacaa gaccgccaag cacttcagcc tgcacatcac cgagacacag 300
cctgaggata gcgccgtgta cttttgcgcc gccagcgacc tgaattttgg caagggcaca 360
agcctgctgg tcacccctca catccagaat ccggagcccg ccgtatacca gctgaaggac 420
cctagaagcc aggacagcac cctgtgcctg ttcaccgact tcgacagcca gatcaacgtg 480
cccaagacca tggaaagcgg caccttcatc accgacaaga cagtgctgga catgaaggcc 540
atggacagca agtccaacgg cgcaatcgcc tggtccaacc agaccagctt cacatgccag 600
gacatcttca aagagacaaa cgccacatac cccagcagcg acgtgccctg tgatgccacc 660
ctgacagaga agtccttcga gacagacatg aacctgaact tccagaatct gtccgtgatg 720
ggcctgagaa tcctgctgct gaaggtggcc ggcttcaatc tgctgatgac cctgcggctg 780
tggtccagct ga 792
<210> 75
<211> 921
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 75
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagca gcctggtgtc cagagtggat 360
ggctacacat ttggcagcgg caccagactg acagtggtgg aagatctccg gaacgtgacc 420
ccccctaaag tgaccctgtt cgaacccagc aaggccgaga tcgccaacaa gcagaaagcc 480
accctcgtgt gcctggccag aggcttcttc cccgaccatg tggaactgtc ttggtgggtc 540
aacggcaaag aggtgcacag cggagtgtcc accgaccctc aggcctacaa agagagcaac 600
tacagctact gcctgagcag cagactgcgg gtgtccgcca ccttctggca caacccccgg 660
aaccacttca gatgccaggt gcagtttcac ggcctgagcg aagaggacaa gtggcccgaa 720
ggctccccca agcccgtgac ccagaatatc tctgccgagg cctggggcag agccgactgt 780
ggaattacca gcgccagcta ccaccagggc gtgctgtctg ccaccatcct gtacgagatc 840
ctgctgggca aggccaccct gtacgccgtg ctggtgtctg gcctggtgct gatggccatg 900
gtcaagaaga agaacagctg a 921
<210> 76
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 76
gacagcgcca gcaactac 18
<210> 77
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 77
atcagatcca acgtgggcga g 21
<210> 78
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 78
tgcgccgctc acacacctgg ctacagcacc ctgacattt 39
<210> 79
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 79
agcgagcaca accgg 15
<210> 80
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 80
ttccagaacg aggcccag 18
<210> 81
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 81
tgtgctagct ctcctagagc cggcggagag acacagtatt tc 42
<210> 82
<211> 394
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 82
atgaccagca tccgggccgt gttcatcttc ctgtggctgc agctggacct ggtcaacggc 60
gagaatgtgg aacagcaccc cagcacactg agcgtgcaag agggcgattc tgccgtgatc 120
aagtgcacct acagcgacag cgccagcaac tacttcccct ggtacaagca agaactcggc 180
aagggccctc agctgatcat cgacatcaga tccaacgtgg gcgagaagaa ggaccagcgg 240
attgccgtga cactgaacaa gaccgccaag cacttcagcc tgcacatcac cgagacacag 300
cctgaggata gcgccgtgta cttctgcgcc gctcacacac ctggctacag caccctgaca 360
tttggcaagg gcaccatgct gctggtgtcc ccag 394
<210> 83
<211> 400
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 83
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtacctg tgtgctagct ctcctagagc cggcggagag 360
acacagtatt tcggccctgg aacacggctg ctggttctgg 400
<210> 84
<211> 807
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 84
atgaccagca tccgggccgt gttcatcttc ctgtggctgc agctggacct ggtcaacggc 60
gagaatgtgg aacagcaccc cagcacactg agcgtgcaag agggcgattc tgccgtgatc 120
aagtgcacct acagcgacag cgccagcaac tacttcccct ggtacaagca agaactcggc 180
aagggccctc agctgatcat cgacatcaga tccaacgtgg gcgagaagaa ggaccagcgg 240
attgccgtga cactgaacaa gaccgccaag cacttcagcc tgcacatcac cgagacacag 300
cctgaggata gcgccgtgta cttctgcgcc gctcacacac ctggctacag caccctgaca 360
tttggcaagg gcaccatgct gctggtgtcc ccagacatcc agaatccgga gcccgccgta 420
taccagctga aggaccctag aagccaggac agcaccctgt gcctgttcac cgacttcgac 480
agccagatca acgtgcccaa gaccatggaa agcggcacct tcatcaccga caagacagtg 540
ctggacatga aggccatgga cagcaagtcc aacggcgcaa tcgcctggtc caaccagacc 600
agcttcacat gccaggacat cttcaaagag acaaacgcca cataccccag cagcgacgtg 660
ccctgtgatg ccaccctgac agagaagtcc ttcgagacag acatgaacct gaacttccag 720
aatctgtccg tgatgggcct gagaatcctg ctgctgaagg tggccggctt caatctgctg 780
atgaccctgc ggctgtggtc cagctga 807
<210> 85
<211> 921
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 85
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtacctg tgtgctagct ctcctagagc cggcggagag 360
acacagtatt tcggccctgg aacacggctg ctggttctgg aagatctccg gaacgtgacc 420
ccccctaaag tgaccctgtt cgaacccagc aaggccgaga tcgccaacaa gcagaaagcc 480
accctcgtgt gcctggccag aggcttcttc cccgaccatg tggaactgtc ttggtgggtc 540
aacggcaaag aggtgcacag cggagtgtcc accgaccctc aggcctacaa agagagcaac 600
tacagctact gcctgagcag cagactgcgg gtgtccgcca ccttctggca caacccccgg 660
aaccacttca gatgccaggt gcagtttcac ggcctgagcg aagaggacaa gtggcccgaa 720
ggctccccca agcccgtgac ccagaatatc tctgccgagg cctggggcag agccgactgt 780
ggaattacca gcgccagcta ccaccagggc gtgctgtctg ccaccatcct gtacgagatc 840
ctgctgggca aggccaccct gtacgccgtg ctggtgtctg gcctggtgct gatggccatg 900
gtcaagaaga agaacagctg a 921
<210> 86
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 86
accagcatca acaac 15
<210> 87
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 87
atcagaagca acgagagaga g 21
<210> 88
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 88
tgcgccactg gcgatcagac cggcgccaac aatctgttct tt 42
<210> 89
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 89
agcgagcaca accgg 15
<210> 90
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 90
ttccagaacg aggcccag 18
<210> 91
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 91
tgtgccagca gcctgaccag aaccgagaag ctgtttttc 39
<210> 92
<211> 397
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 92
atggaaacac tgctgggcgt gtccctggtc atcctgtggc tgcaactggc cagagtgaac 60
agccagcagg gcgaagaaga tccccaggct ctgtctatcc aagagggcga gaacgccacc 120
atgaactgca gctacaagac cagcatcaac aacctgcagt ggtacagaca gaacagcggc 180
agaggactgg tgcacctgat cctgatcaga agcaacgaga gagagaagca ctccggcaga 240
ctgagagtga ccctggacac cagcaagaag tccagcagcc tgctgatcac cgcctctaga 300
gctgccgata ccgccagcta cttttgcgcc actggcgatc agaccggcgc caacaatctg 360
ttctttggca ccggaaccag gctgacagtg atccctt 397
<210> 93
<211> 397
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 93
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagca gcctgaccag aaccgagaag 360
ctgtttttcg gcagcggcac ccagctgtct gttctgg 397
<210> 94
<211> 810
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 94
atggaaacac tgctgggcgt gtccctggtc atcctgtggc tgcaactggc cagagtgaac 60
agccagcagg gcgaagaaga tccccaggct ctgtctatcc aagagggcga gaacgccacc 120
atgaactgca gctacaagac cagcatcaac aacctgcagt ggtacagaca gaacagcggc 180
agaggactgg tgcacctgat cctgatcaga agcaacgaga gagagaagca ctccggcaga 240
ctgagagtga ccctggacac cagcaagaag tccagcagcc tgctgatcac cgcctctaga 300
gctgccgata ccgccagcta cttttgcgcc actggcgatc agaccggcgc caacaatctg 360
ttctttggca ccggaaccag gctgacagtg atcccttaca tccagaatcc ggagcccgcc 420
gtataccagc tgaaggaccc tagaagccag gacagcaccc tgtgcctgtt caccgacttc 480
gacagccaga tcaacgtgcc caagaccatg gaaagcggca ccttcatcac cgacaagaca 540
gtgctggaca tgaaggccat ggacagcaag tccaacggcg caatcgcctg gtccaaccag 600
accagcttca catgccagga catcttcaaa gagacaaacg ccacataccc cagcagcgac 660
gtgccctgtg atgccaccct gacagagaag tccttcgaga cagacatgaa cctgaacttc 720
cagaatctgt ccgtgatggg cctgagaatc ctgctgctga aggtggccgg cttcaatctg 780
ctgatgaccc tgcggctgtg gtccagctga 810
<210> 95
<211> 918
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 95
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagca gcctgaccag aaccgagaag 360
ctgtttttcg gcagcggcac ccagctgtct gttctggaag atctccggaa cgtgaccccc 420
cctaaagtga ccctgttcga acccagcaag gccgagatcg ccaacaagca gaaagccacc 480
ctcgtgtgcc tggccagagg cttcttcccc gaccatgtgg aactgtcttg gtgggtcaac 540
ggcaaagagg tgcacagcgg agtgtccacc gaccctcagg cctacaaaga gagcaactac 600
agctactgcc tgagcagcag actgcgggtg tccgccacct tctggcacaa cccccggaac 660
cacttcagat gccaggtgca gtttcacggc ctgagcgaag aggacaagtg gcccgaaggc 720
tcccccaagc ccgtgaccca gaatatctct gccgaggcct ggggcagagc cgactgtgga 780
attaccagcg ccagctacca ccagggcgtg ctgtctgcca ccatcctgta cgagatcctg 840
ctgggcaagg ccaccctgta cgccgtgctg gtgtctggcc tggtgctgat ggccatggtc 900
aagaagaaga acagctga 918
<210> 96
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 96
gacagcgcca gcaactac 18
<210> 97
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 97
atcagatcca acgtgggcga g 21
<210> 98
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 98
tgtgccggca gaggcaagct gaccttt 27
<210> 99
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 99
agcgagcaca accgg 15
<210> 100
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 100
ttccagaacg aggcccag 18
<210> 101
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 101
tgtgccagtt ctctcgtgcg ggacgagaag ctgtttttc 39
<210> 102
<211> 382
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 102
atgaccagca tccgggccgt gttcatcttc ctgtggctgc agctggacct ggtcaacggc 60
gagaatgtgg aacagcaccc cagcacactg agcgtgcaag agggcgattc tgccgtgatc 120
aagtgcacct acagcgacag cgccagcaac tacttcccct ggtacaagca agaactcggc 180
aagggccctc agctgatcat cgacatcaga tccaacgtgg gcgagaagaa ggaccagcgg 240
attgccgtga cactgaacaa gaccgccaag cacttcagcc tgcacatcac cgagacacag 300
cctgaggata gcgccgtgta cttctgtgcc ggcagaggca agctgacctt tggcacaggc 360
acccggctga caatcatccc ta 382
<210> 103
<211> 397
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 103
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagtt ctctcgtgcg ggacgagaag 360
ctgtttttcg gcagcggcac acagctgagc gttctgg 397
<210> 104
<211> 795
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 104
atgaccagca tccgggccgt gttcatcttc ctgtggctgc agctggacct ggtcaacggc 60
gagaatgtgg aacagcaccc cagcacactg agcgtgcaag agggcgattc tgccgtgatc 120
aagtgcacct acagcgacag cgccagcaac tacttcccct ggtacaagca agaactcggc 180
aagggccctc agctgatcat cgacatcaga tccaacgtgg gcgagaagaa ggaccagcgg 240
attgccgtga cactgaacaa gaccgccaag cacttcagcc tgcacatcac cgagacacag 300
cctgaggata gcgccgtgta cttctgtgcc ggcagaggca agctgacctt tggcacaggc 360
acccggctga caatcatccc taacatccag aatccggagc ccgccgtata ccagctgaag 420
gaccctagaa gccaggacag caccctgtgc ctgttcaccg acttcgacag ccagatcaac 480
gtgcccaaga ccatggaaag cggcaccttc atcaccgaca agacagtgct ggacatgaag 540
gccatggaca gcaagtccaa cggcgcaatc gcctggtcca accagaccag cttcacatgc 600
caggacatct tcaaagagac aaacgccaca taccccagca gcgacgtgcc ctgtgatgcc 660
accctgacag agaagtcctt cgagacagac atgaacctga acttccagaa tctgtccgtg 720
atgggcctga gaatcctgct gctgaaggtg gccggcttca atctgctgat gaccctgcgg 780
ctgtggtcca gctga 795
<210> 105
<211> 918
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 105
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagtt ctctcgtgcg ggacgagaag 360
ctgtttttcg gcagcggcac acagctgagc gttctggaag atctccggaa cgtgaccccc 420
cctaaagtga ccctgttcga acccagcaag gccgagatcg ccaacaagca gaaagccacc 480
ctcgtgtgcc tggccagagg cttcttcccc gaccatgtgg aactgtcttg gtgggtcaac 540
ggcaaagagg tgcacagcgg agtgtccacc gaccctcagg cctacaaaga gagcaactac 600
agctactgcc tgagcagcag actgcgggtg tccgccacct tctggcacaa cccccggaac 660
cacttcagat gccaggtgca gtttcacggc ctgagcgaag aggacaagtg gcccgaaggc 720
tcccccaagc ccgtgaccca gaatatctct gccgaggcct ggggcagagc cgactgtgga 780
attaccagcg ccagctacca ccagggcgtg ctgtctgcca ccatcctgta cgagatcctg 840
ctgggcaagg ccaccctgta cgccgtgctg gtgtctggcc tggtgctgat ggccatggtc 900
aagaagaaga acagctga 918
<210> 106
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 106
agcgtgttca gcagc 15
<210> 107
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 107
gttgtgacag gcggcgaagt g 21
<210> 108
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 108
tgtgccggcg ctggcaacaa cgacatgaga ttt 33
<210> 109
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 109
agcgagcaca accgg 15
<210> 110
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 110
ttccagaacg aggcccag 18
<210> 111
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 111
tgtgcctctt ctctcgtgcg gggcatcgag gcctttttt 39
<210> 112
<211> 382
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 112
atggtgctga agttcagcgt gtccatcctg tggatccagc tggcctgggt ttccacacag 60
ctgctggaac agagccctca gttcctgagc atccaagagg gcgagaacct gaccgtgtac 120
tgcaacagca gcagcgtgtt cagcagcctg cagtggtaca gacaagagcc tggcgaagga 180
cctgtgctgc tggtcacagt tgtgacaggc ggcgaagtga agaagctgaa gcggctgacc 240
ttccagttcg gcgacgccag aaaggatagc tccctgcaca ttaccgccgc tcagacaggc 300
gataccggcc tgtatctttg tgccggcgct ggcaacaacg acatgagatt tggcgccgga 360
accagactga ccgtgaagcc ta 382
<210> 113
<211> 397
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 113
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgcctctt ctctcgtgcg gggcatcgag 360
gccttttttg gccaaggcac cagactgacc gtggtgg 397
<210> 114
<211> 795
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 114
atggtgctga agttcagcgt gtccatcctg tggatccagc tggcctgggt ttccacacag 60
ctgctggaac agagccctca gttcctgagc atccaagagg gcgagaacct gaccgtgtac 120
tgcaacagca gcagcgtgtt cagcagcctg cagtggtaca gacaagagcc tggcgaagga 180
cctgtgctgc tggtcacagt tgtgacaggc ggcgaagtga agaagctgaa gcggctgacc 240
ttccagttcg gcgacgccag aaaggatagc tccctgcaca ttaccgccgc tcagacaggc 300
gataccggcc tgtatctttg tgccggcgct ggcaacaacg acatgagatt tggcgccgga 360
accagactga ccgtgaagcc taacatccag aatccggagc ccgccgtata ccagctgaag 420
gaccctagaa gccaggacag caccctgtgc ctgttcaccg acttcgacag ccagatcaac 480
gtgcccaaga ccatggaaag cggcaccttc atcaccgaca agacagtgct ggacatgaag 540
gccatggaca gcaagtccaa cggcgcaatc gcctggtcca accagaccag cttcacatgc 600
caggacatct tcaaagagac aaacgccaca taccccagca gcgacgtgcc ctgtgatgcc 660
accctgacag agaagtcctt cgagacagac atgaacctga acttccagaa tctgtccgtg 720
atgggcctga gaatcctgct gctgaaggtg gccggcttca atctgctgat gaccctgcgg 780
ctgtggtcca gctga 795
<210> 115
<211> 918
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 115
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgcctctt ctctcgtgcg gggcatcgag 360
gccttttttg gccaaggcac cagactgacc gtggtggaag atctccggaa cgtgaccccc 420
cctaaagtga ccctgttcga acccagcaag gccgagatcg ccaacaagca gaaagccacc 480
ctcgtgtgcc tggccagagg cttcttcccc gaccatgtgg aactgtcttg gtgggtcaac 540
ggcaaagagg tgcacagcgg agtgtccacc gaccctcagg cctacaaaga gagcaactac 600
agctactgcc tgagcagcag actgcgggtg tccgccacct tctggcacaa cccccggaac 660
cacttcagat gccaggtgca gtttcacggc ctgagcgaag aggacaagtg gcccgaaggc 720
tcccccaagc ccgtgaccca gaatatctct gccgaggcct ggggcagagc cgactgtgga 780
attaccagcg ccagctacca ccagggcgtg ctgtctgcca ccatcctgta cgagatcctg 840
ctgggcaagg ccaccctgta cgccgtgctg gtgtctggcc tggtgctgat ggccatggtc 900
aagaagaaga acagctga 918
<210> 116
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 116
gacagctcct ccacctac 18
<210> 117
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 117
attttttcaa atatggacat g 21
<210> 118
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 118
tgtgcagaga aatggatcat cttt 24
<210> 119
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 119
agcgagcaca accgg 15
<210> 120
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 120
ttccagaacg aggcccag 18
<210> 121
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 121
tgtgccagca gcctgaccac acctgacggc tacacattt 39
<210> 122
<211> 382
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 122
atgaagacat ttgctggatt ttcgttcctg tttttgtggc tgcagctgga ctgtatgagt 60
agaggagagg atgtggagca gagtcttttc ctgagtgtcc gagagggaga cagctccgtt 120
ataaactgca cttacacaga cagctcctcc acctacttat actggtataa gcaagaacct 180
ggagcaggtc tccagttgct gacgtatatt ttttcaaata tggacatgaa acaagaccaa 240
agactcactg ttctattgaa taaaaaggat aaacatctgt ctctgcgcat tgcagacacc 300
cagactgggg actcagctat ctacttctgt gcagagaaat ggatcatctt tggaaaaggg 360
acacgacttc atattctccc ca 382
<210> 123
<211> 397
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的智人序列
<400> 123
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagca gcctgaccac acctgacggc 360
tacacatttg gcagcggcac cagactgacc gtggtgg 397
<210> 124
<211> 795
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 124
atgaagacat ttgctggatt ttcgttcctg tttttgtggc tgcagctgga ctgtatgagt 60
agaggagagg atgtggagca gagtcttttc ctgagtgtcc gagagggaga cagctccgtt 120
ataaactgca cttacacaga cagctcctcc acctacttat actggtataa gcaagaacct 180
ggagcaggtc tccagttgct gacgtatatt ttttcaaata tggacatgaa acaagaccaa 240
agactcactg ttctattgaa taaaaaggat aaacatctgt ctctgcgcat tgcagacacc 300
cagactgggg actcagctat ctacttctgt gcagagaaat ggatcatctt tggaaaaggg 360
acacgacttc atattctccc caacatccag aatccggagc ccgccgtata ccagctgaag 420
gaccctagaa gccaggacag caccctgtgc ctgttcaccg acttcgacag ccagatcaac 480
gtgcccaaga ccatggaaag cggcaccttc atcaccgaca agacagtgct ggacatgaag 540
gccatggaca gcaagtccaa cggcgcaatc gcctggtcca accagaccag cttcacatgc 600
caggacatct tcaaagagac aaacgccaca taccccagca gcgacgtgcc ctgtgatgcc 660
accctgacag agaagtcctt cgagacagac atgaacctga acttccagaa tctgtccgtg 720
atgggcctga gaatcctgct gctgaaggtg gccggcttca atctgctgat gaccctgcgg 780
ctgtggtcca gctga 795
<210> 125
<211> 918
<212> DNA
<213> 人工序列
<220>
<223> 具有鼠源化恒定区的人(密码子优化)
<400> 125
atgggcacaa gcctgctgtg ttggatggcc ctgtgtctgc tgggagccga tcatgccgat 60
acgggagtgt ctcagaaccc cagacacaag atcaccaagc ggggccagaa cgtgaccttc 120
agatgcgacc ctatcagcga gcacaaccgg ctgtactggt acagacagac actcggccag 180
ggacctgagt tcctgaccta cttccagaac gaggcccagc tggaaaagag cagactgctg 240
agcgacagat tcagcgccga aagacccaag ggcagcttca gcaccctgga aatccagaga 300
accgagcagg gcgacagcgc catgtatctg tgtgccagca gcctgaccac acctgacggc 360
tacacatttg gcagcggcac cagactgacc gtggtggaag atctccggaa cgtgaccccc 420
cctaaagtga ccctgttcga acccagcaag gccgagatcg ccaacaagca gaaagccacc 480
ctcgtgtgcc tggccagagg cttcttcccc gaccatgtgg aactgtcttg gtgggtcaac 540
ggcaaagagg tgcacagcgg agtgtccacc gaccctcagg cctacaaaga gagcaactac 600
agctactgcc tgagcagcag actgcgggtg tccgccacct tctggcacaa cccccggaac 660
cacttcagat gccaggtgca gtttcacggc ctgagcgaag aggacaagtg gcccgaaggc 720
tcccccaagc ccgtgaccca gaatatctct gccgaggcct ggggcagagc cgactgtgga 780
attaccagcg ccagctacca ccagggcgtg ctgtctgcca ccatcctgta cgagatcctg 840
ctgggcaagg ccaccctgta cgccgtgctg gtgtctggcc tggtgctgat ggccatggtc 900
aagaagaaga acagctga 918
<210> 126
<211> 31
<212> PRT
<213> 智人
<400> 126
Ala Arg Phe Ala Glu Gly Leu Glu Lys Leu Lys Glu Cys Val Leu His
1 5 10 15
Asp Asp Leu Leu Glu Ala Arg Arg Pro Arg Ala His Glu Cys Leu
20 25 30
<210> 127
<211> 5
<212> PRT
<213> 智人
<400> 127
Asp Asp Leu Leu Glu
1 5
Claims (15)
1.对次要组织相容性抗原1(HA-1)的一种等位基因变体具有特异性的分离的T细胞受体(TCR)。
2.根据权利要求1所述的分离的TCR,其中HA-1的所述等位基因变体是HA-1H。
3.根据前述权利要求中任一项所述的分离的TCR,其中所述TCR特异性识别氨基酸序列SEQ ID NO:2或其片段。
4.根据前述权利要求中任一项所述的分离的TCR,其中所述TCR不识别氨基酸序列SEQID NO:4或其片段。
5.根据前述权利要求中任一项所述的分离的TCR,其中所述TCR的识别基序至少包含SEQ ID NO:127所示的序列。
6.根据前述实施方案中任一项所述的分离的TCR,其中所述TCR包含
a)-TCRα链,包含具有SEQ ID NO:5的氨基酸序列的CDR1、具有SEQ ID NO:6的氨基酸序列的CDR2和具有SEQ ID NO:7的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:8的氨基酸序列的CDR1、具有SEQ ID NO:9的氨基酸序列的CDR2和具有SEQ ID NO:10的序列的CDR3;或
b)-TCRα链,包含具有SEQ ID NO:15的氨基酸序列的CDR1、具有SEQ ID NO:16的氨基酸序列的CDR2和具有SEQ ID NO:17的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:18的氨基酸序列的CDR1、具有SEQ ID NO:19的氨基酸序列的CDR2和具有SEQ ID NO:20的序列的CDR3;或
c)-TCRα链,包含具有SEQ ID NO:25的氨基酸序列的CDR1、具有SEQ ID NO:26的氨基酸序列的CDR2和具有SEQ ID NO:27的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:28的氨基酸序列的CDR1、具有SEQ ID NO:29的氨基酸序列的CDR2和具有SEQ ID NO:30的序列的CDR3;
d)-TCRα链,包含具有SEQ ID NO:35的氨基酸序列的CDR1、具有SEQ ID NO:36的氨基酸序列的CDR2和具有SEQ ID NO:37的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:38的氨基酸序列的CDR1、具有SEQ ID NO:39的氨基酸序列的CDR2和具有SEQ ID NO:40的序列的CDR3;或
e)-TCRα链,包含具有SEQ ID NO:45的氨基酸序列的CDR1、具有SEQ ID NO:46的氨基酸序列的CDR2和具有SEQ ID NO:47的序列的CDR3,
-TCRβ链,包含具有SEQ ID NO:48的氨基酸序列的CDR1、具有SEQ ID NO:49的氨基酸序列的CDR2和具有SEQ ID NO:50的序列的CDR3;或
f)-TCRα链,包含具有SEQ ID NO:55的氨基酸序列的CDR1、具有SEQ ID NO:56的氨基酸序列的CDR 2和具有SEQ ID NO:57的序列的CDR 3,
-TCRβ链,包含具有SEQ ID NO:58的氨基酸序列的CDR1、具有SEQ ID NO:59的氨基酸序列的CDR2和具有SEQ ID NO:60的序列的CDR3。
7.根据前述权利要求中任一项所述的分离的TCR,其中所述TCR包含
a)具有SEQ ID NO:11的氨基酸序列的可变TCRα区和具有SEQ ID NO:12的氨基酸序列的可变TCRβ区;或
b)具有SEQ ID NO:21的氨基酸序列的可变TCRα区和具有SEQ ID NO:22的氨基酸序列的可变TCRβ区;或
c)具有SEQ ID NO:31的氨基酸序列的可变TCRα区和具有SEQ ID NO:32的氨基酸序列的可变TCRβ区;或
d)具有SEQ ID NO:41的氨基酸序列的可变TCRα区和具有SEQ ID NO:42的氨基酸序列的可变TCRβ区;或
e)具有SEQ ID NO:51的氨基酸序列的可变TCRα区和具有SEQ ID NO:52的氨基酸序列的可变TCRβ区;或
f)具有SEQ ID NO:61的氨基酸序列的可变TCRα区和具有SEQ ID NO:62的氨基酸序列的可变TCRβ区。
8.分离的多肽,包含权利要求1至7中任一项所述的TCR的功能部分,其中所述功能部分包含以下氨基酸序列中的至少一个:SEQ ID NO:7、SEQ ID NO:17、SEQ ID NO:27、SEQ IDNO:37、SEQ ID NO:47、SEQ ID NO:57、SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:30、SEQ IDNO:40、SEQ ID NO:50和SEQ ID NO:60。
9.多价TCR复合物,包含至少两个如权利要求1至7中任一项所述的TCR。
10.编码根据权利要求1至7中任一项所述的TCR或编码根据权利要求8所述的多肽的核酸。
11.包含权利要求10所述的核酸的载体。
12.表达根据权利要求1至7所述的TCR的细胞。
13.与根据权利要求1至7所述的TCR的一部分特异性结合的抗体或其抗原结合片段,所述部分介导对HA-1的一种等位基因变体的特异性。
14.根据权利要求1至7所述的TCR、根据权利要求8所述的多肽、根据权利要求9中任一项所述的多价TCR复合物、根据权利要求10所述的核酸、根据权利要求11所述的载体、根据权利要求12所述的细胞、或根据权利要求13所述的抗体,用于作为药物。
15.根据权利要求1至7所述的TCR、根据权利要求8所述的多肽、根据权利要求9所述的多价TCR复合物、根据权利要求10所述的核酸、根据权利要求11所述的载体或根据权利要求12所述的细胞,用于在治疗癌症中使用,其中所述癌症优选是血液学癌症。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18187539.4 | 2018-08-06 | ||
EP18187539 | 2018-08-06 | ||
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