CN114401995A - TGF-β陷阱 - Google Patents
TGF-β陷阱 Download PDFInfo
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- CN114401995A CN114401995A CN202080063795.4A CN202080063795A CN114401995A CN 114401995 A CN114401995 A CN 114401995A CN 202080063795 A CN202080063795 A CN 202080063795A CN 114401995 A CN114401995 A CN 114401995A
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Abstract
提供了用于抑制TGF‑β的组合物和方法。提供了陷阱分子,其中2型转化生长因子‑β受体(TGFβRII)的配体结合结构域与含有N‑末端免疫球蛋白铰链区的免疫球蛋白Fc结构域融合,其中所述铰链区的至少一个未配对的半胱氨酸残基被丝氨酸残基替代。
Description
交叉引用
本申请要求2019年8月15日提交的美国临时专利申请号62/887,272的权益,其全部内容通过引用并入本文。
对序列表的引用
本申请含有以电子文本文件提交的序列表,名为“8774-14-PCT_Seq_Listing_ST25.txt”,大小为68字节,并且创建于2020年8月14日。根据37CFR§1.52(e)(5)的规定,本电子文件中包含的信息特此通过引用以其全文并入。
技术领域
提供了用于抑制转化生长因子β(TGF-β)活性的组合物和方法。
背景技术
TGF-β是多功能细胞因子家族,其参与细胞增殖和分化、胚胎发育、细胞外基质形成、骨骼发育、伤口愈合、造血、以及免疫和炎症性响应。已在多种癌症中研究了TGF-β表达,这些癌症包括前列腺癌、乳腺癌、肺癌、结肠直肠癌、胰腺癌、肝癌、皮肤癌、和神经胶质瘤。在早期肿瘤中,升高的TGF-β的水平与良好的预后相关,而在晚期肿瘤中,升高的TGF-β的水平与肿瘤侵袭性和不良的预后相关。更具体地,TGF-β促进癌细胞运动、侵袭、上皮至间质转化(EMT)、和细胞干性,有利于肿瘤进展和转移。
人TGF-β有三种亚型:TGF-β1、TGF-β2和TGF-β3。每种亚型都作为25kDa同二聚体出现,其中两个112个氨基酸的单体通过链间二硫桥连接。TGF-β1与TGF-β2和TGF-β3不同,差异分别在于27和22个(主要是保守的)氨基酸变化。TGF-β的失调与许多疾病有关,如出生缺陷、癌症、慢性炎症性疾病、自身免疫性疾病和纤维化疾病。
TGF-β信号传导通过受体超家族发生,这些受体可分为两组跨膜蛋白:I型和II型丝氨酸/苏氨酸激酶。首先结合I型还是II型受体是配体依赖性的,然后募集第二个I型或II型受体以形成异聚信号传导复合物。功能性受体复合物具有一个二聚体配体,该二聚体配体与两个I型和两个II型受体相互作用。I型受体被称为激活素样激酶(ALK),而II型受体针对它们结合的配体而命名。该II型受体以高亲和力结合TGF-β1和TGF-β3,但以低得多的亲和力结合TGF-β2。该I型和II型受体一起形成TGF-β的抗增殖信号的转导必需的异二聚体信号传导复合物。还存在TGF-βIII型受体,但其细胞质结构域缺乏明显的信号传导基序,并且该受体可能不直接参与信号转导。
已经使用多种方法实现了TGF-β的全身性抑制,这些方法包括抗体和所谓的含有与抗体Fc结构域融合的TGF-β受体结构域的陷阱分子。参见例如Gramont等人,Oncoimmunology[肿瘤免疫学]6:e1257453(2017)和De Crescenzo等人在TransformingGrowth Factor-βin Cancer Therapy[癌症疗法中的转化生长因子-β],第II卷第671-684页(2008)中的“Engineering TGF-βTraps:Artificially Dimerized ReceptorEctodomains as High-affinity Blockers of TGF-βAction[工程化TGF-β陷阱:人工二聚化受体胞外域作为TGF-β作用的高亲和力阻断剂]”。使用敲除小鼠的研究已表明,TGF-β功能的全身性丧失能够导致伤口愈合减少、免疫调节丧失和炎症性响应增加。因此,以局限于肿瘤的方式抑制TGF-β活性将是优选的。
发明内容
所提供的是TGF-β陷阱,该TGF-β陷阱含有与2型转化生长因子-β受体(TGFβRII)的配体结合结构域融合的免疫球蛋白Fc结构域,其中该陷阱不含有Sushi结构域,并且其中该免疫球蛋白Fc结构域进一步含有N-末端免疫球蛋白铰链区,其中该铰链区的至少一个未配对的半胱氨酸残基被丝氨酸残基替代。在一个方面,该TGFβRII经由柔性肽接头部分与该Fc区连接。在某些非限制性实施例中,该TGFβRII的配体结合结构域经由该柔性肽接头部分与该Fc结构域的羧基末端(C-末端)连接,而在其他非限制性实施例中,该配体结合结构域经由该柔性肽接头部分与该Fc结构域的铰链区的氨基末端(N-末端)连接。在一些方面,该铰链区的C27残基被丝氨酸残基替代。
在某些实施例中,该陷阱可具有结构:NH2-铰链-Fc-接头-TGFβRII-CO2H。在某些实施例中,该陷阱可具有结构NH2-TGFβRII-接头-铰链-Fc-CO2H。在一个方面,该柔性接头包含G4S重复,如三、四、五、或更多个G4S重复。
在一个实施例中,该陷阱包含与SEQ ID NO:24至少85%相同或与SEQ ID NO:25至少85%相同的氨基酸序列。
还提供了编码如上所述的陷阱的核酸分子,其中该陷阱可以任选地与N-末端肽信号序列融合。该核酸分子可以包含在表达载体中。该表达载体中的启动子可以与编码该陷阱的核酸分子可操作地连接。在某些实施例中,该启动子可以是诱导型启动子。在一个方面,该诱导型启动子是TGF-β诱导型启动子。在某些方面,该启动子可以是组成型活性的,如巨细胞病毒(CMV)启动子。
还提供了用如上所述的载体转化的宿主细胞。在某些非限制性实施例中,该宿主细胞可以是哺乳动物细胞,如CHO细胞或人类细胞如NK-92细胞。
在其他实施例中,本发明涉及用于在受试者或患者中抑制TGF-β的活性的方法,这些方法包括向有需要的受试者施用有效量的如上所述的陷阱。
在另外的实施例中,本发明涉及用于在受试者中抑制TGF-β的活性的方法,这些方法包括以足以产生有效量的TGF-β陷阱的量向有需要的受试者施用含有如上所述的宿主细胞的组合物。
在其他实施例中,本发明涉及用于在受试者中治疗瘤形成的方法,这些方法包括向有需要的受试者施用治疗有效量的含有如上所述的宿主细胞的组合物。在一个方面,这些宿主细胞可以经肠胃外、静脉内、瘤周、或通过输注施用。
在本文披露的任一治疗的方法中,可以向该受试者或患者施用另外的治疗剂。
附图说明
图1A和1B示出了组成型活性的TGF-β陷阱构建体对TGF-β响应的抑制。这些CMV驱动的表达构建体含有Sushi结构域(Sushi)、未修饰的铰链(AltH)、带有或不带有TGFBRII(陷阱)的Fc结构域(Fc),相比于经修饰的铰链((C27S)H)、带有或不带有TGFBRII(陷阱)的Fc。
图2A和2B示出了TGF-β诱导型陷阱构建体对TGF-β响应的抑制。用TGF-β响应元件(TGFBRE)驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,比较Sushi结构域(Sushi)、未修饰的铰链(AltH)、带有或不带有TGFBRII(陷阱)的Fc结构域(Fc)相比于经修饰的铰链((C27S)H)、带有或不带有TGFBRII(陷阱)的Fc。
图3示出了在稳定转染的293T细胞中的TGF-β陷阱表达构建体的测试。用TGF-β响应元件(TGFBRE)驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,这些表达构建体具有Sushi结构域(Sushi)、未修饰的铰链(AltH)、带有或不带有TGFBRII(陷阱)的Fc相比于经修饰的铰链((C27S)H)、带有或不带有TGFBRII(陷阱)的Fc。
图4示出了在稳定转染的293T细胞中的与TGF-β陷阱的N-末端和C-末端融合体的测试。用CMV驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,比较带有经修饰的铰链((C27S)H)的C-末端(C-端)相比于N-末端(N-端)TGF-βRII(陷阱)Fc融合蛋白。
图5A和5B示出了TGF-β陷阱中和TGF-β2的能力。用CMV驱动的或TGF-β响应元件(TGFBRE)驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,然后用TGF-β2的滴定进行刺激。
图6A和6B示出了TGF-β陷阱中和小鼠TGF-β2的能力。用CMV驱动的或TGF-β响应元件(TGFBRE)驱动的表达构建体(DNA序列示出在SEQ ID NO:8和16中)转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,然后用小鼠TGF-β1(mTGF-β1)的滴定进行刺激。将细胞孵育过夜,并在24小时后测量所得的荧光素酶活性。
图7示出了Sushi结构域和铰链修饰对TGF-β-陷阱的产生的影响。用CMV驱动的TGFBRII陷阱Fc融合蛋白表达构建体转染293T细胞系,这些构建体含有Sushi结构域和原始的未修饰的铰链序列(AltH)、无Sushi结构域且带有AltH、或无Sushi且带有修饰的铰链((C27S)H)。将这些细胞在无血清培养基中静置并培养24小时,并浓缩所得的上清液并测量人IgG FC的水平。
具体实施方式
提供了TGF-β陷阱分子,该TGF-β陷阱分子含有与2型转化生长因子-β受体(TGFβRII)的配体结合结构域连接的免疫球蛋白Fc结构域。该免疫球蛋白Fc结构域含有改善的N-末端免疫球蛋白铰链区,其中该铰链区的至少一个未配对的半胱氨酸残基例如被丝氨酸残基替代。在某些实施例中,该陷阱分子不含有Sushi结构域。提供了编码该陷阱分子的核酸分子——连同载体和表达构建体,其可用于转染细胞和表达该陷阱分子。还提供了用核酸构建体转染的细胞,其中这些陷阱分子的表达处于TGF-β诱导型启动子的控制下。还提供了使用这些陷阱、核酸分子和转染的细胞治疗疾病(如癌症)的方法。
配体结合结构域
这些陷阱分子含有衍生自转化生长因子β受体II(TGFβRII)的细胞外配体结合部分的TGF-β结合结构域。TGFβRII的氨基酸序列是:
其中该受体的细胞外结构域加下划线。这些陷阱分子可以含有细胞外结构域的一些或全部,条件是该结构域保留结合配体的能力。有利地,该陷阱分子含有下文示出的配体结合序列。技术人员将认识到可以从该结构域的N-和/或C-末端添加或缺失氨基酸,条件是保留该结构域的配体结合特性。
免疫球蛋白Fc结构域
该配体结合结构域与延长该配体结合结构域的体内血浆半衰期的稳定化蛋白结构域连接。尽管原则上可以使用任何延长长度的氨基酸作为稳定化结构域,但在某些优选的实施例中,该稳定化结构域是免疫球蛋白恒定(Fc)结构域。该Fc有利地是人Fc并且可以是任何同种型,尽管最常用的是IgG1和IgG2同种型。用于该目的的合适的Fc结构域在本领域中是熟知的。参见例如US 5,428,130;Economides等人,Nature Medicine[自然医学]9:47(2003);和Czajkowsky等人,EMBO Mol Med.[欧洲分子生物学组织分子医学]4:1015-28(2012)。合适的Fc序列在下文示出。技术人员将认识到可以从该结构域的N-和/或C-末端添加或缺失氨基酸,条件是保留该结构域的稳定化特性。
铰链区
天然存在的免疫球蛋白的配体结合结构域经由柔性铰链区与该Fc结构域连接,并且如本文所述的陷阱分子还含有与该Fc区的N-末端融合的经修饰的铰链区。该铰链区可以充当柔性系链,并且还含有形成链间二硫键的半胱氨酸部分。天然存在的铰链区也含有未配对的半胱氨酸残基。已令人惊讶地发现,用亲水性残基(例如丝氨酸)替代这些未配对的半胱氨酸残基中的至少一个不仅在重组宿主细胞中产生这些陷阱分子时提供更高水平的蛋白表达,而且还在结合TGF-β方面提供陷阱的增加的活性。有利地,用亲水性残基替代该铰链区的至少第一个(最接近N-末端)半胱氨酸。这对应于天然存在的铰链区的C27位置或下文示出的SEQ ID NO:29的位置C5。经修饰的铰链的这种修饰在本文中称为((C27S)H)。示例性的经修饰的铰链区在下文示出,其中加下划线的丝氨酸残基指示半胱氨酸对丝氨酸取代的位置:
EPKSSDKTHTCPPCP(SEQ ID NO:4)
示例性的未修饰的天然存在的人IgG1的铰链序列是:EPKSCDKTHTCPPCPAPELLGGP(SEQ ID NO:29)(Nezlin,R.General Characteristics of Immunoglobulin Molecules[免疫球蛋白分子的一般特征],The Immunoglobulins[免疫球蛋白],1998)
柔性接头
该陷阱分子含有置于该配体结合结构域和该Fc区之间的柔性亲水性接头结构域。有利地,如在通常用于例如ScFv分子等的熟知的(G4S)n接头中,该接头也缺乏二级结构并且由甘氨酸和丝氨酸残基组构成。该接头可以是大约5-35个氨基长,并且有利地是大约15-30个氨基酸长。示例性接头含有G4S的5个重复。如下文更详细描述的,该接头可以将该Fc的C-末端与该配体结合结构域的N-末端直接连接,或者可以将该配体结合结构域的C-末端与该铰链区的N-末端连接。
分泌信号序列
如本文所述的陷阱分子产生于重组真核宿主细胞(在细胞培养物中、或者在向患者或受试者施用的体内宿主细胞中)。因此,编码该陷阱分子的核酸分子也编码将新合成的蛋白引导到宿主细胞的分泌途径中的N-末端信号肽。该信号肽在分泌过程中与蛋白的其余部分切割开来,产生成熟的陷阱蛋白。合适的信号肽在本领域中是熟知的。参见例如vonHeijne,Eur.J.Biochem.[欧洲生物化学杂志]133:17-21(1983);Martoglio和Dobberstein,Trends Cell Biol.[细胞生物学趋势]8:410-15(1988);Hegde和Bernstein.,Trends Biochem Sci[生化科学趋势]31:563-71(2006)。有利地,该信号肽是免疫球蛋白信号肽。示例性信号肽序列在下文示出:
MDWIWRILFLVGAATGAHSAQPA(SEQ ID NO:5)
陷阱分子的结构
如上所述,该铰链区与该Fc结构域的N-末端融合,并且该配体结合结构域经由柔性接头肽与铰链-Fc结构融合。该配体结合结构域可以相对于该Fc区位于N-末端或C-末端。当该配体结合结构域位于C-末端时,该成熟的陷阱蛋白具有以下结构域结构:
NH2-铰链-Fc-接头-TGFβRII-CO2H。
具有这种结构的示例性陷阱分子在本文中作为SEQ ID NO:24给出。在某些实施例中,该陷阱分子可以与SEQ ID NO:24具有至少85%的同一性,例如与SEQ ID NO:24具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%的同一性,条件是与SEQ ID NO:24具有“X%”同一性的分子总是被理解为在与SEQ ID NO:24的位置5对应的位置处具有丝氨酸,而不管哪些其他氨基酸可能相对于SEQ ID NO:24序列改变。
当该配体结合结构域位于N-末端时,该成熟的陷阱蛋白具有结构域结构:
NH2-TGFβRII-接头-铰链-Fc-CO2H。
具有这种结构的示例性陷阱分子在本文中作为SEQ ID NO:25给出。在某些实施例中,该陷阱分子可以与SEQ ID NO:25具有至少85%的同一性,例如与SEQ ID NO:25具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%的同一性,条件是与SEQ ID NO:25具有“X%”同一性的分子总是被理解为在与SEQ ID NO:25的位置166对应的位置处具有丝氨酸,而不管哪些其他氨基酸可能相对于SEQ ID NO:25序列改变。
核酸和载体
提供了编码该陷阱分子的核酸分子和载体。合成这些核酸分子的方法在本领域中是熟知的。该核酸序列可以包含在适合于染色体外复制的载体中,该载体如噬菌体、病毒、质粒、噬菌粒、粘粒、YAC、或附加体。对于蛋白表达,该载体是表达载体,即,含有插入的蛋白编码序列的转录和翻译所需的控制元件的载体。合适的表达系统包括病毒(例如,牛痘病毒、腺病毒等)感染的哺乳动物细胞系统;病毒(例如,杆状病毒)感染的昆虫细胞系统;微生物(如含有酵母载体的酵母,或用噬菌体DNA、质粒DNA、或粘粒DNA转化的细菌)。适用于此类宿主-载体系统的转录和翻译元件在本领域中是熟知的。用于制备核酸分子、克隆、和蛋白表达的一般技术描述于例如“Molecular Cloning:A Laboratory Manual[分子克隆:实验室手册]”,第二版(Sambrook,1989);“Oligonucleotide Synthesis[寡核苷酸合成]”(Gait,1984);“Animal Cell Culture[动物细胞培养]”(Freshney,1987);“Methods inEnzymology[酶学方法]”“Handbook of Experimental Immunology[实验免疫学手册]”(Weir,1996);“Gene Transfer Vectors for Mammalian Cells[哺乳动物细胞的基因转移载体]”(Miller和Calos,1987);“Current Protocols in Molecular Biology[当代分子生物学实验手册]”(Ausubel,1987);“PCR:The Polymerase Chain Reaction[PCR:聚合酶链式反应]”(Mullis,1994);和“Current Protocols in Immunology[当代免疫学实验手册]”(Coligan,1991)。
在某些实施例中,含有TGF-β响应元件的诱导型启动子控制陷阱分子表达。将编码处于诱导型启动子的控制下的陷阱分子的合适载体引入合适的宿主细胞中。在某些实施例中,选择宿主细胞是基于其可以被引入到待用该陷阱分子治疗的患者或受试者中。肿瘤对TGF-β的表达诱导在该肿瘤附近产生该陷阱,降低或消除这附近的TGF-β活性。这种方法仅在表达TGF-β的肿瘤的附近有利地压制或抑制TGF-β活性,同时避免潜在的不希望的全身性作用。合适的TGF-β响应元件在本领域中是已知的。参见例如Zhang和Derynck,J.Biol.Chem.[生物化学杂志]275:16979(2000);Grotendorst等人,Cell Growth Differ.[细胞生长与分化]7:469-80(1996);Riccio等人,Mol.Cell Biol.[分子细胞生物学]12:1846-55(1992);还参见SEQ ID NO:26-28。含有合适的响应元件的表达载体是可商购的。参见pGL4.28(普洛麦格公司(Promega),麦迪逊市(Madison),威斯康星州),其含有作为minP启动子元件的一部分的TGF-β响应元件,并在下文进一步详细描述。
可以通过以下产生该陷阱分子:将编码带有N-末端信号序列的陷阱分子的DNA表达载体引入宿主细胞中,在足以表达该陷阱分子并允许该陷阱分子二聚化的条件下在培养基中培养该宿主细胞,并从这些宿主细胞或培养基中纯化二聚体可溶性陷阱分子。当离体产生和纯化该陷阱分子时,该表达载体有利地含有编码处于CMV组成型启动子控制下的多肽的DNA。
可替代地,该宿主细胞可以是可被引入到患者或受试者中并原位产生该陷阱分子的哺乳动物细胞,尤其是人细胞系。在这种情况下,该宿主细胞有利地含有编码处于启动子控制下的陷阱分子的表达载体,该启动子含有TGF-β响应元件。
在获得变体生物活性TGFβRII、铰链、接头、或Fc结构域编码序列方面,本领域普通技术人员将认识到可以在不丧失或减少生物活性的情况下通过某些氨基酸取代、添加、缺失、和翻译后修饰来修饰这些多肽。特别地,众所周知,保守氨基酸取代,即用一个氨基酸取代具有相似大小、电荷、极性和构象的另一个氨基酸不太可能显著改变蛋白功能。作为蛋白成分的20种标准氨基酸可被大致分类为如下的四组保守氨基酸:非极性(疏水)组包括丙氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、色氨酸和缬氨酸;极性(不带电荷的,中性的)组包括天冬酰胺、半胱氨酸、谷氨酰胺、甘氨酸、丝氨酸、苏氨酸和酪氨酸;带正电荷的(碱性)组含有精氨酸、组氨酸和赖氨酸;并且带负电荷的(酸性)组含有天冬氨酸和谷氨酸。蛋白中的一种氨基酸被在同一组中的另一种氨基酸取代不太可能对该蛋白的生物活性产生不利影响。在其他情况下,可以对氨基酸位置进行修饰以降低或增强蛋白的生物活性。可以基于一个或多个靶残基的已知或假定的结构或功能特性将此类变化随机引入或经由位点特异性突变引入。在表达变体蛋白后,可以使用结合或功能测定容易地评估由于修饰引起的生物活性的变化。
可以通过DNA杂交分析来确定核苷酸序列之间的序列同一性,其中双链DNA杂交体的稳定性取决于发生的碱基配对的程度。高温和/或低盐含量的条件降低了杂交体的稳定性,并且可以改变以防止具有低于所选同一性程度的序列的退火。例如,对于具有约55%G-C含量的序列,40-50C、6x SSC(氯化钠/柠檬酸钠缓冲液)和0.1%SDS(十二烷基硫酸钠)的杂交和洗涤条件表明约60%-70%的同一性;50℃-65℃、1x SSC和0.1%SDS的杂交和洗涤条件表明约82%-97%的同一性;并且52℃、0.1x SSC和0.1%SDS的杂交和洗涤条件表明约99%-100%的同一性。还可获得用于比较核苷酸和氨基酸序列(并且测量同一性程度)的各种计算机程序,并且在Ausubel等人(1999)的文献中发现了提供可商购和免费软件来源的列表。
蛋白表达
为了产生纯化的陷阱蛋白,有利地使用哺乳动物细胞,特别是CHO、J558、NSO、或SP2-O细胞。其他合适的宿主包括例如,昆虫细胞,如Sf9。可以使用的哺乳动物细胞系的非限制性实例包括CHO dhfr细胞(Urlaub和Chasm,Proc.Natl.Acad.Sci.USA[美国国家科学院院刊],77:4216(1980))、293细胞(Graham等人,J Gen.Virol.[普通病毒学杂志],36:59(1977))或骨髓瘤细胞,像SP2或NSO(Galfre和Milstein,Meth.Enzymol.[酶学方法],73(B):3(1981))。采用常规培养条件。参见,Sambrook,同上。然后可以选择稳定转化或转染的细胞系。表达陷阱分子的细胞可以通过已知的程序鉴定。例如,该陷阱分子的表达可以通过对该陷阱分子的结构域(如结合结构域或Fc结构域)特异的ELISA和/或通过免疫印迹确定。
对于被引入到患者中并以TGF-β依赖性方式表达该陷阱分子的宿主细胞,使用人宿主细胞。可以使用多种人宿主细胞,包括可以从该患者取出的患者的自身细胞。然而,有利地,该宿主细胞是非MHC限制的自然杀伤(NK)细胞,并因此它基本上可以用于任何患者,而不会在该患者中引起针对该宿主细胞的免疫响应。合适的NK细胞系是本领域已知的NK-92细胞系。参见例如美国专利号7,618,817和Zhang等人,Frontiers in Immunol.[免疫学前沿],第8卷,文章533(2017)。在特定的实施例中,用合适的核酸构建体转染NK-92细胞,该核酸构建体编码处于TGF-β诱导型控制元件的控制下的陷阱分子,然后通过例如静脉内或腹膜内输注、或直接注射到实体瘤或其他癌性病变中而将该NK-92细胞引入到患者中。
可以通过用于转染细胞的标准技术将编码该陷阱分子的核酸引入宿主细胞中。术语“转染(“transfecting”或“transfection”)”旨在涵盖用于将核酸引入宿主细胞的所有常规技术,包括磷酸钙共沉淀、DEAE-葡聚糖介导的转染、脂质转染、电穿孔、显微注射、病毒转导和/或整合。用于转染宿主细胞的适合的方法可以在Sambrook等人,同上,和其他实验室教材中发现。
可以使用各种启动子(转录起始调节区)控制本文所述的分子的表达。适合的启动子的选择取决于所提出的表达宿主。可以使用来自异源来源的启动子,只要它们在所选的宿主中起作用即可。如上所述,有利地使用并入TGF-β响应元件的启动子或CMV启动子。
通常使用选择性标志物,该标志物可以是表达构建体的一部分或与其分开(例如,由表达载体携带),使得该标志物可以在与目的基因不同的位点处整合。实例包括赋予抗生素抗性(例如,对于大肠杆菌(E.coli)宿主细胞,bla赋予氨苄青霉素抗性;对于多种原核和真核细胞,nptII赋予卡那霉素抗性)或允许宿主在基本培养基上生长(例如,HIS4使巴斯德毕赤酵母(P.pastoris)或His-酿酒酵母(S.cerevisiae)在缺乏组氨酸的情况下生长)的标志物。选择性标志物具有其自身的转录和翻译起始和终止调节区,以允许标志物的独立表达。如果使用抗生素抗性作为标志物,则用于选择的抗生素的浓度将根据抗生素而变化,范围通常为从10至600μg抗生素/mL介质。
可以通过使用已知的重组DNA技术组装表达构建体(Sambrook等人,1989;Ausubel等人,1999)。限制酶消化和连接是用于连接DNA的两个片段的基本步骤。DNA片段的末端可能需要在连接之前进行修饰,并且这可以通过以下来实现:填充突出端、用核酸酶(例如,ExoIII)使一个或多个片段的末端部分缺失、定点诱变或通过PCR添加新的碱基对。可以使用多聚接头和衔接子来促进所选片段的连接。表达构建体典型地在使用多轮限制、连接和大肠杆菌转化的阶段中组装。
适用于构建表达构建体的许多克隆载体是本领域已知的(λZAP和pBLUESCRIPTSK-1,Stratagene公司,拉由拉市(La Jolla),加利福尼亚州;pET,诺瓦根公司(NovagenInc.),麦迪逊市,威斯康辛州,在Ausubel等人,1999中引用)。克隆载体的选择将受所选择的用于将表达构建体引入宿主细胞的基因转移系统的影响。在每个阶段结束时,可以通过限制、DNA序列、杂交和PCR分析来分析所得构建体。
可以将表达构建体作为克隆载体构建体(线性的或环状的)转化到宿主中,或者可以从克隆载体中去除并按原样使用或引入到递送载体上。递送载体有助于在所选的宿主细胞类型中引入和维持表达构建体。通过许多已知的基因转移系统(例如,天然感受态、化学介导的转化、原生质体转化、电穿孔、生物射弹转化、转染或缀合)中的任何一种将表达构建体引入宿主细胞中(参见Ausubel或Sambrook,同上)。取决于所用的宿主细胞和载体系统选择基因转移系统。
可以将标准蛋白纯化技术用于从培养基或从收获的细胞中分离目的陷阱分子蛋白。特别地,可以将纯化技术用于从各种实施装置(包括转瓶、旋式烧瓶、组织培养平板、生物反应器、或发酵罐)大规模地表达和纯化所希望的融合蛋白(即,以至少毫克的量)。
可以通过已知方法分离和纯化表达的陷阱蛋白。典型地,将培养基离心或过滤,并然后通过亲和色谱法或免疫亲和色谱法(例如蛋白-A或蛋白-G亲和色谱法或包括使用结合表达的陷阱分子的抗体或其他结合分子的免疫亲和方案)纯化上清液。可以通过已知技术的适当组合分离和纯化这些陷阱分子。这些方法包括,例如,利用溶解度的方法(如盐沉淀和溶剂沉淀);利用分子量差异的方法(如透析、超滤、凝胶过滤和SDS-聚丙烯酰胺凝胶电泳);利用电荷差异的方法(如离子交换柱色谱法);利用特异性亲和力的方法(如亲和色谱法);利用疏水性差异的方法(如反相高效液相色谱法);和利用等电点差异的方法(如等电点聚焦电泳),金属亲和柱(如Ni-NTA)。一般参见Sambrook或Ausubel,同上。
陷阱分子有利地是基本上纯的。即,融合蛋白已经与天然伴随其的细胞取代物分离,使得这些融合蛋白优选以至少80%或90%至95%均质性(w/w)存在。具有至少98%至99%均质性(w/w)的融合蛋白对于许多药物、临床和研究应用是最优选的。一旦基本上纯化,融合蛋白应基本上不含对于治疗应用的污染物。一旦部分纯化或达到基本纯度,可以将可溶性融合蛋白用于治疗、或用于进行如本文披露的体外或体内测定。可通过多种标准技术(如色谱法和凝胶电泳)确定基本纯度。
药物治疗剂
提供了含有用作治疗剂的陷阱分子的药物组合物。这些陷阱分子可以作为蛋白治疗剂施用或者可以通过以TGF依赖性方式从宿主细胞分泌而原位提供。
在一个方面,将该陷阱分子全身性施用,例如,配制在药学上可接受的缓冲液(如生理盐水)中。优选的施用途径包括,例如,滴注到膀胱中,皮下、静脉内、腹膜内、肌内、瘤内或皮内注射,其在患者体内提供连续、持续或有效水平的组合物。使用在生理学上可接受的运载体中的治疗有效量的本文鉴定的治疗剂进行人患者或其他动物的治疗。适合的运载体和其配制品描述于例如,由E.W.Martin编辑的Remington's Pharmaceutical Sciences[雷明顿药物科学]中。
待施用的治疗剂的量根据施用方式、患者的年龄和体重、以及瘤形成的临床症状而变化。例如,剂量的变化可以从在约1μg陷阱/kg体重至约5000mg陷阱/kg体重之间;或从约5mg/kg体重至约4,000mg/kg体重或从约10mg/kg体重至约3,000mg/kg体重;或从约50mg/kg体重至约2000mg/kg体重;或从约100mg/kg体重至约1000mg/kg体重;或从约150mg/kg体重至约500mg/kg体重。例如,剂量是约1、5、10、25、50、75、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1,000、1,050、1,100、1,150、1,200、1,250、1,300、1,350、1,400、1,450、1,500、1,600、1,700、1,800、1,900、2,000、2,500、3,000、3,500、4,000、4,500、或5,000mg/kg体重。可替代地,剂量在约5mg化合物/kg体重至约20mg化合物/kg体重的范围内。在另一实例中,剂量为约8、10、12、14、16或18mg/kg体重。优选地,陷阱分子以0.5mg/kg至约10mg/kg(例如,0.5、1、3、5、10mg/kg)施用。在某些实施例中,如通过本领域技术人员已知的方法确定,按以下剂量施用该陷阱:该剂量增强受试者的免疫响应,或降低瘤形成细胞、感染的细胞、或自身免疫细胞的增殖、存活、或侵袭性。
如上所述,可以向患者施用以TGF-β依赖性方式分泌陷阱分子的宿主细胞。可以经由静脉内或腹膜内输注,或通过本领域已知的其他方法,例如通过直接注射到实体瘤或其他病变中来递送这些细胞。在某些实施例中,将向该患者施用至少103个细胞,例如至少104、至少105、至少106、至少107、至少108、或至少109个细胞。
药物组合物的配制品
陷阱分子的施用可以通过任何合适的方法进行,该方法导致与其他组分组合的治疗剂的浓度有效抑制TGF-β活性。陷阱分子可以以任何合适的量包含在任何合适的运载体物质中,并且通常以组合物的总重量的1%-95%重量的量存在(例如,至少10%w/w、至少15%w/w、至少20%w/w、至少25%w/w、至少30%w/w、至少40%w/w、至少50%w/w、至少60%w/w、至少70%w/w、至少75%w/w、至少80%w/w、至少85%w/w、至少90%w/w、和95%w/w或约95%w/w)。可以按适合于肠胃外(例如,皮下、静脉内、肌内、囊内、瘤内或腹膜内)施用途径的剂型提供组合物。例如,根据常规的药学实践配制药物组合物(参见例如,Remington:TheScience and Practice of Pharmacy[雷明顿:药学的科学与实践](第20版)A.R.Gennaro,Lippincott Williams&Wilkins编辑,2000和Encyclopedia of PharmaceuticalTechnology[制药技术百科全书],J.Swarbrick和J.C.Boylan编辑,1988-1999,马塞尔·德克尔公司(Marcel Dekker),纽约)。
人体剂量最初通过从小鼠或非人灵长类动物中使用的化合物的量外推来确定,因为技术人员认识到与动物模型相比,修饰人的剂量在本领域中是常规的。例如,剂量的变化可以从在约1μg化合物/kg体重至约5000mg化合物/kg体重之间;或从约5mg/kg体重至约4,000mg/kg体重或从约10mg/kg体重至约3,000mg/kg体重;或从约50mg/kg体重至约2000mg/kg体重;或从约100mg/kg体重至约1000mg/kg体重;或从约150mg/kg体重至约500mg/kg体重。例如,剂量是约1、5、10、25、50、75、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1,000、1,050、1,100、1,150、1,200、1,250、1,300、1,350、1,400、1,450、1,500、1,600、1,700、1,800、1,900、2,000、2,500、3,000、3,500、4,000、4,500、或5,000mg/kg体重。可替代地,剂量在约5mg化合物/kg体重至约20mg化合物/kg体重的范围内。在另一实例中,剂量为约8、10、12、14、16或18mg/kg体重。优选地,按0.5mg/kg-约10mg/kg(例如,0.5、1、3、5、10mg/kg)施用陷阱分子。当然,取决于初始临床试验的结果和特定患者的需要,如在此类治疗方案中常规进行的那样,该剂量可以向上或向下调整。
在某些实施例中,如本文所述的陷阱分子可以与适当的赋形剂一起配制成药物组合物,该药物组合物在施用后以受控方式释放该陷阱分子。实例包括单或多单位片剂或胶囊组合物、油溶液、悬浮液、乳液、微胶囊、微球、分子复合物、纳米颗粒、贴剂和脂质体。优选地,将陷阱分子配制在适用于肠胃外施用的赋形剂中。
肠胃外组合物
将包含陷阱分子的药物组合物通过注射、输注或植入(皮下、静脉内、肌内、瘤内、囊内、腹膜内),以剂型、配制品或经由适合的递送装置或含有常规无毒的药学上可接受的运载体和佐剂的植入物肠胃外施用。此类组合物的配制品和制剂对于药物配制品领域的技术人员是熟知的。配制品可以在Remington:The Science and Practice of Pharmacy[雷明顿:药学的科学与实践](同上)中找到。以单位剂型(例如,以单剂量安瓿)提供包含用于肠胃外使用的陷阱分子的组合物。可替代地,将组合物提供在含有若干个剂量的小瓶中,并且其中可以添加适合的防腐剂。组合物呈溶液、悬浮液、乳液、输注装置或用于植入的递送装置的形式,或呈现为在使用前用水或另一适合的媒介物重构的干粉末。该组合物可以包括合适的肠胃外可接受的运载体和/或赋形剂,并且可以包括悬浮剂、增溶剂、稳定剂、pH调节剂、张力调节剂、和/或分散剂。
如上所指示,含有陷阱分子的药物组合物可以呈适合用于无菌注射的形式。为了制备这样的组合物,将陷阱分子溶解或悬浮在肠胃外可接受的液体媒介物中。可以使用的可接受的媒介物和溶剂是水,通过添加适量的盐酸、氢氧化钠或合适的缓冲液调节至合适的pH的水,1,3-丁二醇,林格氏溶液和等渗氯化钠溶液和右旋糖溶液。水性配制品还可含有一种或多种防腐剂(例如,对羟基苯甲酸甲酯、对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)。在其中一种化合物仅微量或微溶于水的情况下,可以添加溶解增强剂或增溶剂,或溶剂可以包括10%-60%w/w的丙二醇。
本披露提供抑制TGF-β活性或治疗瘤形成、传染性疾病或自身免疫性疾病或其症状的方法,这些方法包括向受试者(例如哺乳动物,如人)施用治疗有效量的包含如本文所述的陷阱分子的药物组合物。因此,一个实施例是治疗患有或易患瘤形成、传染性疾病或自身免疫性疾病或其症状的受试者的方法。该方法包括以下步骤:在治疗疾病或障碍的条件下,向哺乳动物施用治疗量的足以治疗疾病或障碍或其症状的量的陷阱分子。还通过以下提供了抑制TGF-β活性的方法:向哺乳动物施用以下量的陷阱分子,该量足以将患者或受试者中的TGF-β活性抑制到提供所希望的治疗益处(如减缓或抑制肿瘤生长)的程度。鉴定需要这种治疗的受试者可以是受试者或健康护理专业人员的判断,并且可以是主观的(例如意见)或客观的(例如通过测试或诊断方法可测量)。
这些治疗方法和预防性方法通常包括向有需要的受试者(例如,动物、人,包括哺乳动物,特别是人)施用治疗有效量的陷阱分子。这种治疗将适当地向期望在其中抑制TGF-β活性的受试者(特别是人)施用。此类患者可患有、具有、或易患瘤形成、传染性疾病、自身免疫性疾病、障碍或其症状或处于患瘤形成、传染性疾病、障碍或其症状的风险中。通过诊断测试或受试者或健康护理提供者的意见(例如,基因测试、酶或蛋白标志物、生物标志物、家族史等)进行任何客观或主观确定可以做出对“处于风险中”的那些受试者的确定。这些陷阱分子可用于治疗其中希望降低TGF-β活性的任何其他障碍。
还提供了监测治疗进展的方法。这些方法包括,例如,在受试者中确定诊断标志物或诊断测量值的水平(例如TGF-β水平),其中该受试者已施用治疗量的陷阱分子或分泌陷阱分子的宿主细胞。
可以将该方法中确定的诊断标志物或测量值的水平与健康正常对照或其他患病患者中的标志物的已知水平进行比较,以确立该受试者的疾病状态。在一些情况下,在比第一水平的确定更晚的时间点处确定该受试者中的标志物的第二水平,并且比较这两个水平以监测疾病的进程或疗法的功效。在某些方面,根据本文披露的方法在开始治疗之前确定该受试者中的标志物的治疗前水平;然后可以将该标志物的治疗前水平与治疗开始后该受试者中标志物的水平进行比较,以确定治疗的功效。
组合疗法
任选地,将该陷阱分子与任何其他标准疗法组合施用;此类方法是本领域技术人员已知的并且在Remington’s Pharmaceutical Sciences[雷明顿药物科学]中由E.W.Martin.进行了描述。如果需要,将该陷阱分子与任何常规的抗肿瘤疗法或其他疗法(包括但不限于免疫疗法、治疗性抗体、靶向疗法、手术、放射疗法、或化疗)组合施用。
试剂盒或药物系统
可以将包含该陷阱分子或表达该陷阱分子的宿主细胞的药物组合物组装成试剂盒或药物系统,用于在受试者或患者中抑制TGF-β并从而改善疾病(如瘤形成、传染性疾病或自身免疫性疾病)。试剂盒或药物系统可以包括在其中的限定空间中具有一个或多个容器(如小瓶、管、安瓿、瓶等)的运载体(如盒子、纸箱、管)。这些试剂盒或药物系统还可包含用于使用该陷阱分子的相关说明书。
定义
“改善”意指减少、压制、减弱、减轻、停滞或稳定疾病的发展或进展。
“类似物”是指不是相同的但是具有类似的功能或结构特征的分子。例如,多肽类似物保留了对应的天然存在的多肽的生物活性,同时相对于天然存在的多肽具有某些增强该类似物的功能的生物化学修饰。此类生物化学修饰可以增加该类似物的蛋白酶抗性、膜通透性或半衰期,而不改变例如配体结合。类似物可以包括非天然氨基酸。
“与分子结合”意指对于该分子具有物理化学亲和力。
“检测”是指鉴定分析物的存在、不存在、或量。
“疾病”意指损害或干扰细胞、组织或器官的正常功能的任何病症或障碍。疾病的实例包括瘤形成、自身免疫反应和病毒感染。
术语配制品或配制品组分的“有效量”和“治疗有效量”是指单独的或呈组合形式的配制品或组分的足以提供所希望的效果的量。例如,“有效量”意指相对于未经治疗的患者,改善疾病症状所需的单独的或呈组合形式的化合物的量。用于实践本文披露的方法以治疗性地治疗疾病的一种或多种活性化合物的有效量随施用方式、受试者的年龄、体重以及总体健康状况而变化。最终地,主治医生或兽医会决定适当的量以及剂量方案。这样的量被称为“有效”量。
术语“分离的”、“纯化的”或“生物学纯的”是指不同程度上不含在天然状态下发现的通常伴随其的组分的物质。“分离”表示与原始来源或周围环境的分离程度。“纯化”表示高于分离的分离度。
“纯化的”或“生物学纯的”蛋白充分地不含其他物质,使得任何杂质不会实质上影响蛋白的生物学特性或引起其他不利后果。即,当通过重组DNA技术产生时,如果如本文所述的核酸或肽基本上不含细胞物质、病毒物质、或培养基时,或当化学合成时基本上不含化学前体或其他化学品时,则如本文所述的核酸或肽是纯化的。纯度和均质性典型地是使用分析化学技术(例如聚丙烯酰胺凝胶电泳或高效液相色谱法)来确定的。术语“纯化的”可以表示核酸或蛋白在电泳凝胶中基本上产生一条带。对于可以进行修饰(例如,磷酸化或糖基化)的蛋白,不同的修饰可以产生不同的分离的蛋白,这些蛋白可以被单独纯化。
类似地,“基本上纯的”意指已经从天然伴随其的组分分离的核苷酸或多肽。典型地,当核苷酸和多肽按重量计至少60%、70%、80%、90%、95%或甚至99%不含与它们天然关联的蛋白和天然存在的有机分子时,它们是基本上纯的。
“分离的核酸”意指核酸,其不含在衍生其的生物的天然存在的基因组中与其侧翼的核苷酸。该术语涵盖例如:(a)DNA,该DNA是天然存在的基因组DNA分子的一部分,但侧翼不是如下两个核酸序列,这两个核酸序列在天然存在该分子的该部分的生物的基因组中侧翼于该分子的该部分;(b)核酸,其以某种方式并入载体或并入原核生物或真核生物的基因组DNA中,使得所得分子与任何天然存在的载体或基因组DNA不同;(c)单独的分子,如cDNA,基因组片段,通过聚合酶链式反应(PCR)产生的片段,或限制性片段;和(d)重组核苷酸序列,其是杂交基因(即,编码融合蛋白的基因)的一部分。根据本披露分离的核酸分子进一步包括合成产生的分子,以及已经被化学改变和/或具有经修饰的骨架的任何核酸。例如,分离的核酸是经纯化的cDNA或RNA多核苷酸。分离的核酸分子还包括信使核糖核酸(mRNA)分子。
“分离的多肽”意指已从天然伴随它的组分中分离的多肽。典型地,当该多肽按重量计至少60%不含与它天然关联的蛋白和天然存在的有机分子时,该多肽是分离的。优选地,该制剂按重量计至少75%,更优选至少90%,并且最优选至少99%是多肽。分离的多肽可以例如通过从天然来源提取、通过表达编码这种多肽的重组核酸、或通过化学合成该蛋白而获得。可以通过任何适当的方法(例如,柱色谱法、聚丙烯酰胺凝胶电泳、或通过HPLC分析)测量纯度。
“标志物”意指具有在与疾病或障碍相关的表达水平或活性方面的改变的任何蛋白或多核苷酸或其他分子。
“瘤形成”意指特征在于过度增殖的疾病或障碍。可以使用本文披露的陷阱分子的示例性肿瘤包括但不限于白血病(例如,急性白血病、急性淋巴细胞白血病、急性髓细胞白血病、急性成髓细胞白血病、急性早幼粒细胞白血病、急性骨髓单核细胞性白血病、急性单核细胞白血病、急性红白血病、慢性白血病、慢性髓细胞白血病、慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤(霍奇金病、非霍奇金病)、华氏巨球蛋白血症、重链病和实体瘤如肉瘤和癌(例如,纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、成肾细胞瘤、宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜细胞瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突胶质细胞瘤、神经鞘瘤、脑膜瘤、黑素瘤、成神经细胞瘤及成视网膜细胞瘤)。在特定的实施例中,瘤形成是多发性骨髓瘤、β细胞淋巴瘤、尿路上皮/膀胱癌、或黑色素瘤。如本文所使用的,如在“获得药剂”中的“获得”包括合成、购买或以其他方式获得药剂。
“减少”意指降低至少5%,例如至少10%、至少25%、至少50%、至少75%、或甚至100%。
“参考”意指标准或对照状况。
“参考序列”是定义的用作序列比较的基础的序列。参考序列可以是指定序列的子集或整体;例如,全长cDNA或基因序列的区段,或完整的cDNA或基因序列。对于多肽而言,参考多肽序列的长度将通常是至少约16个氨基酸、优选至少约20个氨基酸、更优选至少约25个氨基酸,并且甚至更优选约35个氨基酸、约50个氨基酸、或约100个氨基酸。对于核酸而言,参考核酸序列的长度将通常是至少约50个核苷酸、优选至少约60个核苷酸、更优选至少约75个核苷酸,并且甚至更优选约100个核苷酸或约300个核苷酸或它们附近的或者它们之间的任一整数。
“特异性结合”意指化合物或抗体识别并且结合多肽,但是基本上并不识别并且结合样品(例如,天然包括多肽的生物样品)中的其他分子。
在本文披露的方法中有用的核酸分子包括编码多肽或其片段的任何核酸分子。此类核酸分子不需要与内源核酸序列100%相同,但是将典型地示出基本同一性。与内源序列具有“基本同一性”的多核苷酸典型地能够与双链核酸分子的至少一条链杂交。在本文披露的方法中有用的核酸分子包括编码多肽或其片段的任何核酸分子。此类核酸分子不需要与内源核酸序列100%相同,但是将典型地示出基本同一性。与内源序列具有“基本同一性”的多核苷酸典型地能够与双链核酸分子的至少一条链杂交。“杂交”意指在不同的严格条件下进行配对以在互补的多核苷酸序列(例如,本文描述的基因)或其部分之间形成双链分子。(参见例如Wahl,G.M.和S.L.Berger(1987)Methods Enzymol.[酶学方法]152:399;Kimmel,A.R.(1987)Methods Enzymol.[酶学方法]152:507)。
例如,严格的盐浓度通常将是小于约750mM的NaCl和75mM的柠檬酸三钠,优选小于约500mM的NaCl和50mM的柠檬酸三钠,并且更优选小于约250mM的NaCl和25mM的柠檬酸三钠。在缺少有机溶剂(例如,甲酰胺)下可以获得低严格杂交,而在至少约35%甲酰胺、并且更优选至少约50%甲酰胺存在下可以获得高严格杂交。严格的温度条件将通常包括至少约30℃、更优选地是至少约37℃、并且最优选地是至少约42℃的温度。不同的额外的参数,如杂交时间、洗涤剂(例如,十二烷基硫酸钠(SDS))的浓度、以及运载体DNA的包含或排除,对本领域的技术人员是熟知的。根据需要通过组合这些不同的条件实现不同的严格水平。在优选的实施例中,杂交将在30℃、在750mM的NaCl、75mM的柠檬酸三钠、以及1%的SDS中发生。在更优选的实施例中,杂交将在37℃,在500mM的NaCl、50mM的柠檬酸三钠、1%的SDS、35%的甲酰胺、以及100mu.g/ml的变性鲑鱼精子DNA(ssDNA)中发生。在最优选的实施例中,杂交将在42℃、在250mM的NaCl、25mM的柠檬酸三钠、1%的SDS、50%的甲酰胺、以及200μg/ml的ssDNA中发生。这些条件的有用变化对于本领域的技术人员将是容易地显而易见的。
对于大多数应用,杂交之后的洗涤步骤也将会在严格度方面不同。可以通过盐浓度和温度限定洗涤严格条件。如上所述,通过降低盐浓度或通过增加温度可以增加洗涤严格度。例如,用于洗涤步骤的严格的盐浓度将为优选地小于约30mM的NaCl和3mM的柠檬酸三钠,并且最优选地小于约15mM的NaCl和1.5mM的柠檬酸三钠。用于洗涤步骤的严格的温度条件将通常包括至少约25℃、更优选地是至少约42℃、并且甚至更优选地是至少约68℃的温度。在优选的实施例中,洗涤步骤将在25℃、在30mM的NaCl、3mM的柠檬酸三钠、以及0.1%的SDS中发生。在更优选的实施例中,洗涤步骤将在42℃、在15mM的NaCl、1.5mM的柠檬酸三钠、以及0.1%的SDS中发生。在更优选的实施例中,洗涤步骤将在68℃、在15mM的NaCl、1.5mM的柠檬酸三钠、以及0.1%的SDS中发生。这些条件的额外的变化对于本领域的普通技术人员应是容易地显而易见的。杂交技术对本领域技术人员来说是熟知的并且描述于例如Benton和Davis(Science[科学]196:180,1977);Grunstein和Hogness(Proc.Natl.Acad.Sci.,USA[美国国家科学院院刊]72:3961,1975);Ausubel等人(Current Protocols in MolecularBiology[当代分子生物学方案],Wiley Interscience[威利跨学科出版社],纽约,2001);Berger和Kimmel(Guide to Molecular Cloning Techniques[分子克隆技术指南],1987,Academic Press[学术出版社],纽约);以及Sambrook等人,Molecular Cloning:ALaboratory Manual[分子克隆:实验室手册],Cold Spring Harbor Laboratory Press[冷泉港实验室出版社],纽约。
当多肽或核酸分子展现出与参考氨基酸序列(例如,本文所述的任一氨基酸序列)或核酸序列(例如,本文所述的任一核酸序列)至少50%的同一性时,该多肽或核酸分子是“基本上相同的”。优选地,这样的序列与用于比较的序列在氨基酸水平或核酸上至少60%、更优选80%或85%、并且更优选90%、95%或甚至99%同一。在两个或更多个核酸或多肽序列的上下文中,术语“相同”或百分比“同一性”是指当在比较窗口上对于最大对应性进行比较和对齐时,两个或更多个序列或子序列相同或具有指定百分比的相同氨基酸残基或核苷酸。用于本披露目的的氨基酸或核酸序列同一性的程度使用描述于Altschul等人(199)J.Mol.Biol.[分子生物学杂志]215:403-10的BLAST算法确定,该文献可通过国家生物技术信息中心(National Center for Biotechnology Information)(网址为www.ncbi.nlm.nih.gov)提供的软件公开获得。该算法通过鉴定查询序列中长度W的短字来鉴定高得分序列对(HSPS),这些短字在与数据库序列中相同长度的字比对时,匹配或满足一些正值阈值得分T。T称为邻域字(neighborhood word)得分阈值(Altschul等人,同上)。最初的邻域字命中点充当启动搜索以查找含有它们的较长HSP的种子。然后字命中点沿着每个序列在两个方向上延伸,直到可以增加累积比对得分为止。对于核苷酸序列,使用参数M(一对匹配残基的奖励得分;总是>0)和N(错配残基的罚分;总是<0)计算累积得分。对于氨基酸序列,使用得分矩阵来计算累积得分。当出现以下情形时,字命中点向各方向的延伸终止:累积比对得分从其最大实现值下降了数量X;由于一个或多个负得分残基比对的累积,累积得分变为零或更低;或到达任一序列的末端。对于确定氨基酸序列或核酸序列的同一性百分比,可以使用BLAST程序的默认参数。对于氨基酸序列的分析,BLASTP默认值为:字长(W),3;期望值(E),10;以及BLOSUM62得分矩阵。对于核酸序列的分析,BLASTN程序默认值为字长(W),11;期望值(E),10;M=5;N=-4;以及两条链的比较。TBLASTN程序(使用蛋白序列查询核苷酸序列数据库)使用以下作为默认值:字长(W)为3,期望值(E)为10,以及BLOSUM62得分矩阵。(参见Henikoff&Henikoff(1989)Proc.Natl.Acad.Sci.USA[美国国家科学院院刊]89:10915)。
除了计算序列百分比同一性之外,BLAST算法还对两个序列之间的相似性进行统计分析(参见例如,Karlin&Altschul(1993)Proc.Nat'l.Acad.Sci.USA[美国国家科学院院刊]90:5873-87)。最小总和概率(P(N))提供了两个核苷酸或氨基酸序列之间偶然发生匹配的概率的指示。例如,如果在测试核酸与参考核酸的比较中最小总和概率小于约0.01,则认为核酸与参考序列相似。
术语“治疗(“treating”和“treatment”)”是指将药剂或配制品施用至患有不良病症、障碍或疾病的临床症状性个体,以便实现症状严重性和/或频次的降低、消除症状和/或其潜在原因、和/或促进损害的改善或补救。应理解的是,尽管不能排除,治疗障碍或病症并不要求完全地消除该障碍、病症或与其相关的症状。
术语“预防(“preventing”和“prevention”)”是指将药剂或组合物施用至易感或易患特定不良病症、障碍或疾病的临床无症状的个体,并因此涉及预防症状的发生和/或其潜在原因。
除非具体地规定或从上下文显而易见,否则如本文所使用的,术语“或”被理解为包括在内。除非具体地规定或从上下文显而易见,否则如本文所使用的,术语“一个、一种(a、an)”和“该(the)”被理解为单数的或复数的。
除非具体地规定或从上下文显而易见,否则如本文所使用的,术语“约(about)”被理解为在本领域的正常公差范围内,例如,在平均数的2个标准偏差之内。“约”可以被理解为在规定的值的10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%、或0.01%之内。
给出以下实例是为了给本领域普通技术人员提供如何进行和使用测定、筛选和治疗方法的完整披露和描述。这些实例不旨在限制如本文所要求保护的本发明的范围。
实例
材料和方法:
TGF-β报告细胞系.根据制造商推荐的方案,使用Lipofectamine,通过用pGL4.28(普洛麦格公司)转染HEK-293T细胞来创建TGF-β响应性稳定细胞系,pGL4.28是含有由TGF-β响应元件驱动的荧光素酶的表达质粒。持续两个月使用潮霉素选择转染的细胞。
转染.使用推荐的方案用Lipofectamine(赛默飞世尔公司(Thermo Fisher))将TGF-β陷阱构建体瞬时转染到TGF-β报告293T细胞系中,然后孵育过夜。然后用如在这些图中所指示的浓度的TGF-β1、TGF-β2或小鼠TGF-β1(细胞信号传导技术公司(Cell SignalingTechnology))刺激这些细胞持续18小时。刺激后,根据推荐的方案使用荧光素酶测定系统(普洛麦格公司)测定响应。
IgG滴度测量:使用ForteBio Octet Red96仪器上的蛋白A生物传感器测量TGF-β陷阱IgG融合物滴度。用TGF-β陷阱构建体转染HEK-293T细胞并孵育18小时,然后收集并浓缩细胞培养上清液。将浓缩的上清液在1x PBS中稀释10倍至最终体积为200μl并置于96孔板中。在测量之前,将蛋白A生物传感器在1x PBS中孵育10分钟。测定在25℃下进行并读数,并且通过与用在PBS中稀释的纯化抗体的已知浓度生成的标准曲线进行比较来确定每个样品的IgG浓度。
实例1:组成型活性的TGF-β陷阱构建体对TGF-β响应的抑制
用CMV驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,比较Sushi结构域(Sushi)、未修饰的铰链(AltH)、带有或不带有TGFBRII(陷阱)的Fc结构域(Fc)与经修饰的铰链((C27S)H)、带有或不带有TGFBRII(陷阱)的Fc(SEQ ID NO:15、17、19和21;具有对应的SEQ ID NO:14、16、18和20的DNA序列)。将细胞孵育过夜,洗涤并在所指示浓度下用TGF-β刺激。18小时后测量所得的荧光素酶活性。图1A和1B中示出的数据表明这些陷阱构建体在低水平(0-1ng/ml)下抑制TGF-β,但只有具有经修饰的铰链的构建体在高浓度下有效。
实例2:TGF-β诱导型陷阱构建体对TGF-β响应的抑制
用TGF-β响应元件(TGFBRE)驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,比较Sushi结构域(Sushi)、未修饰的铰链(AltH)、带有或不带有TGFBRII(陷阱)的Fc结构域(Fc)相比于经修饰的铰链((C27S)H)、带有或不带有TGFBRII(陷阱)的Fc(SEQ ID NO:7、9、11和13;具有对应的SEQ ID NO:6、8、10和12的DNA序列)。将细胞孵育过夜,洗涤并在所指示浓度下用TGF-β刺激。18小时后测量所得的荧光素酶活性并且将数据示出在图2A和2B中。原始构建体不能以诱导形式阻断TGF-β活性,而经修饰的构建体在低浓度(0.1ng/ml)下有效,并且在中至高浓度(1-10ng/ml)下仍表现出中和活性。
实例3:以293T-TGF-β稳定体系测试TGF-β陷阱表达构建体
用TGF-β响应元件(TGFBRE)驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,这些表达构建体具有Sushi结构域(Sushi)、未修饰的铰链(AltH)、带有或不带有TGFBRII(陷阱)的FC相比于经修饰的铰链((C27S)H)、带有或不带有TGFBRII(陷阱)的Fc(SEQ ID NO:7、9、11和13;具有对应的SEQ ID NO:6、8、10和12的DNA序列)。将细胞孵育过夜,洗涤并在如所指示的“较低”滴定下用TGF-β刺激。24小时后测量所得的荧光素酶活性。图3中示出的数据指示,具有经修饰的铰链的构建体明显更有效。
实例4:以293T-TGF-β稳定体系测试N-端相比于C-端融合TGF-β陷阱
用CMV驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,比较带有经修饰的铰链((C27S)H)的C-末端(C-端)相比于N-末端(N-端)TGF-βRII(陷阱)Fc融合蛋白(SEQ ID NO:17、21和23;具有对应的SEQ ID NO:16、20和22的DNA序列)。将细胞孵育过夜,洗涤并用如所指示的TGF-β刺激。24小时后测量所得的荧光素酶活性。图4中的数据示出了C-末端相比于N-末端融合蛋白之间的活性没有可观察到的差异。
实例5:确定TGF-β陷阱可中和TGF-β2的能力
用CMV驱动的或TGF-β响应元件(TGFBRE)驱动的表达构建体转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,然后用TGF-β2的滴定进行刺激。将细胞孵育过夜,并在24小时后测量所得的荧光素酶活性。图5A和5B中的数据示出了CMV驱动的构建体的部分能力以及TGFBRE驱动的构建体抑制TGF-β2的最小能力;然而,TGFBRE驱动的构建体没有可辨别的中和TGF-β2的能力。
实例6:确定TGF-β陷阱可中和小鼠TGF-β2的能力
用CMV驱动的或TGF-β响应元件(TGFBRE)驱动的表达构建体(DNA序列示出在SEQID NO 8和16中)转染稳定表达TGF-β诱导的荧光素酶的293T细胞系,然后用小鼠TGF-β1(mTGF-β1)的滴定进行刺激。将细胞孵育过夜,并在24小时后测量所得的荧光素酶活性。图6A和6B中示出的数据指示CMV驱动的和TGFBRE驱动的陷阱表达构建体两者都能够抑制小鼠TGF-β诱导的荧光素酶活性。
实例7:确定Sushi结构域和铰链修饰对TGF-β-陷阱的产生的影响
用CMV驱动的TGFBRII陷阱Fc融合蛋白表达构建体转染293T细胞系,这些构建体含有Sushi结构域和原始的未修饰的铰链序列(AltH)、无Sushi结构域且带有AltH、或无Sushi且带有修饰的铰链((C27S)H)。将这些细胞在无血清培养基中静置并培养24小时,并浓缩所得的上清液并测量人IgG Fc的水平。图7中示出的数据示出了无Sushi的C27S铰链产物展现出最高的浓度。
其他实施例
虽然本发明参考其特定实施例已经进行了具体显示和描述,本领域的技术人员应当理解的是,在不偏离由所附权利要求书所涵盖的范围的情况下,可以做出在形式和细节方面的多种改变。
序列表
<110> 南特比奥有限公司(NantBio Inc.)
Liu, Philip
Higashide, Wendy
Olson, C. Anders
Niazi, Kayvan
<120> TGF-β陷阱
<130> 8774-14-PCT
<140> 未指定
<141> 2020-08-14
<150> 62/887,272
<151> 2019-08-15
<160> 29
<170> PatentIn 3.5版
<210> 1
<211> 566
<212> PRT
<213> 智人
<400> 1
Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu
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Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro
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Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln
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Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro
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Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr
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Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile
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Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys
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Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn
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Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu
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Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu
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Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn
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Arg Gln Gln Lys Leu Ser Ser Thr Trp Glu Thr Gly Lys Thr Arg Lys
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Leu Met Glu Phe Ser Glu His Cys Ala Ile Ile Leu Glu Asp Asp Arg
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Ser Asp Ile Ser Ser Thr Cys Ala Asn Asn Ile Asn His Asn Thr Glu
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Leu Leu Pro Ile Glu Leu Asp Thr Leu Val Gly Lys Gly Arg Phe Ala
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Glu Val Tyr Lys Ala Lys Leu Lys Gln Asn Thr Ser Glu Gln Phe Glu
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Thr Val Ala Val Lys Ile Phe Pro Tyr Glu Glu Tyr Ala Ser Trp Lys
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Thr Glu Lys Asp Ile Phe Ser Asp Ile Asn Leu Lys His Glu Asn Ile
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Leu Gln Phe Leu Thr Ala Glu Glu Arg Lys Thr Glu Leu Gly Lys Gln
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Tyr Trp Leu Ile Thr Ala Phe His Ala Lys Gly Asn Leu Gln Glu Tyr
325 330 335
Leu Thr Arg His Val Ile Ser Trp Glu Asp Leu Arg Lys Leu Gly Ser
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Ser Leu Ala Arg Gly Ile Ala His Leu His Ser Asp His Thr Pro Cys
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Gly Arg Pro Lys Met Pro Ile Val His Arg Asp Leu Lys Ser Ser Asn
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Ile Leu Val Lys Asn Asp Leu Thr Cys Cys Leu Cys Asp Phe Gly Leu
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Leu Arg Leu Asp Pro Thr Leu Ser Val Asp Asp Leu Ala Asn Ser Gly
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Gln Val Gly Thr Ala Arg Tyr Met Ala Pro Glu Val Leu Glu Ser Arg
420 425 430
Met Asn Leu Glu Asn Val Glu Ser Phe Lys Gln Thr Asp Val Tyr Ser
435 440 445
Met Ala Leu Val Leu Trp Glu Met Thr Ser Arg Cys Asn Ala Val Gly
450 455 460
Glu Val Lys Asp Tyr Glu Pro Pro Phe Gly Ser Lys Val Arg Glu His
465 470 475 480
Pro Cys Val Glu Ser Met Lys Asp Asn Val Leu Arg Asp Arg Gly Arg
485 490 495
Pro Glu Ile Pro Ser Phe Trp Leu Asn His Gln Gly Ile Gln Met Val
500 505 510
Cys Glu Thr Leu Thr Glu Cys Trp Asp His Asp Pro Glu Ala Arg Leu
515 520 525
Thr Ala Gln Cys Val Ala Glu Arg Phe Ser Glu Leu Glu His Leu Asp
530 535 540
Arg Leu Ser Gly Arg Ser Cys Ser Glu Glu Lys Ile Pro Glu Asp Gly
545 550 555 560
Ser Leu Asn Thr Thr Lys
565
<210> 2
<211> 136
<212> PRT
<213> 智人
<400> 2
Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr
1 5 10 15
Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp
20 25 30
Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys
35 40 45
Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val
50 55 60
Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp
65 70 75 80
Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro
85 90 95
Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met
100 105 110
Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu
115 120 125
Glu Tyr Asn Thr Ser Asn Pro Asp
130 135
<210> 3
<211> 217
<212> PRT
<213> 智人
<400> 3
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
115 120 125
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215
<210> 4
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 智人IgG Fc铰链区的突变变体
<400> 4
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 5
<211> 23
<212> PRT
<213> 智人
<400> 5
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser Ala Gln Pro Ala
20
<210> 6
<211> 1557
<212> DNA
<213> 人工序列
<220>
<223> TGF-β RE minP - Sushi - 未修饰的铰链 - IgG1 Fc - TGFBRII
<400> 6
agtatgtcta gactgaagta tgtctagact gaagtatgtc tagactgaag cttagacact 60
agagggtata taatggaagc tcgacttcca gcttggcaat ccggtactgt tggtaaagcc 120
accatggact ggatctggcg gattctgttt ctcgtgggag ctgccacagg cgctcattct 180
gctcagcctg ccatcacgtg tcctcctcct atgtccgtgg aacacgcaga catctgggtc 240
aagagctaca gcttgtactc cagggagcgg tacatttgta actctggttt caagcgtaaa 300
gccggcacgt ccagcctgac ggagtgcgtg ttgaacaagg ccacgaatgt cgcccactgg 360
acaaccccca gtctcaaatg cattagagag ccgaaatctt gtgacaaaac tcacacatgc 420
ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 480
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 540
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 600
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 660
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 720
gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 780
caggtgtaca ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 840
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 900
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 960
tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1020
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctcctggt 1080
aaaggaggag gtggctccgg aggcggtggc tccggtggag gtggctccgg aggtggcggt 1140
tccggtatcc ccccccacgt gcagaagtcc gttaacaacg acatgatcgt gaccgacaac 1200
aacggcgccg tgaagttccc ccagctgtgc aagttctgcg acgtgaggtt ctccacctgc 1260
gacaaccaga agtcctgcat gtccaactgc tccatcacct ccatctgcga gaagcctcag 1320
gaggtgtgcg tggctgtgtg gcggaagaac gacgagaaca tcaccctgga gaccgtgtgc 1380
cacgacccca agctgcccta ccacgacttc atcctggagg acgccgcctc ccccaagtgc 1440
atcatgaagg agaagaagaa gcccggcgag accttcttta tgtgctcctg ctccagcgac 1500
gagtgcaacg acaacatcat cttctccgag gagtacaaca cctccaaccc cgactga 1557
<210> 7
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> TGF-β RE minP - Sushi - 未修饰的铰链 - IgG1 Fc - TGFBRII
<400> 7
Met Glu Ala Arg Leu Pro Ala Trp Gln Ser Gly Thr Val Gly Lys Ala
1 5 10 15
Thr Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr
20 25 30
Gly Ala His Ser Ala Gln Pro Ala Ile Thr Cys Pro Pro Pro Met Ser
35 40 45
Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg
50 55 60
Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser
65 70 75 80
Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp
85 90 95
Thr Thr Pro Ser Leu Lys Cys Ile Arg Glu Pro Lys Ser Cys Asp Lys
100 105 110
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
115 120 125
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
130 135 140
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
145 150 155 160
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
165 170 175
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
180 185 190
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
195 200 205
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
210 215 220
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
225 230 235 240
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
245 250 255
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
260 265 270
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
275 280 285
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
290 295 300
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
305 310 315 320
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
325 330 335
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
340 345 350
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn
355 360 365
Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln
370 375 380
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
385 390 395 400
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
405 410 415
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
420 425 430
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
435 440 445
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
450 455 460
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
465 470 475 480
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
485 490
<210> 8
<211> 1362
<212> DNA
<213> 人工序列
<220>
<223> TGF-β RE minP - C27S铰链 - IgG1 Fc - TGFBRII
<400> 8
agtatgtcta gactgaagta tgtctagact gaagtatgtc tagactgaag cttagacact 60
agagggtata taatggaagc tcgacttcca gcttggcaat ccggtactgt tggtaaagcc 120
accatggact ggatctggcg gattctgttt ctcgtgggag ctgccacagg cgctcattct 180
gctcagcctg ccgagccgaa atcttctgac aaaactcaca catgcccacc gtgcccagca 240
cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 300
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 360
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 420
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 480
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 540
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 600
cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 660
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 720
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 780
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 840
ctgcacaacc actacacgca gaagagcctc tccctgtctc ctggtaaagg aggaggtggc 900
tccggaggcg gtggctccgg tggaggtggc tccggaggtg gcggttccgg tatccccccc 960
cacgtgcaga agtccgttaa caacgacatg atcgtgaccg acaacaacgg cgccgtgaag 1020
ttcccccagc tgtgcaagtt ctgcgacgtg aggttctcca cctgcgacaa ccagaagtcc 1080
tgcatgtcca actgctccat cacctccatc tgcgagaagc ctcaggaggt gtgcgtggct 1140
gtgtggcgga agaacgacga gaacatcacc ctggagaccg tgtgccacga ccccaagctg 1200
ccctaccacg acttcatcct ggaggacgcc gcctccccca agtgcatcat gaaggagaag 1260
aagaagcccg gcgagacctt ctttatgtgc tcctgctcca gcgacgagtg caacgacaac 1320
atcatcttct ccgaggagta caacacctcc aaccccgact ga 1362
<210> 9
<211> 429
<212> PRT
<213> 人工序列
<220>
<223> TGF-β RE minP - C27S铰链 - IgG1 Fc - TGFBRII
<220>
<221> 尚未归类的特征
<222> (41)..(55)
<223> 铰链区
<220>
<221> 尚未归类的特征
<222> (56)..(272)
<223> Fc区
<220>
<221> 尚未归类的特征
<222> (294)..(429)
<223> TGFBRII结合结构域
<400> 9
Met Glu Ala Arg Leu Pro Ala Trp Gln Ser Gly Thr Val Gly Lys Ala
1 5 10 15
Thr Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr
20 25 30
Gly Ala His Ser Ala Gln Pro Ala Glu Pro Lys Ser Ser Asp Lys Thr
35 40 45
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
50 55 60
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
65 70 75 80
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
85 90 95
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
100 105 110
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
115 120 125
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
130 135 140
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
145 150 155 160
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
165 170 175
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
180 185 190
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
195 200 205
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
210 215 220
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
225 230 235 240
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
245 250 255
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
260 265 270
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
275 280 285
Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn Asn
290 295 300
Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu
305 310 315 320
Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser
325 330 335
Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu
340 345 350
Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu
355 360 365
Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu
370 375 380
Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly
385 390 395 400
Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn
405 410 415
Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
420 425
<210> 10
<211> 1082
<212> DNA
<213> 人工序列
<220>
<223> TGF-β RE minP - Sushi - 未修饰的铰链 - IgG1 Fc
<400> 10
ggtatgtcta gactgaagta tgtctagact gaagtatgtc tagactgaag cttagacact 60
agagggtata taatggaagc tcgacttcca gcttggcaat ccggtactgt tggtaaagcc 120
accatggact ggatctggcg gattctgttt ctcgtgggag ctgccacagg cgctcattct 180
gctcagcctg ccatcacgtg tcctcctcct atgtccgtgg aacacgcaga catctgggtc 240
aagagctaca gcttgtactc cagggagcgg tacatttgta actctggttt caagcgtaaa 300
gccggcacgt ccagcctgac ggagtgcgtg ttgaacaagg ccacgaatgt cgcccactgg 360
acaaccccca gtctcaaatg cattagagag ccgaaatctt gtgacaaaac tcacacatgc 420
ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 480
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 540
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 600
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 660
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 720
gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 780
caggtgtaca ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 840
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 900
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 960
tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1020
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctcctggt 1080
aa 1082
<210> 11
<211> 337
<212> PRT
<213> 人工序列
<220>
<223> TGF-β RE minP - Sushi - 未修饰的铰链 - IgG1 Fc
<400> 11
Met Glu Ala Arg Leu Pro Ala Trp Gln Ser Gly Thr Val Gly Lys Ala
1 5 10 15
Thr Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr
20 25 30
Gly Ala His Ser Ala Gln Pro Ala Ile Thr Cys Pro Pro Pro Met Ser
35 40 45
Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg
50 55 60
Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser
65 70 75 80
Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp
85 90 95
Thr Thr Pro Ser Leu Lys Cys Ile Arg Glu Pro Lys Ser Cys Asp Lys
100 105 110
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
115 120 125
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
130 135 140
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
145 150 155 160
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
165 170 175
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
180 185 190
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
195 200 205
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
210 215 220
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
225 230 235 240
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
245 250 255
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
260 265 270
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
275 280 285
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
290 295 300
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
305 310 315 320
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
325 330 335
Lys
<210> 12
<211> 888
<212> DNA
<213> 人工序列
<220>
<223> TGF-β RE minP - C27S铰链 - IgG1 Fc
<400> 12
agtatgtcta gactgaagta tgtctagact gaagtatgtc tagactgaag cttagacact 60
agagggtata taatggaagc tcgacttcca gcttggcaat ccggtactgt tggtaaagcc 120
accatggact ggatctggcg gattctgttt ctcgtgggag ctgccacagg cgctcattct 180
gctcagcctg ccgagccgaa atcttctgac aaaactcaca catgcccacc gtgcccagca 240
cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 300
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 360
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 420
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 480
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 540
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 600
cccccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 660
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 720
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 780
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 840
ctgcacaacc actacacgca gaagagcctc tccctgtctc ctggtaaa 888
<210> 13
<211> 272
<212> PRT
<213> 人工序列
<220>
<223> TGF-β RE minP - C27S铰链 - IgG1 Fc
<400> 13
Met Glu Ala Arg Leu Pro Ala Trp Gln Ser Gly Thr Val Gly Lys Ala
1 5 10 15
Thr Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr
20 25 30
Gly Ala His Ser Ala Gln Pro Ala Glu Pro Lys Ser Ser Asp Lys Thr
35 40 45
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
50 55 60
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
65 70 75 80
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
85 90 95
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
100 105 110
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
115 120 125
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
130 135 140
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
145 150 155 160
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
165 170 175
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
180 185 190
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
195 200 205
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
210 215 220
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
225 230 235 240
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
245 250 255
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
260 265 270
<210> 14
<211> 2414
<212> DNA
<213> 人工序列
<220>
<223> CMV - Sushi - 未修饰铰链 - IgG1 Fc - TGFBRII
<400> 14
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc 660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagg 720
tcgtttagtg aaccgtcaga tcactagtag ctttattgcg gtagtttatc acagttaaat 780
tgctaacgca gtcagtgctc gactgatcac aggtaagtat caaggttaca agacaggttt 840
aaggaggcca atagaaactg ggcttgtcga gacagagaag attcttgcgt ttctgatagg 900
cacctattgg tcttactgac atccactttg cctttctctc cacaggggta ccgaagccgc 960
tagcgctacc ggtcgccacc atggactgga tctggcggat tctgtttctc gtgggagctg 1020
ccacaggcgc tcattctgct cagcctgcca tcacgtgtcc tcctcctatg tccgtggaac 1080
acgcagacat ctgggtcaag agctacagct tgtactccag ggagcggtac atttgtaact 1140
ctggtttcaa gcgtaaagcc ggcacgtcca gcctgacgga gtgcgtgttg aacaaggcca 1200
cgaatgtcgc ccactggaca acccccagtc tcaaatgcat tagagagccg aaatcttgtg 1260
acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga ccgtcagtct 1320
tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct gaggtcacat 1380
gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg 1440
gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac agcacgtacc 1500
gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag gagtacaagt 1560
gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc aaagccaaag 1620
ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga 1680
accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc gccgtggagt 1740
gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg ctggactccg 1800
acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg cagcagggga 1860
acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg cagaagagcc 1920
tctccctgtc tcctggtaaa ggaggaggtg gctccggagg cggtggctcc ggtggaggtg 1980
gctccggagg tggcggttcc ggtatccccc cccacgtgca gaagtccgtt aacaacgaca 2040
tgatcgtgac cgacaacaac ggcgccgtga agttccccca gctgtgcaag ttctgcgacg 2100
tgaggttctc cacctgcgac aaccagaagt cctgcatgtc caactgctcc atcacctcca 2160
tctgcgagaa gcctcaggag gtgtgcgtgg ctgtgtggcg gaagaacgac gagaacatca 2220
ccctggagac cgtgtgccac gaccccaagc tgccctacca cgacttcatc ctggaggacg 2280
ccgcctcccc caagtgcatc atgaaggaga agaagaagcc cggcgagacc ttctttatgt 2340
gctcctgctc cagcgacgag tgcaacgaca acatcatctt ctccgaggag tacaacacct 2400
ccaaccccga ctga 2414
<210> 15
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> CMV - Sushi - 未修饰的铰链 - IgG1 Fc - TGFBRII
<400> 15
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser Ala Gln Pro Ala Ile Thr Cys Pro Pro Pro Met Ser Val
20 25 30
Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu
35 40 45
Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser
50 55 60
Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr
65 70 75 80
Thr Pro Ser Leu Lys Cys Ile Arg Glu Pro Lys Ser Cys Asp Lys Thr
85 90 95
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
100 105 110
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
115 120 125
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
130 135 140
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
145 150 155 160
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
165 170 175
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
180 185 190
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
195 200 205
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
210 215 220
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
225 230 235 240
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
245 250 255
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
260 265 270
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
275 280 285
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
290 295 300
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
305 310 315 320
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
325 330 335
Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn Asn
340 345 350
Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu
355 360 365
Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser
370 375 380
Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu
385 390 395 400
Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu
405 410 415
Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu
420 425 430
Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly
435 440 445
Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn
450 455 460
Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
465 470 475
<210> 16
<211> 2219
<212> DNA
<213> 人工序列
<220>
<223> CMV - C27S铰链 - IgG1 Fc - TGFBRII
<400> 16
acaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc 660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagg 720
tcgtttagtg aaccgtcaga tcactagtag ctttattgcg gtagtttatc acagttaaat 780
tgctaacgca gtcagtgctc gactgatcac aggtaagtat caaggttaca agacaggttt 840
aaggaggcca atagaaactg ggcttgtcga gacagagaag attcttgcgt ttctgatagg 900
cacctattgg tcttactgac atccactttg cctttctctc cacaggggta ccgaagccgc 960
tagcgctacc ggtcgccacc atggactgga tctggcggat tctgtttctc gtgggagctg 1020
ccacaggcgc tcattctgct cagcctgccg agccgaaatc ttctgacaaa actcacacat 1080
gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc ttccccccaa 1140
aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg gtggtggacg 1200
tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg gaggtgcata 1260
atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc 1320
tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag gtctccaaca 1380
aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag ccccgagaac 1440
cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag gtcagcctga 1500
cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag agcaatgggc 1560
agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc tccttcttcc 1620
tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc ttctcatgct 1680
ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc ctgtctcctg 1740
gtaaaggagg aggtggctcc ggaggcggtg gctccggtgg aggtggctcc ggaggtggcg 1800
gttccggtat ccccccccac gtgcagaagt ccgttaacaa cgacatgatc gtgaccgaca 1860
acaacggcgc cgtgaagttc ccccagctgt gcaagttctg cgacgtgagg ttctccacct 1920
gcgacaacca gaagtcctgc atgtccaact gctccatcac ctccatctgc gagaagcctc 1980
aggaggtgtg cgtggctgtg tggcggaaga acgacgagaa catcaccctg gagaccgtgt 2040
gccacgaccc caagctgccc taccacgact tcatcctgga ggacgccgcc tcccccaagt 2100
gcatcatgaa ggagaagaag aagcccggcg agaccttctt tatgtgctcc tgctccagcg 2160
acgagtgcaa cgacaacatc atcttctccg aggagtacaa cacctccaac cccgactga 2219
<210> 17
<211> 412
<212> PRT
<213> 人工序列
<220>
<223> CMV - C27S铰链 - IgG1 Fc - TGFBRII
<400> 17
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser Ala Gln Pro Ala Glu Pro Lys Ser Ser Asp Lys Thr His
20 25 30
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
35 40 45
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
50 55 60
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
65 70 75 80
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
85 90 95
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
100 105 110
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
115 120 125
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
130 135 140
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
145 150 155 160
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
165 170 175
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
180 185 190
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
195 200 205
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
210 215 220
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
225 230 235 240
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
260 265 270
Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp
275 280 285
Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys
290 295 300
Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys
305 310 315 320
Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val
325 330 335
Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr
340 345 350
Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp
355 360 365
Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu
370 375 380
Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile
385 390 395 400
Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
405 410
<210> 18
<211> 1940
<212> DNA
<213> 人工序列
<220>
<223> CMV - Sushi - 未修饰的铰链 - IgG1 Fc
<400> 18
gcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc 660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagg 720
tcgtttagtg aaccgtcaga tcactagtag ctttattgcg gtagtttatc acagttaaat 780
tgctaacgca gtcagtgctc gactgatcac aggtaagtat caaggttaca agacaggttt 840
aaggaggcca atagaaactg ggcttgtcga gacagagaag attcttgcgt ttctgatagg 900
cacctattgg tcttactgac atccactttg cctttctctc cacaggggta ccgaagccgc 960
tagcgctacc ggtcgccacc atggactgga tctggcggat tctgtttctc gtgggagctg 1020
ccacaggcgc tcattctgct cagcctgcca tcacgtgtcc tcctcctatg tccgtggaac 1080
acgcagacat ctgggtcaag agctacagct tgtactccag ggagcggtac atttgtaact 1140
ctggtttcaa gcgtaaagcc ggcacgtcca gcctgacgga gtgcgtgttg aacaaggcca 1200
cgaatgtcgc ccactggaca acccccagtc tcaaatgcat tagagagccg aaatcttgtg 1260
acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga ccgtcagtct 1320
tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct gaggtcacat 1380
gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg 1440
gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac agcacgtacc 1500
gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag gagtacaagt 1560
gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc aaagccaaag 1620
ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga 1680
accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc gccgtggagt 1740
gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg ctggactccg 1800
acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg cagcagggga 1860
acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg cagaagagcc 1920
tctccctgtc tcctggtaaa 1940
<210> 19
<211> 320
<212> PRT
<213> 人工序列
<220>
<223> CMV - Sushi - 未修饰的铰链 - IgG1 Fc
<400> 19
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser Ala Gln Pro Ala Ile Thr Cys Pro Pro Pro Met Ser Val
20 25 30
Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu
35 40 45
Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser
50 55 60
Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr
65 70 75 80
Thr Pro Ser Leu Lys Cys Ile Arg Glu Pro Lys Ser Cys Asp Lys Thr
85 90 95
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
100 105 110
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
115 120 125
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
130 135 140
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
145 150 155 160
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
165 170 175
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
180 185 190
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
195 200 205
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
210 215 220
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
225 230 235 240
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
245 250 255
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
260 265 270
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
275 280 285
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
290 295 300
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
305 310 315 320
<210> 20
<211> 1745
<212> DNA
<213> 人工序列
<220>
<223> CMV - C27S铰链 - IgG1 Fc
<400> 20
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc 660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagg 720
tcgtttagtg aaccgtcaga tcactagtag ctttattgcg gtagtttatc acagttaaat 780
tgctaacgca gtcagtgctc gactgatcac aggtaagtat caaggttaca agacaggttt 840
aaggaggcca atagaaactg ggcttgtcga gacagagaag attcttgcgt ttctgatagg 900
cacctattgg tcttactgac atccactttg cctttctctc cacaggggta ccgaagccgc 960
tagcgctacc ggtcgccacc atggactgga tctggcggat tctgtttctc gtgggagctg 1020
ccacaggcgc tcattctgct cagcctgccg agccgaaatc ttctgacaaa actcacacat 1080
gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc ttccccccaa 1140
aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg gtggtggacg 1200
tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg gaggtgcata 1260
atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc 1320
tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag gtctccaaca 1380
aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag ccccgagaac 1440
cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag gtcagcctga 1500
cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag agcaatgggc 1560
agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc tccttcttcc 1620
tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc ttctcatgct 1680
ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc ctgtctcctg 1740
gtaaa 1745
<210> 21
<211> 255
<212> PRT
<213> 人工序列
<220>
<223> CMV - C27S铰链 - IgG1 Fc
<400> 21
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser Ala Gln Pro Ala Glu Pro Lys Ser Ser Asp Lys Thr His
20 25 30
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
35 40 45
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
50 55 60
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
65 70 75 80
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
85 90 95
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
100 105 110
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
115 120 125
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
130 135 140
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
145 150 155 160
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
165 170 175
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
180 185 190
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
195 200 205
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
210 215 220
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
225 230 235 240
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250 255
<210> 22
<211> 2228
<212> DNA
<213> 人工序列
<220>
<223> CMV - TGFBRII - (G4S)25多聚接头 - C27S铰链 - IgG1 Fc
<400> 22
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc 660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagg 720
tcgtttagtg aaccgtcaga tcactagtag ctttattgcg gtagtttatc acagttaaat 780
tgctaacgca gtcagtgctc gactgatcac aggtaagtat caaggttaca agacaggttt 840
aaggaggcca atagaaactg ggcttgtcga gacagagaag attcttgcgt ttctgatagg 900
cacctattgg tcttactgac atccactttg cctttctctc cacaggggta ccgaagccgc 960
tagcgctacc ggtcgccacc atggactgga tctggcggat tctgtttctc gtgggagctg 1020
ccacaggcgc tcattctgct cagcctgcca tcccccccca cgtgcagaag tccgttaaca 1080
acgacatgat cgtgaccgac aacaacggcg ccgtgaagtt cccccagctg tgcaagttct 1140
gcgacgtgag gttctccacc tgcgacaacc agaagtcctg catgtccaac tgctccatca 1200
cctccatctg cgagaagcct caggaggtgt gcgtggctgt gtggcggaag aacgacgaga 1260
acatcaccct ggagaccgtg tgccacgacc ccaagctgcc ctaccacgac ttcatcctgg 1320
aggacgccgc ctcccccaag tgcatcatga aggagaagaa gaagcccggc gagaccttct 1380
ttatgtgctc ctgctccagc gacgagtgca acgacaacat catcttctcc gaggagtaca 1440
acacctccaa ccccgacgga ggaggtggct ccggaggcgg tggctccggt ggaggtggct 1500
ccggaggtgg cggttccggt ggcggtggct ccgagccgaa atcttctgac aaaactcaca 1560
catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc ctcttccccc 1620
caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc gtggtggtgg 1680
acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc gtggaggtgc 1740
ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt gtggtcagcg 1800
tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc aaggtctcca 1860
acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg cagccccgag 1920
aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac caggtcagcc 1980
tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg gagagcaatg 2040
ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac ggctccttct 2100
tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac gtcttctcat 2160
gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc tccctgtctc 2220
ctggtaaa 2228
<210> 23
<211> 416
<212> PRT
<213> 人工序列
<220>
<223> CMV - TGFBRII - (G4S)25多聚接头 - C27S铰链 - IgG1 Fc
<400> 23
Met Asp Trp Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Ser Ala Gln Pro Ala Ile Pro Pro His Val Gln Lys Ser Val
20 25 30
Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro
35 40 45
Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln
50 55 60
Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro
65 70 75 80
Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr
85 90 95
Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile
100 105 110
Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys
115 120 125
Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn
130 135 140
Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Gly
145 150 155 160
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr
180 185 190
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
195 200 205
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
210 215 220
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
225 230 235 240
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
245 250 255
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
260 265 270
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
275 280 285
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
290 295 300
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
305 310 315 320
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
325 330 335
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
340 345 350
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
355 360 365
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
370 375 380
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
385 390 395 400
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
405 410 415
<210> 24
<211> 389
<212> PRT
<213> 人工序列
<220>
<223> 示例性陷阱分子
<400> 24
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro
245 250 255
His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn
260 265 270
Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe
275 280 285
Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr
290 295 300
Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys
305 310 315 320
Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu
325 330 335
Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile
340 345 350
Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys
355 360 365
Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn
370 375 380
Thr Ser Asn Pro Asp
385
<210> 25
<211> 393
<212> PRT
<213> 人工序列
<220>
<223> 示例性陷阱分子
<400> 25
Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr
1 5 10 15
Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp
20 25 30
Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys
35 40 45
Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val
50 55 60
Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp
65 70 75 80
Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro
85 90 95
Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met
100 105 110
Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu
115 120 125
Glu Tyr Asn Thr Ser Asn Pro Asp Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
165 170 175
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
180 185 190
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
195 200 205
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
210 215 220
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
225 230 235 240
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
245 250 255
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
260 265 270
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
275 280 285
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
290 295 300
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
305 310 315 320
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
325 330 335
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
340 345 350
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
355 360 365
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
370 375 380
Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390
<210> 26
<211> 38
<212> DNA
<213> 小家鼠
<400> 26
ccaccacagc cagaccacag gccagacatg acgtggag 38
<210> 27
<211> 50
<212> DNA
<213> 智人
<400> 27
tggagtgtgc cagctttttc agacggagga atgctgagtg tcaaggggtc 50
<210> 28
<211> 67
<212> DNA
<213> 智人
<400> 28
caagtcctag acagacaaaa cctagacaat cacgtggctg gctgcatgcc ctgtggctgt 60
tgggctg 67
<210> 29
<211> 23
<212> PRT
<213> 智人
<220>
<221> 尚未归类的特征
<222> (1)..(23)
<223> IgG1 Fc铰链区
<400> 29
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro
20
权利要求书(按照条约第19条的修改)
1.一种TGF-β陷阱,该TGF-β陷阱包含与2型转化生长因子-β受体(TGFβRII)的配体结合结构域融合的免疫球蛋白恒定(Fc)结构域,
其中所述陷阱不含有Sushi结构域,
其中所述免疫球蛋白Fc结构域进一步包含N-末端免疫球蛋白铰链区,其中所述铰链区的至少一个未配对的半胱氨酸残基被丝氨酸残基替代,并且其中所述陷阱具有结构NH2-铰链-Fc-接头-TGFβRII-COOH。
2.根据权利要求1所述的陷阱,其中所述TGFβRII经由柔性肽接头部分与所述Fc区连接。
3.根据权利要求2所述的陷阱,其中TGFβRII的所述配体结合结构域经由所述柔性肽接头部分与所述Fc结构域的羧基末端连接。
4.根据权利要求1-3中任一项所述的陷阱,其中所述铰链区的C27残基被丝氨酸残基替代。
5.根据前述权利要求中任一项所述的陷阱,其中所述柔性接头包含G4S重复。
6.根据权利要求5所述的陷阱,其中所述接头包含五个G4S重复。
7.根据权利要求1所述的陷阱,其中所述陷阱包含与SEQ ID NO:24至少85%相同或与SEQ ID NO:25至少85%相同的氨基酸序列。
8.根据前述权利要求中任一项所述的陷阱,其中肽信号序列融合至该陷阱的氨基末端。
9.一种核酸分子,该核酸分子编码根据前述权利要求中任一项所述的陷阱。
10.一种表达载体,该表达载体包含根据权利要求9所述的核酸。
11.根据权利要求10所述的载体,其中所述核酸与诱导型启动子可操作地连接。
12.根据权利要求11所述的载体,其中所述诱导型启动子包含TGF-β诱导型启动子。
13.根据权利要求10所述的载体,其中所述核酸与组成型活性的启动子可操作地连接。
14.根据权利要求13所述的载体,其中所述组成型活性的启动子是CMV启动子。
15.一种宿主细胞,该宿主细胞包含根据权利要求10-14中任一项所述的载体。
16.根据权利要求15所述的宿主细胞,其中所述宿主细胞是IL-2依赖性自然杀伤细胞。
17.一种在受试者中抑制TGF-β的活性的方法,该方法包括向有需要的受试者施用有效量的根据权利要求1-7中任一项所述的陷阱。
18.一种在受试者中抑制TGF-β的活性的方法,该方法包括以足以产生有效量的所述TGF-β陷阱的量向有需要的受试者施用包含根据权利要求15或16所述的宿主细胞的组合物。
19.一种在受试者中治疗瘤形成的方法,该方法包括向有需要的受试者施用治疗有效量的包含根据权利要求15或16所述的宿主细胞的组合物。
20.根据权利要求18或19所述的方法,其中所述宿主细胞经肠胃外、静脉内、瘤周、或通过输注施用。
21.根据权利要求17-20中任一项所述的方法,该方法进一步包括向该受试者施用另外的治疗剂。
Claims (24)
1.一种TGF-β陷阱,该TGF-β陷阱包含与2型转化生长因子-β受体(TGFβRII)的配体结合结构域融合的免疫球蛋白恒定(Fc)结构域,
其中所述陷阱不含有Sushi结构域,并且
其中所述免疫球蛋白Fc结构域进一步包含N-末端免疫球蛋白铰链区,其中所述铰链区的至少一个未配对的半胱氨酸残基被丝氨酸残基替代。
2.根据权利要求1所述的陷阱,其中所述TGFβRII经由柔性肽接头部分与所述Fc区连接。
3.根据权利要求2所述的陷阱,其中TGFβRII的所述配体结合结构域经由所述柔性肽接头部分与所述Fc结构域的羧基末端连接。
4.根据权利要求2所述的陷阱,其中TGFβRII的所述配体结合结构域经由所述柔性肽接头部分与所述Fc结构域的所述铰链区的氨基末端连接。
5.根据权利要求1-4中任一项所述的陷阱,其中所述铰链区的C27残基被丝氨酸残基替代。
6.根据权利要求1-3或5中任一项所述的陷阱,其中所述陷阱具有以下结构:NH2-铰链-Fc-接头-TGFβRII-CO2H。
7.根据权利要求1、2、4或5中任一项所述的陷阱,其中所述陷阱具有以下结构:NH2-TGFβRII-接头-铰链-Fc-CO2H。
8.根据前述权利要求中任一项所述的陷阱,其中所述柔性接头包含G4S重复。
9.根据权利要求8所述的陷阱,其中所述接头包含五个G4S重复。
10.根据权利要求1所述的陷阱,其中所述陷阱包含与SEQ ID NO:24至少85%相同或与SEQ ID NO:25至少85%相同的氨基酸序列。
11.根据前述权利要求中任一项所述的陷阱,其中肽信号序列融合至该陷阱的氨基末端。
12.一种核酸分子,该核酸分子编码根据前述权利要求中任一项所述的陷阱。
13.一种表达载体,该表达载体包含根据权利要求12所述的核酸。
14.根据权利要求13所述的载体,其中所述核酸与诱导型启动子可操作地连接。
15.根据权利要求14所述的载体,其中所述诱导型启动子包含TGF-β诱导型启动子。
16.根据权利要求13所述的载体,其中所述核酸与组成型活性的启动子可操作地连接。
17.根据权利要求16所述的载体,其中所述组成型活性的启动子是CMV启动子。
18.一种宿主细胞,该宿主细胞包含根据权利要求13-17中任一项所述的载体。
19.根据权利要求18所述的宿主细胞,其中所述宿主细胞是IL-2依赖性自然杀伤细胞。
20.一种在受试者中抑制TGF-β的活性的方法,该方法包括向有需要的受试者施用有效量的根据权利要求1-10中任一项所述的陷阱。
21.一种在受试者中抑制TGF-β的活性的方法,该方法包括以足以产生有效量的所述TGF-β陷阱的量向有需要的受试者施用包含根据权利要求18或19所述的宿主细胞的组合物。
22.一种在受试者中治疗瘤形成的方法,该方法包括向有需要的受试者施用治疗有效量的包含根据权利要求18或19所述的宿主细胞的组合物。
23.根据权利要求21或22所述的方法,其中所述宿主细胞经肠胃外、静脉内、瘤周、或通过输注施用。
24.根据权利要求20-23中任一项所述的方法,该方法进一步包括向该受试者施用另外的治疗剂。
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CA2909701C (en) * | 2013-04-17 | 2022-12-06 | Baylor College Of Medicine | Immunosuppressive tgf-.beta. signal converter |
US20190119387A1 (en) * | 2016-04-05 | 2019-04-25 | Glaxosmithkline Intellectual Property Development Limited | Inhibition of tgfbeta in immunotherapy |
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