CN115724942A - TGFβRII活性改造突变体及其应用 - Google Patents
TGFβRII活性改造突变体及其应用 Download PDFInfo
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- CN115724942A CN115724942A CN202111026881.0A CN202111026881A CN115724942A CN 115724942 A CN115724942 A CN 115724942A CN 202111026881 A CN202111026881 A CN 202111026881A CN 115724942 A CN115724942 A CN 115724942A
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Abstract
本发明提出了一种TGFβRII活性改造突变体及其应用，该TGFβRII突变体片段相较于TGFβRII胞外结构域的氨基酸序列，具有如下位点的突变：第49位、第50位氨基酸中的至少之一位，或第49位、第53位中的至少之一位和第27位、第30位、第50位、第51位、第52位、第55位、第77位氨基酸中的至少之一位。根据本发明所述的TGFβRII突变体片段可有效与TGFβ1结合且不与TGFβ3结合，包含所述片段的TGFβRII突变体的胞外区制备的融合蛋白同样具备与TGFβ1结合且不与TGFβ3结合的生物特点，所述融合蛋白可有效预防和治疗肿瘤，且其成药毒性显著降低。
Description
技术领域
本发明涉及生物医药领域，具体地，涉及TGFβRII活性改造突变体及其应用，更具体地，涉及TGFβRII突变体片段、编码TGFβRII突变体的核酸分子、融合蛋白、编码融合蛋白的核酸分子、表达载体、重组细胞、药物组合物、所述TGFβRII突变体或融合蛋白或核酸分子或表达载体或重组细胞在制备药物中的用途、制备所述融合蛋白的方法、降低融合蛋白生产过程中碎片含量的方法。
背景技术
转化生长因子β(transforming growth factor-β,TGFβ)是属于调节细胞生长和分化的TGFβ超家族。
TGFβ1是Tuker等在1984年发现的一种与多种上皮性肿瘤生长有关的多肽性细胞生长负调控因子，广泛参与体内各种病理生理过程，与炎症、创伤、器官纤维化等多种疾病的发生、发展关系密切，尤其是在肿瘤的发生、发展中的调节作用，对肿瘤的研究具有极其深远的意义。
TGFβ2在细胞的增殖、分化、胚胎发育、胞外基质形成、骨的形成和重建以及肿瘤的抑制和转移扩散等方面也起着重要的作用。TGFβ2被指出可以抑制IL-2依赖的T细胞的生长，并且能抑制肿瘤发展中的免疫监视，因而以一种自分泌的方式促进肿瘤生长。TGFβ2可以影响杀伤细胞的活力和降低IL-2，IL-6，IL-10，IFN-γ等细胞因子的表达。
TGFβ3在组织修复过程中刺激靶细胞(成纤维细胞、血管内皮细胞等)细胞外基质合成和加快血管化进程，且促进创面愈合和减轻瘢痕形成。TGFβ3在哺乳动物胚胎发育过程中，能够促进形态发生、并对脊椎形成、肢端发芽、出牙、面骨形成及心脏瓣膜的形成起重要作用。TGFβ3可调控骨形成，可影响成年骨再生。研究发现骨质疏松症患者血清中TGFβ3浓度上升，其水平可能反映出骨组织中TGFβ3活性下降，从而促使骨质疏松的病理过程。
近年的研究发现，肿瘤微环境中TGFβ增加与免疫逃逸相关，TGFβ的增加会增加T细胞排斥，阻断TH1效应T细胞的浸润。研究发现TGFβ阻断使小鼠肝转移癌症模型对PD1/PDL1疗法更敏感，更有研究报道了TGFβ阻断和PD-L1抗体联用，可以下调基质细胞的TGFβ信号通路，促进T细胞渗透进肿瘤中，激活强烈的抗肿瘤免疫反应。
发明内容
本申请是基于发明人对以下问题的发现和认识作出的：
TGFβRII可以与TGFβ1和TGFβ3进行结合，在肿瘤的发生、发展过程中TGFβ1发挥了重要的调节作用，而TGFβ3在对哺乳动物胚胎发育中起重要作用，可以调控骨的形成，但研究发现骨质疏松患者血清中TGFβ3浓度上升，因此，发明人经过大量实验，意外地获得一种对TGFβ1具有高亲和力，而不与TGFβ3进行结合的TGFβRII突变体，所述突变体成药时可有效预防和治疗肿瘤，且药物毒性显著降低。
在本发明的第一方面，本发明提出了一种TGFβRII突变体片段。根据本发明的实施例，相较于TGFβRII胞外结构域的氨基酸序列，所述TGFβRII突变体片段具有如下位点的突变：第49位、第53位氨基酸中的至少之一位，或第49位、第53位中的至少之一位和第27位、第30位、第50位、第51位、第52位、第55位、第77位氨基酸中的至少之一位。鉴于现有技术生产的TGFβRII既可以与TGFβ1结合也可以与TGFβ3结合，TGFβRII与TGFβ3结合会对机体的正常生理功能产生影响，产生成药毒性，发明人创造性的发现，根据本发明实施例的TGFβRII突变体片段可有效与TGFβ1结合且不与TGFβ3结合，包含所述片段的所述融合蛋白可有效预防和治疗肿瘤，且其成药毒性及对机体的正常功能的影响显著降低。
在本发明的第二方面，本发明提出了一种TGFβRII突变体。根据本发明的实施例，包括胞外区、跨膜区和胞内区，所述胞外区包括第一方面所述的TGFβRII突变体片段。鉴于现有技术生产的TGFβRII既可以与TGFβ1结合也可以与TGFβ3结合，TGFβRII与TGFβ3结合会对机体的正常生理功能产生影响，产生成药毒性，发明人创造性的发现，根据本发明实施例的TGFβRII突变体可有效与TGFβ1结合且不与TGFβ3结合，包含所述TGFβRII突变体的胞外区的融合蛋白可有效预防和治疗肿瘤，且其成药毒性及对机体的正常功能的影响显著降低。
在本发明的第三方面，本发明提出了一种核酸分子。根据本发明的实施例，所述核酸分子编码第一方面所述的TGFβRII突变体片段或第二方面所述的TGFβRII突变体。根据本发明实施例的核酸分子编码的所述TGFβRII突变体片段可有效与TGFβ1结合且不与TGFβ3结合，根据本发明实施例的核酸分子编码的所述TGFβRII突变体同样具有与TGFβ1结合且不与TGFβ3结合的特性，包含所述TGFβRII突变体片段或所述TGFβRII突变体胞外区的融合蛋白可有效预防和治疗肿瘤，且其成药毒性及对机体的正常功能的影响极显著降低。
在本发明的第四方面，本发明提出了一种融合蛋白。根据本发明的实施例，包括：1)第一方面所述的TGFβRII突变体片段；以及2)免疫球蛋白Fc片段，所述TGFβRII突变体片段通过连接肽与所述免疫球蛋白Fc片段相连。发明人对TGFβRII胞外结构域的氨基酸序列进行前面所述的突变后，获得的TGFβRII突变体具有与TGFβ1结合且不与TGFβ3结合的特性更加显著，所述融合蛋白的成药毒性及对机体的正常功能的影响极显著降低，在TGFβRII突变体片段上加入免疫球蛋白Fc片段后，获得融合蛋白同样具有与TGFβ1结合且不与TGFβ3结合的特性更加显著，所述融合蛋白的成药毒性及对机体的正常功能的影响极显著降低、提高了其成药性及体内半衰期，所述融合蛋白可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
在本发明的第五方面，本发明提出了一种核酸分子。根据本发明的实施例，所述核酸分子编码第四方面所述的融合蛋白。根据本发明实施例的核酸分子编码的所述融合蛋白具有与TGFβ1结合且不与TGFβ3结合的特性，所述融合蛋白的成药毒性及对机体的正常功能的影响显著降低、提高了其成药性及体内半衰期，所述融合蛋白可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
在本发明的第六方面，本发明提出了一种表达载体。根据本发明的实施例，包含第三方面或第五方面所述的核酸分子。
在本发明的第七方面，本发明提出了一种重组细胞。根据本发明的实施例，携带第三方面或第五方面所述的核酸分子、或第六方面所述的表达载体。根据本发明实施例的重组细胞可以表达前面所述的融合蛋白，所述融合蛋白具有与TGFβ1结合且不与TGFβ3结合的特性，所述融合蛋白的成药毒性及对机体的正常功能的影响显著降低、提高了其成药性及体内半衰期，所述融合蛋白可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
在本发明的第八方面，本发明提出了一种药物组合物。根据本发明的实施例，包含第一方面所述的TGFβRII突变体片段、或第二方面所述的TGFβRII突变体、或第三方面所述的核酸分子、或第四方面所述的融合蛋白、或第五方面所述的核酸分子、或第六方面所述的表达载体、或第七方面所述的重组细胞。根据本发明的药物组合物成药毒性及对机体的正常功能的影响较低，可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
在本发明的第九方面，本发明提出了第一方面所述的TGFβRII突变体片段、或第二方面所述的TGFβRII突变体、或第三方面所述的核酸分子、或第四方面所述的融合蛋白、第五方面所述的核酸分子、第六方面所述的表达载体、第七方面所述的重组细胞在制备药物中的用途。根据本发明的实施例，所述药物用于预防或治疗肿瘤。本发明提供的药物具有长效与TGFβ1结合，且不与TGFβ3结合的特性，以达到治疗或预防肿瘤的目的。
在本发明的第十方面，本发明提出了一种制备第四方面所述的融合蛋白的方法。根据本发明的实施例，包括以下步骤：1)构建第六方面所述的表达载体；2)将所述表达载体导入宿主细胞中，获得重组细胞，以表达所述融合蛋白。根据本发明实施例的方法可高效获得所述融合蛋白，且所述融合蛋白具有与TGFβ1结合且不与TGFβ3结合的特性，其成药毒性及对机体的正常功能的影响较低，可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
在本发明的第十一方面，本发明提出了一种预防或治疗肿瘤的方法。根据本发明的实施例，包括向受试者施用以下中的至少之一：1)第一方面所述的TGFβRII突变体片段；1)第二方面所述的TGFβRII突变体；3)第四方面所述的融合蛋白；3)第三方面和第五方面所述的分离的核酸分子；4)第六方面所述的表达载体；5)第七方面所述的重组细胞；以及6)第八方面所述的药物组合物。根据本发明实施例的方法可以通过控制肿瘤细胞周围表达上调的TGFβ1的含量，从而有效预防或治疗肿瘤。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1是根据本发明实施例的TGFβRII trap融合蛋白与人源TGFβ1和人源TGFβ3的ELISA结合活性检测结果图；
图2是根据本发明实施例的TGFβRII trap融合蛋白对T细胞增殖影响的结果图。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在本发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
“TGFβRII胞外结构域”是指野生型TGFβRII细胞外自N端开始的一段长136个氨基酸残基的肽段，具有如SEQ ID NO：1所示的氨基酸序列。
本发明提供一种TGFβRII突变体片段。相较于TGFβRII胞外结构域的氨基酸序列，所述TGFβRII突变体片段具有如下位点的突变：第49位、第53位氨基酸中的至少之一位，或第49位、第53位中的至少之一位和第27位、第30位、第50位、第51位、第52位、第55位、第77位氨基酸中的至少之一位。鉴于现有技术生产的TGFβRII既可以与TGFβ1结合也可以与TGFβ3结合，TGFβRII与TGFβ3结合会对机体的正常生理功能产生影响，产生成药毒性，发明人创造性的发现，根据本发明实施例的突变方式对TGFβRII胞外结构域的氨基酸序列(SEQ ID NO：1)进行突变后，获得的TGFβRII突变体片段可有效与TGFβ1结合且不与TGFβ3结合，包含所述片段的TGFβRII突变体同样具备与TGFβ1结合且不与TGFβ3结合的特性，利用所述TGFβRII突变体的胞外区制备的融合蛋白可有效预防和治疗肿瘤，且其成药毒性及对机体的正常功能的影响显著降低。
IPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPD(SEQ IDNO：1)。
根据本发明的一个具体的实施例，所述TGFβRII突变体片段相较于TGFβRII胞外结构域的氨基酸序列具有如下突变中的至少之一：1)第49位的S替换为N，或2)第53位的I替换为K，3)第49位的S替换为N，第27位的L替换为S，或4)第49位的S替换为N，第30位的F替换为E，或5)第49位的S替换为N，第50位的I替换为W，或6)第49位的S替换为N，第51位的T替换为I，或7)第49位的S替换为N，第51位的T替换为W，或8)第49位的S替换为N，第51位的T替换为R，或9)第49位的S替换为N，第52位的S替换为D，或10)第49位的S替换为N，第53位的I替换为K，或11)第49位的S替换为N，第55位的E替换为W，或12)第49位的S替换为N，第55位的E替换为R，或13)第49位的S替换为N，第77位的V替换为W，或14)第53位的I替换为K，第27位的L替换为S，或15)第53位的I替换为K，第30位的F替换为E，或16)第53位的I替换为K，第50位的I替换为W，或17)第53位的I替换为K，第51位的T替换为I，或18)第53位的I替换为K，第51位的T替换为W，或19)第53位的I替换为K，第51位的T替换为R，或20)第53位的I替换为K，第52位的S替换为D，或21)第53位的I替换为K，第55位的E替换为W，或22)第53位的I替换为K，第55位的E替换为R，或23)第53位的I替换为K，第77位的V替换为W，或24)第50位的I替换为W，或25)第51位的T替换为I，或26)第55位的E替换为W，或27)第77位的V替换为W。根据本发明具体实施例的突变方式获得的TGFβRII突变体片段具备与TGFβ1结合且不与TGFβ3结合的特性，包含所述片段的TGFβRII突变体同样具备与TGFβ1结合且不与TGFβ3结合的特性，利用所述TGFβRII突变体的胞外区制备的融合蛋白可有效预防和治疗肿瘤，且其成药毒性及对机体的正常功能的影响极显著降低。
根据本发明的一个具体的实施例，所述TGFβRII突变体片段具有SEQ ID NO：2～28任一所示的氨基酸序列。
根据本发明的一个优选的实施例，所述TGFβRII突变体片段相较于TGFβRII胞外结构域的氨基酸序列具有如下突变中的至少之一：1)第49位的S替换为N，或2)第53位的I替换为K，3)第49位的S替换为N，第27位的L替换为S，或4)第49位的S替换为N，第30位的F替换为E，或5)第49位的S替换为N，第50位的I替换为W，或6)第49位的S替换为N，第51位的T替换为I，或7)第49位的S替换为N，第51位的T替换为W，或8)第49位的S替换为N，第51位的T替换为R，或9)第49位的S替换为N，第52位的S替换为D，或10)第49位的S替换为N，第53位的I替换为K，或11)第49位的S替换为N，第55位的E替换为W，或12)第49位的S替换为N，第55位的E替换为R，或13)第49位的S替换为N，第77位的V替换为W，或14)第53位的I替换为K，第27位的L替换为S，或15)第53位的I替换为K，第30位的F替换为E，或16)第53位的I替换为K，第50位的I替换为W，或17)第53位的I替换为K，第51位的T替换为I，或18)第53位的I替换为K，第51位的T替换为W，或19)第53位的I替换为K，第51位的T替换为R，或20)第53位的I替换为K，第52位的S替换为D，或21)第53位的I替换为K，第55位的E替换为W，或22)第53位的I替换为K，第55位的E替换为R，或23)第53位的I替换为K，第77位的V替换为W。
根据本发明的一个优选的实施例，所述TGFβRII突变体片段具有SEQ ID NO：2～24任一所示的氨基酸序列。
根据本发明的一个优选的实施例，所述TGFβRII突变体片段相较于TGFβRII胞外结构域的氨基酸序列具有如下突变中的至少之一：1)第49位的S替换为N，或2)第53位的I替换为K。
根据本发明的一个优选的实施例，所述TGFβRII突变体片段具有SEQ ID NO：2或SEQ ID NO：3所示的氨基酸序列。
本发明提供一种核酸分子，所述核酸分子编码前面所述的TGFβRII突变体片段或TGFβRII突变体。根据本发明具体实施例的核酸分子编码的所述TGFβRII突变体片段具有与TGFβ1结合且不与TGFβ3结合的特性，根据本发明具体实施例的核酸分子编码的所述TGFβRII突变体同样具备与TGFβ1结合且不与TGFβ3结合的特性，利用所述TGFβRII突变体的胞外区制备的所述融合蛋白的成药毒性及对机体的正常功能的影响极显著降低，可有效预防和治疗肿瘤。
本发明提供一种融合蛋白，包括：1)前面所述的TGFβRII突变体片段；以及2)免疫球蛋白Fc片段，所述TGFβRII突变体片段通过连接肽与所述免疫球蛋白Fc片段相连。发明人对SEQ ID NO：1所示的野生型TGFβRII进行前面所述的突变后，获得的TGFβRII突变体具有与TGFβ1结合且不与TGFβ3结合的特性更加显著，所述融合蛋白的成药毒性及对机体的正常功能的影响极显著降低，在TGFβRII突变体片段上加入免疫球蛋白Fc片段后，获得融合蛋白同样具有与TGFβ1结合且不与TGFβ3结合的特性更加显著，所述融合蛋白的成药毒性及对机体的正常功能的影响极显著降低、提高了其成药性及体内半衰期，所述融合蛋白可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
根据本发明的一个具体的实施例，所述连接肽的N端与所述免疫球蛋白Fc片段的C端相连，所述连接肽的C端与所述的TGFβRII突变体片段的N端相连。
根据本发明的一个具体的实施例，所述免疫球蛋白Fc片段来源于人源IgG抗体分子。
根据本发明的一个具体的实施例，所述免疫球蛋白Fc片段包含hIgG1抗体的Fc重链片段。
根据本发明的一个具体的实施例，所述免疫球蛋白Fc片段C末端的赖氨酸被突变为丙氨酸，所述免疫球蛋白Fc片段具有如SEQ ID NO：25所示氨基酸序列。将所述免疫球蛋白Fc片段C末端的赖氨酸被突变为丙氨酸后可以减少融合蛋白的切割水解，从而降低生产融合蛋白过程中碎片的含量。
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGA(SEQ ID NO：29)。
根据本发明的一个具体的实施例，所述连接肽为柔性连接肽。所述连接肽不受特别限制，本领域常规的柔性片段均可使用。
根据本发明的一个具体的实施例，所述连接肽包含(G4S)XG氨基酸序列，其中，X为大于0的整数。根据本发明的一个具体的实施例，所述连接肽包含(G4S)4G氨基酸序列(SEQID NO：30)。
GGGGSGGGGSGGGGSGGGGSG(SEQ ID NO：30)。
根据本发明的一个具体的实施例，所述融合蛋白具有如SEQ ID NO：31～36任一所示的氨基酸序列。SEQ ID NO：31～36所示的氨基酸序列中，下方标注点线的为免疫球蛋白Fc片段C末端被突变后的丙氨酸，如：SEQ ID NO：31序列中的A；下方标注单实线的为连接肽的氨基酸序列，如：SEQ ID NO：31序列中的GGGGSGGGGSGGGGSGGGGSG；下方标注双实线的为TGFβRII突变体被突变后的氨基酸，如：SEQ ID NO：31序列中的
根据本发明的一个优选的实施例，所述融合蛋白具有如SEQ ID NO：31或SEQ IDNO：32所示的氨基酸序列。
本发明提供一种核酸分子，所述核酸分子编码前面所述的融合蛋白。根据本发明的具体实施例的核酸分子编码的所述融合蛋白具有与TGFβ1结合且不与TGFβ3结合的特性，所述融合蛋白的成药毒性及对机体的正常功能的影响显著降低、提高了其成药性及体内半衰期，所述融合蛋白可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
本发明提供一种表达载体，包含前面所述的编码TGFβRII突变体片段或TGFβRII突变体或融合蛋白的核酸分子。在将上述核酸分子连接到载体上时，可以将核酸分子与载体上的控制元件直接或者间接相连，只要这些控制元件能够控制核酸分子的翻译和表达等即可。当然这些控制元件可以直接来自于载体本身，也可以是外源性的，即并非来自于载体本身。当然，核酸分子与控制元件进行可操作地连接即可。本文中“可操作地连接”是指将外源基因连接到载体上，使得载体内的控制元件，例如转录控制序列和翻译控制序列等等，能够发挥其预期的调节外源基因的转录和翻译的功能。
根据本发明的一个具体的实施例，所述表达载体为真核表达载体。
本发明提供一种重组细胞，携带前面所述的编码TGFβRII突变体片段或TGFβRII突变体的核酸分子、或编码融合蛋白的核酸分子、或表达载体。根据本发明的具体实施例的重组细胞可以表达前面所述的融合蛋白，所述融合蛋白具有与TGFβ1结合且不与TGFβ3结合的特性，所述融合蛋白的成药毒性及对机体的正常功能的影响显著降低、提高了其成药性及体内半衰期，所述融合蛋白可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
根据本发明的一个具体的实施例，所述重组细胞为哺乳动物细胞，哺乳动物为：哺乳动物例如人、猴、兔、犬、牛等；哺乳动物细胞如：人HEK-293F细胞或CHO-K1细胞。
根据本发明的一个具体实施例，所述重组细胞不包括动物生殖细胞、受精卵或胚胎干细胞。
本发明提供一种药物组合物，包含前面所述的TGFβRII突变体片段、或TGFβRII突变体、或编码TGFβRII突变体片段或TGFβRII突变体的核酸分子、或融合蛋白、或编码融合蛋白的核酸分子、或表达载体、或重组细胞。所述药物组合物可包括：药学上可接受的辅剂，所述药学上可接受的辅剂包括稳定剂、湿润剂、乳化剂、粘合剂、等渗剂的至少之一；所述药物组合物呈片剂、颗粒剂、散剂、胶囊剂、溶液剂、悬浮剂、冻干制剂的至少一种。根据本发明的药物组合物成药毒性及对机体的正常功能的影响较低，可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
本发明提供前面所述的TGFβRII突变体片段、或TGFβRII突变体、或编码TGFβRII突变体片段或TGFβRII突变体的核酸分子、融合蛋白、编码融合蛋白的核酸分子、表达载体、重组细胞在制备药物中的用途。根据本发明的具体实施例，所述药物用于预防或治疗肿瘤。本发明提供的药物具有长效与TGFβ1结合，且不与TGFβ3结合的特性，以达到治疗或预防肿瘤的目的。
本发明提供一种制备前面所述的融合蛋白的方法，包括以下步骤：1)构建前面所述的表达载体；2)将所述表达载体导入宿主细胞中，获得重组细胞，以表达所述融合蛋白。根据本发明的具体实施例的方法可高效获得所述融合蛋白，且所述融合蛋白具有与TGFβ1结合且不与TGFβ3结合的特性，其成药毒性及对机体的正常功能的影响较低，可以控制肿瘤细胞周围表达上调的TGFβ的含量，从而长效、有效的预防或治疗肿瘤。
根据本发明的一个具体实施例，所述重组细胞不包括动物生殖细胞、受精卵或胚胎干细胞。
本发明提供一种预防或治疗肿瘤的方法，包括向受试者施用以下中的至少之一：1)前面所述的TGFβRII突变体片段或TGFβRII突变体；2)前面所述的融合蛋白；3)前面所述的核酸分子；4)前面所述的表达载体；5)前面所述的重组细胞；以及6)前面所述的药物组合物。根据本发明具体实施例的方法可以通过控制肿瘤细胞周围表达上调的TGFβ的含量，从而有效预防或治疗肿瘤。
这些肿瘤可以是任何不受调控的细胞生长。具体地，可以是非小细胞肺癌、乳头状甲状腺癌、多形性成胶质细胞瘤、结肠直肠癌、黑色素瘤、胆管癌或肉瘤、急性骨髓性白血病、大细胞神经内分泌癌、成神经细胞瘤、前列腺癌、成神经细胞瘤、胰腺癌、黑色素瘤、头颈鳞状细胞癌或胃癌等等。
下面参考具体实施例，对本发明进行描述，需要说明的是，这些实施例仅仅是描述性的，而不以任何方式限制本发明。
实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1 TGFβRII trap融合蛋白的表达
利用同源重组技术，发明人以(G4S)4G作为连接肽(SEQ ID NO：30)，将hIgG1抗体的Fc重链片段(SEQ ID NO：29)的C末端氨基酸与具有不同突变位点(表1)的TGFβRII突变体片段连接，形成TGFβRII trap融合蛋白。
在融合结合处，将hIgG1抗体的Fc重链片段的C末端赖氨酸残基(K)被突变成丙氨酸(A)，减少融合蛋白的切割水解。对于TGFβRII trap融合蛋白，采用瞬时转染或稳定转染的标准方案用位于相同表达载体或分开的表达载体中的编码Fc-TGFβRII受体的DNA来转染哺乳动物细胞，瞬时转染人HEK-293F细胞制备TGFβRII trap融合蛋白，稳定转染CHO-K1细胞制备TGFβRII trap融合蛋白，得到TGFβRII trap融合蛋白。
TGFβRII trap融合蛋白、TGFβRII突变体片段的序列描述及其突变位点如表1所示。
表1
表1中，例如，L27S代表TGFβRII胞外结构域的氨基酸序列第27位的L突变为S。
实施例2 TGFβRII trap融合蛋白纯化
细胞培养液高速离心后收集上清，利用亲合层析进行第一步纯化。层析介质为与Fc相互作用的Protein A或者衍生填料，如GE的Mabselect。平衡缓冲液为1×PBS，平衡5倍管柱体积后，将细胞上清上样结合，流速控制为样品在管柱上保留时间≥1min。上样结束后，用1×PBS(pH7.4)冲洗管柱，直至A280紫外吸收降至基线。然后用0.1M甘胺酸(pH3.0)的洗脱缓冲液冲洗层析管柱，根据A280紫外吸收峰收集洗脱峰，收集的洗脱样品用1M Tris(pH8.5)中和。
将上述中和后的洗脱样品超滤浓缩后进行体积排阻层析，缓冲液为1×PBS，层析管柱为XK26/60Superdex200(GE)，流速控制在4mL/min，上样体积小于5mL，根据A280紫外吸收合并目的蛋白峰。收集的TGFβRII trap融合蛋白经SEC-HPLC鉴定纯度。
实施例3 TGFβRII trap融合蛋白的ELISA结合检测
TGFβRII trap融合蛋白Trap端结合检测所用蛋白为human TGFβ1(CA59，购自Novoprotein)和human TGFβ3(CJ44，购自Novoprotein)，检测流程如下：
a.用1×磷酸盐缓冲液(PBS)稀释TGFβ至0.5μg/mL，100μL/孔包被96孔酶标板，4℃过夜；
b.250μL 1×PBST(PBS+0.5％Tween20)洗涤3次，加入200μL含2％牛血清白蛋白(BSA)的PBS室温封闭1小时；
c.250μL 1×PBST洗涤3次，加入梯度稀释的TGFβRII trap融合蛋白，室温孵育2小时；
d.250μL 1×PBST洗涤3次，每孔加入100μL稀释好的Goat-anti-human Fc-HRP藕联抗体(Sigma，1:15k)，室温孵育1小时；
e.250μL 1×PBST洗涤3次，每孔加入100μL TMB显色液，室温避光孵育10min，加入50μL 2NH2SO4终止反应；
f.用iX3酶标仪(Molecular Device公司)读取450nM处的吸收值，分析作图。
TGFβRII trap融合蛋白与人源TGFβ1和人源TGFβ3的ELISA结合活性检测结果如图1所示，可以看出：相比于野生型WT组，L27S、F30E、T51W、T51R、S52D突变的TGFβRII trap融合蛋白会同时大幅度削弱TGFβ1与TGFβRII的结合以及TGFβ3与TGFβRII的结合，说明这5个位点的改变可能对于TGFβRII的结构影响较大；另外，我们观察到S49N、I50W、T51I、I53K、E55W、V77W这6个位点突变的TGFβRII trap融合蛋白可以大幅度削弱TGFβ3与TGFβRII的结合；更加值得注意的是，S49N、I53K的TGFβ1与TGFβRII的结合活性EC50与野生型WT组接近，I53K更是可以达到保留TGFβ1与TGFβRII结合的同时TGFβ3完全不与TGFβRII结合。
实施例4 TGFβRII trap融合蛋白的阻断活性检测
构建稳定转染表达人TGFβRII的CHO细胞(CHO-hTGFβRII)，挑取单克隆建系。采用如下方法对抗TGFβRII trap的阻断活性进行检测。
a.对CHO-hTGFβRII细胞进行计数，将细胞以2×105个/每孔的密度铺至96孔U底板；
b.细胞离心，300g，4℃，5min，弃上清液。
c.用含1％BSA的1×PBS稀释TGFβRII trap融合蛋白，起始浓度为50nM，稀释倍数为4倍，8个梯度，同时稀释TGFβ1-biotin(购自Acrobiosystem)，浓度为1μg/mL。
d.将融合蛋白稀释液和TGFβ1-botin稀释液按1:1的体积比例混匀，室温放置30min。
e.将混合样品加入CHO-TGFβRⅡ细胞中，100μL/孔，4℃放置30min。室温离心，300g，5min，甩去上清液。
f.加入SA-PE(400倍稀释，Jackson immunoresearch，016-110-084)，100μL/孔，轻微混匀，4℃放置1小时。
g.室温离心，300g，5min，甩去上清液。细胞中加入含1％BSA的1×PBS，100μL/孔，重悬细胞，流式上机检测。
TGFβRII trap融合蛋白对T细胞增殖影响的结果图如图2所示，相较于野生型WT组，L27S、S49N、I50W、I53K、E55W、V77W突变的TGFβRII trap融合蛋白展现出对TGFβ1的阻断活性；其中，S49N和I53K的阻断活性较好，S49N的EC50值为0.2544nM，优于野生型WT组，而I53K的EC50值为0.4037nM，与野生型WT组接近。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
SEQUENCE LISTING
<110> 广东菲鹏制药股份有限公司
<120> TGFβRII活性改造突变体及其应用
<130> SI4210199
<160> 36
<170> PatentIn version 3.5
<210> 1
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 1
<400> 1
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> 2
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 2
<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
Asn 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> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 3
<400> 3
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 Lys 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> 4
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 4
<400> 4
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 Ser 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
Asn 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> 5
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 5
<400> 5
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 Glu Cys Asp
20 25 30
Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys
35 40 45
Asn 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> 6
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 6
<400> 6
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
Asn Trp 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> 7
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 7
<400> 7
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
Asn Ile Ile 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> 8
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 8
<400> 8
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
Asn Ile Trp 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> 9
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 9
<400> 9
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
Asn Ile Arg 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> 10
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 10
<400> 10
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
Asn Ile Thr Asp 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> 11
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 11
<400> 11
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
Asn Ile Thr Ser Lys 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> 12
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 12
<400> 12
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
Asn Ile Thr Ser Ile Cys Arg 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> 13
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 13
<400> 13
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
Asn Ile Thr Ser Ile Cys Trp 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> 14
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 14
<400> 14
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
Asn 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 Trp 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> 15
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 15
<400> 15
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 Ser 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 Lys 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> 16
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 16
<400> 16
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 Glu 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 Lys 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> 17
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 17
<400> 17
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 Trp Thr Ser Lys 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> 18
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 18
<400> 18
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 Ile Ser Lys 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> 19
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 19
<400> 19
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 Trp Ser Lys 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> 20
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 20
<400> 20
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 Arg Ser Lys 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> 21
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 21
<400> 21
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 Asp Lys 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> 22
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 22
<400> 22
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 Lys Cys Arg 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> 23
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 23
<400> 23
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 Lys Cys Trp 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> 24
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 24
<400> 24
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 Lys 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 Trp 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> 25
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 25
<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 Trp 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> 26
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 26
<400> 26
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 Ile 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> 27
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 27
<400> 27
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 Trp 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> 28
<211> 136
<212> PRT
<213> Artificial Sequence
<220>
<223> 28
<400> 28
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 Trp 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> 29
<211> 227
<212> PRT
<213> Artificial Sequence
<220>
<223> 29
<400> 29
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala
225
<210> 30
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> 30
<400> 30
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly
20
<210> 31
<211> 384
<212> PRT
<213> Artificial Sequence
<220>
<223> 31
<400> 31
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser
245 250 255
Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe
260 265 270
Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn
275 280 285
Gln Lys Ser Cys Met Ser Asn Cys Asn Ile Thr Ser Ile Cys Glu Lys
290 295 300
Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile
305 310 315 320
Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe
325 330 335
Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys
340 345 350
Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys
355 360 365
Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
370 375 380
<210> 32
<211> 384
<212> PRT
<213> Artificial Sequence
<220>
<223> 32
<400> 32
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser
245 250 255
Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe
260 265 270
Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn
275 280 285
Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Lys Cys Glu Lys
290 295 300
Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile
305 310 315 320
Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe
325 330 335
Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys
340 345 350
Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys
355 360 365
Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
370 375 380
<210> 33
<211> 384
<212> PRT
<213> Artificial Sequence
<220>
<223> 33
<400> 33
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser
245 250 255
Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe
260 265 270
Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn
275 280 285
Gln Lys Ser Cys Met Ser Asn Cys Ser Trp Thr Ser Ile Cys Glu Lys
290 295 300
Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile
305 310 315 320
Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe
325 330 335
Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys
340 345 350
Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys
355 360 365
Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
370 375 380
<210> 34
<211> 384
<212> PRT
<213> Artificial Sequence
<220>
<223> 34
<400> 34
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser
245 250 255
Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe
260 265 270
Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn
275 280 285
Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Ile Ser Ile Cys Glu Lys
290 295 300
Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile
305 310 315 320
Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe
325 330 335
Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys
340 345 350
Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys
355 360 365
Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
370 375 380
<210> 35
<211> 384
<212> PRT
<213> Artificial Sequence
<220>
<223> 35
<400> 35
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser
245 250 255
Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe
260 265 270
Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn
275 280 285
Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Trp Lys
290 295 300
Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile
305 310 315 320
Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe
325 330 335
Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys
340 345 350
Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys
355 360 365
Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
370 375 380
<210> 36
<211> 384
<212> PRT
<213> Artificial Sequence
<220>
<223> 36
<400> 36
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser
245 250 255
Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe
260 265 270
Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn
275 280 285
Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys
290 295 300
Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile
305 310 315 320
Thr Leu Glu Thr Trp Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe
325 330 335
Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys
340 345 350
Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys
355 360 365
Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
370 375 380
Claims (10)
1.一种TGFβRII突变体片段，其特征在于，相较于TGFβRII胞外结构域的氨基酸序列，所述TGFβRII突变体片段具有如下位点的突变：
第49位、第53位氨基酸中的至少之一位，或第49位、第53位中的至少之一位和第27位、第30位、第50位、第51位、第52位、第55位、第77位氨基酸中的至少之一位。
2.根据权利要求1所述TGFβRII突变体片段，其特征在于，相较于TGFβRII胞外结构域的氨基酸序列，所述TGFβRII突变体片段具有如下突变中的至少之一：
1)第49位的S替换为N，或
2)第53位的I替换为K，或
3)第49位的S替换为N，第27位的L替换为S，或
4)第49位的S替换为N，第30位的F替换为E，或
5)第49位的S替换为N，第50位的I替换为W，或
6)第49位的S替换为N，第51位的T替换为I，或
7)第49位的S替换为N，第51位的T替换为W，或
8)第49位的S替换为N，第51位的T替换为R，或
9)第49位的S替换为N，第52位的S替换为D，或
10)第49位的S替换为N，第53位的I替换为K，或
11)第49位的S替换为N，第55位的E替换为W，或
12)第49位的S替换为N，第55位的E替换为R，或
13)第49位的S替换为N，第77位的V替换为W，或
14)第53位的I替换为K，第27位的L替换为S，或
15)第53位的I替换为K，第30位的F替换为E，或
16)第53位的I替换为K，第50位的I替换为W，或
17)第53位的I替换为K，第51位的T替换为I，或
18)第53位的I替换为K，第51位的T替换为W，或
19)第53位的I替换为K，第51位的T替换为R，或
20)第53位的I替换为K，第52位的S替换为D，或
21)第53位的I替换为K，第55位的E替换为W，或
22)第53位的I替换为K，第55位的E替换为R，或
23)第53位的I替换为K，第77位的V替换为W，或
24)第50位的I替换为W，或
25)第51位的T替换为I，或
26)第55位的E替换为W，或
27)第77位的V替换为W。
3.根据权利要求1或2所述TGFβRII突变体片段，其特征在于，所述TGFβRII突变体片段具有SEQ ID NO：2～28任一所示的氨基酸序列。
4.一种融合蛋白，其特征在于，包括：
1)权利要求1～3任一项所述的TGFβRII突变体片段；以及
2)免疫球蛋白Fc片段，所述TGFβRII突变体片段通过连接肽与所述免疫球蛋白Fc片段相连。
5.根据权利要求4所述融合蛋白，其特征在于，所述连接肽的N端与所述免疫球蛋白Fc片段的C端相连，所述连接肽的C端与权利要求1～3任一项所述的TGFβRII突变体片段N端相连。
6.根据权利要求4或5所述融合蛋白，其特征在于，所述免疫球蛋白Fc片段来源于人源IgG抗体分子。
7.一种核酸分子，其特征在于，所述核酸分子编码权利要求1～3任一项所述的TGFβRII突变体片段，或权利要求4～6任一项所述的融合蛋白。
8.一种表达载体，其特征在于，包含权利要求7所述的核酸分子。
9.一种重组细胞，其特征在于，携带权利要求8所述的表达载体。
10.一种药物组合物，其特征在于，其包含权利要求1～3任一项所述的TGFβRII突变体片段或权利要求4～6任一项所述的融合蛋白。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111026881.0A CN115724942A (zh) | 2021-09-02 | 2021-09-02 | TGFβRII活性改造突变体及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111026881.0A CN115724942A (zh) | 2021-09-02 | 2021-09-02 | TGFβRII活性改造突变体及其应用 |
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| Publication Number | Publication Date |
|---|---|
| CN115724942A true CN115724942A (zh) | 2023-03-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111026881.0A Pending CN115724942A (zh) | 2021-09-02 | 2021-09-02 | TGFβRII活性改造突变体及其应用 |
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| Country | Link |
|---|---|
| CN (1) | CN115724942A (zh) |
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2021
- 2021-09-02 CN CN202111026881.0A patent/CN115724942A/zh active Pending
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