CN110381983A - 基于tigit和light的嵌合蛋白 - Google Patents
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Abstract
本发明尤其涉及组合物和方法,其包括可用于治疗疾病诸如癌症和炎性疾病的基于TIGIT和/或LIGHT的嵌合蛋白。
Description
优先权
本申请要求2017年2月27日提交的美国临时申请号62/464,002 的权益和优先权,所述临时申请的内容特此以引用的方式整体并入。
电子提交的文本文件的描述
本申请包含序列表。它已作为名称为“SHK-001PC1_SequenceListing_ST25”的ASCII文本文件通过 EFS-Web以电子方式提交。序列表的大小为141,613字节,并且创建于2018年2月27日左右。序列表特此以引用的方式整体并入。
技术领域
本发明尤其涉及组合物和方法,包括可用于治疗疾病的嵌合蛋白,诸如癌症和自身免疫性疾病的免疫疗法。
背景技术
免疫系统是身体对于可能导致疾病的外来物质的应答的中心。然而,许多癌症通过例如递送或传播免疫抑制信号而发展了避免免疫系统的机制。因此,仍然需要开发被赋予多种功能性的治疗剂-例如,逆转免疫抑制信号和刺激抗癌免疫应答。
发明内容
因此,在各个方面,本发明提供了可用于癌症免疫疗法的组合物和方法。例如,本发明部分涉及特异性嵌合蛋白,其在提供免疫活化或共刺激信号的同时逆转或抑制免疫抑制信号。尤其重要的是,本发明提供了改进的嵌合蛋白,其可以在不希望受理论束缚的情况下基于包括一个或多个二硫键的接头区域中的稳定化来维持稳定且可产生的多聚体状态。因此,本发明的组合物和方法克服了产生双特异性剂的各种缺陷。
在一些方面,嵌合蛋白具有以下一般结构:N末端–(a)–(b)–(c) –C末端,其中(a)是包含I型跨膜蛋白的细胞外结构域的第一结构域, (b)是包含至少一个能够形成二硫键的半胱氨酸残基的接头(包括但不限于衍生自人IgG4的铰链-CH2-CH3 Fc结构域),并且(c)是包含II 型跨膜蛋白的细胞外结构域的第二结构域,其中所述接头连接第一结构域和第二结构域并任选地包含一个或多个如本文所述的连接接头。
例如,在实施方案中,I型跨膜蛋白的细胞外结构域来自TIGIT (VSIG9,VSTM3)。
在实施方案中,嵌合蛋白具有以下一般结构:N末端–(a)–(b)– (c)–C末端,其中(a)是包含I型跨膜蛋白的细胞外结构域的第一结构域,所述跨膜蛋白是TIGIT,(b)是包含至少一个能够形成二硫键的半胱氨酸残基的接头(包括但不限于衍生自人IgG4的铰链-CH2-CH3 Fc 结构域),并且(c)是包含II型跨膜蛋白的细胞外结构域的第二结构域,所述跨膜蛋白选自4-1BBL(TNFSF9)、GITRL(TNFSF18)、TL1A (TNFSF15)和LIGHT(TNFSF14),其中所述接头连接第一结构域和第二结构域并任选地包含一个或多个如本文所述的连接接头。
例如,在实施方案中,II型跨膜蛋白的细胞外结构域来自LIGHT。
在实施方案中,嵌合蛋白具有以下一般结构:N末端–(a)–(b)– (c)–C末端,其中(a)是包含I型跨膜蛋白的细胞外结构域的第一结构域,所述跨膜蛋白选自PD-1、CD172a(SIRPα)和TIGIT,(b)是包含至少一个能够形成二硫键的半胱氨酸残基的接头(包括但不限于衍生自人IgG4的铰链-CH2-CH3 Fc结构域),并且(c)是包含II型跨膜蛋白的细胞外结构域的第二结构域,所述跨膜蛋白是LIGHT,其中所述接头连接第一结构域和第二结构域并任选地包含一个或多个如本文所述的连接接头。
在一些方面,提供了一种用于治疗癌症或炎性疾病的方法,其包括施用有效量的前述嵌合蛋白的药物组合物。在实施方案中,当与嵌合蛋白的第二结构域结合时,受试者的T细胞被活化,并且(a)当与嵌合蛋白的第一结构域结合时,预防一种或多种肿瘤细胞传递免疫抑制信号,(b)受试者的外周血中的可定量的细胞因子应答被活化,并且 /或者(c)与用针对I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,有需要的受试者中的肿瘤生长减少。在实施方案中,所述方法刺激LIGHT、4-1BBL、GITRL和TL1A中的一种或多种的信号传导,并且活化抗原呈递细胞。在实施方案中,与未治疗的受试者或用针对I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述方法减少调节T细胞(Treg)的量或活性。在实施方案中,与未治疗的受试者或用针对I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述方法增加受试者的引流淋巴结中效应T 细胞的引发。在实施方案中,与未治疗的受试者或用针对I型或II 型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述方法引起免疫抑制细胞的总体降低和朝向更具炎性的肿瘤环境的转移。
本文描述的任何方面或实施方案都可以与如本文所公开的任何其他方面或实施方案结合。
附图说明
图1A至图1D示出了I型膜蛋白和II型膜蛋白(图1A和图1C) 如何可以进行工程化的示意图,其中跨膜结构域和细胞内结构域被去除并使用接头序列连接(图1B)以产生单一嵌合蛋白,其中I型膜蛋白和II型膜蛋白的细胞外结构域各自在单一嵌合蛋白中面向外。图1B 描绘了通过去除每种蛋白质的跨膜结构域和细胞内结构域进行的I型膜蛋白和II型膜蛋白的连接,并且其中来自每种蛋白质的释放的细胞外结构域(ECD)已经通过接头序列连接。本描述中的ECD可以包括通常位于细胞膜外的候选I型蛋白或II型蛋白的完整氨基酸序列,或其保留与预期受体或配体结合的任何部分。图1D描绘了线性构建体中的连接的细胞外结构域,其中I型膜蛋白的细胞外结构域面向构建体的“左”侧,并且II型膜蛋白的细胞外结构域面向构建体的“右”侧。
图2A,使用PD-1-Fc-OX40L嵌合蛋白作为实例,示出了肿瘤细胞可以在细胞表面表达PD-L1,其可以结合由T细胞表达的PD-1(图 2B)。此相互作用抑制T细胞的活化。包含与OX40L的细胞外结构域连接的PD-1的细胞外结构域的嵌合蛋白可以与肿瘤细胞表面上的PD-L1结合,从而防止与T细胞表面上的PD-1结合(图2C)。然后嵌合蛋白可以“悬挂”在肿瘤细胞表面,并且然后嵌合蛋白的OX40L部分可以与T细胞表面上表达的OX40结合。这将导致用共刺激OX40L 信号替换抑制性PD-L1信号,以增强T细胞的抗肿瘤活性。图2D示出了由肿瘤细胞与T细胞之间的嵌合蛋白形成的突触。图2A至图2C 示出了PD-1-Fc-OX40L嵌合蛋白与其靶分子结合以在细胞之间产生突触的机制;因此,PD-1-Fc-OX40L说明了本发明的嵌合蛋白操作的机制。
图3A示出了在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上运行的鼠TIGIT-Fc-OX40L嵌合蛋白的蛋白质印迹。
图3B示出了在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上运行的人TIGIT-Fc-OX40L嵌合蛋白的蛋白质印迹。在两种情况下,每个结构域的特异性检测由抗TIGIT、抗 Fc和抗OX40L印迹指示。
图4A是示出在以下条件下进行的鼠TIGIT-Fc-OX40L嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP检测(顶部左侧),CD155/PVR-His捕获并用IgG检测(顶部右侧),OX40-His捕获并用针对mOX40L的抗体检测(底部左侧),以及OX40-Fc捕获并用重组 CD155检测(底部右侧)。图4B是示出在以下条件下进行的人 TIGIT-Fc-OX40L嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP 检测(顶部左侧),CD155/PVR-His捕获并用IgG检测(顶部右侧),OX40-His捕获并用针对mOX40L的抗体检测(底部左侧),以及 OX40-Fc捕获并用重组CD155、CD112或CD113蛋白检测(底部右侧)。
图5A示出了生成以过表达人PVR(CHOK1/PVR)的细胞系,其可以用于检测通过含有TIGIT的构建体进行的结合(在图5A中,未染色的和同种型是重叠的)。
图5B示出了生成以过表达结合素-2(CHOK1/结合素2)的细胞系,其可以用于检测通过含有TIGIT的构建体进行的结合。
图5C示出了生成以过表达结合素-3(CHOK1/结合素3)的细胞系,其可以用于检测通过含有TIGIT的构建体进行的结合(在图5C中,未染色的、同种型和检测Ab是重叠的)。
图6是示出小鼠TIGIT-Fc-OX40L与表达小鼠PVR的CHO-K1 细胞(顶部左侧)、缺乏PVR的亲本CHO-K1细胞(底部左侧)或表达小鼠OX40的CHO-K1细胞(右侧)的结合的图。
图7是示出来自含有大约6,000个人膜蛋白的微阵列的人 TIGIT-Fc-OX40L的鉴定的结合配偶体的结果的表。在每种情况下,每种候选分子的预期的结合配偶体通过筛选鉴定。没有证据显示与其他人蛋白的非特异性结合,并且在所有含有Fc的融合蛋白的筛选中看到与Galectin-1的结合。
图8A示出了在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上运行的鼠mCD172a(SIRPα)-Fc-LIGHT嵌合蛋白的蛋白质印迹。
图8B示出了在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上运行的人CD172a(SIRPα)-Fc-LIGHT嵌合蛋白的蛋白质印迹。
图9A是示出在以下条件下进行的鼠 mCD172a(SIRPα)-Fc-LIGHT嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP检测(顶部左侧),CD47-His捕获并用IgG检测(顶部右侧),mLTBR-His捕获并用针对mLIGHT的抗体检测(底部左侧),以及LTBR His+GST捕获并用针对SIRPα的抗体检测(底部右侧)。图 9B是示出在以下条件下进行的人CD172a(SIRPα)-Fc-LIGHT嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP检测(顶部左侧), CD47-His捕获并用IgG检测(顶部右侧),人LTBR-His捕获并用针对人LIGHT的抗体检测(底部左侧),以及LTBR His+GST捕获并用针对SIRPα的抗体检测(底部右侧)。
图10A是示出小鼠CD172a(SIRPα)-Fc-LIGHT与表达小鼠CD47 的CHO-K1细胞(左侧)或表达小鼠LTbR的CHO-K1细胞(右侧)的结合的图。图10B是示出人CD172a(SIRPα)-Fc-LIGHT与表达小鼠CD47 的CHO-K1细胞的结合的图(仅检测Ab对照峰在最左侧,剩下的峰以增加的浓度从左向右分布(即,250在最右侧))。
图11A是示出与CD47特异性抗体(克隆CC2C6或CC900002) 相比人CD172a(SIRPα)-Fc-LIGHT和CD172a(SIRPα)-Fc-CD40L与食蟹猴红细胞的结合的图,顶部左侧。每种处理后食蟹猴红细胞的裂解在底部左侧以滴定曲线示出,并且示例性平板在右侧示出。Triton-X用作引起食蟹猴红细胞的裂解的阳性对照(针对参考,在顶部图中,在X轴点2nM处,从上到下的曲线是抗CD47/IgG-APC、抗 CD47-FITC、SIRPα-Fc-LIGHT和SIRPα-Fc-CD40L,而在底部图中,在X轴点2处,从上到下的曲线是Triton-X100、抗CD47(CC2C6) 和抗CD47(CC9002)、SIRPα-Fc-LIGHT和SIRPα-Fc-CD40L,全部覆盖)。图11B是示出与CD47特异性抗体(克隆CC2C6或CC900002) 相比人CD172a(SIRPα)-Fc-LIGHT和CD172a(SIRPα)-Fc-CD40L与人红细胞的结合的图,来自3种不同人血供体中的每个。图11C,每种处理后人红细胞的裂解在左侧以滴定曲线示出,并且示例性平板在右侧示出。Triton-X用作引起食蟹猴红细胞的裂解的阳性对照。示出3 种人红细胞供体的数据。
图12A示出了在还原条件下,用N+O去糖基化酶处理后,和/ 或在煮沸之后在SDS-PAGE上运行的鼠PD-1-Fc-LIGHT嵌合蛋白的蛋白质印迹。图12B示出了在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上运行的人PD-1-Fc-LIGHT嵌合蛋白的蛋白质印迹。
图13A是示出在以下条件下进行的鼠PD-1-Fc-LIGHT嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP检测(左侧),mLTBR-His 捕获并用针对mLIGHT的抗体检测(中部),以及mPD-L1捕获并用针对mLIGHT的抗体检测(右侧)。图13B是示出在以下条件下进行的人 PD-1-Fc-LIGHT嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP 检测(左侧),hLTBR-Fc His捕获并用针对生物素酰化的hLIGHT检测 (中部),以及hPDL1-Fc捕获并用hLTBR-His/6x His-HRP检测(右侧)。
图14A是示出小鼠PD-1-Fc-LIGHT与表达小鼠PD-L1的 CHO-K1细胞(左侧)或表达小鼠LTbR的CHO-K1细胞(右侧)的结合的图。图14B是示出人PD-1-Fc-LIGHT与表达人PD-L1的CHO-K1 细胞的结合的图。
图15A示出了在还原条件下,用N+O去糖基化酶处理后,和/ 或在煮沸之后在SDS-PAGE上运行的鼠TIGIT-Fc-LIGHT嵌合蛋白的蛋白质印迹。图15B示出了在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上运行的人TIGIT-Fc-LIGHT嵌合蛋白的蛋白质印迹。
图16A是示出在以下条件下进行的鼠TIGIT-Fc-LIGHT嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP检测(左侧),CD155/PVR 捕获并用Fc-HRP检测(中部),以及mLTBR-His捕获并用针对 mLIGHT的抗体检测(右侧)。图16B是示出在以下条件下进行的人 TIGIT-Fc-LIGHT嵌合蛋白的ELISA的图:重+轻链捕获并用Fc-HRP 检测(左侧),CD155-His捕获并用IgG检测(中部),以及hCD155-Fc 捕获并用hLTBR-His/6x His-HRP检测(右侧)。
图17是示出小鼠TIGIT-Fc-LIGHT与表达小鼠PVR的CHO-K1 细胞(左侧)或表达小鼠LTbR的CHO-K1细胞(右侧)的结合的图。
图18A是示出使用八隅体系统通过生物膜干涉技术采集的结合亲和力测量值的图,其证明人TIGIT-Fc-LIGHT、 CD172a(SIRPα)-Fc-LIGHT和PD-1-Fc-LIGHT与人LTbR的结合(从上到下的所有图:30,10,3.3,0)。图18B是使用八隅体系统通过生物膜干涉技术采集的结合亲和力测量值,其证明在一系列浓度下人 PD-1-Fc-LIGHT与重组人PD-L1和PD-L2的结合(从上到下:500nM ARC x PD-L1,500nM ARC x PD-L2,166nM ARC x PD-L1,166nM ARCx PD-L2,56nM ARC x PD-L1,56nM ARC x PD-L2,无ARC)。
图19A是示出使用八隅体系统通过生物膜干涉技术采集的结合亲和力测量值的图,其证明与一侧TIGIT-Fc融合蛋白对照相比人 TIGIT-Fc-OX40L和TIGIT-Fc-LIGHT与重组人CD155/PVR的结合(从上到下:TIGIT-Fc-LIGHT,TIGIT-Fc-Ox40L,TIGIT-Fc)。图19B是使用八隅体系统通过生物膜干涉技术采集的结合亲和力测量值,其证明与单侧CD172a(SIRPα)-Fc对照或两种CD47特异性抗体对照中的一种相比人CD172a(SIRPα)-Fc-LIGHT与重组人CD47的结合(从上到下:SIRPa-Fc-LIGHT,抗CD47,抗CD47 CC2C6和SIRP-Fc)。图 19C是使用八隅体系统通过生物膜干涉技术采集的结合亲和力测量值,其证明与单侧PD-1-Fc对照或抗PD-L1对照(阿特珠单抗 (Atezolizumab))相比人PD-1-Fc-LIGHT与重组人PD-L1的结合(从上到下:PD-1-Fc-LIGHT,抗PDL1和PD-1-Fc)。图19D是使用八隅体系统通过生物膜干涉技术采集的结合亲和力测量值,其证明与单侧 LIGHT-Fc融合蛋白对照或抗LTbR抗体相比人 CD172a(SIRPα)-Fc-LIGHT、TIGIT-Fc-LIGHT或PD-1-Fc-LIGHT与重组人LTbR的结合(从上到下:TIGIT-Fc-LIGHT,Sirp1a-Fc-LIGHT,抗LTbR,PD-1-Fc-LIGHT和LIGHT-Fc)。
图20A和图20B示出了超抗原细胞因子释放测定,其证明各种抗体小鼠TIGIT-Fc-OX40L、小鼠CD172a(SIRPα)-Fc-LIGHT、小鼠 TIGIT-Fc-LIGHT和小鼠PD-1-Fc-LIGHT嵌合蛋白对于通过葡萄球菌肠毒素B(SEB)活化的小鼠外周血白细胞的影响。图20A测定IL2分泌,并且图20B测定TNFα分泌。对于图20A和图20B,每个SEB 浓度的条件的顺序从左向右反映,在图例中列出的条件从上到下反映 (例如,α-PD-1(RMP1-14)在图例中是从上数第三个,并且因此在图中是从左数第三个,PD-1-Fc-LIGHT(10nM)在图例中是从下数第三个,并且因此在图中是从右数第三个等等)。图20C示出了在多个超抗原 (SEB)浓度上数据的编译(同样,每个SEB浓度的条件的顺序从左向右反映,图例中列出的条件从上向下反映)。
图21A至图21C示出了超抗原细胞因子释放测定,其证明各种抗体人TIGIT-Fc-LIGHT(图21A)、人TIGIT-Fc-OX40L(图21B)、人 PD-1-Fc-LIGHT和人CD172a(SIRPα)-Fc-LIGHT(图21C)嵌合蛋白对于通过葡萄球菌肠毒素B(SEB)活化的人外周血白细胞的影响。
图22A至图22B示出了来自体内肿瘤研究的结果,其证明与单克隆抗体TIGIT、CD47、OX40、PD-1或TIGIT和OX40的组合相比, mTIGIT-Fc-OX40L、mCD172a(SIRPα)-Fc-LIGHT、mTIGIT-Fc-LIGHT 和mPD-1-Fc-LIGHT嵌合蛋白的抗肿瘤功效。将CT26肿瘤植入到Balb/c小鼠中,之后用指示的方案处理。图22A示出了在肿瘤接种之后40天内每组的肿瘤大小的演变。图22B示出了在肿瘤接种之后40 天内小鼠的总体存活百分比,并且完全肿瘤排斥者的数量在嵌入的表中指示。在图22A和图22B中,处理条件通过字母识别。
图23不希望受理论束缚地示出了PD-1-Fc-OX40L嵌合蛋白的四种潜在构型。
图24示出了在非还原条件下、在还原条件下以及在还原条件下并用肽-N-糖苷酶F(PNGaseF)处理的在SDS-PAGE上运行的 PD-1-Fc-OX40L嵌合蛋白的蛋白质印迹。
图25示出了在尺寸排阻色谱(SEC)上运行的PD-1-Fc-OX40L嵌合蛋白的色谱图。
图26示出了在非还原条件(“-”)或还原条件(“+”)下运行的 PD-1-Fc-OX40L嵌合蛋白的SDS-PAGE凝胶和天然(非SDS)PAGE 凝胶。
图27示出了缺乏Fc结构域的PD-1-No Fc-OX40L嵌合蛋白的天然(非SDS)PAGE凝胶。
图28不希望受理论束缚地示出了六聚体和多联体如何由本发明的嵌合蛋白形成的模型。
图29A至图29Q示出了通过蛋白质印迹分析进行的具有不同连接接头序列的PD-1-Fc-OX40L嵌合蛋白的表征。在下文实施例部分中提供了不同连接接头的序列。具体地,使用α-PD-1、α-Fc或α-OX40L 抗体探测融合构建体的每个个体结构域。在每个图中,将所有印迹中未处理的PD-1-Fc-OX40L嵌合蛋白样品(例如对照)加载到泳道1中 (无β-巯基乙醇或PNGase)。将泳道2中的样品用还原剂β-巯基乙醇处理,而将泳道3中的样品用PNGase处理。
图30示出了通过针对蛋白质的中心Fc区的基于ELISA的捕获和检测测定进行的具有不同连接接头序列的PD-1-Fc-OX40L嵌合蛋白的表征。确定具有不同连接接头序列(#1至#17)的每种 PD-1-Fc-OX40L嵌合蛋白的蛋白质浓度。
图31A至图31P示出了通过对PD-L1或OX40的FACS分析进行的具有不同连接接头序列的PD-1-Fc-OX40L嵌合蛋白的流式细胞术曲线。计算具有不同连接接头序列(#2至#17-参见以下实施例中接头身份的X轴标记和图表)的每种PD-1-Fc-OX40L嵌合蛋白的EC50值。
图32是示出可以组合成例示性模块接头的连接接头和Fc接头的表。所示的例示性模块接头可以与本文所述的I型蛋白和II型蛋白和 /或本文所述的I型蛋白和II型蛋白的细胞外结构域组合,以形成本发明的嵌合蛋白。
具体实施方式
本发明部分基于以下发现:嵌合蛋白可以利用这些蛋白质的取向 (例如,I型相对于II型的取向)的方式由免疫调节跨膜蛋白的细胞外区域或效应子区域进行工程化,因此允许递送免疫刺激信号和/或免疫抑制信号,所述递送包括例如在癌症治疗中掩蔽免疫抑制信号并用免疫刺激信号替换免疫抑制信号,具体地,基于LIGHT和/或TIGIT 的嵌合蛋白具有医疗用途。
嵌合蛋白
在一些方面,嵌合蛋白具有以下一般结构:N末端–(a)–(b)–(c) –C末端,其中(a)是包含I型跨膜蛋白的细胞外结构域的第一结构域, (b)是具有至少一个能够形成二硫键的半胱氨酸残基的接头(包括但不限于衍生自人IgG4的铰链-CH2-CH3 Fc结构域),并且(c)是包含II 型跨膜蛋白的细胞外结构域的第二结构域,其中所述接头连接第一结构域和第二结构域并任选地包含一个或多个如本文所述的连接接头,其中所述第一细胞外结构域和第二细胞外结构域中的一个是免疫抑制信号,并且所述第一细胞外结构域和第二细胞外结构域中的一个是免疫刺激信号。
在实施方案中,嵌合蛋白是指重组融合蛋白,例如具有本文所述的细胞外结构域的单一多肽。例如,在实施方案中,嵌合蛋白在细胞中被翻译为单个单元。在实施方案中,嵌合蛋白是指多个多肽的重组蛋白,所述多个多肽例如是本文所述的多个细胞外结构域,其例如在体外(例如,用本文所述的一个或多个合成接头)连接以产生单个单元。
在实施方案中,嵌合蛋白作为一个多肽进行化学合成,或者可以单独化学合成每个结构域,然后组合。在实施方案中,翻译嵌合蛋白的一部分,并化学合成一部分。
在实施方案中,细胞外结构域是指能够与细胞外环境相互作用的跨膜蛋白的一部分。在实施方案中,细胞外结构域是指足以与配体或受体结合并将信号有效传递到细胞的跨膜蛋白的一部分。在实施方案中,细胞外结构域是在细胞或细胞膜外部的跨膜蛋白的整个氨基酸序列。在实施方案中,细胞外结构域是在细胞或细胞膜外部的跨膜蛋白的氨基酸序列的一部分,并且对于信号转导和/或配体结合是所需的,如可以使用本领域已知的方法测定(例如,体外配体结合和/或细胞活化测定)。
在实施方案中,免疫抑制信号是指减弱或消除免疫应答的信号。例如,在肿瘤学的背景下,此类信号可以减弱或消除抗肿瘤免疫。在正常生理条件下,抑制信号可用于维持自身耐受性(例如,预防自身免疫性疾病),并且还可在免疫系统对病原性感染作出应答时保护组织免受损伤。例如但不限于,当阻断这种抑制信号时,可以通过检测细胞增殖、细胞因子产生、细胞杀伤活性或吞噬活性的增加来鉴定免疫抑制信号。
在实施方案中,免疫刺激信号是指增强免疫应答的信号。例如,在肿瘤学的背景下,此类信号可以增强抗肿瘤免疫。例如但不限于,可以通过直接刺激白细胞的增殖、细胞因子产生、杀伤活性或吞噬活性来鉴定免疫刺激信号。具体实例包括使用受体激动剂抗体或使用编码TNF超家族受体的配体(分别为OX40L、LIGHT、4-1BBL、TL1A) 的嵌合蛋白直接刺激TNF超家族受体,诸如OX40、LTbR、4-1BB 或TNFRSF25。来自这些受体中的任一种的刺激都可以直接刺激个体 T细胞亚群的增殖和细胞因子产生。另一个实例包括通过抑制免疫抑制细胞活性的受体直接刺激这种免疫抑制细胞。这将包括,例如,用 GITR激动剂抗体或含有GITRL的嵌合蛋白刺激CD4+FoxP3+调节T 细胞,这将降低那些调节T细胞抑制常规CD4+或CD8+T细胞增殖的能力。在另一个实例中,这将包括使用CD40激动剂抗体或含有 CD40L的嵌合蛋白刺激抗原呈递细胞表面上的CD40,从而引起抗原呈递细胞的活化,包括增强这些细胞在适当的天然共刺激分子(包括 B7或TNF超家族中的那些)的情况下呈递抗原的能力。在另一个实例中,这将包括使用含有LIGHT的嵌合蛋白刺激淋巴细胞或基质细胞表面上的LTBR,从而引起淋巴细胞的活化和/或产生促炎细胞因子或趋化因子以进一步刺激任选地在肿瘤内的免疫应答。
膜蛋白通常由细胞外结构域、一个或一系列跨膜结构域和细胞内结构域组成。不希望受理论束缚,膜蛋白的细胞外结构域负责与可溶性或膜结合受体或配体相互作用。不希望受理论束缚,一个或多个跨膜结构域负责将蛋白质定位于质膜。不希望受理论束缚,膜蛋白的细胞内结构域负责协调与细胞信号分子的相互作用以协调对细胞外环境的细胞内应答(或反之亦然)。存在两种类型的单通膜蛋白,即具有细胞外氨基末端和细胞内羧基末端的那些蛋白质(I型)以及具有细胞外羧基末端和细胞内氨基末端的那些蛋白质(II型)。I型和II型膜蛋白二者都可以是受体或配体。对于I型膜蛋白,蛋白质的氨基末端面向细胞外,因此含有负责与细胞外环境中的其他结合配偶体(配体或受体)相互作用的功能性结构域。对于II型膜蛋白,蛋白质的羧基末端面向细胞外,因此含有负责与细胞外环境中的其他结合配偶体(配体或受体)相互作用的功能性结构域。因此,这两种类型的蛋白质具有彼此相反的取向。
因为I型和II型膜蛋白的面向外的结构域是相反的,所以可以连接I型膜蛋白和II型膜蛋白的细胞外结构域,使得分子的‘面向外’结构域的取向也彼此相反(图1D)。因此,所得构建体将由使用接头序列连接到分子‘右’侧的II型膜蛋白的细胞外结构域的分子‘左’侧的I型膜蛋白的细胞外结构域组成。此构建体可以通过将这三个片段(I型蛋白的细胞外结构域,接着是接头序列,接着是II型蛋白的细胞外结构域)克隆到载体(质粒、病毒或其他)中来产生,其中完整序列的氨基末端对应于含有I型蛋白的分子的‘左’侧,并且完整序列的羧基末端对应于含有II型蛋白的分子的‘右’侧。因此,在实施方案中,本发明的嵌合蛋白如此进行工程化。
在实施方案中,细胞外结构域可以用于产生可溶性蛋白质,以竞争性地抑制所述受体的配体的信号传导。在实施方案中,细胞外结构域可以用于提供人工信号传导。
在实施方案中,I型跨膜蛋白的细胞外结构域是免疫抑制信号。在实施方案中,II型跨膜蛋白的细胞外结构域是免疫刺激信号。
在实施方案中,本发明的嵌合蛋白包含I型跨膜蛋白的细胞外结构域或其功能性片段。在实施方案中,本发明的嵌合蛋白包含II型跨膜蛋白的细胞外结构域或其功能性片段。在实施方案中,本发明的嵌合蛋白包含I型跨膜蛋白的细胞外结构域或其功能性片段,以及II 型跨膜蛋白的细胞外结构域或其功能性片段。
在实施方案中,本发明的嵌合蛋白可以被工程化以靶向驻留在人白细胞上的一种或多种分子,其包括但不限于以下的细胞外结构域 (如果适用的话):SLAMF4、IL-2Rα、4-1BB/TNFRSF9、IL-2Rβ、 ALCAM、BTLA、B7-1、IL-4R、B7-H3、BLAME/SLAMFS、CEACAM1、 IL-6R、IL-7Rα、IL-10Rα、IL-10Rβ、IL-12Rβ1、IL-12Rβ2、CD2、IL-13Rα1、IL-13、CD3、CD4、ILT2/CDS5j、ILT3/CDS5k、 ILT4/CDS5d、ILT5/CDS5a、lutegrinα4/CD49d、CDS、整联蛋白α E/CD103、CD6、整联蛋白αM/CD 11b、CDS、整联蛋白αX/CD11c、整联蛋白β2/CDIS、KIR/CD15S、CD27/TNFRSF7、KIR2DL1、CD2S、 KIR2DL3、CD30/TNFRSFS、KIR2DL4/CD15Sd、CD31/PECAM-1、KIR2DS4、CD40配体/TNFSF5、CD43、LAIR1、CD45、LAIR2、CDS3、白三烯B4-R1、CDS4/SLAMF5、NCAM-L1、CD94、NKG2A、CD97、 NKG2C、CD229/SLAMF3、NKG2D、CD2F-10/SLAMF9、NT-4、CD69、NTB-A/SLAMF6、共用γ链/IL-2Rγ、骨桥蛋白、CRACC/SLAMF7、 PD-1、CRTAM、PSGL-1、CTLA-4、RANK/TNFRSF11A、CX3CR1、 CX3CL1、L-选择素、SIRPβ1、SLAM、TCCR/WSX-1、DNAM-1、胸腺生成素、EMMPRIN/CD147、TIM-1、EphB6、TIM-2、 Fas/TNFRSF6、TIM-3、Fas配体/TNFSF6、TIM-4、FcγRIII/CD16、 TIM-6、TNFR1/TNFRSF1A、颗粒溶解素、TNF RIII/TNFRSF1B、 TRAIL RI/TNFRSFIOA、ICAM-1/CD54、TRAIL R2/TNFRSF10B、 ICAM-2/CD102、TRAILR3/TNFRSF10C、IFN-γR1、 TRAILR4/TNFRSF10D、IFN-γR2、TSLP、IL-1R1、LIGHT、LTBR (TNFRSF3)和TSLP R。
调节T细胞的活化受到共刺激和共抑制信号的严重影响。两种主要的共刺激分子家族包括B7和肿瘤坏死因子(TNF)家族。这些分子分别与属于CD28或TNF受体家族的T细胞上的受体结合。许多明确定义的共抑制因子及其受体属于B7和CD28家族。
在实施方案中,本发明的嵌合蛋白可以被工程化以靶向参与免疫抑制的一种或多种分子,包括例如TIGIT。
在实施方案中,本发明的嵌合蛋白包含免疫抑制剂的细胞外结构域,包括例如TIGIT。
在实施方案中,本发明的嵌合蛋白包含具有免疫抑制特性的I型膜蛋白的细胞外结构域。在实施方案中,嵌合蛋白被工程化以破坏、阻断、减少和/或抑制免疫抑制信号的传递。
在实施方案中,本发明的嵌合蛋白包含免疫刺激信号的细胞外结构域,其是LIGHT(CD258)。
在实施方案中,嵌合蛋白模拟抑制信号配体与其同源受体(例如, TIGIT与CD155/PVR、结合素-2、结合素-3和/或结合素-4)的结合但抑制抑制信号传递到免疫细胞(例如,T细胞、巨噬细胞或其他白细胞)。
在实施方案中,嵌合蛋白包含免疫抑制受体细胞外结构域和免疫刺激配体细胞外结构域,其可以但不限于在掩蔽肿瘤细胞的免疫抑制信号的同时向T细胞递送免疫刺激。在实施方案中,嵌合蛋白递送具有T细胞活化的最终结果的信号。
在实施方案中,嵌合蛋白包含免疫抑制信号,其是免疫抑制信号的受体的ECD,并且免疫抑制信号作用于携带免疫抑制信号的同源配体的肿瘤细胞。在实施方案中,嵌合蛋白包含免疫刺激信号,其是免疫刺激信号的配体的ECD,并且免疫刺激信号作用于携带免疫刺激信号的同源受体的T细胞。在实施方案中,嵌合蛋白包含以下两者: (i)免疫抑制信号,其是免疫抑制信号的受体,并且免疫抑制信号作用于携带免疫抑制信号的同源配体的肿瘤细胞和(ii)免疫刺激信号,其是免疫刺激信号的配体,并且免疫刺激信号作用于携带免疫刺激信号的同源受体的T细胞。
在实施方案中,本发明的嵌合蛋白包含Mahoney,Nature Reviews DrugDiscovery 2015:14;561-585中描述的一种或多种免疫调节剂的细胞外结构域,所述文献的全部内容特此以引用的方式并入。
在实施方案中,嵌合蛋白能够结合一种或多种鼠配体/受体。
在实施方案中,嵌合蛋白能够结合一种或多种人配体/受体
在实施方案中,本发明的嵌合蛋白包含具有免疫刺激特性的II 型膜蛋白的细胞外结构域。在实施方案中,嵌合蛋白被工程化以增强、增加和/或刺激免疫刺激信号的传递。
例如,在实施方案中,I型跨膜蛋白的细胞外结构域来自TIGIT。
TIGIT是脊髓灰质炎病毒受体(PVR)样蛋白,一种在T细胞上表达的含有免疫球蛋白和基于免疫受体酪氨酸的抑制基序(ITIM)结构域的免疫受体。由此,TIGIT充当T细胞和自然杀伤(NK)细胞两者上的抑制免疫检查点,从而提供靶向免疫系统的适应性臂和先天臂两者的机会。
TIGIT在NK细胞和活化、记忆和调节T细胞的子组上表达,并且具体地在第二淋巴样器官内在滤泡辅助T细胞上表达。CD155/PVR 在内皮细胞上通过IFN-γ上调,并且在未成熟胸腺细胞、淋巴结树突细胞以及上皮和神经元来源的肿瘤细胞上高度表达。在实施方案中,本发明的嵌合蛋白(例如,包含TIGIT ECD)调节以上刚刚描述的任何细胞(例如,在免疫突触的环境下)。
TIGIT结合CD155/PVR、结合素-2、结合素-3和结合素-4。在实施方案中,本发明的嵌合蛋白(例如,包含TIGIT ECD)调节TIGIT与 CD155/PVR的结合(例如,减少或破坏结合或信号传递)。在实施方案中,本发明的嵌合蛋白(例如,包含TIGIT ECD)调节TIGIT与结合素-2的结合(例如,减少或破坏结合或信号传递)。在实施方案中,本发明的嵌合蛋白(例如,包含TIGIT ECD)调节TIGIT与结合素-3的结合 (例如,减少或破坏结合或信号传递)。在实施方案中,本发明的嵌合蛋白(例如,包含TIGIT ECD)调节TIGIT与结合素-4的结合(例如,减少或破坏结合或信号传递)。
在实施方案中,嵌合蛋白具有以下一般结构:N末端–(a)–(b)– (c)–C末端,其中(a)是包含I型跨膜蛋白的细胞外结构域的第一结构域,所述跨膜蛋白是TIGIT,(b)是包含至少一个能够形成二硫键的半胱氨酸残基的接头(包括但不限于衍生自人IgG4的铰链-CH2-CH3 Fc 结构域),并且(c)是包含II型跨膜蛋白的细胞外结构域的第二结构域,所述跨膜蛋白选自4-1BBL、GITRL、TL1A和LIGHT,其中所述接头连接第一结构域和第二结构域并任选地包含一个或多个如本文所述的连接接头。
在实施方案中,嵌合蛋白包含免疫抑制剂TIGIT的细胞外结构域,并且如下与免疫刺激剂配对:TIGIT/OX-40L;TIGIT/4-1BBL, TIGIT/LIGHT;TIGIT/GITRL;TIGIT/CD70;TIGIT/CD30L; TIGIT/CD40L;TIGIT/CD137L;TIGIT/TL1A;和TIGIT/OX40L。在实施方案中,嵌合蛋白是TIGIT-Fc-4-1BBL、TIGIT-Fc-GITRL、 TIGIT-Fc-LIGHT、TIGIT-Fc-OX40L或TIGIT-Fc-TL1A,其中Fc代表包含抗体的Fc结构域的至少一部分并且包含至少一个能够形成二硫键的半胱氨酸残基的接头。
例如,在实施方案中,II型跨膜蛋白的细胞外结构域来自LIGHT。
LIGHT(HVEM-L、TNFSF14或CD258)是TNF超家族的成员,是与淋巴毒素同源的实体,具有可诱导性质,并且能够与单纯疱疹病毒糖蛋白D竞争疱疹病毒侵入介体(HVEM)/肿瘤坏死因子(TNF)相关 2。它是29-kDa II型跨膜蛋白,作为同源三聚体在活化T细胞以及 DC上表达,并且具有三种受体,即HVEM、LT-β受体(LTβR,TNFRSF3) 和诱骗受体3(DcR3)。不希望受理论束缚,已知具有不同的细胞表达模式的三种受体与LIGHT相互作用:HVEM(TNFRSF14,CD270),在活化DC细胞、T细胞和B细胞、NK细胞、单核细胞和内皮细胞上检测到;LTβR,存在于滤泡DC和基质细胞上并且结合LIGHT;可溶性实体诱骗受体3(DcR3),在多样的癌细胞诸如多种骨髓瘤和弥漫性大B细胞淋巴瘤上检测到。在实施方案中,本发明的嵌合蛋白可以破坏或降低LIGHT与这三种受体中的一种或多种的相互作用。
LIGHT结合LTBR,并且潜在地结合HVEM以及DcR3。在实施方案中,本发明的嵌合蛋白(例如,包含LIGHT ECD)调节LIGHT与 LTBR的结合(例如,增加或促进结合或信号传递)。LTBR由内脏、淋巴样和其他基质、上皮和髓样细胞表达,但是不由淋巴细胞表达在实施方案,本发明的嵌合蛋白(例如,包含LIGHT ECD)调节内脏、淋巴样和其他基质、上皮和髓样细胞中的一种或多种。在实施方案中,本发明的嵌合蛋白(例如,包含LIGHT ECD)调节LIGHT与HVEM的结合(例如,增加或促进结合或信号传递)。在实施方案中,本发明的嵌合蛋白(例如,包含LIGHT ECD)调节LIGHT与DcR3的结合(例如,增加或促进结合或信号传递)。
在实施方案中,嵌合蛋白具有以下一般结构:N末端–(a)–(b)– (c)–C末端,其中(a)是包含I型跨膜蛋白的细胞外结构域的第一结构域,所述跨膜蛋白选自PD-1、CD172a(SIRPα)和TIGIT,(b)是包含至少一个能够形成二硫键的半胱氨酸残基的接头(包括但不限于衍生自人IgG4的铰链-CH2-CH3 Fc结构域),并且(c)是包含II型跨膜蛋白的细胞外结构域的第二结构域,所述跨膜蛋白是LIGHT,其中所述接头连接第一结构域和第二结构域并任选地包含一个或多个如本文所述的连接接头。
在实施方案中,嵌合蛋白包含免疫刺激剂LIGHT的细胞外结构域,并且如下与免疫抑制剂配对:PD-1/LIGHT, CD172a(SIRPα)/LIGHT,和TIGIT/LIGHT。在实施方案中,嵌合蛋白是PD-1-Fc-LIGHT、CD172a(SIRPα)-Fc-LIGHT和TIGIT-Fc-LIGHT,其中Fc代表包含抗体的Fc结构域的至少一部分并且包含至少一个能够形成二硫键的半胱氨酸残基的接头。
在实施方案中,嵌合蛋白包含免疫抑制剂的细胞外结构域,并且与免疫刺激剂配对。在实施方案中,嵌合蛋白与同源受体或配体结合,其中KD为约1nM至约5nM,例如约1nM、约1.5nM、约2nM、约2.5nM、约3nM、约3.5nM、约4nM、约4.5nM或约5nM。在实施方案中,嵌合蛋白与同源受体或配体结合,其中KD为约5nM至约15nM,例如约5nM、约5.5nM、约6nM、约6.5nM、约7nM、约7.5nM、约8nM、约8.5nM、约9nM、约9.5nM、约10nM、约 10.5nM、约11nM、约11.5nM、约12nM、约12.5nM、约13nM、约13.5nM、约14nM、约14.5nM或约15nM。
在实施方案中,嵌合蛋白表现出增强的稳定性和蛋白质半衰期。在实施方案中,嵌合蛋白以高亲和力与FcRn结合。在实施方案中,嵌合蛋白可以与FcRn结合,其中KD为约1nM至约80nM。例如,嵌合蛋白可以与FcRn结合,其中KD为约1nM、约2nM、约3nM、约4nM、约5nM、约6nM、约7nM、约8nM、约9nM、约10nM、约15nM、约20nM、约25nM、约30nM、约35nM、约40nM、约45nM、约50nM、约55nM、约60nM、约65nM、约70nM、约71nM、约72nM、约73nM、约74nM、约75nM、约76nM、约77nM、约78nM、约79nM或约80nM。在实施方案中,嵌合蛋白可以与FcRn结合,其中KD为约9nM。在实施方案中,嵌合蛋白基本上不与具有效应子功能的其他Fc受体(即,除FcRn之外的受体) 结合。
在实施方案中,提供了一种通过向受试者施用PD-1-Fc-LIGHT、 CD172a(SIRPα)-Fc-LIGHT和TIGIT-Fc-LIGHT嵌合蛋白中的一种或多种来治疗癌症和/或炎性疾病(例如,本文其他地方所述的那些中的任一种)的方法,其中代表包含抗体的Fc结构域的至少一部分并且包含至少一个能够形成二硫键的半胱氨酸残基的接头。在实施方案中,所述方法产生记忆应答,其例如能够预防复发。在实施方案中,所述方法包括PD-1-Fc-LIGHT、CD172a(SIRPα)-Fc-LIGHT和 TIGIT-Fc-LIGHT中的一种或多种的持续治疗效果,例如,由于细胞外结构域组分以缓慢的解离速率(Kd或Koff)与其各自的结合配偶体的结合,以任选地提供持续的负信号掩蔽效果和/或更长的正信号效果,例如,以使效应细胞被充分刺激用于抗肿瘤效果。
在实施方案中,提供了一种通过向受试者施用TIGIT-Fc-4-1BBL、TIGIT-Fc-GITRL、TIGIT-Fc-TL1A和TIGIT-Fc-LIGHT嵌合蛋白中的一种或多种来治疗癌症或炎性疾病(例如,本文其他地方所述的那些中的任一种)的方法,其中代表包含抗体的Fc结构域的至少一部分并且包含至少一个能够形成二硫键的半胱氨酸残基的接头。在实施方案中,所述方法产生记忆应答,其例如能够预防复发。在实施方案中,所述方法包括TIGIT-Fc-4-1BBL、TIGIT-Fc-GITRL、TIGIT-Fc-TL1A 和TIGIT-Fc-LIGHT中的一种或多种的持续治疗效果,例如,由于细胞外结构域组分以缓慢的解离速率(Kd或Koff)与其各自的结合配偶体的结合,以任选地提供持续的负信号掩蔽效果和/或更长的正信号效果,例如,以使效应细胞被充分刺激用于抗肿瘤效果。
在实施方案中,本发明的嵌合蛋白可以包含本文所述的细胞外结构域的变体,例如,与所公开的细胞外结构域中的任一种的已知氨基酸或核酸序列具有至少约60%、或至少约61%、或至少约62%、或至少约63%、或至少约64%、或至少约65%、或至少约66%、或至少约67%、或至少约68%、或至少约69%、或至少约70%、或至少约71%、或至少约72%、或至少约73%、或至少约74%、或至少约 75%、或至少约76%、或至少约77%、或至少约78%、或至少约79%、或至少约80%、或至少约81%、或至少约82%、或至少约83%、或至少约84%、或至少约85%、或至少约86%、或至少约87%、或至少约88%、或至少约89%、或至少约90%、或至少约91%、或至少约92%、或至少约93%、或至少约94%、或至少约95%、或至少约 96%、或至少约97%、或至少约98%、或至少约99%)序列同一性的序列,所述细胞外结构域例如人细胞外结构域,例如SEQ ID NO:2、 4、7、10、13、16、19、22、25、27、29、31、37或41中的一个或多个。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域 (SEQ ID NO:2)。
在实施方案中,本发明的嵌合蛋白包含PD-1的细胞外结构域(SEQ ID NO:4)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域 (SEQ ID NO:10)。
在实施方案中,本发明的嵌合蛋白包含CD172a(SIRPα)的细胞外结构域(SEQ IDNO:7)。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域 (SEQ ID NO:2)和PD-1的细胞外结构域(SEQ ID NO:4)。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域 (SEQ ID NO:2)和TIGIT的细胞外结构域(SEQ ID NO:10)。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域 (SEQ ID NO:2)和CD172a(SIRPα)的细胞外结构域(SEQ ID NO:7)。
在实施方案中,本发明的嵌合蛋白包含来自人IgG4抗体序列的铰链-CH2-CH3结构域(SEQ ID NO:46、47或48)。
在实施方案中,本发明的嵌合蛋白包含来自人IgG4抗体序列的铰链-CH2-CH3结构域(SEQ ID NO:46、47或48),并且此序列由选自以下的至少一种连接接头侧接:SKYGPPCPSCP(SEQ ID NO:49)、 SKYGPPCPPCP(SEQ ID NO:50)、IEGRMD SEQ ID NO:52(任选地 SKYGPPCPSCP(SEQ ID NO:49)或SKYGPPCPPCP(SEQ ID NO:50) 是N末端,并且IEGRMDSEQ ID NO:52中的一个是C末端)。
在实施方案中,嵌合蛋白包含模块接头,如图32所示。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域和PD-1的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3 结构域作为接头(此PD-1-Fc-LIGHT嵌合体是SEQ ID NO:5)。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域和TIGIT的细胞外结构域,使用来自人IgG4抗体序列的铰链 -CH2-CH3结构域作为接头(此TIGIT-Fc-LIGHT嵌合体是SEQ ID NO: 11)。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域和CD172a(SIRPα)的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3结构域作为接头(此CD172a(SIRPα)-Fc-LIGHT嵌合体是 SEQ ID NO:8)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域 (SEQ ID NO:10)。
在实施方案中,本发明的嵌合蛋白包含4-1BBL的细胞外结构域 (SEQ ID NO:13)。
在实施方案中,本发明的嵌合蛋白包含GITRL的细胞外结构域 (SEQ ID NO:16)。
在实施方案中,本发明的嵌合蛋白包含TL1A的细胞外结构域 (SEQ ID NO:19)。
在实施方案中,本发明的嵌合蛋白包含LIGHT的细胞外结构域(SEQ ID NO:2)。
在实施方案中,本发明的嵌合蛋白包含OX40L的细胞外结构域 (SEQ ID NO:22)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域 (SEQ ID NO:10)和4-1BBL的细胞外结构域(SEQ ID NO:13)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域 (SEQ ID NO:10)和GITRL的细胞外结构域(SEQ ID NO:16)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域(SEQ ID NO:10)和TL1A的细胞外结构域(SEQ ID NO:19)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域 (SEQ ID NO:10)和LIGHT的细胞外结构域(SEQ ID NO:2)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域 (SEQ ID NO:10)和OX40L的细胞外结构域(SEQ ID NO:22)。
在实施方案中,本发明的嵌合蛋白包含来自人IgG4抗体序列的铰链-CH2-CH3结构域(SEQ ID NO:46、47或48)。
在实施方案中,本发明的嵌合蛋白包含来自人IgG4抗体序列的铰链-CH2-CH3结构域(SEQ ID NO:46、47或48),并且此序列由选自以下的至少一种连接接头侧接:SKYGPPCPSCP(SEQ ID NO:49)、 SKYGPPCPPCP(SEQ ID NO:50)、IEGRMD SEQ ID NO:52(任选地 SKYGPPCPSCP(SEQ ID NO:49)或SKYGPPCPPCP(SEQ ID NO:50) 是N末端,并且IEGRMDSEQ ID NO:52中的一个是C末端)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域和 4-1BBL的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3 结构域作为接头(此TIGIT-Fc-4-1BBL嵌合体是SEQ ID NO:14)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域和 GITRL的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3 结构域作为接头(此TIGIT-Fc-GITRL嵌合体是SEQ ID NO:17)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域和 TL1A的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3 结构域作为接头(此TIGIT-Fc-TL1A嵌合体是SEQ ID NO:20)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域和 LIGHT的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3 结构域作为接头(此TIGIT-Fc-LIGHT嵌合体是SEQ ID NO:11)。
在实施方案中,本发明的嵌合蛋白包含TIGIT的细胞外结构域和 OX40L的细胞外结构域,使用来自人IgG4抗体序列的铰链-CH2-CH3 结构域作为接头(此TIGIT-Fc-OX40L嵌合体是SEQ ID NO:23)。
在实施方案中,嵌合蛋白可以包含来自本文鉴定的序列的细胞外结构域,其与来自本文鉴定的另一个序列的细胞外结构域组合。例如, TIGIT-Fc-TL1A嵌合蛋白的序列可以包含如以上公开的在SEQ ID NO:10中的TIGIT的细胞外结构域和如以上公开的在SEQ IDNO:19 中的TL1A的细胞外结构域。
在实施方案中,另外的嵌合蛋白和使用另外的嵌合蛋白的方法 (例如,在治疗癌症和/或治疗炎性疾病中):TIGIT-Fc-4-1BBL、 TIGIT-Fc-CD30L、TIGIT-Fc-FasL、TIGIT-Fc-GITRL、TIGIT-Fc-TL1A 和TIGIT-Fc-TRAIL。4-1BBL、CD30L、FasL、GITRL、TL1A和TRAIL的氨基酸序列分别包括SEQ ID NO:12、26、30、15、18和40。4-1BBL、 CD30L、FasL、GITRL、TL1A和TRAIL的细胞外结构域的氨基酸序列分别是SEQ ID NO:13、27、31、16、19和41。
在实施方案中,本发明的嵌合蛋白可以是本文所述的变体,例如,本发明的嵌合蛋白可以具有与本发明的嵌合蛋白的氨基酸序列具有至少约60%、或至少约61%、或至少约62%、或至少约63%、或至少约64%、或至少约65%、或至少约66%、或至少约67%、或至少约68%、或至少约69%、或至少约70%、或至少约71%、或至少约 72%、或至少约73%、或至少约74%、或至少约75%、或至少约76%、或至少约77%、或至少约78%、或至少约79%、或至少约80%、或至少约81%、或至少约82%、或至少约83%、或至少约84%、或至少约85%、或至少约86%、或至少约87%、或至少约88%、或至少约89%、或至少约90%、或至少约91%、或至少约92%、或至少约 93%、或至少约94%、或至少约95%、或至少约96%、或至少约97%、或至少约98%、或至少约99%)序列同一性的序列,所述本发明的嵌合蛋白的氨基酸序列例如SEQ ID NO:5、8、11、14、17、20、23、42、43、44或45中的一个或多个。
在实施方案中,本发明的嵌合蛋白包含如PCT/US2016/054598 的表1中所述的人I型跨膜蛋白的细胞外结构域或其功能性片段。在实施方案中,本发明的嵌合蛋白包含如PCT/US2016/054598的表2 中所述的人II型跨膜蛋白的细胞外结构域或其功能性片段。在实施方案中,本发明的嵌合蛋白包含如PCT/US2016/054598的表1中所述的 I型跨膜蛋白的细胞外结构域或其功能性片段,以及如 PCT/US2016/054598的表2中所述的II型跨膜蛋白的细胞外结构域或其功能性片段。PCT/US2016/054598的全部内容特此以引用的方式并入。
在实施方案中,嵌合蛋白可以包含相对于本文所述的任何蛋白质序列具有一个或多个氨基酸突变的氨基酸序列。在实施方案中,一个或多个氨基酸突变可以独立地选自取代、插入、缺失和截短。
在实施方案中,氨基酸突变是氨基酸取代,并且可以包括保守取代和/或非保守取代。
例如,“保守取代”可以基于所涉及的氨基酸残基的极性、电荷、大小、溶解度、疏水性、亲水性和/或两亲性质的相似性来完成。20 种天然存在的氨基酸可以分为以下六个标准氨基酸组:(1)疏水性: Met、Ala、Val、Leu、Ile;(2)中性亲水的:Cys、Ser、Thr、Asn、 Gln;(3)酸性的:Asp、Glu;(4)碱性的:His、Lys、Arg;(5)影响链取向的残基:Gly、Pro;和(6)芳族的:Trp、Tyr、Phe。
如本文所用,“保守取代”定义为氨基酸被上文所示的六个标准氨基酸组的相同组中列出的另一种氨基酸交换。例如,由Glu交换Asp 在如此修饰的多肽中保留一个负电荷。此外,甘氨酸和脯氨酸可以基于它们破坏α-螺旋的能力而彼此取代。
如本文所用,“非保守取代”定义为氨基酸被上文所示的六个标准氨基酸组(1)至(6)的不同组中列出的另一种氨基酸交换。
在实施方案中,取代还可以包括非经典氨基酸(一般例如,硒代半胱氨酸、吡咯赖氨酸、N-甲酰甲硫氨酸β-丙氨酸、GABA和δ-氨基乙酰丙酸、4-氨基苯甲酸(PABA)、常见氨基酸的D型异构体、2,4- 二氨基丁酸、α-氨基异丁酸、4-氨基丁酸、Abu、2-氨基丁酸、γ-Abu、ε-Ahx、6-氨基己酸、Aib、2-氨基异丁酸、3-氨基丙酸、鸟氨酸、正亮氨酸、正缬氨酸、羟基脯氨酸、肌氨酸(sarcosme)、瓜氨酸、高瓜氨酸、磺丙氨酸、叔丁基甘氨酸、叔丁基丙氨酸、苯基甘氨酸、环己基丙氨酸、β-丙氨酸、氟代氨基酸、设计产生氨基酸(designer amino acids)(诸如β甲基氨基酸、Cα-甲基氨基酸、Nα-甲基氨基酸)以及氨基酸类似物)。
还可以通过参考遗传密码(包括考虑密码子简并性)对嵌合蛋白的核苷酸序列进行突变。
在实施方案中,嵌合蛋白包含接头。在实施方案中,接头包含至少一个能够形成二硫键的半胱氨酸残基。如本文其他地方所述,不希望受理论束缚,这种至少一个能够形成二硫键的半胱氨酸残基负责维持嵌合蛋白的适当多聚体状态并允许有效生产。
在实施方案中,接头可以衍生自天然存在的多结构域蛋白或者是经验接头,如例如在Chichili等,(2013),Protein Sci.22(2):153-167, Chen等,(2013),Adv Drug DelivRev.65(10):1357-1369中所述,所述文献的全部内容特此以引用的方式并入。在实施方案中,接头可以使用接头设计数据库和计算机程序来设计,诸如Chen等,(2013),Adv DrugDeliv Rev.65(10):1357-1369和Crasto等,(2000),Protein Eng. 13(5):309-312中所述的那些数据库和计算机程序,所述文献的全部内容特此以引用的方式并入。
在实施方案中,接头是合成接头,诸如PEG。
在实施方案中,接头是多肽。在实施方案中,接头长度小于约 500个氨基酸、长约450个氨基酸、长约400个氨基酸、长约350个氨基酸、长约300个氨基酸、长约250个氨基酸、长约200个氨基酸、长约150个氨基酸或长约100个氨基酸。例如,接头长度可以小于约 100、约95、约90、约85、约80、约75、约70、约65、约60、约 55、约50、约45、约40、约35、约30、约25、约20、约19、约 18、约17、约16、约15、约14、约13、约12、约11、约10、约9、约8、约7、约6、约5、约4、约3或约2个氨基酸。在实施方案中,接头是柔性的。在另一个实施方案中,接头是刚性的。
在实施方案中,接头基本上包含甘氨酸和丝氨酸残基(例如,约 30%、或约40%、或约50%、或约60%、或约70%、或约80%、或约90%、或约95%、或约97%、或约98%、或约99%、或约100%的甘氨酸和丝氨酸)。
在实施方案中,接头是抗体的铰链区(例如IgG、IgA、IgD和IgE 的铰链区,包括亚类(例如,IgG1、IgG2、IgG3和IgG4以及IgA1和IgA2))。存在于IgG、IgA、IgD和IgE类抗体中的铰链区充当柔性间隔区,从而允许Fab部分在空间中自由移动。与恒定区相反,铰链结构域在结构上是多样的,在免疫球蛋白类和亚类中在序列和长度二者方面均变化。例如,铰链区的长度和柔性在IgG亚类中变化。IgG1 的铰链区包含氨基酸216-231,并且因为它是自由柔性的,所以Fab 片段可以围绕它们的对称轴旋转并在以两个重链间二硫桥中的第一个为中心的球内移动。IgG2具有比IgG1更短的铰链,具有12个氨基酸残基和4个二硫桥。IgG2的铰链区缺少甘氨酸残基,相对较短,并含有通过额外的重链间二硫桥稳定的刚性聚脯氨酸双螺旋。这些特性限制了IgG2分子的柔性。IgG3与其他亚类的不同之处在于其独特的延伸铰链区(IgG1铰链的约4倍),含有62个氨基酸(包括21个脯氨酸和11个半胱氨酸),形成非柔性的聚脯氨酸双螺旋。在IgG3中, Fab片段离Fc片段相对较远,从而使分子具有更大的柔性。与其他亚类相比,IgG3中的细长铰链也是其较高分子量的原因。IgG4的铰链区比IgG1的铰链区更短,并且其柔性介于IgG1与IgG2之间。据报道,铰链区的柔性按IgG3>IgG1>IgG4>IgG2的顺序降低。在实施方案中,接头可以衍生自人IgG4并含有一个或多个突变以增强二聚化(包括S228P)或FcRn结合。
根据晶体学研究,免疫球蛋白铰链区可以进一步在功能上细分为三个区域:上铰链区、核心区和下铰链区。参见Shin等,1992 Immunological Reviews 130:87。上铰链区包括从CH1的羧基末端到限制运动的铰链中的第一个残基(通常是在两个重链之间形成链间二硫键的第一个半胱氨酸残基)的氨基酸。上铰链区的长度与抗体的节段柔性相关。核心铰链区含有重链间二硫键,并且下铰链区连接CH2结构域的氨基末端并包括CH2中的残基。同上。野生型人IgG1的核心铰链区含有序列Cys-Pro-Pro-Cys,当通过二硫键形成二聚化时,其产生被认为充当枢轴的环状八肽,从而赋予柔性。在实施方案中,本发明的接头包含任何抗体(例如IgG、IgA、IgD和IgE,包括亚类(例如, IgG1、IgG2、IgG3和IgG4以及IgA1和IgA2))的上铰链区、核心区和下铰链区中的一个或两个或三个。铰链区还可以含有一个或多个糖基化位点,其包括许多结构上不同类型的碳水化合物附着位点。例如, IgA1在铰链区的17个氨基酸的区段内含有五个糖基化位点,从而赋予铰链区多肽对肠蛋白酶的抗性,被认为是分泌型免疫球蛋白的有利特性。在实施方案中,本发明的接头包含一个或多个糖基化位点。
在实施方案中,接头包含抗体的Fc结构域(例如IgG、IgA、IgD 和IgE的铰链区,包括亚类(例如,IgG1、IgG2、IgG3和IgG4以及 IgA1和IgA2))。在实施方案中,接头包含衍生自人IgG4抗体的铰链 -CH2-CH3 Fc结构域。在实施方案中,接头包含衍生自人IgG1抗体的铰链-CH2-CH3 Fc结构域。在实施方案中,Fc结构域表现出对新生儿Fc受体(FcRn)的增加的亲和力和增强的结合。在实施方案中, Fc结构域包括一个或多个突变,其增加与FcRn的亲和力并增强与 FcRn的结合。不希望受理论束缚,据信与FcRn的增加的亲和力和增强的结合增加了本发明的嵌合蛋白的体内半衰期。
在实施方案中,Fc结构域接头在氨基酸残基250、252、254、256、 308、309、311、416、428、433或434(根据Kabat编号,如在Kabat, 等,Sequences of Proteins ofImmunological Interest,第5版Public Health Service,National Institutes ofHealth,Bethesda,Md.(1991)中所述,其以引用的方式明确并入本文)或其等效物处含有一个或多个氨基酸取代。在一个实施方案中,氨基酸残基250处的氨基酸取代是用谷氨酰胺进行的取代。在一个实施方案中,氨基酸残基252处的氨基酸取代是用酪氨酸、苯丙氨酸、色氨酸或苏氨酸进行的取代。在一个实施方案中,氨基酸残基254处的氨基酸取代是用苏氨酸进行的取代。在一个实施方案中,氨基酸残基256处的氨基酸取代是用丝氨酸、精氨酸、谷氨酰胺、谷氨酸、天冬氨酸或苏氨酸进行的取代。在一个实施方案中,氨基酸残基308处的氨基酸取代是用苏氨酸进行的取代。在一个实施方案中,氨基酸残基309处的氨基酸取代是用脯氨酸进行的取代。在一个实施方案中,氨基酸残基311处的氨基酸取代是用丝氨酸进行的取代。在一个实施方案中,氨基酸残基385处的氨基酸取代是用精氨酸、天冬氨酸、丝氨酸、苏氨酸、组氨酸、赖氨酸、丙氨酸或甘氨酸进行的取代。在一个实施方案中,氨基酸残基386处的氨基酸取代是用苏氨酸、脯氨酸、天冬氨酸、丝氨酸、赖氨酸、精氨酸、异亮氨酸或甲硫氨酸进行的取代。在一个实施方案中,氨基酸残基387处的氨基酸取代是用精氨酸、脯氨酸、组氨酸、丝氨酸、苏氨酸或丙氨酸进行的取代。在一个实施方案中,氨基酸残基389处的氨基酸取代是用脯氨酸、丝氨酸或天冬酰胺进行的取代。在一个实施方案中,氨基酸残基416处的氨基酸取代是用亮氨酸进行的取代。在一个实施方案中,氨基酸残基428处的氨基酸取代是用丝氨酸进行的取代。在一个实施方案中,氨基酸残基433处的氨基酸取代是用精氨酸、丝氨酸、异亮氨酸、脯氨酸或谷氨酰胺进行的取代。在一个实施方案中,氨基酸残基434处的氨基酸取代是用组氨酸、苯丙氨酸或酪氨酸进行的取代。
在实施方案中,Fc结构域接头(例如,包含IgG恒定区)包含一个或多个突变,诸如在氨基酸残基252、254、256、433、434或436(根据Kabat编号,如在Kabat,等,Sequences ofProteins of Immunological Interest,第5版Public Health Service,NationalInstitutes of Health, Bethesda,Md.(1991)中所述,其以引用的方式明确并入本文)处的一个或多个突变。在一个实施方案中,IgG恒定区包括三重 M252Y/S254T/T256E突变或YTE突变。在另一个实施方案中,IgG 恒定区包括三重H433K/N434F/Y436H突变或KFH突变。在又一个实施方案中,IgG恒定区包括组合的YTE和KFH突变。
在实施方案中,本发明的修饰的人源化抗体包含IgG恒定区,其含有在氨基酸残基250、253、307、310、380、416、428、433、434 和435处的一个或多个突变。例示性突变包括T250Q、M428L、T307A、 E380A、I253A、H310A、R416S、M428L、H433K、N434A、N434F、 N434S和H435A。在一个实施方案中,IgG恒定区包括M428L/N434S 突变或LS突变。在另一个实施方案中,IgG恒定区包括T250Q/M428L 突变或QL突变。在另一个实施方案中,IgG恒定区包括N434A突变。在另一个实施方案中,IgG恒定区包括T307A/E380A/N434A突变或 AAA突变。在另一个实施方案中,IgG恒定区包括 I253A/H310A/H435A突变或IHH突变。在另一个实施方案中,IgG 恒定区包括H433K/N434F突变。在另一个实施方案中,IgG恒定区包括组合的M252Y/S254T/T256E和H433K/N434F突变。
IgG恒定区中的另外的例示性突变描述于以下中:例如,Robbie, 等,Antimicrobial Agents and Chemotherapy(2013),57(12):6147-6153, Dall’Acqua等,JBC(2006),281(33):23514-24,Dall’Acqua等,Journal of Immunology(2002),169:5171-80,Ko等Nature(2014)514:642-645, Grevys等Journal of Immunology.(2015),194(11):5497-508,和美国专利号7,083,784,其全部内容特此以引用的方式并入。
在实施方案中,接头包含SEQ ID NO:46的氨基酸序列,或与其具有至少90%、或93%、或95%、或97%、或98%、或99%同一性的氨基酸序列。在实施方案中,对SEQ ID NO:46进行突变以增加稳定性和/或半衰期。例如,在实施方案中,接头具有SEQ ID NO:47 的氨基酸序列,或与其具有至少90%、或93%、或95%、或97%、或98%、或99%同一性的氨基酸序列。在实施方案中,接头包含SEQ ID NO:48的氨基酸序列,或与其具有至少90%、或93%、或95%、或97%、或98%、或99%同一性的氨基酸序列。
不希望受理论束缚,在嵌合蛋白中包括包含至少一部分Fc结构域的接头,有助于避免形成不可溶的并且可能是非功能性的蛋白质多联体和/或聚集体。这部分地是由于Fc结构域中存在能够在嵌合蛋白之间形成二硫键的半胱氨酸。
例示性Fc稳定化突变体是S228P。例示性Fc半衰期延长突变体是T250Q、M428L、V308T、L309P和Q311S,并且本发明的接头可以包含这些突变体中的1个、或2个、或3个、或4个、或5个。
此外,可以采用一个或多个连接接头来连接接头中的Fc结构域 (例如,SEQ IDNO:46、SEQ ID NO:47或SEQ ID NO:48中的一个,或与其具有至少90%、或93%、或95%、或97%、或98%、或99%同一性的结构域)和细胞外结构域。例如,SEQ ID NO:49、SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54 中的任一个或其变体可以连接如本文所述的细胞外结构域和如本文所述的接头。任选地,SEQ ID NO:49、SEQ ID NO:50、SEQ ID NO: 51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54中的任一个或其变体在如本文所述的细胞外结构域与如本文所述的接头之间置换。任选地,SEQ ID NO:49至95中的任一个或其变体位于如本文所述的细胞外结构域与如本文所述的Fc结构域之间。在实施方案中,嵌合蛋白包含Fc结构域之前的一个连接接头以及Fc结构域之后的第二连接接头;因此,嵌合蛋白可以具有以下结构:
ECD 1–连接接头1–Fc结构域–连接接头2–ECD 2。
在实施方案中,第一连接接头和第二连接接头可以是不同的或者它们可以是相同的。
例示性接头的氨基酸序列在以下表1中提供:
表1:例示性接头(Fc结构域接头和连接接头)
另外的例示性连接接头包括但不限于具有以下序列的接头:LE、 GGGGS(SEQ IDNO:70)、(GGGGS)n(n=1-4)(SEQ ID NO:70-73)、 (Gly)8(SEQ ID NO:79)、(Gly)6(SEQ IDNO:80)、(EAAAK)n(n=1-3) (SEQ ID NO:81-83)、A(EAAAK)nA(n=2-5)(SEQ ID NO:84-87)、AEAAAKEAAAKA(SEQ ID NO:84)、A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:88)、PAPAP(SEQ IDNO:89)、 KESGSVSSEQLAQFRSLD(SEQ ID NO:90)、EGKSSGSGSESKST (SEQ ID NO:57)、GSAGSAAGSGEF(SEQ ID NO:91)和(XP)n,其中 X表示任何氨基酸,例如Ala、Lys或Glu。
在实施方案中,连接接头基本上包含甘氨酸和丝氨酸残基(例如,约30%、或约40%、或约50%、或约60%、或约70%、或约80%、或约90%、或约95%、或约97%、或约98%、或约99%、或约100%甘氨酸和丝氨酸)。例如,在实施方案中,连接接头是(Gly4Ser)n,其中n为约1至约8,例如1、2、3、4、5、6、7或8(分别为SEQ ID NO: 70至SEQ ID NO:77)。在实施方案中,连接接头序列是 GGSGGSGGGGSGGGGS(SEQ ID NO:78)。另外的例示性连接接头包括但不限于具有以下序列的接头:LE、(Gly)8(SEQ ID NO:79)、 (Gly)6(SEQ ID NO:80)、(EAAAK)n(n=1-3)(SEQ ID NO:81-SEQ ID NO:83)、A(EAAAK)nA(n=2-5)(SEQ ID NO:84–SEQ IDNO:87)、 A(EAAAK)4ALEA(EAAAK)4A(SEQ ID NO:88)、PAPAP(SEQ ID NO: 89)、KESGSVSSEQLAQFRSLD(SEQ ID NO:90)、GSAGSAAGSGEF (SEQ ID NO:91)和(XP)n,其中X表示任何氨基酸,例如Ala、Lys 或Glu。在实施方案中,连接接头是GGS。
在实施方案中,连接接头是以下中的一个或多个:GGGSE(SEQ ID NO:92)、GSESG(SEQ ID NO:93)、GSEGS(SEQ ID NO:94)、 GEGGSGEGSSGEGSSSEGGGSEGGGSEGGGSEGGS(SEQID NO: 95)以及每4个氨基酸间隔随机放置G、S和E的连接接头。
在实施方案中,嵌合蛋白包含模块接头,如图32所示。
在实施方案中,接头可以是柔性的,包括但不限于高度柔性的。在实施方案中,接头可以是刚性的,包括但不限于刚性α螺旋。
在实施方案中,接头可以是功能性的。例如但不限于,接头可以起到改善本发明的嵌合蛋白的折叠和/或稳定性、改善表达、改善药代动力学和/或改善其生物活性的作用。在另一个实例中,接头可以起到将嵌合蛋白靶向特定细胞类型或位置的作用。
在实施方案中,本发明的嵌合蛋白能够促进免疫活化(例如,针对肿瘤)并且可以用于包括促进免疫活化(例如,针对肿瘤)的方法。在实施方案中,本发明的嵌合蛋白能够抑制免疫抑制(例如,允许肿瘤存活)并且可以用于包括抑制免疫抑制(例如,允许肿瘤存活)的方法。本发明的嵌合蛋白由于构建体的嵌合性质提供的信号传导的近似性而提供改善的免疫活化和/或改善的对免疫抑制的抑制。
在实施方案中,本发明的嵌合蛋白能够或可以用于包括调节免疫应答的幅度的方法中,例如,调节效应子输出的水平。在实施方案中,例如,当用于治疗癌症时,与免疫抑制相比,本发明的嵌合蛋白改变免疫刺激的程度以增加T细胞应答的幅度,其包括但不限于刺激细胞因子产生、增殖或靶向杀伤潜力的水平增加。
在实施方案中,本发明的嵌合蛋白在实施方案中能够或可用于涉及在肿瘤细胞表面上掩蔽抑制配体以及用免疫刺激配体替换所述免疫抑制配体的方法中。因此,本发明的嵌合蛋白在实施方案中能够或可用于涉及降低或消除抑制免疫信号和/或增加或活化免疫刺激信号的方法中。例如,携带抑制信号(并因此逃避免疫应答)的肿瘤细胞可以被结合在T细胞上的正信号取代,然后T细胞可以攻击肿瘤细胞。因此,在实施方案中,本发明的构建体掩蔽抑制免疫信号并活化刺激免疫信号。通过本发明的嵌合蛋白的单一构建方法增强了此类有益特性。例如,信号替换可以几乎同时实现,并且信号替换被定制为在临床重要部位(例如,肿瘤微环境)处是局部的。另外的实施方案将相同的原理应用于其他嵌合蛋白构建体,例如像,(i)TIGIT的细胞外结构域和(ii)4-1BBL的细胞外结构域;(i)TIGIT的细胞外结构域和(ii) GITRL的细胞外结构域;(i)TIGIT的细胞外结构域和(ii)TL1A的细胞外结构域;(i)TIGIT的细胞外结构域和(ii)LIGHT的细胞外结构域;以及(i)PD-1的细胞外结构域和(ii)LIGHT的细胞外结构域;以及(i) CD172a(SIRPα)的细胞外结构域和(ii)LIGHT的细胞外结构域;以及 (i)TIGIT的细胞外结构域和(ii)LIGHT的细胞外结构域;等等。
在实施方案中,本发明的嵌合蛋白能够或可用于包括刺激或增强免疫刺激受体/配体对的结合的方法中。例示性T细胞共刺激受体及其配体包括OX-40:OX40-L、CD27:CD70、CD30:CD30-L、CD40:CD40-L、CD137:CD137-L、HVEM:LIGHT、GITR:GITR-L、 TNFRSF25:TL1A、DR5:TRAIL和BTLA:HVEM。在实施方案中,本发明的嵌合蛋白能够或可用于包括抑制或降低免疫抑制受体/配体对的结合的方法中。例示性T细胞共抑制受体及其配体包括,例如,CTLA-4:CD80/CD86、PD-1:PD-L1/PD-L2、BTLA:HVEM、TIM-3:半乳凝素-9/磷脂酰丝氨酸、TIGIT/CD155或CD112、VISTA/VSIG8、 CD172a(SIRPα)/CD47、B7H3R/B7H3、B7H4R/B7H4、CD244/CD48、 TMIGD2/HHLA2等等。
在实施方案中,本发明的嵌合蛋白阻断、降低和/或抑制PD-1以及PD-L1或PD-L2和/或PD-1与PD-L1或PD-L2的结合。在实施方案中,本发明的嵌合蛋白阻断、降低和/或抑制CTLA-4的活性和/或 CTLA-4与AP2M1、CD80、CD86、SHP-2和PPP2R5A中的一种或多种的结合。在实施方案中,本发明的嵌合蛋白增加和/或刺激GITR 和/或GITR与GITR配体中的一种或多种的结合。在实施方案中,本发明的嵌合蛋白增加和/或刺激OX40和/或OX40与OX40配体中的一种或多种的结合。
在实施方案中,本发明的嵌合蛋白能够或可用于涉及增强、恢复、促进和/或刺激免疫调节的方法中。在实施方案中,本文所述的本发明的嵌合蛋白恢复、促进和/或刺激一种或多种针对肿瘤细胞的免疫细胞的活性或活化,所述免疫细胞包括但不限于:T细胞、细胞毒性 T淋巴细胞、T辅助细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、抗肿瘤巨噬细胞(例如M1巨噬细胞)、B细胞和树突细胞。在实施方案中,本发明的嵌合蛋白增强、恢复、促进和/或刺激T细胞的活性和/或活化,作为非限制性实例,包括活化和/或刺激一种或多种 T细胞固有信号,其包括促存活信号;自分泌或旁分泌生长信号;p38 MAPK-、ERK-、STAT-、JAK-、AKT-或PI3K-介导的信号;抗细胞凋亡信号;和/或促进以下中的一种或多种和/或以下中的一种或多种必需的信号:促炎细胞因子产生、或T细胞迁移、或T细胞肿瘤浸润。
在实施方案中,本发明的嵌合蛋白能够或可用于涉及引起进入肿瘤或肿瘤微环境内的一种或多种T细胞(包括但不限于细胞毒性T淋巴细胞、T辅助细胞、自然杀伤T(NKT)细胞)、B细胞、自然杀伤(NK) 细胞、自然杀伤T(NKT)细胞、树突细胞、单核细胞和巨噬细胞(例如, M1和M2中的一种或多种)增加的方法中。在实施方案中,本发明的嵌合蛋白能够或可用于涉及抑制和/或致使降低免疫抑制细胞(例如,髓样抑制细胞(MDSC)、调节T细胞(Treg)、肿瘤相关嗜中性粒细胞 (TAN)、M2巨噬细胞和肿瘤相关巨噬细胞(TAM))到肿瘤和/或肿瘤微环境(TME)中的募集的方法中。在实施方案中,本发明的疗法可以改变肿瘤部位和/或TME中M1巨噬细胞相对于M2巨噬细胞的比例,以有利于M1巨噬细胞。
在实施方案中,本发明的嵌合蛋白能够并且可以用于包括抑制和 /或降低T细胞失活和/或对肿瘤的免疫耐受性的方法中,所述方法包括向受试者施用有效量的本文所述的嵌合蛋白。在实施方案中,本发明的嵌合蛋白能够增加各种细胞因子的血清水平,所述细胞因子包括但不限于IFNγ、TNFα、IL-2、IL-4、IL-5、IL-6、IL-9、IL-10、IL-13、 IL-17A、IL-17F和IL-22中的一种或多种。在实施方案中,本发明的嵌合蛋白能够增强治疗的受试者血清中的IL-2、IL-4、IL-5、IL-10、 IL-13、IL-17A、IL-22、TNFα或IFNγ。在实施方案中,本发明的嵌合蛋白的施用能够增强TNFα分泌。在一个具体实施方案中,本发明的嵌合蛋白的施用能够增强白细胞的超抗原介导的TNFα分泌。检测这种细胞因子应答可以提供确定所指示的嵌合蛋白的最佳给药方案的方法。
在实施方案中,本发明的嵌合蛋白抑制、阻断和/或减少抗肿瘤 CD8+和/或CD4+T细胞的细胞死亡;或者刺激、诱导和/或增加促肿瘤T细胞的细胞死亡。T细胞耗竭是T细胞功能障碍的一种状态,其特征在于增殖和效应子功能的进行性丧失,从而最终导致克隆缺失。因此,促肿瘤T细胞是指在许多慢性感染和癌症期间出现的T细胞功能障碍的一种状态。这种功能障碍被定义为较差的增殖和/或效应子功能、抑制受体的持续表达以及与功能效应T细胞或记忆T细胞的转录状态不同的转录状态。耗竭防止感染和肿瘤的最佳控制。此外,抗肿瘤CD8+和/或CD4+T细胞是指可以对肿瘤产生免疫应答的T细胞。例示性促肿瘤T细胞包括但不限于Treg、表达一种或多种检查点抑制受体的CD4+和/或CD8+T细胞、Th2细胞和Th17细胞。检查点抑制受体是指在免疫细胞上表达的预防或抑制非受控免疫应答的受体。
在实施方案中,本发明的嵌合蛋白能够并且可以用于包括增加效应T细胞与调节T细胞的比例的方法中。例示性效应T细胞包括 ICOS+效应T细胞;细胞毒性T细胞(例如,αβTCR、CD3+、CD8+、 CD45RO+);CD4+效应T细胞(例如,αβTCR、CD3+、CD4+、CCR7+、 CD62Lhi、IL-7R/CD127+);CD8+效应T细胞(例如,αβTCR、CD3+、 CD8+、CCR7+、CD62Lhi、IL-7R/CD127+);效应记忆T细胞(例如, CD62L低、CD44+、TCR、CD3+、IL-7R/CD127+、IL-15R+、CCR7 低);中枢记忆T细胞(例如,CCR7+、CD62L+、CD27+;或CCR7hi、 CD44+、CD62Lhi、TCR、CD3+、IL-7R/CD127+、IL-15R+);CD62L+效应T细胞;CD8+效应记忆T细胞(TEM),包括早期效应记忆T细胞(CD27+CD62L-)和晚期效应记忆T细胞(CD27-CD62L-)(分别为 TemE和TemL);CD127(+)CD25(低/-)效应T细胞;CD127(-)CD25(-) 效应T细胞;CD8+干细胞记忆效应细胞(TSCM)(例如, CD44(低)CD62L(高)CD122(高)sca(+));TH1效应T细胞(例如, CXCR3+、CXCR6+和CCR5+;或αβTCR、CD3+、CD4+、IL-12R+、 IFNγR+、CXCR3+);TH2效应T细胞(例如,CCR3+、CCR4+和CCR8+;或αβTCR、CD3+、CD4+、IL-4R+、IL-33R+、CCR4+、IL-17RB+、CRTH2+); TH9效应T细胞(例如,αβTCR、CD3+、CD4+);TH17效应T细胞(例如,αβTCR、CD3+、CD4+、IL-23R+、CCR6+、IL-1R+); CD4+CD45RO+CCR7+效应T细胞,CD4+CD45RO+CCR7(-)效应T细胞;以及分泌IL-2、IL-4和/或IFN-γ的效应T细胞。例示性调节T 细胞包括ICOS+调节T细胞、CD4+CD25+FOXP3+调节T细胞、CD4+CD25+调节T细胞、CD4+CD25-调节T细胞、CD4+CD25高调节 T细胞、TIM-3+PD-1+调节T细胞、淋巴细胞活化基因-3(LAG-3)+调节T细胞、CTLA-4/CD152+调节T细胞、神经纤毛蛋白-1(Nrp-1)+调节T细胞、CCR4+CCR8+调节T细胞、CD62L(L-选择素)+调节T细胞、CD45RB低调节T细胞、CD127低调节T细胞、LRRC32/GARP+调节T细胞、CD39+调节T细胞、GITR+调节T细胞、LAP+调节T 细胞、1B11+调节T细胞、BTLA+调节T细胞、1型调节T细胞(Tr1 细胞)、T辅助3型(Th3)细胞、自然杀伤T细胞表型的调节细胞(NKTreg)、CD8+调节T细胞、CD8+CD28-调节T细胞和/或分泌IL-10、 IL-35、TGF-β、TNF-α、半乳凝素-1、IFN-γ和/或MCP1的调节T细胞。
在实施方案中,嵌合蛋白产生记忆应答,其可以例如能够预防复发,或保护动物免于再次攻击。因此,用嵌合蛋白处理的动物稍后能够在用嵌合蛋白初始处理之后被再次攻击时攻击肿瘤细胞和/或预防肿瘤发展。因此,本发明的嵌合蛋白刺激活性肿瘤破坏,也刺激肿瘤抗原的免疫识别,这对于设计能够预防复发的记忆应答是必需的。
在实施方案中,本发明的嵌合蛋白能够并且可以用于包括瞬时刺激效应T细胞不超过约12小时、约24小时、约48小时、约72小时或约96小时或者约1周或约2周的方法中。在实施方案中,本发明的嵌合蛋白能够并且可以用于包括瞬时消耗或抑制调节T细胞不超过约12小时、约24小时、约48小时、约72小时或约96小时或者约1周或约2周的方法中。在实施方案中,效应T细胞的瞬时刺激和 /或调节T细胞的瞬时消耗或抑制基本上发生在患者的血液中或特定组织/位置(包括淋巴组织,例如像骨髓、淋巴结、脾脏、胸腺、粘膜相关淋巴组织(MALT),非淋巴组织)中或肿瘤微环境中。
在实施方案中,本发明的嵌合蛋白质提供包括但不限于易于施用和易于生产的优点。这是因为将两种不同的免疫治疗剂组合成了单一产品,这允许单一制造过程代替两个独立的制造过程。此外,施用单一剂代替两种单独的剂允许更容易的施用和更大的患者依从性。此外,与例如单克隆抗体相比,所述单克隆抗体是含有许多二硫键和翻译后修饰(诸如糖基化)的大型多聚体蛋白质,本发明的嵌合蛋白更容易制造并且更具成本效益。
在实施方案中,本发明的嵌合蛋白可作为可分泌的和完全功能的单一多肽链在哺乳动物宿主细胞中产生。
在实施方案中,本发明的嵌合蛋白意外地提供细胞外结构域组分以缓慢的解离速率(Kd或Koff)与其各自的结合配偶体的结合。在实施方案中,这提供了受体与配体(并且反之亦然)的意外长的相互作用。这种效果允许持续的负信号掩蔽效果。此外,在实施方案中,这提供了更长的正信号效果,例如,以允许效应细胞被充分刺激用于抗肿瘤效果。例如,本发明的嵌合蛋白,例如通过长解离速率结合,允许足够的信号传递以提供T细胞增殖并允许抗肿瘤攻击。作为另一实例,本发明的嵌合蛋白,例如通过长解离速率结合,允许足够的信号传递以提供刺激信号(例如像细胞因子)的释放。
由本发明的剂促进的细胞的稳定突触(例如,具有负信号的肿瘤细胞和可以攻击肿瘤的T细胞)提供空间取向以有利于肿瘤减少-诸如定位T细胞以攻击肿瘤细胞和/或在空间上防止肿瘤细胞递送负信号,其包括超出本发明的嵌合蛋白掩蔽的那些信号的负信号。
在实施方案中,与嵌合蛋白的血清t1/2相比,这提供了更长的靶上(例如,肿瘤内)半衰期(t1/2)。此类特性可以具有降低脱靶毒性的组合优点,这可能与嵌合蛋白的全身分布有关。
在实施方案中,本发明的剂允许某些免疫细胞例如以抗肿瘤方式通过TIGIT阻断信号来预防和/或破坏NK细胞和/或活化、记忆和/ 或调节T细胞和/或辅助T细胞的子组来起作用,并且任选地通过基于4-1BBL和/或GITRL和/或TL1A-和/或LIGHT的刺激信号传导产生进一步的免疫应答。
在实施方案中,本发明的剂允许某些免疫细胞例如以抗肿瘤方式通过刺激和/或增加例如内脏和/或淋巴样和/或其他基质和/或上皮和/ 或髓样细胞上的刺激性的基于LIGHT的信号传导来起作用,并且任选地通过阻断或减少基于PD-1和/或CD172a(SIRPα)和/或TIGIT的抑制性信号传导来产生进一步的免疫应答。
此外,在实施方案中,本发明的嵌合蛋白提供协同治疗效果,因为它允许改善两种免疫治疗剂的位点特异性相互作用。
在实施方案中,本发明的嵌合蛋白提供用于降低位点外毒性和/ 或全身毒性的潜力。
在实施方案中,相对于目前的免疫疗法,例如如本文所述的针对检查点分子的抗体,本发明的嵌合蛋白提供减少的副作用,例如GI 并发症。例示性GI并发症包括腹痛、食欲减退、自身免疫效应、便秘、痉挛、脱水、腹泻、进食问题、疲劳、胃肠胀气、腹腔积液或腹水、胃肠道(GI)生态失调、GI粘膜炎、炎性肠病、肠易激综合征(IBS-D 和IBS-C)、恶心、疼痛、粪便或尿液变化、溃疡性结肠炎、呕吐、保留液重量增加和/或虚弱。
疾病;治疗方法和患者选择
在实施方案中,本发明涉及癌症和/或肿瘤;例如,癌症和/或肿瘤的治疗或预防。如本文其他地方所述,在实施方案中,癌症的治疗可以涉及用本发明的嵌合蛋白调节免疫系统以相对于免疫抑制有利于免疫刺激。
癌症或肿瘤是指不受控制的细胞生长和/或异常增加的细胞存活和/或细胞凋亡的抑制,这干扰身体器官和系统的正常功能。包括良性和恶性癌症、息肉、增生、以及休眠肿瘤或微转移。还包括具有不受免疫系统阻碍的异常增殖的细胞(例如,病毒感染的细胞)。癌症可以是原发性癌症或转移性癌症。原发性癌症可以是在临床上可检测的起源部位的癌细胞区域,并且可以是原发性肿瘤。相比之下,转移性癌症可以是疾病从一个器官或部分到另一个非相邻器官或部分的扩散。转移性癌症可能由癌细胞引起,所述癌细胞获得穿透并浸润局部区域中的周围正常组织的能力,从而形成新肿瘤,其可以是局部转移。癌症还可能由癌细胞引起,所述癌细胞获得穿透淋巴管和/或血管壁的能力,之后癌细胞能够通过血液(由此成为循环肿瘤细胞)循环到身体的其他部位和组织。癌症可以是由于诸如淋巴或血液扩散等的过程。癌症还可能由肿瘤细胞引起,所述肿瘤细胞到达以停留在另一个部位,再次穿透血管或壁,继续繁殖,并最终形成另一个临床上可检测的肿瘤。癌症可以是这种新的肿瘤,其可以是转移性(或继发性)肿瘤。
癌症还可能由已经转移的肿瘤细胞引起,其可以是继发性或转移性肿瘤。肿瘤细胞可以与原始肿瘤中的细胞相似。例如,如果乳腺癌或结肠癌转移到肝脏,则存在于肝脏中的继发性肿瘤由异常的乳腺细胞或结肠细胞组成,而不是由异常的肝细胞组成。因此,肝脏中的肿瘤可以是转移性乳腺癌或转移性结肠癌,而不是肝癌。
癌症可能来源于任何组织。癌症可能来源于黑色素瘤、结肠、乳腺或前列腺,并因此可能分别由最初是皮肤、结肠、乳腺或前列腺的细胞组成。癌症也可以是血液恶性肿瘤,其可以是白血病或淋巴瘤。癌症可能侵入诸如肝脏、肺、膀胱或肠道等组织。
本发明的代表性癌症和/或肿瘤包括但不限于基底细胞癌,胆道癌;膀胱癌;骨癌;脑和中枢神经系统癌症;乳腺癌;腹膜癌;宫颈癌;绒毛膜癌;结直肠癌;结缔组织癌;消化系统的癌症;子宫内膜癌;食道癌;眼癌;头颈癌;胃癌(包括胃肠癌);胶质母细胞瘤;肝癌;肝细胞癌;上皮内肿瘤;肾癌;喉癌;白血病;肝癌;肺癌(例如,小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌);黑色素瘤;骨髓瘤;神经母细胞瘤;口腔癌(唇、舌、口和咽);卵巢癌;胰腺癌;前列腺癌;视网膜母细胞瘤;横纹肌肉瘤;直肠癌;呼吸系统癌症;唾液腺癌;肉瘤;皮肤癌;鳞状细胞癌;胃癌;睾丸癌;甲状腺癌;子宫或子宫内膜癌;泌尿系统癌症;外阴癌;淋巴瘤包括霍奇金淋巴瘤和非霍奇金淋巴瘤以及B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(NHL)、小淋巴细胞(SL)NHL;中级/滤泡性NHL;中级弥漫性 NHL;高级免疫母细胞NHL;高级淋巴细胞NHL;高级小非裂解细胞NHL;巨大肿块NHL;套细胞淋巴瘤;艾滋病相关淋巴瘤;和华氏巨球蛋白血症;慢性淋巴细胞白血病(CLL);急性淋巴细胞白血病 (ALL);毛细胞白血病;慢性成髓细胞白血病;以及其他癌和肉瘤;和移植后淋巴组织增生性障碍(PTLD)以及与瘢痣病、水肿(诸如与脑肿瘤相关的水肿)和麦格综合征相关的异常血管增生。
在实施方案中,嵌合蛋白用于治疗患有治疗难治性癌症的受试者。在实施方案中,嵌合蛋白用于治疗用一种或多种免疫调节剂难以治疗的受试者。例如,在实施方案中,嵌合蛋白用于治疗在治疗12 周左右之后对治疗没有应答或甚至进展的受试者。例如,在实施方案中,受试者用PD-1和/或PD-L1和/或PD-L2剂难以治疗,包括例如纳武单抗(ONO-4538/BMS-936558、MDX1106、OPDIVO,BRISTOL MYERS SQUIBB)、派姆单抗(KEYTRUDA,MERCK)、匹地利珠单抗(pidilizumab)(CT-011,CURE TECH)、MK-3475(MERCK)、BMS 936559(BRISTOLMYERS SQUIBB)、依鲁替尼 (PHARMACYCLICS/ABBVIE)、阿特珠单抗(TECENTRIQ,GENENTECH)和/或MPDL328OA(ROCHE)难治性患者。例如,在实施方案中,受试者用抗CTLA-4剂难以治疗,例如易普利姆玛 (YERVOY)难治性患者(例如,黑色素瘤患者)。因此,在实施方案中,本发明提供了癌症治疗方法,其拯救对各种疗法(包括一种或多种免疫调节剂的单一疗法)无应答的患者。
在实施方案中,本发明提供了靶向肿瘤微环境内的细胞或组织的嵌合蛋白。在实施方案中,肿瘤微环境内的细胞或组织表达嵌合蛋白的一种或多种靶标或者结合配偶体。肿瘤微环境是指细胞环境,包括细胞、分泌蛋白、生理小分子和肿瘤存在的血管。在实施方案中,肿瘤微环境内的细胞或组织是以下中的一种或多种:肿瘤脉管系统;肿瘤浸润淋巴细胞;成纤维细胞网状细胞;内皮祖细胞(EPC);癌症相关成纤维细胞;周细胞;其他基质细胞;细胞外基质(ECM)的组分;树突细胞;抗原呈递细胞;T细胞;调节T细胞;巨噬细胞;嗜中性粒细胞;和位于肿瘤附近的其他免疫细胞。在实施方案中,本发明的嵌合蛋白靶向癌细胞。在实施方案中,癌细胞表达嵌合蛋白的靶标或者结合配偶体中的一种或多种。
在实施方案中,本发明的嵌合蛋白可以靶向表达TIGIT的细胞( 例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达CD155/PVR的细胞(例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达结合素-2的细胞(例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达结合素-3的细胞(例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达结合素-4的细胞(例如,癌细胞或免疫细胞)。
在实施方案中,本发明的嵌合蛋白可以靶向表达LIGHT的细胞( 例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达LTBR的细胞(例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达HVEM的细胞(例如,癌细胞或免疫细胞)。在实施方案中,本发明的嵌合蛋白可以靶向表达DcR3的细胞(例如,癌细胞或免疫细胞)。
在实施方案中,本发明的方法提供了在另外的剂难以治疗的患者中使用嵌合蛋白的治疗,此类在本文其他地方描述的“另外的剂”包括但不限于本文所述的各种化学治疗剂。
在实施方案中,嵌合蛋白用于治疗、控制或预防一种或多种炎性疾病或病状。炎性疾病的非限制性实例包括寻常痤疮、急性炎症、过敏性鼻炎、哮喘、动脉粥样硬化、特应性皮炎、自身免疫性疾病、自身炎症性疾病、常染色体隐性痉挛性共济失调、支气管扩张、乳糜泻、慢性胆囊炎、慢性炎症、慢性前列腺炎、结肠炎、憩室炎、家族性嗜酸性粒细胞增多症(fe)、肾小球肾炎、甘油激酶缺乏症、化脓性汗腺炎、过敏、炎症、炎性肠病、炎性盆腔疾病、间质性膀胱炎、喉炎性疾病、Leigh综合征、扁平苔癣、肥大细胞活化综合征、肥大细胞增多症、眼部炎性疾病、中耳炎、疼痛、盆腔炎性疾病、再灌注损伤、呼吸系统疾病、再狭窄、风湿热、类风湿性关节炎、鼻炎、结节病、感染性休克、矽肺病和其他尘肺病、移植排斥、肺结核和血管炎。
在实施方案中,炎性疾病是自身免疫性疾病或病状,诸如多发性硬化、糖尿病、狼疮、乳糜泻、克罗恩病、溃疡性结肠炎、格林-巴利综合征、硬皮病、古德帕斯彻氏综合症、韦格纳肉芽肿病、自身免疫性癫痫、拉斯穆森脑炎、原发性胆汁硬化、硬化性胆管炎、自身免疫性肝炎、艾迪生病、桥本氏甲状腺炎、纤维肌痛、梅尼尔综合征、移植排斥(例如,预防同种异体移植物排斥)、恶性贫血、类风湿性关节炎、系统性红斑狼疮、皮肌炎、干燥综合征、红斑狼疮、多发性硬化症、重症肌无力、赖特氏综合症、格雷夫氏病和其他自身免疫性疾病。
在一些方面,本发明的嵌合剂用于消除细胞内病原体。在一些方面,本发明的嵌合剂用于治疗一种或多种感染。在实施方案中,本发明的嵌合蛋白用于治疗病毒感染(包括例如HIV和HCV)、寄生虫感染(包括例如疟疾)和细菌感染的方法中。在实施方案中,感染诱导免疫抑制。例如,HIV感染经常在受感染的受试者中导致免疫抑制。因此,如本文其他地方所述,在实施方案中,此类感染的治疗可以涉及用本发明的嵌合蛋白调节免疫系统以相对于免疫抑制有利于免疫刺激。或者,本发明提供了用于治疗诱导免疫活化的感染的方法。例如,肠蠕虫感染与慢性免疫活化相关。在这些实施方案中,此类感染的治疗可以涉及用本发明的嵌合蛋白调节免疫系统以相对于免疫刺激有利于免疫抑制。
在实施方案中,本发明提供了治疗病毒感染的方法,所述病毒感染包括但不限于急性或慢性病毒感染,例如呼吸道感染、乳头瘤病毒感染、单纯疱疹病毒(HSV)感染、人免疫缺陷病毒(HIV)感染以及内脏器官的病毒感染,诸如肝炎病毒感染。在实施方案中,病毒感染由黄病毒科(Flaviviridae)的病毒引起。在实施方案中,黄病毒科的病毒选自黄热病病毒、西尼罗河病毒、登革热病毒、日本脑炎病毒、圣路易斯脑炎病毒和丙型肝炎病毒。在实施方案中,病毒感染由小核糖核酸病毒科(Picornaviridae)的病毒(例如,脊髓灰质炎病毒、鼻病毒、柯萨奇病毒)引起。在实施方案中,病毒感染由正粘病毒科 (Orthomyxoviridae)的成员(例如,流感病毒)引起。在实施方案中,病毒感染由逆转录病毒科(Retroviridae)的成员(例如,慢病毒)引起。在实施方案中,病毒感染是由副粘病毒科(Paramyxoviridae)的成员(例如呼吸道合胞病毒、人副流感病毒、腮腺炎病毒属(例如腮腺炎病毒)、麻疹病毒和人偏肺病毒)引起。在实施方案中,病毒感染由本扬病毒科(Bunyaviridae)的成员(例如,汉坦病毒)引起。在实施方案中,病毒感染由呼肠孤病毒科(Reoviridae)的成员(例如,轮状病毒)引起。
在实施方案中,本发明提供了治疗寄生虫感染(诸如原生动物或蠕虫感染)的方法。在实施方案中,寄生虫感染由原生动物寄生虫引起。在实施方案中,oritiziab寄生虫选自肠原生动物、组织原生动物或血液原生动物。例示性原生动物寄生虫包括但不限于溶组织内阿米巴(Entamoeba hystolytica)、蓝氏贾第鞭毛虫(Giardia lamblia)、小鼠隐孢子虫(Cryptosporidium muris)、Trypanosomatida gambiense、 Trypanosomatidarhodesiense、克氏锥虫(Trypanosomatida crusi)、墨西哥利什曼虫(Leishmaniamexicana)、巴西利什曼原虫(Leishmania braziliensis)、热带利什曼虫(Leishmaniatropica)、杜氏利什曼虫 (Leishmania donovani)、刚地弓形虫(Toxoplasma gondii)、间日疟原虫 (Plasmodium vivax)、卵形疟原虫(Plasmodium ovale)、三日疟原虫(Plasmodium malariae)、恶性疟原虫(Plasmodium falciparum)、阴道毛滴虫(Trichomonas vaginalis)和黑头组织滴虫(Histomonas meleagridis)。在实施方案中,寄生虫感染是通过蠕虫寄生虫,诸如线虫(例如,有腺纲(Adenophorea))。在实施方案中,寄生虫选自侧尾腺口纲(例如,毛首鞭形线虫(Trichuris trichiura)、似蚓蛔线虫 (Ascarislumbricoides)、蠕形住肠线虫(Enterobius vermicularis)、十二指肠钩虫(Ancylostomaduodenale)、美洲板口线虫(Necator americanus)、粪类圆线虫(Strongyloidesstercoralis)、班氏吴策线虫 (Wuchereria bancrofti)、麦地那龙线虫(Dracunculusmedinensis))。在实施方案中,寄生虫选自吸虫(例如,血吸虫、肝吸虫、肠吸虫和肺吸虫)。在实施方案中,寄生虫选自:曼氏血吸虫(Schistosoma mansoni)、埃及血吸虫(Schistosoma haematobium)、日本血吸虫 (Schistosoma japonicum)、牛羊肝吸虫(Fasciola hepatica)、巨片吸虫 (Fasciola gigantica)、异形吸虫(Heterophyes)、卫氏肺吸虫 (Paragonimus westermani)。在实施方案中,寄生虫选自绦虫(例如,猪肉绦虫(Taenia solium)、牛肉绦虫(Taenia saginata)、短膜壳绦虫 (Hymenolepis nana)、细粒棘球绦虫(Echinococcus granulosus))。
在实施方案中,本发明提供了治疗细菌感染的方法。在实施方案中,细菌感染是通过革兰氏阳性细菌、革兰氏阴性细菌、好氧细菌和 /或厌氧细菌。在实施方案中,细菌选自但不限于葡萄球菌属 (Staphylococcus)、乳杆菌(Lactobacillus)、链球菌(Streptococcus)、八联球菌属(Sarcina)、埃希氏菌属(Escherichia)、肠杆菌属(Enterobacter)、克雷伯氏菌属(Klebsiella)、假单胞菌属(Pseudomonas)、不动杆菌属(Acinetobacter)、分枝杆菌(Mycobacterium)、变形杆菌属(Proteus)、弯曲杆菌(Campylobacter)、柠檬酸杆菌属(Citrobacter)、奈瑟氏菌属 (Nisseria)、芽孢杆菌属(Bacillus)、拟杆菌属(Bacteroides)、消化球菌属(Peptococcus)、梭菌属(Clostridium)、沙门氏菌属(Salmonella)、志贺氏菌属(Shigella)、沙雷氏菌属(Serratia)、嗜血杆菌属(Haemophilus)、布鲁氏菌属(Brucella)以及其他生物体。在实施方案中,细菌选自但不限于铜绿假单胞菌(Pseudomonas aeruginosa)、荧光假单胞菌 (Pseudomonasfluorescens)、食酸假单胞菌(Pseudomonas acidovorans)、产碱假单胞菌(Pseudomonasalcaligenes)、恶臭假单胞菌(Pseudomonas putida)、嗜麦芽寡养单胞菌(Stenotrophomonas maltophilia)、洋葱伯克霍尔德菌(Burkholderia cepacia)、嗜水气单胞菌(Aeromonas hydrophilia)、大肠杆菌(Escherichia coli)、弗氏柠檬酸杆菌(Citrobacter freundii)、鼠伤寒沙门氏菌(Salmonella typhimurium)、伤寒沙门氏菌(Salmonella typhi)、甲型副伤寒沙门氏菌(Salmonella paratyphi)、肠炎沙门氏菌(Salmonella enteritidis)、痢疾志贺氏菌(Shigella dysenteriae)、福氏志贺氏菌(Shigella flexneri)、宋内氏志贺菌(Shigella sonnei)、阴沟肠杆菌(Enterobactercloacae)、产气肠杆菌(Enterobacter aerogenes)、肺炎克雷伯氏菌(Klebsiellapneumoniae)、产酸克雷伯氏菌(Klebsiella oxytoca)、粘质沙雷氏菌(Serratiamarcescens)、土拉弗朗西斯菌 (Francisella tularensis)、摩氏摩根菌(Morganellamorganii)、奇异变形杆菌(Proteus mirabilis)、普通变形杆菌(Proteus vulgaris)、产碱普罗威登斯菌(Providencia alcalifaciens)、雷氏普罗威登斯菌(Providenciarettgeri)、斯氏普罗威登斯菌(Providencia stuartii)、鲍曼不动杆菌 (Acinetobacterbaumannii)、醋酸钙不动杆菌(Acinetobacter calcoaceticus)、溶血不动杆菌(Acinetobacter haemolyticus)、小肠结肠炎耶尔森菌(Yersinia enterocolitica)、鼠疫耶尔森菌(Yersinia pestis)、假结核耶尔森菌(Yersinia pseudotuberculosis)、中间耶尔森菌(Yersinia intermedia)、百日咳博代氏杆菌(Bordetella pertussis)、副百日咳博代氏杆菌(Bordetella parapertussis)、支气管炎博代氏杆菌(Bordetellabronchiseptica)、流感嗜血杆菌(Haemophilus influenzae)、副流感嗜血杆菌(Haemophilus parainfluenzae)、溶血嗜血杆菌(Haemophilus haemolyticus)、副溶血嗜血杆菌(Haemophilus parahaemolyticus)、杜克嗜血杆菌(Haemophilus ducreyi)、多杀巴斯德菌(Pasteurella multocida)、溶血巴斯德菌(Pasteurella haemolytica)、粘膜炎布兰汉菌 (Branhamella catarrhalis)、幽门螺杆菌(Helicobacter pylori)、胎儿弯曲杆菌(Campylobacter fetus)、空肠弯曲杆菌(Campylobacter jejuni)、大肠弯曲杆菌(Campylobacter coli)、伯氏疏螺旋体(Borrelia burgdorferi)、霍乱弧菌(Vibriocholerae)、副溶血弧菌(Vibrio parahaemolyticus)、嗜肺军团菌(Legionellapneumophila)、单核细胞增生李斯特菌(Listeria monocytogenes)、淋病奈瑟菌(Neisseria gonorrhoeae)、脑膜炎奈瑟菌 (Neisseria meningitidis)、金氏菌属(Kingella)、莫拉氏菌属(Moraxella)、阴道加德菌(Gardnerella vaginalis)、脆弱拟杆菌(Bacteroides fragilis)、狄氏拟杆菌(Bacteroides distasonis)、拟杆菌属3452A同源组、普通拟杆菌(Bacteroides vulgatus)、卵形拟杆菌(Bacteroides ovalus)、多形拟杆菌(Bacteroides thetaiotaomicron)、单形拟杆菌(Bacteroides uniformis)、埃氏拟杆菌(Bacteroides eggerthii)、内脏拟杆菌(Bacteroides splanchnicus)、艰难梭菌(Clostridium difficile)、结核分枝杆菌 (Mycobacterium tuberculosis)、鸟分枝杆菌(Mycobacterium avium)、胞内分枝杆菌(Mycobacterium intracellulare)、麻风分枝杆菌(Mycobacterium leprae)、白喉棒状杆菌(Corynebacterium diphtheriae)、溃疡棒状杆菌(Corynebacterium ulcerans)、肺炎链球菌(Streptococcus pneumoniae)、无乳链球菌(Streptococcus agalactiae)、酿脓链球菌 (Streptococcus pyogenes)、粪肠球菌(Enterococcus faecalis)、屎肠球菌 (Enterococcus faecium)、金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、腐生葡萄球菌(Staphylococcus saprophyticus)、中间葡萄球菌(Staphylococcus intermedius)、猪葡萄球菌亚种hyicus(Staphylococcus hyicus subsp. hyicus)、溶血葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌 (Staphylococcus hominis)或解糖葡萄球菌(Staphylococcus saccharolyticus)。
在一些方面,本发明的嵌合剂用于治疗一种或多种自身免疫性疾病或病症。在实施方案中,自身免疫性疾病或病症的治疗可以涉及用本发明的嵌合蛋白调节免疫系统以相对于免疫刺激有利于免疫抑制。可用本发明的嵌合蛋白治疗的例示性自身免疫性疾病或病症包括身体自身抗原成为免疫应答的靶标的那些疾病或病症,例如像类风湿性关节炎、系统性红斑狼疮、糖尿病、强直性脊柱炎、干燥综合征、炎性肠病(例如溃疡性结肠炎、克罗恩病)、多发性硬化症、结节病、牛皮癣、格雷夫氏病、桥本氏甲状腺炎、牛皮癣、过敏反应(例如过敏、花粉症、哮喘和急性水肿引起I型过敏反应)和血管炎。
在再一其他方面,本发明涉及治疗和预防T细胞介导的疾病和病症的方法,所述疾病和病症诸如但不限于本文其他地方描述的疾病或病症以及炎性疾病或病症、移植物抗宿主病(GVHD)、移植排斥和T 细胞增殖性障碍。
在一些方面,本发明的嵌合剂用于例如通过具有免疫刺激信号的细胞外结构域活化T细胞的方法中。
在一些方面,本发明的嵌合剂用于防止免疫抑制信号的细胞传递的方法中。
组合疗法和缀合
在实施方案中,本发明提供了嵌合蛋白和方法,所述方法还包括向受试者施用另外的剂。在实施方案中,本发明涉及共同施用和/ 或共制剂。本文所述的任何组合物可以共同配制和/或共同施用。
在实施方案中,本文所述的任何嵌合蛋白在与另一种剂共同施用时以协同方式起作用,并且以低于在此类剂用作单一疗法时通常采用的剂量进行施用。在实施方案中,本文提及的任何剂都可以与本文所述的任何嵌合蛋白组合使用。
在包括但不限于癌症应用的实施方案中,本发明涉及化学治疗剂作为另外的剂。化学治疗剂的实例包括但不限于烷化剂,诸如噻替哌和CYTOXAN环磷酰胺;烷基磺酸盐,诸如白消安、英丙舒凡 (improsulfan)和哌泊舒凡(piposulfan);氮丙啶,诸如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌 (uredopa);乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺、三乙烯三聚氰胺、三乙烯磷酰胺、三乙烯硫代磷酰胺和三羟甲基三聚氰胺;多聚乙酰(例如,布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包括合成类似物拓扑替康);苔藓抑素;卡莉他汀(callystatin);CC-1065 (包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);念珠藻素(例如,念珠藻素1和念珠藻素8);尾海兔素;多卡霉素(duocarmycin)(包括合成类似物KW-2189和CB 1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥,诸如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌氮芥、异环磷酰胺、盐酸氮芥(mechlorethamine)、盐酸甲氧氮芥、美法仑、新恩比兴、苯芥胆甾醇(phenesterine)、泼尼氮芥、三芥环磷酰胺、乌拉莫司汀;亚硝基脲类,诸如卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素,诸如烯二炔抗生素(例如,加利车霉素,特别是加利车霉素γ和加利车霉素ω(参见例如,Agnew,Chem.Intl.Ed.Engl.,33:183-186(1994));达内霉素,包括达内霉素A;二膦酸盐,诸如氯膦酸盐;拉霉素;以及新制癌菌素生色团和有关色蛋白烯二炔抗生素生色团)、阿克拉霉素、放射菌素、氨茴霉素、重氮丝氨酸、博来霉素、放线菌素C、卡柔比星、洋红霉素、嗜癌素、色霉素、放线菌素D、柔红霉素、地托比星、 6-重氮-5-氧代-L-正亮氨酸、ADRIAMYCIN阿霉素(包括吗啉-阿霉素、氰基吗啉-阿霉素、2-吡咯啉-阿霉素和脱氧阿霉素)、表阿霉素、依索比星、去甲氧基柔红霉素、麻西罗霉素、丝裂霉素(诸如丝裂霉素C)、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物,诸如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、甲氨喋呤、蝶罗呤、曲美沙特;嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如环胞苷、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他宾、氟尿苷;雄激素,诸如卡鲁睾酮、屈他雄酮丙酸酯、环硫雄醇、美雄烷、睾内脂;抗肾上腺素,诸如氨鲁米特(minoglutethimide)、米托担、曲洛司坦;叶酸补充物,诸如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;倍思塔布(bestrabucil);比山群;依达曲沙(edatraxate);地美可辛;地吖醌(diaziquone);依氟鸟氨酸;依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美登素类化合物,诸如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;硝胺;喷司他丁;苯来美特;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;甲基苄肼;PSK多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生;根霉菌素;西佐喃(sizofuran);锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2”-三氯三乙胺;单端孢霉烯(例如,T-2毒素、疣孢菌素A (verracurin A)、漆斑菌素A和蛇形毒素(anguidine));尿烷;长春地辛;达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加西托新(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷类,例如TAXOL紫杉醇(Bristol-Myers Squibb Oncology,Princeton, N.J.)、无氢化蓖麻油的ABRAXANE、紫杉醇的白蛋白工程化的纳米颗粒制剂(American Pharmaceutical Partners,Schaumberg,111.)和 TAXOTERE多烯紫杉醇(Rhone-Poulenc Rorer,Antony,France);苯丁酸氮芥;GEMZAR吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨喋呤;铂类似物,诸如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;NAVELBINE长春瑞滨;盐酸米托恩醌;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(Camptosar,CPT-11)(包括伊立替康与5-FU和甲酰四氢叶酸的治疗方案);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维生素A,诸如视黄酸;卡培他滨;康普瑞汀;甲酰四氢叶酸(LV);奥沙利铂,包括奥沙利铂治疗方案(FOLFOX);拉帕替尼(TYKERB);降低细胞增殖的PKC-α、Raf、H-Ras、EGFR(例如厄洛替尼(Tarceva))和VEGF-A的抑制剂以及以上任一种的药学上可接受的盐、酸或衍生物。此外,治疗方法还可以包括使用放射。此外,治疗方法还可以包括使用光动力治疗。
在包括但不限于癌症应用的实施方案中,本发明的另外的剂是一种或多种免疫调节剂,其选自阻断、降低和/或抑制PD-1和PD-L1 或PD-L2和/或PD-1与PD-L1或PD-L2的结合的剂(非限制性地例如以下中的一种或多种:纳武单抗(ONO-4538/BMS-936558、MDX1106、OPDIVO,BRISTOL MYERS SQUIBB)、派姆单抗(KEYTRUDA, Merck)、MK-3475(MERCK)、BMS936559(BRISTOL MYERS SQUIBB)、阿特珠单抗(TECENTRIQ,GENENTECH)、MPDL328OA(ROCHE)),增加和/或刺激CD137(4-1BB)和/或CD137(4-1BB)与一种或多种4-1BB配体的结合的剂(非限制性地例如,urelumab (BMS-663513和抗4-1BB抗体),以及阻断、降低和/或抑制CTLA-4 的活性和/或CTLA-4与AP2M1、CD80、CD86、SHP-2和PPP2R5A 中的一种或多种的结合和/或OX40与OX40L的结合的剂(非限制性地例如,GBR 830(GLENMARK)、MEDI6469(MEDIMMUNE))。
在包括但不限于感染性疾病应用的实施方案中,本发明涉及抗感染药物作为另外的剂。在实施方案中,抗感染药物是抗病毒剂,包括但不限于阿巴卡韦、阿昔洛韦、阿德福韦、安普那韦、阿扎那韦、西多福韦、地瑞那韦、地拉夫定、地达诺新、二十二烷醇、依法韦仑、埃替格韦、恩曲他滨、恩夫韦肽、依曲韦林、泛昔洛韦和膦甲酸。在实施方案中,抗感染药物是抗菌剂,包括但不限于,头孢菌素类抗生素(头孢氨苄、头孢呋辛、头孢羟氨苄、头孢唑啉、头孢噻吩、头孢克罗、头孢孟多、头孢西丁、头孢丙烯和头孢托罗);氟喹诺酮类抗生素(环丙沙星、左氟沙星、氧氟沙星、加替沙星、莫西沙星和诺氟沙星);四环素类抗生素(四环素、米诺环素、土霉素和多西环素);青霉素类抗生素(阿莫西林、氨苄西林、青霉素V、双氯青霉素、羧苄西林、万古霉素和甲氧西林);单环类抗生素(氨曲南);和碳青霉烯抗生素(厄他培南、多利培南、亚胺培南/西司他丁和美罗培南)。在实施方案中,抗感染药物包括抗疟疾剂(例如氯喹、奎宁、甲氟喹、伯氨喹、多西环素、蒿甲醚/苯芴醇、阿托夸酮/氯胍和磺胺多辛/乙胺嘧啶)、甲硝唑、替硝唑、伊维菌素、双羟萘酸噻嘧啶和阿苯达唑。
在包括但不限于自身免疫性疾病应用的实施方案中,另外的剂是免疫抑制剂。在实施方案中,免疫抑制剂是抗炎剂,诸如甾体抗炎剂或非甾体抗炎剂(NSAID)。类固醇,特别是肾上腺皮质类固醇及其合成类似物,是本领域熟知的。可用于本发明的皮质类固醇的实例包括但不限于羟基曲安西龙、α-甲基地塞米松、β-甲基倍他米松、二丙酸倍氯米松、苯甲酸倍他米松、二丙酸倍他米松、戊酸倍他米松、戊酸氯倍他索、羟泼尼缩松、去羟米松、地塞米松、双乙酸双氟拉松、戊酸双氟可龙、氟雄诺龙(fluadrenolone)、氟氯缩松、特戊酸氟米松、氟轻松缩丙酮(fluosinolone acetonide)、氟轻松乙酸酯、氟可丁酯 (flucortinebutylesters)、氟可龙(fluocortolone)、乙酸氟泼尼定 (fluprednidene/fluprednylidene)、氟氢缩松(flurandrenolone)、哈西奈德、乙酸氢化可的松、丁酸氢化可的松、甲基泼尼松龙、曲安奈德、可的松、可托多松、肤轻松(flucetonide)、氟氢可的松、双乙酸双氟若松 (difluorosone diacetate)、氟若卓龙缩丙酮(fluradrenoloneacetonide)、甲羟松、安西那飞、安西非特、倍他米松以及其平衡酯、氯泼尼松、可洛替龙(clocortelone)、可洛西龙(clescinolone)、双氯松、二氟泼尼酯、氟氯奈德(flucloronide)、氟尼缩松、氟米龙、氟培龙、氟泼尼龙、氢化可的松、甲泼尼松、帕拉米松、波尼松龙、泼尼松、二丙酸倍氯米松。可用于本发明的(NSAIDS)包括但不限于水杨酸、乙酰水杨酸、水杨酸甲酯、水杨酸乙二醇酯、水杨酰胺、苄基-2,5-二乙酰氧基苯甲酸、布洛芬、富林酸、萘普生、酮洛芬、依托芬那酯、保泰松和吲哚美辛。在实施方案中,免疫抑制剂可以是细胞抑制剂,诸如烷化剂、抗代谢物(例如,咪唑硫嘌呤、甲氨蝶呤)、细胞毒性抗生素、抗体(例如巴利昔单抗、达克珠单抗和莫罗单抗(muromonab))、抗免疫亲和素 (例如环孢菌素、他克莫司、西罗莫司)、干扰素、阿片类药物、TNF 结合蛋白、霉酚酸酯和小生物剂(例如,芬戈莫德、多球壳菌素 (myriocin))。
在实施方案中,本文所述的嵌合蛋白(和/或另外的剂)包括经修饰的衍生物,即通过任何类型的分子与组合物的共价连接,使得共价连接不会妨碍组合物的活性。例如但不限于,衍生物包括通过尤其是糖基化、脂化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知保护 /封闭基团的衍生化、蛋白水解性裂解、与细胞配体或其他蛋白质的连接等进行修饰的组合物。可以通过已知技术进行许多化学修饰中的任一种,所述技术包括但不限于特定的化学裂解、乙酰化、甲酰化、衣霉素(turicamycin)的代谢合成等。另外,衍生物可以含有一种或多种非经典氨基酸。在再其他实施方案中,本文所述的嵌合蛋白(和/或另外的剂)还包括细胞毒性剂,在例示性实施方案中,其包括毒素、化学治疗剂、放射性同位素以及引起细胞凋亡或细胞死亡的剂。此类剂可以与本文所述的组合物缀合。
因此本文所述的嵌合蛋白(和/或另外的剂)可以经翻译后修饰以添加效应子部分(诸如化学接头)、可检测部分(例如像荧光染料、酶、底物、生物发光物质、放射性物质和化学发光部分)、或功能性部分(例如像抗生蛋白链菌素、抗生物素蛋白、生物素、细胞毒素、细胞毒性剂和放射性物质)。
制剂
本文所述的嵌合蛋白(和/或另外的剂)可以具有足够的可以与无机酸或有机酸反应以形成药学上可接受的盐的碱性官能团,或者可以与无机碱或有机碱反应以形成药学上可接受的盐的羧基基团。药学上可接受的酸加成盐由药学上可接受的酸形成,如本领域已熟知的。此类盐包括例如以下中列出的药学上可接受的盐:Journal of PharmaceuticalScience,66,2-19(1977)和The Handbook of Pharmaceutical Salts;Properties,Selection,and Use.P.H.Stahl和C.G. Wermuth(编),Verlag,Zurich(Switzerland)2002,其特此以引用的方式整体并入。
在某些实施方案中,本文所述的组合物呈药学上可接受的盐的形式。
此外,本文所述的任何嵌合蛋白(和/或另外的剂)可以作为包含药学上可接受的载体或媒介物的组合物的组分向受试者施用。此类组合物可以任选地包含合适量的药学上可接受的赋形剂以便提供用于适当施用的形式。药物赋形剂可以是液体,诸如水和油,包括石油、动物、植物或者合成来源的那些,诸如花生油、大豆油、矿物油、芝麻油等等。药物赋形剂可以是例如盐水、阿拉伯树胶、明胶、淀粉糊、滑石、角蛋白、硅胶、尿素等等。此外,可以使用助剂、稳定剂、增稠剂、润滑剂以及着色剂。在一个实施方案中,当向受试者施用时,药学上可接受的赋形剂是无菌的。当静脉内施用本文所述的任何剂时,水是可用的赋形剂。盐溶液和葡萄糖水溶液以及甘油溶液也可以用作液体赋形剂,特别是对于可注射的溶液而言。合适的药物赋形剂还包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂乳粉、甘油、丙烯、乙二醇、水、乙醇等等。如果需要,本文所述的任何剂还可以包含少量的润湿剂或乳化剂或pH缓冲剂。
在实施方案中,本文所述的组合物重悬浮在盐水缓冲液(包括但不限于TBS、PBS等)中。
在实施方案中,嵌合蛋白可以通过与另一种剂缀合和/或融合来延长半衰期或以其他方式改善药效动力学和药代动力学特性。在实施方案中,嵌合蛋白可以与PEG、XTEN(例如,作为rPEG)、聚唾液酸(POLYXEN)、白蛋白(例如,人血清白蛋白或HAS)、弹性蛋白样蛋白(ELP)、PAS、HAP、GLK、CTP、转铁蛋白等等中的一种或多种融合或缀合。在实施方案中,每种个体嵌合蛋白与BioDrugs(2015) 29:215–239中描述的一种或多种剂融合,所述文献的全部内容特此以引用的方式并入。
施用、给药和治疗方案
本发明包括呈各种制剂形式的所述嵌合蛋白(和/或另外的剂)。本文所述的任何嵌合蛋白(和/或另外的剂)可以采取以下形式:溶液、悬浮剂、乳剂、滴剂、片剂、丸剂、微丸剂、胶囊、含有液体的胶囊、散剂、缓释制剂、栓剂、乳剂、气雾剂、喷雾剂、悬浮剂或适合使用的任何其他形式。也可以使用编码蛋白质序列的DNA或RNA构建体。在一个实施方案中,所述组合物呈胶囊的形式(参见例如,美国专利号5,698,155)。合适的药物赋形剂的其他实例描述于Remington’s Pharmaceutical Sciences 1447-1676(Alfonso R.Gennaro编,第19版,1995)中,其以引用的方式并入本文。
必要时,包含嵌合蛋白(和/或另外的剂)的制剂还可以包含增溶剂。另外,可以用本领域已知的合适的媒介物或递送装置来递送所述剂。本文概述的组合疗法可以在单个递送媒介物或递送装置中共同递送。用于施用的组合物可以任选地包含局部麻醉剂,例如像利多卡因,以减轻注射部位的疼痛。
包含本发明的嵌合蛋白(和/或另外的剂)的制剂可以方便地以单位剂量的形式提供并且可以通过制药领域所熟知的任何方法进行制备。此类方法一般包括使治疗剂与由一种或多种附加成分所构成的载体缔合的步骤。通常,通过将治疗剂均一且紧密地与液态载体、细化的固态载体或两者缔合,然后在必要时将产品成型为所需制剂的剂量形式(例如,湿法或干法制粒、粉末共混等,然后使用本领域已知的常规方法压片),来制备所述制剂。
在一个实施方案中,本文所述的任何嵌合蛋白(和/或另外的剂) 根据常规程序作为适合于本文所述的施用模式的组合物进行配制。
施用路径包括例如:皮内、肌肉内、腹膜内、静脉内、皮下、鼻内、硬膜外、口服、舌下、鼻内、脑内、阴道内、经皮、直肠、通过吸入、或局部,特别是施用到耳、鼻、眼、或皮肤。在实施方案中,所述施用通过口服或通过肠胃外注射实现。在大多数情况下,施用导致本文所述的任何剂释放到血液中。
本文所述的任何嵌合蛋白(和/或另外的剂)可以通过口服施用。此类嵌合蛋白(和/或另外的剂)也可以通过任何其他常规途径施用,例如通过静脉内输注或推注、通过经上皮或粘膜皮肤衬层(例如口腔粘膜、直肠和肠粘膜等)吸收,并且可以与另一种生物活性剂一起施用。施用可为全身性或局部的。不同递送系统为已知的,例如脂质体、微粒、微胶囊、胶囊等中的包囊化,并且可以用于施用。
在具体实施方案中,可能希望向需要治疗的区域局部施用。在一个实施方案中,例如在癌症的治疗中,嵌合蛋白(和/或另外的剂)在肿瘤微环境(例如,围绕肿瘤细胞和/或为肿瘤细胞提供营养的细胞、分子、细胞外基质和/或血管,其包括例如肿瘤脉管系统;肿瘤浸润淋巴细胞;成纤维细胞网状细胞;内皮祖细胞(EPC);癌症相关成纤维细胞;周细胞;其他基质细胞;细胞外基质(ECM)的组分;树突细胞;抗原呈递细胞;T细胞;调节T细胞;巨噬细胞;嗜中性粒细胞;和位于肿瘤附近的其他免疫细胞)或淋巴结中进行施用并且/或者靶向肿瘤微环境或淋巴结。在实施方案中,例如在癌症的治疗中,嵌合蛋白 (和/或另外的剂)在肿瘤内施用。
在各种实施方案中,本发明的嵌合蛋白允许双重效果,其提供的副作用比常规免疫疗法(例如,使用OPDIVO、KEYTRUDA、YERVOY 和TECENTRIQ中的一种或多种的治疗)中所见的更少。例如,本发明的嵌合蛋白降低或预防通常观察到的影响各种组织和器官的免疫相关不良事件,所述组织和器官包括皮肤、胃肠道、肾脏、外周和中枢神经系统、肝脏、淋巴结、眼睛、胰腺和内分泌系统;所述免疫相关不良事件诸如垂体炎、结肠炎、肝炎、肺炎、皮疹和风湿性疾病。此外,本发明的局部施用,例如肿瘤内施用,避免了与常规免疫疗法 (例如,使用OPDIVO、KEYTRUDA、YERVOY和TECENTRIQ中的一种或多种的治疗)一起使用时标准全身施用(例如静脉内输注)中所见的不良事件。
适用于肠胃外施用(例如,静脉内、肌肉内、腹膜内、皮下和关节内注射和输注)的剂型包括例如溶液、悬浮剂、分散体、乳剂等。它们也可以制造成无菌固体组合物(例如,冻干组合物)的形式,其可以在即将使用前溶解或悬浮在无菌可注射介质中。它们可以含有例如本领域已知的悬浮剂或分散剂。
本文所述的任何嵌合蛋白(和/或另外的剂)的剂量以及给药方案可以取决于各种参数,其包括但不限于所治疗的疾病、受试者的一般健康状况和施用医师的判断。可以在向有需要的受试者施用另外的剂之前(例如,之前5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、 1周、2周、3周、4周、5周、6周、8周或12周)、同时、或之后(例如,之后5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、 2周、3周、4周、5周、6周、8周或12周)施用本文所述的任何嵌合蛋白。在实施方案中,本文所述的任何嵌合蛋白和另外的剂的施用间隔1分钟、间隔10分钟、间隔30分钟、间隔小于1小时、间隔1 小时、间隔1小时至2小时、间隔2小时至3小时、间隔3小时至4 小时、间隔4小时至5小时、间隔5小时至6小时、间隔6小时至7 小时、间隔7小时至8小时、间隔8小时至9小时、间隔9小时至 10小时、间隔10小时至11小时、间隔11小时至12小时、间隔1 天、间隔2天、间隔3天、间隔4天、间隔5天、间隔6天、间隔1 周、间隔2周、间隔3周、或间隔4周。
在实施方案中,本发明涉及诱导先天免疫应答的嵌合蛋白以及诱导适应性免疫应答的另一种嵌合蛋白的共同施用。在此类实施方案中,诱导先天免疫应答的嵌合蛋白可以在施用诱导适应性免疫应答的嵌合蛋白之前、同时或之后施用。例如,嵌合蛋白的施用可以间隔1 分钟、间隔10分钟、间隔30分钟、间隔小于1小时、间隔1小时、间隔1小时至2小时、间隔2小时至3小时、间隔3小时至4小时、间隔4小时至5小时、间隔5小时至6小时、间隔6小时至7小时、间隔7小时至8小时、间隔8小时至9小时、间隔9小时至10小时、间隔10小时至11小时、间隔11小时至12小时、间隔1天、间隔2 天、间隔3天、间隔4天、间隔5天、间隔6天、间隔1周、间隔2 周、间隔3周、或间隔4周。在例示性实施方案中,诱导先天免疫应答的嵌合蛋白和诱导适应性应答的嵌合蛋白间隔1周施用,或者在隔周施用(即,施用诱导先天免疫应答的嵌合蛋白1周后施用诱导适应性免疫应答的嵌合蛋白,等等)。
本文所述的任何嵌合蛋白(和/或另外的剂)的剂量可以取决于若干种因素,其包括病状的严重性,病状是否被治疗或预防以及待治疗的受试者的年龄、体重和健康。另外,关于具体受试者的药物基因组 (基因型对治疗剂的药代动力学、药效动力学或功效的曲线的作用)信息可以影响所使用的剂量。此外,精确的个体剂量可以根据多种因素稍微调整,所述因素包括正在施用的剂的特定组合、施用的时间、施用的路径、制剂的性质、排泄的速率、所治疗的特定疾病、病症的严重性以及病症的解剖学位置。可以预期一些剂量变化。
对于通过肠胃外注射施用本文所述的任何嵌合蛋白(和/或另外的剂),剂量可以是每天约0.1mg至约250mg、每天约1mg至约20mg、或每天约3mg至约5mg。一般来讲,当通过口服或肠胃外施用时,本文所述的任何剂的剂量可以是每天约0.1mg至约1500mg、或每天约0.5mg至约10mg、或每天约0.5mg至约5mg、或每天约200至约1,200mg(例如,每天约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1,000mg、约1,100 mg、约1,200mg)。
在实施方案中,本文所述的嵌合蛋白(和/或另外的剂)的施用是通过肠胃外注射,其剂量为每次治疗约0.1mg至约1500mg、或每次治疗约0.5mg至约10mg、或每次治疗约0.5mg至约5mg、或每次治疗约200至约1,200mg(例如,每次治疗约200mg、约300mg、约 400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1,000mg、约1,100mg、约1,200mg)。
在实施方案中,嵌合蛋白(和/或另外的剂)的合适剂量在约0.01 mg/kg至约100mg/kg体重、或约0.01mg/kg至约10mg/kg受试者体重的范围内,例如,约0.01mg/kg、约0.02mg/kg、约0.03mg/kg、约0.04mg/kg、约0.05mg/kg、约0.06mg/kg、约0.07mg/kg、约0.08mg/kg、约0.09mg/kg、约0.1mg/kg、约0.2mg/kg、约0.3mg/kg、约0.4mg/kg、约0.5mg/kg、约0.6mg/kg、约0.7mg/kg、约0.8mg/kg、约0.9mg/kg、约1mg/kg、约1.1mg/kg、约1.2mg/kg、约1.3mg/kg、约1.4mg/kg、约1.5mg/kg、约1.6mg/kg、约1.7mg/kg、约1.8mg/kg、 1.9mg/kg、约2mg/kg、约3mg/kg、约4mg/kg、约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg体重,包括它们之间的所有值和范围。
在另一个实施方案中,递送可以是在囊泡中,具体地是在脂质体中(参见,Langer,1990,Science 249:1527-1533;Treat等,in Liposomes in therapy of InfectiousDisease and Cancer,Lopez-Berestein 和Fidler(编),Liss,New York,第353-365页(1989)。
本文所述的任何嵌合蛋白(和/或另外的剂)可以通过控释或缓释方式或者通过本领域普通技术人员熟知的递送装置进行施用。实例包括但不限于美国专利号:3,845,770;3,916,899;3,536,809;3,598,123; 4,008,719;5,674,533;5,059,595;5,591,767;5,120,548;5,073,543; 5,639,476;5,354,556;和5,733,556中所述的那些;所述专利中各自以引用的方式并入本文。此类剂型可以适用于使用例如羟丙基甲基纤维素、其他聚合物基质、凝胶、可渗透性膜、渗透系统、多层包衣、微粒、脂质体、微球体或其组合来提供一种或多种活性成分的控释或缓释,从而以不同比例提供所需的释放曲线。活性成分的控释或缓释可以通过各种条件来刺激,所述条件包括但不限于pH的变化、温度的变化、通过适当波长的光的刺激、酶的浓度或利用度、水的浓度或利用度或者其他生理学条件或化合物。
在另一个实施方案中,可以使用聚合材料(参见Medical Applications ofControlled Release,Langer和Wise(编),CRC Pres., Boca Raton,Florida(1974);Controlled Drug Bioavailability,Drug Product Design and Performance,Smolen和Ball(编),Wiley,New York (1984);Ranger和Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61;还参见Levy等,1985,Science 228:190; During等,1989,Ann.Neurol.25:351;Howard等,1989,J. Neurosurg.71:105)。
在另一个实施方案中,控释系统可以放置在待治疗的靶标区域附近,由此仅需要全身剂量的一部分(参见例如,Goodson,在 Medical Applications of ControlledRelease中,同上,第2卷,第 115-138页(1984))。可以使用在综述Langer,1990,Science249:1527-1533)中讨论的其他控释系统。
本文所述的任何嵌合蛋白(和/或另外的剂)的施用可以独立地为每天一至四次,或每月一至四次,或每年一至六次,或者每两年、三年、四年或五年一次。施用可以持续一天或一个月、两个月、三个月、六个月、一年、两年、三年的持续时间,并且可以甚至持续受试者的一生。
利用本文所述的任何嵌合蛋白(和/或另外的剂)的给药方案可以根据多种因素进行选择,所述因素包括受试者的类型、种族、年龄、体重、性别以及医学病状;待治疗的病状的严重性;施用的路径;受试者的肾功能或肝功能;个体的药物基因组组成;以及所采用的本发明的特定化合物。本文所述的任何嵌合蛋白(和/或另外的剂)可以单一日剂量进行施用,或者总日剂量可以每日两次、三次或四次的分剂量进行施用。此外,本文所述的任何嵌合蛋白(和/或另外的剂)可以贯穿剂量方案连续地而不是间歇地进行施用。
细胞和核酸
在实施方案中,本发明提供了一种表达载体,其包含编码本文所述的嵌合蛋白的核酸。在实施方案中,表达载体包含DNA或RNA。在实施方案中,表达载体是哺乳动物表达载体。
原核载体和真核载体均可以用于表达嵌合蛋白。原核载体包括基于大肠杆菌序列的构建体(参见例如,Makrides,Microbiol Rev 1996, 60:512-538)。可以用于在大肠杆菌中表达的调节区的非限制性实例包括lac、trp、lpp、phoA、recA、tac、T3、T7和λPL。原核表达载体的非限制性实例可以包括λgt载体系列诸如如λgt11(Huynh等,在“DNA CloningTechniques,Vol.I:A Practical Approach,”中1984,(D. Glover编),第49-78页,IRLPress,Oxford),以及pET载体系列(Studier 等,Methods Enzymol 1990,185:60-89)。然而,原核宿主-载体体系不能对哺乳动物细胞进行大量的翻译后加工。因此,真核宿主-载体体系可能特别有用。多种调节区可以用于在哺乳动物宿主细胞中表达嵌合蛋白。例如,可以使用SV40早期和晚期启动子、巨细胞病毒(CMV) 立即早期启动子和劳斯肉瘤病毒长末端重复序列(RSV-LTR)启动子。可以用于哺乳动物细胞的诱导型启动子包括但不限于与金属硫蛋白 II基因、小鼠乳腺肿瘤病毒糖皮质激素反应性长末端重复序列 (MMTV-LTR)、β-干扰素基因和hsp70基因相关的启动子(参见, Williams等,Cancer Res 1989,49:2735-42;和Taylor等,Mol Cell Biol 1990,10:165-75)。热休克启动子或应激启动子也可能有利于驱动重组宿主细胞中嵌合蛋白的表达。
在实施方案中,本发明的表达载体包含编码嵌合蛋白(和/或另外的剂)的核酸或其互补物,其可操作地连接到在哺乳动物细胞中是功能性的表达控制区或其互补物。表达控制区能够驱动可操作地连接的阻断剂和/或刺激剂编码核酸的表达,使得在经所述表达载体转化的人细胞中产生所述阻断剂和/或刺激剂。
表达控制区是影响可操作地连接的核酸的表达的调节聚核苷酸( 在本文中有时称为元件),诸如启动子和增强子。本发明的表达载体的表达控制区能够使可操作地连接的编码核酸在人细胞中表达。在一个实施方案中,细胞是肿瘤细胞。在另一个实施方案中,细胞是非肿瘤细胞。在实施方案中,表达控制区使得可操作地连接的核酸的表达可调节。信号(有时称为刺激物)可以增加或减少可操作地连接到这种表达控制区的核酸的表达。响应于信号而增加表达的此类表达控制区通常称为诱导性。响应于信号而减少表达的此类表达控制区通常称为阻遏性。通常,由此类元件所赋予的增加或减少的量与所存在信号的量成比例;信号量越大,表达的增加或减少越大。
在实施方案中,本发明考虑使用能够响应于提示瞬时实现高水平表达的诱导型启动子。例如,当与肿瘤细胞接近时,通过将转化细胞暴露于适当的提示,诱导经包含这种表达控制序列的嵌合蛋白( 和/或另外的剂)的表达载体转化的细胞,以瞬时产生高水平的剂。例示性诱导型表达控制区包括包含用提示(诸如小分子化合物)刺激的诱导型启动子的诱导型表达控制区。具体的实例可以见于,例如,美国专利号5,989,910、5,935,934、6,015,709和6,004,941中,所述专利各自以引用的方式整体并入本文。
表达控制区和基因座控制区包括全长启动子序列(诸如天然启动子和增强子元件),以及保留全部或部分全长或非变异型功能的子序列或聚核苷酸变体。如本文所用,术语“功能性”和其语法变体当在提及核酸序列、子序列或片段的情况下使用时,意指所述序列具有天然核酸序列(例如非变异型或未修饰序列)的一种或多种功能。
如本文所用,“可操作的连接”是指所述组分的实体并置关系允许其以预定方式起作用。在表达控制元件与核酸可操作地连接的实例中,所述关系使得控制元件调节所述核酸的表达。通常,调节转录的表达控制区并置于所转录核酸的5'端附近(即“上游”)。表达控制区还可以位于所转录序列的3'端(即“下游”)或在转录物内(例如在内含子中)。表达控制元件可以位于离所转录序列一定距离处(例如离所述核酸100至500、500至1000、2000至5000或更多个核苷酸)。表达控制元件的特定实例是启动子,其通常位于所转录序列的5'。表达控制元件的另一个实例是增强子,其可以位于所转录序列的5'或3' ,或在所转录序列的内部。
在人细胞中具功能性的表达体系在本领域中是熟知的,并且包括病毒体系。一般来讲,在人细胞中具功能性的启动子是能够结合哺乳动物RNA聚合酶并起始下游(3')编码序列转录成mRNA的任何 DNA序列。启动子将具有转录起始区,其通常置于编码序列5'端附近,并且TATA盒通常位于转录起始位点上游25-30个碱基对处。认为TATA盒引导RNA聚合酶II在正确位点开始RNA合成。启动子通常还含有上游启动子元件(增强子元件),其通常位于TATA盒上游 100至200个碱基对内。上游启动子元件决定转录起始速率并且可以任何取向起作用。来自哺乳动物病毒基因的启动子特别适合用作启动子,因为病毒基因通常是高表达的并且具有广泛的宿主范围。实例包括SV40早期启动子、小鼠哺乳动物肿瘤病毒LTR启动子、腺病毒主要晚期启动子、单纯疱疹病毒启动子和CMV启动子。
通常,由哺乳动物细胞识别的转录终止和聚腺苷酸化序列是位于转录终止密码子3'的调节区,并且因此连同启动子元件一起侧接编码序列。成熟mRNA的3'末端由位点特异性翻译后裂解和聚腺苷酸化形成。转录终止子和聚腺苷酸化信号的实例包括来源于SV40的那些。表达构建体中还可以包括内含子。
存在多种可用于将核酸引入活细胞中的技术。适用于在体外将核酸转移至哺乳动物细胞中的技术包括使用脂质体、电穿孔、微注射、细胞融合、基于聚合物的体系、DEAE-葡聚糖、病毒转导、磷酸钙沉淀法等。对于体内基因转移,也可以使用多种技术和试剂,包括脂质体;基于天然聚合物的递送媒介物,诸如壳聚糖和明胶;病毒载体也适用于体内转导。在一些情况下,希望提供靶向剂,诸如对于肿瘤细胞表面膜蛋白具有特异性的抗体或配体。在采用脂质体的情况下,结合与内吞作用相关联的细胞表面膜蛋白的蛋白质可以用于靶向和/或促进摄取,例如亲近特定细胞类型的衣壳蛋白或其片段、在循环中进行内化的蛋白质的抗体、靶向细胞内定位并增强细胞内半衰期的蛋白质。例如,受体介导的内吞作用的技术描述于,例如,Wu等,J.Biol. Chem.262,4429-4432(1987);和Wagner等,Proc.Natl.Acad.Sci.USA 87,3410-3414(1990)。
适当时,还可以采用基因递送剂,例如像整合序列。许多整合序列在本领域中是已知的(参见例如,Nunes-Duby等,Nucleic Acids Res.26:391-406,1998;Sadwoski,J.Bacteriol.,165:341-357,1986; Bestor,Cell,122(3):322-325,2005;Plasterk等,TIG15:326-332,1999; Kootstra等,Ann.Rev.Pharm.Toxicol.,43:413-439,2003)。这些包括重组酶和转座酶。实例包括Cre(Sternberg和Hamilton,J.Mol.Biol., 150:467-486,1981)、λ(lambda)(Nash,Nature,247,543-545,1974)、Flp (Broach,等,Cell,29:227-234,1982)、R(Matsuzaki,等,J.Bacteriology, 172:610-618,1990)、cpC31(参见例如,Groth等,J. Mol.Biol.335:667-678,2004)、mariner家族的转座子睡美人(sleeping beauty)(Plasterk等,同上)以及用于整合病毒(诸如AAV、逆转录病毒和抗病毒)的部件,其具有提供病毒整合的部件,诸如逆转录病毒或慢病毒的LTR序列和AAV的ITR序列(Kootstra等,Ann.Rev. Pharm.Toxicol.,43:413-439,2003)。此外,可以使用直接和靶向遗传整合策略来插入编码嵌合蛋白的核酸序列,所述策略包括 CRISPR/CAS9、锌指、TALEN和大范围核酸酶基因编辑技术。
在一方面,本发明提供用于表达嵌合蛋白(和/或另外的剂)的表达载体,其为病毒载体。许多可用于基因疗法的病毒载体是已知的(参见例如,Lundstrom,TrendsBiotechnol.,21:1 17,122,2003。例示性病毒载体包括选自抗病毒(LV)、逆转录病毒(RV)、腺病毒(AV)、腺相关病毒(AAV)和α病毒的载体,但是也可以使用其他病毒载体。对于体内用途,适合使用不整合到宿主基因组中的病毒载体,诸如α病毒和腺病毒。α病毒的例示性类型包括辛德毕斯病毒(Sindbis virus)、委内瑞拉马脑炎(Venezuelan equineencephalitis;VEE)病毒和塞姆利基森林病毒(Semliki Forest virus;SFV)。对于体外使用,整合到宿主基因组中的病毒载体是合适的,诸如逆转录病毒、AAV和抗病毒。在一个实施方案中,本发明提供体内转导人细胞的方法,其包括在体内使实体肿瘤与本发明的病毒载体接触。
在实施方案中,本发明提供一种宿主细胞,其包含表达载体,所述表达载体包含本文所述的嵌合蛋白。
可以将表达载体引入宿主细胞中,用于产生本发明的嵌合蛋白。例如,可以在体外培养细胞或对细胞进行遗传工程化。可用的哺乳动物宿主细胞包括但不限于衍生自人、猴和啮齿动物的细胞(参见例如, Kriegler在“Gene Transfer and Expression:ALaboratory Manual,”中 1990,New York,Freeman&Co.)。这些包括由SV40转化的猴肾细胞系(例如,COS-7、ATCC CRL 1651);人胚胎肾细胞系(例如,293、 293-EBNA或用于悬浮培养生长的亚克隆的293细胞,Graham等,J Gen Virol 1977,36:59);幼仓鼠肾细胞(例如,BHK、ATCC CCL 10);中国仓鼠卵巢细胞-DHFR(例如,CHO,Urlaub和Chasin,Proc Natl Acad SciUSA 1980,77:4216);DG44 CHO细胞、CHO-K1细胞、小鼠塞托利细胞(Mather,Biol Reprod1980,23:243-251);小鼠成纤维细胞 (例如,NIH-3T3)、猴肾细胞(例如,CV1 ATCC CCL70);非洲绿猴肾细胞(例如,VERO-76、ATCC CRL-1587);人宫颈癌细胞(例如, HELA、ATCCCCL 2);犬肾细胞(例如,MDCK、ATCC CCL 34);布法罗大鼠肝细胞(例如,BRL 3A、ATCC CRL1442);人肺细胞(例如,W138、ATCC CCL 75);人肝细胞(例如,Hep G2、HB 8065);和小鼠乳腺肿瘤细胞(例如,MMT 060562、ATCC CCL51)。用于表达本文所述的嵌合蛋白的例示性癌细胞类型包括小鼠成纤维细胞系 NIH3T3、小鼠Lewis肺癌细胞系LLC、小鼠肥大细胞瘤细胞系P815、小鼠淋巴瘤细胞系EL4及其卵清蛋白转染子E.G7、小鼠黑色素瘤细胞系B16F10、小鼠纤维肉瘤细胞系MC57以及人小细胞肺癌细胞系 SCLC#2和SCLC#7。
宿主细胞可以从正常受试者或受影响的受试者(包括健康人、癌症患者以及患有感染性疾病的患者)、私人实验室存储物、诸如美国典型培养物保藏中心(American TypeCulture Collection)的公共培养物收集物、或商业供应商获得。
可以用于体外、离体和/或体内产生本发明的嵌合蛋白的细胞包括但不限于上皮细胞、内皮细胞、角质细胞、成纤维细胞、肌细胞、肝细胞;血细胞诸如T淋巴细胞、B淋巴细胞、单核细胞、巨噬细胞、嗜中性粒细胞、嗜酸性粒细胞、巨核细胞、粒细胞;各种干细胞或祖细胞,特别是造血干细胞或祖细胞(例如,从骨髓、脐带血、外周血、胎肝等获得)。细胞类型的选择取决于所治疗或预防的肿瘤或感染性疾病的类型,并且可以由本领域技术人员确定。
含Fc的大分子(诸如单克隆抗体)的产生和纯化已成为标准化过程,其中产物之间具有微小修改。例如,许多含Fc的大分子由人胚胎肾(HEK)细胞(或其变体)或者中国仓鼠卵巢(CHO)细胞(或其变体) 产生,或者在某些情况下通过细菌或合成方法产生。产生之后,由HEK或CHO细胞分泌的含Fc的大分子通过与蛋白A柱结合进行纯化,并且随后使用各种方法‘抛光’。一般来讲,纯化的含Fc的大分子以液体形式储存一段时间、冷冻较长时间或在一些情况下冻干。在实施方案中,与传统的含Fc的大分子相比,本文考虑的嵌合蛋白的产生可以具有独特的特征。在某些实例中,可以使用特定的色谱树脂或使用不依赖于蛋白A捕获的色谱方法来纯化嵌合蛋白。在实施方案中,嵌合蛋白可以寡聚状态或多种寡聚状态进行纯化,并使用特定方法富集特定的寡聚状态。不受理论束缚,这些方法可以包括用特定缓冲液处理,其包括指定的盐浓度、pH和添加剂组成。在其他实例中,此类方法可以包括相对于一种寡聚状态有利于另一种寡聚状态的处理。可以使用本领域指定的方法另外‘抛光'本文获得的嵌合蛋白。在实施方案中,嵌合蛋白是高度稳定的并且能够耐受广泛的pH暴露(在 pH 3-12之间),能够耐受大量的冻/融应力(大于3个冷冻/解冻循环) 并且能够耐受在高温下的延长温育(在40摄氏度下长于2周)。在实施方案中,示出嵌合蛋白在此类应力条件下保持完整,没有降解、脱酰胺等迹象。
受试者和/或动物
在实施方案中,受试者和/或动物是哺乳动物,例如人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪、兔、绵羊或非人灵长类动物,诸如猴、黑猩猩或狒狒。在实施方案中,受试者和/或动物是非哺乳动物,例如像斑马鱼。在实施方案中,受试者和/或动物可以包含荧光标记的细胞(例如用GFP)。在实施方案中,受试者和/或动物是包含荧光细胞的转基因动物。
在实施方案中,受试者和/或动物是人。在实施方案中,人是幼儿。在实施方案中,人是成人。在实施方案中,人是老年人。在实施方案中,人可以称为患者。
在某些实施方案中,人的年龄范围为约0个月至约6个月、约6 至约12个月、约6至约18个月、约18至约36个月、约1至约5岁、约5至约10岁、约10至约15岁、约15至约20岁、约20至约25 岁、约25至约30岁、约30至约35岁、约35至约40岁、约40至约45岁、约45至约50岁、约50至约55岁、约55至约60岁、约 60至约65岁、约65至约70岁、约70至约75岁、约75至约80岁、约80至约85岁、约85至约90岁、约90至约95岁或约95至约100 岁。
在实施方案中,受试者是非人动物,并且因此本发明涉及兽医用途。在一个具体实施方案中,非人动物是家庭宠物。在另一个具体实施方案中,非人动物是家畜动物。
试剂盒
本发明提供了可以简化本文所述的任何剂的施用的试剂盒。本发明的例示性试剂盒包含单位剂型的本文所述的任何组合物。在一个实施方案中,单位剂型是容器,诸如预填充注射器,其可以是无菌的,含有本文所述的任何剂和药学上可接受的载体、稀释剂、赋形剂或媒介物。试剂盒可以进一步包含指示本文所述的任何剂的使用的标签或印刷说明书。试剂盒还可以包含开睑器、局部麻醉剂和用于施用位置的清洁剂。试剂盒还可以进一步包含一种或多种本文所述的另外的剂。在一个实施方案中,试剂盒包含容器,其含有有效量的本发明的组合物和有效量的另一种组合物,诸如本文所述的那些组合物。
本文描述的任何方面或实施方案都可以与如本文所公开的任何其他方面或实施方案结合
本发明将在以下实施例中进一步描述,这些实施例不限制权利要求书中所述的本发明范围。
实施例
实施例1:TIGIT-Fc-OX40L嵌合蛋白的表征
在此实施例中,以生物化学和功能性方式表征包含TIGIT和 OX40L结构域的嵌合蛋白。
制备鼠TIGIT-Fc-OX40L嵌合蛋白和人TIGIT-Fc-OX40L嵌合蛋白;其示意图在图3A和图3B的顶部示出。在还原条件下,用N+O 去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上分离 mTIGIT-Fc-OX40L和hTIGIT-Fc-OX40L嵌合蛋白。 mTIGIT-Fc-OX40L和hTIGIT-Fc-OX40L嵌合蛋白的蛋白质印迹指示在非还原泳道中存在占优势的二聚体条带(图3A和图3B,每个印迹中的泳道2),其在还原剂β-巯基乙醇的存在下被还原为糖基化的单体条带(图3A和图3B,每个印迹中的泳道3)。如图3A和图3B每个印迹中的泳道3所示,在还原剂(β-巯基乙醇)和内切糖苷酶(PNGase)两者的存在下,嵌合蛋白作为单体分离。
然后测定mTIGIT-Fc-OX40L嵌合蛋白和hTIGIT-Fc-OX40L嵌合蛋白的结合亲和力。对于每种嵌合蛋白,在以下条件下进行ELISA:重+轻链捕获并用Fc-HRP检测(图4A和图4B,顶部左侧), CD155/PVR-His捕获并用IgG检测(图4A和图4B,顶部右侧),以及 OX40-His捕获并用针对mOX40L的抗体检测(图4A和图4B,底部左侧)。将mTIGIT-Fc-OX40L嵌合蛋白用OX40-Fc捕获并用重组 CD155检测(图4A,底部右侧,“双重ELISA”),并且将 hTIGIT-Fc-OX40L嵌合蛋白用OX40-Fc捕获并用重组CD155、CD112 或CD113蛋白检测(图4A,底部右侧,“双重ELISA”)。这些数据指示mTIGIT-Fc-OX40L嵌合蛋白和hTIGIT-Fc-OX40L嵌合结合其靶标中的每个,并且可以同时结合两个靶标。
实施另外的分析以确定mTIGIT-Fc-OX40L嵌合蛋白是否可以结合其在活细胞表面上的靶标。生成细胞系以过表达人PVR(即, CHOK1/PVR);这些细胞可用于检测含有TIGIT的构建体与细胞膜相关PVR的结合。参见图5A。生成细胞系以过表达结合素-2(即, CHOK1/结合素2);这些细胞可用于检测含有TIGIT的构建体与细胞膜相关结合素-2的结合。参见图5B。生成细胞系以过表达结合素-3 (即,CHOK1/结合素3);这些细胞可用于检测含有TIGIT的构建体与细胞膜相关结合素-3的结合。参见图5C。制备过表达mOX40(即, CHOK1-mOX40)的另一种细胞系。每种细胞系基于中国仓鼠卵巢K1 (CHOK1)。
将mTIGIT-Fc-OX40L嵌合蛋白或mPD-1-Fc-OX40L嵌合蛋白与亲本和过表达细胞系一起温育2小时。将细胞收集,洗涤并用抗体染色,用于通过流式细胞术检测嵌合蛋白结合。如图6所示(底部左侧和右侧),并且如所预期,嵌合蛋白不以嵌合蛋白的任何浓度结合亲本细胞系。然而,mTIGIT-Fc-OX40L以浓度依赖性方式结合 CHOK1/PVR工程化细胞系;基于此数据,计算的EC50值为4.634nM。参见图6(顶部左侧)。相比之下,mPD-1-Fc-OX40L不与任何工程化细胞系结合。与CHOK1/PVR工程化细胞系一样,mTIGIT-Fc-OX40L 嵌合蛋白也以浓度依赖性方式结合CHOK1-mOX40工程化细胞系;基于此数据,计算的EC50值为1.7nM。参见图6(右侧)。这些数据指示嵌合蛋白的不同组分各自能够结合其各自在活细胞上的受体/配体。
接下来实施微阵列筛选以进一步鉴定hTIGIT-Fc-OX40L的结合配偶体。图7是示出来自微阵列(含有约6,000个人膜蛋白)的 hTIGIT-Fc-OX40L的鉴定的结合配偶体的结果的表。通过筛选鉴定 hTIGIT-Fc-OX40L的每个预期的结合配偶体。没有证据显示与其他人蛋白的非特异性结合,并且在所有含有Fc的融合蛋白的筛选中看到与Galectin-1的结合。
实施例2:CD172a(SIRPα)-Fc-LIGHT嵌合蛋白的表征
在此实施例中,以生物化学和功能性方式表征包含LIGHT和 CD172a(SIRPα)结构域的嵌合蛋白。
制备鼠CD172a(SIRPα)-Fc-LIGHT嵌合蛋白和人 CD172a(SIRPα)-Fc-LIGHT嵌合蛋白;其示意图在图8A和图8B的顶部示出。在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上分离mCD172a(SIRPα)-Fc-LIGHT和 hCD172a(SIRPα)-Fc-LIGHT嵌合蛋白。mCD172a(SIRPα)-Fc-LIGHT 和hCD172a(SIRPα)-Fc-LIGHT嵌合蛋白的蛋白质印迹指示在非还原泳道中存在占优势的二聚体条带(图8A和图8B,每个印迹中的泳道 2),其在还原剂β-巯基乙醇的存在下被还原为糖基化的单体条带(图 8A和图8B,每个印迹中的泳道3)。如图8A和图8B每个印迹中的泳道3所示,在还原剂(β-巯基乙醇)和内切糖苷酶(PNGase)两者的存在下,嵌合蛋白作为单体分离。
然后测定mCD172a(SIRPα)-Fc-LIGHT嵌合蛋白和 hCD172a(SIRPα)-Fc-LIGHT嵌合蛋白的结合亲和力。对于每种嵌合蛋白,在以下条件下进行ELISA:重+轻链捕获并用Fc-HRP检测(图9A 和图9B,顶部左侧),CD47-His捕获并用IgG检测(图9A和图9B,顶部右侧),鼠LTBR-His捕获并用针对鼠LIGHT的抗体检测(图9A,底部左侧)或人LTBR-His捕获并用针对人LIGHT的抗体检测(图9B,底部左侧),以及LTBR His+GST捕获并用针对SIRPα的抗体检测(图9A和图9B,底部右侧,“双重ELISA”)。这些数据指示 mCD172a(SIRPα)-Fc-LIGHT嵌合蛋白和hCD172a(SIRPα)-Fc-LIGHT 嵌合结合其靶标中的每个,并且可以同时结合两个靶标。
实施另外的分析以确定mCD172a(SIRPα)-Fc-LIGHT嵌合蛋白是否可以结合其在活细胞表面上的靶标。制备表达鼠CD47的CHO-K1 细胞(图10A,左侧)或表达鼠LTbR的CHO-K1细胞(图10A,右侧)。
将mCD172a(SIRPα)-Fc-LIGHT嵌合蛋白与亲本和过表达细胞系一起温育2小时。将细胞收集,洗涤并用抗体染色,用于通过流式细胞术检测嵌合蛋白结合。如图10A所示(左侧),并且如所预期,嵌合蛋白不以嵌合蛋白的任何浓度结合亲本细胞系。然而, mCD172a(SIRPα)-Fc-LIGHT以浓度依赖性方式结合mCD47工程化细胞系(图10A,左侧)和mLTbR工程化细胞系(图10A,右侧);基于此数据,计算的CD47的EC50值为18nM,并且mCD172a(SIRPα)的EC50值为24nM。另外,将hCD172a(SIRPα)-Fc-LIGHT嵌合蛋白与mCD47 过表达细胞系一起温育。hCD172a(SIRPα)-Fc-LIGHT以浓度依赖性方式结合mCD47工程化细胞系(图10B);基于此数据,计算的EC50值为57nM。这些数据指示嵌合蛋白的不同组分各自能够结合其各自在活细胞上的受体/配体。
然后测试人TIGIT-Fc-OX40L嵌合蛋白不与红细胞结合并由此引起溶血的能力。在此,使hCD172a(SIRPα)-Fc-LIGHT、 hCD172a(SIRPα)-Fc-CD40或CD47特异性抗体(克隆CC2C6或 CC900002)与食蟹猴红细胞(RBC,图11A,左侧顶部和底部)或人RBC (图11B和图11C,所有图)接触。当与用Triton-X的处理(作为阳性对照)相比时,hCD172a(SIRPα)-Fc-LIGHT和 hCD172a(SIRPα)-Fc-CD40均不引起食蟹猴RBC的显著裂解(图11A,底部左侧);示出示例性平板(图11A,右侧)。 hCD172a(SIRPα)-Fc-LIGHT和hCD172a(SIRPα)-Fc-CD40均不与人 RBC显著结合(图11B,所有图)。当与用Triton-X的处理(作为阳性对照)相比时,hCD172a(SIRPα)-Fc-LIGHT或 hCD172a(SIRPα)-Fc-CD40引起几乎不可检测水平的人RBC裂解(图 11C,所有图);示出示例性平板(图11C,右侧)。这些数据指示 hCD172a(SIRPα)-Fc-LIGHT和hCD172a(SIRPα)-Fc-CD40不会引起人 RBC的溶血作为不希望的副作用。
实施例3:PD-1-Fc-LIGHT嵌合蛋白的表征
在此实施例中,以生物化学和功能性方式表征包含LIGHT和 PD-1结构域的嵌合蛋白。
制备鼠PD-1-Fc-LIGHT嵌合蛋白和人PD-1-Fc-LIGHT嵌合蛋白;其示意图在图12A和图12B的顶部示出。在还原条件下,用N+O去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上分离 mPD-1-Fc-LIGHT和hPD-1-Fc-LIGHT嵌合蛋白。mPD-1-Fc-LIGHT 和hPD-1-Fc-LIGHT嵌合蛋白的蛋白质印迹指示在非还原泳道中存在占优势的二聚体条带(图12A和图12B,每个印迹中的泳道2),其在还原剂β-巯基乙醇的存在下被还原为糖基化的单体条带(图12A和图12B,每个印迹中的泳道3)。如图12A和图12B每个印迹中的泳道3 所示,在还原剂(β-巯基乙醇)和内切糖苷酶(PNGase)两者的存在下,嵌合蛋白作为单体分离。
然后测定mPD-1-Fc-LIGHT嵌合蛋白和hPD-1-Fc-LIGHT嵌合蛋白的结合亲和力。对于每种嵌合蛋白,在以下条件下进行ELISA:重 +轻链捕获并用Fc-HRP检测(图13A和图13B,顶部左侧),鼠 LTBR-His捕获并用针对鼠LIGHT检测(图13A,顶部右侧)或人 LTBR-His捕获并用生物素酰化人LIGHT的抗体检测(图13B,顶部右侧),以及mPD-L1捕获并用针对mLIGHT的抗体检测(图13A,底部左侧,“双重ELISA”)或hPDL1-Fc捕获并用hLTBR-His/6x His-HRP检测(图13A,底部左侧,“双重ELISA”)。这些数据指示 mPD-1-Fc-LIGHT嵌合蛋白和hPD-1-Fc-LIGHT嵌合结合其靶标中的每个,并且可以同时结合两个靶标。
实施另外的分析以确定鼠PD-1-Fc-LIGHT嵌合蛋白(图14A)或人 PD-1-Fc-LIGHT嵌合蛋白(图14A)是否可以结合其在活细胞表面上的靶标。制备表达鼠mPD-L1的CHO-K1细胞(图14A,左侧)、表达鼠 LTbR的CHO-K1细胞(图14A,右侧)和表达人mPD-L1的CHO-K1 细胞(图14B,左侧)。将mPD-1-Fc-LIGHT嵌合蛋白与亲本和过表达细胞系一起温育2小时。将细胞收集,洗涤并用抗体染色,用于通过流式细胞术检测嵌合蛋白结合。如图14A所示(左侧和右侧),并且如所预期,mPD-1-Fc-LIGHT嵌合蛋白不以嵌合蛋白的任何浓度结合亲本细胞系。然而,mPD-1-Fc-LIGHT以浓度依赖性方式结合mPD-L1 工程化细胞系(图14A,左侧)和mLTbR工程化细胞系(图14A,右侧)。另外,将hPD-1-Fc-LIGHT嵌合蛋白与hPD-L1过表达细胞系一起温育。hPD-1-Fc-LIGHT以浓度依赖性方式结合hPD-L1工程化细胞系 (图14B);基于此数据,计算的EC50值为48nM。这些数据指示嵌合蛋白的不同组分各自能够结合其各自在活细胞上的受体/配体。
实施例4:TIGIT-Fc-LIGHT嵌合蛋白的表征
在此实施例中,以生物化学和功能性方式表征包含TIGIT和 LIGHT结构域的嵌合蛋白。
制备鼠TIGIT-Fc-LIGHT嵌合蛋白和人TIGIT-Fc-LIGHT嵌合蛋白;其示意图在图15A和图15B的顶部示出。在还原条件下,用N+O 去糖基化酶处理后,和/或在煮沸之后在SDS-PAGE上分离 mTIGIT-Fc-LIGHT和hTIGIT-Fc-LIGHT嵌合蛋白。 mTIGIT-Fc-LIGHT和hTIGIT-Fc-LIGHT嵌合蛋白的蛋白质印迹指示在非还原泳道中存在占优势的二聚体条带(图15A和图15B,每个印迹中的泳道2),其在还原剂β-巯基乙醇的存在下被还原为糖基化的单体条带(图15A和图15B,每个印迹中的泳道3)。如图15A和图15B 每个印迹中的泳道3所示,在还原剂(β-巯基乙醇)和内切糖苷酶(PNGase)两者的存在下,嵌合蛋白作为单体分离。
然后测定mTIGIT-1-Fc-LIGHT嵌合蛋白和hTIGIT-1-Fc-LIGHT 嵌合蛋白的结合亲和力。对于每种嵌合蛋白,在以下条件下进行 ELISA:重+轻链捕获并用Fc-HRP检测(图16A和图16B,顶部左侧), CD155/PVR捕获并用Fc-HRP检测(图16A,顶部右侧)或CD155-His 捕获并用检测(图16B,顶部右侧),以及mLTBR-His捕获并用针对 mLIGHT的抗体检测(图16A,底部左侧)或hCD155-Fc捕获并用 hLTBR-His/6x His-HRP检测(图16B,底部左侧,“双重ELISA”)。这些数据指示mTIGIT-1-Fc-LIGHT嵌合蛋白和hTIGIT-1-Fc-LIGHT嵌合结合其靶标中的每个,并且至少hTIGIT-1-Fc-LIGHT可以同时结合两个靶标。
实施另外的分析以确定鼠TIGIT-1-Fc-LIGHT嵌合蛋白(图17)是否可以结合其在活细胞表面上的靶标。
将mTIGIT-1-Fc-LIGHT嵌合蛋白或mPD-1-Fc-LIGHT嵌合蛋白与表达鼠PVR或表达鼠结合素-2的CHO-K1细胞(图17,左侧顶部)、表达鼠LTbR的CHO-K1细胞(图17A,右侧)或亲本CHO-K1细胞(图 17,右侧和左侧底部)一起温育。
如图17(底部左侧)所示,并且如所预期,mTIGIT-1-Fc-LIGHT 嵌合蛋白和mPD-1-Fc-LIGHT嵌合蛋白均不结合亲本细胞系,除非以最高浓度的嵌合蛋白结合。然而,mTIGIT-1-Fc-LIGHT以浓度依赖性方式结合mPVR工程化细胞系;基于此数据,计算的EC50值为214.9nM(图17,左侧顶部)。mTIGIT-1-Fc-LIGHT也以浓度依赖性方式结合mLTbR工程化细胞系;基于此数据,计算的EC50值为11nM(图 17,右侧)。这些数据指示嵌合蛋白的不同组分各自能够结合其各自在活细胞上的受体/配体。
实施例5:嵌合蛋白的进一步表征
在此实施例中,用人TIGIT-Fc-LIGHT、人 CD172a(SIRPα)-Fc-LIGHT、人PD-1-Fc-LIGHT、鼠PD-1-Fc-LIGHT、人TIGIT-Fc-OX40L、人TIGIT-Fc-LIGHT、人 CD172a(SIRPα)-Fc-LIGHT嵌合蛋白进行进一步实验。
使用八隅体系统通过生物膜干涉技术采集人TIGIT-Fc-LIGHT、 CD172a(SIRPα)-Fc-LIGHT或PD-1-Fc-LIGHT与人LTbR的结合亲和力测量值(参见,图18A,所有图)。使用八隅体系统通过生物膜干涉技术采集在一系列浓度下人PD-1-Fc-LIGHT与重组人PD-L1或 PD-L2的结合亲和力测量值(参见,图18B)。
使用八隅体系统通过生物膜干涉技术采集人TIGIT-Fc-OX40L和 TIGIT-Fc-LIGHT与重组人CD155/PVR(与一侧TIGIT-Fc融合蛋白对照相比)的结合亲和力测量值(参见,图19A)。使用八隅体系统通过生物膜干涉技术采集人CD172a(SIRPα)-Fc-LIGHT与重组人CD47(与一侧CD172a(SIRPα)-Fc对照或两种CD47特异性抗体对照中的一种相比相比)的结合亲和力测量值(参见,图19B)。使用八隅体系统通过生物膜干涉技术采集人PD-1-Fc-LIGHT与重组人PD-L1(与单侧 PD-1-Fc对照或抗PD-L1对照:阿特珠单抗相比)的结合亲和力测量值(参见,图19C)。使用八隅体系统通过生物膜干涉技术采集人 CD172a(SIRPα)-Fc-LIGHT、TIGIT-Fc-LIGHT或PD-1-Fc-LIGHT与重组人LTbR(与单侧LIGHT-Fc融合蛋白对照或抗LTbR抗体相比)的结合亲和力测量值(参见,图19D)。
在超抗原细胞因子释放测定中确定含有LIGHT结构域的嵌合蛋白或含有TIGIT结构域的嵌合蛋白的功能性能力。在此,增加浓度的葡萄球菌肠毒素B(SEB)用于在各种测试剂的存在下活化人外周血白细胞。监测分泌到培养上清液中的IL-2(图20A)或TNFα(图20B)的量作为测试剂阻断抑制性信号传导事件或共刺激免疫活化信号的能力的功能性读数。
图20A和图20B示出了超抗原细胞因子释放测定,其证明各种抗体鼠TIGIT-Fc-OX40L、鼠CD172a(SIRPα)-Fc-LIGHT、鼠 TIGIT-Fc-LIGHT或鼠PD-1-Fc-LIGHT嵌合蛋白对于通过SEB活化的鼠外周血白细胞的影响。图20C示出了在多个超抗原(SEB)浓度下数据的编译。如图20A和图20C所示,当施用50和200ng/ml SEB时,对于mCD172a(SIRPα)-Fc-LIGHT和mPD-1-Fc-LIGHT,三种浓度(10 nM,100nM和250nM)中的每一种比所有的抗体对照均提供显著更大的IL2分泌。如图20B所示,当施用50和200ng/ml SEB时,在 100nm或250nm浓度下,mPD-1-Fc-LIGHT比所有抗体对照均提供显著更大的TNFα分泌;当施用200ng/ml SEB时,所有三种浓度的 mCD172a(SIRPα)-Fc-LIGHT比所有抗体对照均提供显著更大的 TNFα分泌。
此外,图21A至图21C示出了超抗原细胞因子释放测定,其证明各种抗体人TIGIT-Fc-LIGHT(图21A)、人TIGIT-Fc-OX40L(图 21B)、人PD-1-Fc-LIGHT和人CD172a(SIRPα)-Fc-LIGHT(图21C)嵌合蛋白对于通过SEB活化的人外周血白细胞的影响。
因此,以上数据证明如本文所述的含有LIGHT结构域的嵌合蛋白和含有TIGIT结构域的嵌合蛋白能够结合其三种结合配偶体中的每一种;它们在体外功能性地活化原代人白细胞。
实施例6:改善的肿瘤杀死和增加的来自用嵌合蛋白进行的处理的存活
使用CT26小鼠结肠直肠肿瘤模型分析鼠TIGIT-Fc-OX40L、鼠 CD172a(SIRPα)-Fc-LIGHT、鼠TIGIT-Fc-LIGHT和鼠PD-1-Fc-LIGHT 嵌合蛋白的体内抗肿瘤活性。在一组实验中,用CT26肿瘤接种Balb/c 小鼠。当肿瘤直径达到4至5mm时,用mTIGIT-Fc-OX40L、mCD172a(SIRPα)-Fc-LIGHT、mTIGIT-Fc-LIGHT和mPD-1-Fc-LIGHT 嵌合蛋白或抗TIGIT、抗CD47、抗OX40或抗PD-1抗体或抗TIGIT 和抗OX40抗体的组合处理小鼠。
评估每个处理组的肿瘤生长,如图22A所示(左图和右图)。具体地,未处理小鼠快速发展肿瘤,并且用一种或多种抗体进行的处理似乎稍微延迟肿瘤的发展。相比之下,用mTIGIT-Fc-OX40L、 mCD172a(SIRPα)-Fc-LIGHT、mTIGIT-Fc-LIGHT或mPD-1-Fc-LIGHT 嵌合蛋白处理小鼠显著抑制肿瘤生长和/或延迟肿瘤发展。
还评估了在肿瘤接种之后的40天内小鼠的总存活百分比。所有未处理小鼠均在肿瘤接种之后20天内死亡,并且用一种或多种抗体处理的小鼠均不具有大于25%的40天存活百分比;参见图22B,左图。显著地,所有用mTIGIT-Fc-OX40L、mCD172a(SIRPα)-Fc-LIGHT、mTIGIT-Fc-LIGHT或mPD-1-Fc-LIGHT嵌合蛋白处理的小鼠在肿瘤接种后存活超过40天;参见图22B,右图。
这些数据指示用TIGIT-Fc-OX40L、CD172a(SIRPα)-Fc-LIGHT、 TIGIT-Fc-LIGHT或PD-1-Fc-LIGHT嵌合蛋白进行的体内处理抑制肿瘤生长并改善存活。
实施例7:接头中Fc结构域对嵌合蛋白功能性的贡献的表征
在此实施例中,测定了接头中的Fc结构域对本发明的嵌合蛋白功能性的贡献。在此,PD-1-Fc-OX40L用作含Fc的嵌合蛋白的模型。因此,下文呈现的数据与本发明的嵌合蛋白有关。
在其天然状态下,PD-1作为单体存在,而OX40L由于OX40L 结构域之间的静电相互作用而倾向于二聚化;Fc结构域通过二硫键 (例如通过它们的一个或多个半胱氨酸残基)彼此缔合。总之,若干种分子间相互作用可能有助于PD-1-Fc-OX40L的四级结构。存在至少四种PD-1-Fc-OX40L的潜在构型,其中嵌合蛋白作为单体、二聚体、三聚体或六聚体存在。参见图23。
通过将嵌合蛋白暴露于还原条件和非还原条件,然后在SDS-PAGE上分离蛋白质,来测试嵌合蛋白的单体和二聚体构型的存在。在非还原条件下(还原的:“-”),嵌合蛋白在SDS-PAGE中迁移到约200kDa处。在此,分别用针对PD-1、Fc或OX40L的抗体探测蛋白质印迹,如图24中所示的左、中和右印迹。由于嵌合蛋白的预测单体分子量为57.6kDa,预计200kDa的物质是至少二聚体。但是,在还原条件下(还原的:“+”),其还原二硫键(例如,位于Fc结构域之间),嵌合蛋白在SDS-PAGE中迁移到约100kDa处。由于100kDa 的物质比预期重,因此预测额外质量是由于糖基化。最后,用肽-N- 糖苷酶F(PNGaseF“+”)处理嵌合蛋白,并在还原条件下在SDS-PAGE 上分离。在这些条件下,嵌合蛋白迁移到约57.6kDa处。这些数据表明嵌合蛋白是糖基化的并且至少作为二聚体天然存在;其中二聚化可能是由于Fc结构域之间的二硫键,例如通过它们的一个或多个半胱氨酸残基。
SDS-PAGE凝胶方法不能准确预测高电荷和/或大分子量的蛋白质的分子量。因此,接下来使用尺寸排阻色谱法(SEC)表征嵌合蛋白。与其中带负电荷的SDS降低肽之间基于电荷的相互作用的 SDS-PAGE不同,SEC不使用去污剂或还原剂。当PD-1-Fc-OX40L 嵌合蛋白在SEC上分离时,在约200kDa处没有峰。这表明,嵌合蛋白不作为二聚体天然存在。相反,检测到大小大于670kDa的峰。参见图25。此数据和先前数据表明PD-1-Fc-OX40L嵌合蛋白作为六聚体以其天然状态存在。
如上所示,当在非还原条件下或在还原条件下在SDS-PAGE上分离时,样品和/或运行缓冲液中的SDS分别在不存在和存在还原剂的情况下将六聚体PD-1-Fc-OX40L嵌合蛋白转化为主要的二聚体或单体。参见图26(左侧凝胶)。当在缺乏SDS的天然PAGE上分离,并且在不存在还原剂的情况下,嵌合蛋白作为六聚体存在。然而,当在天然PAGE上分离,并且在还原剂(其还原二硫键)的存在下,嵌合蛋白迁移比预期的更重;如图26所示(右侧凝胶,泳道2),其中嵌合蛋白质基本上不能从加样孔中迁移出来。此数据表明嵌合蛋白寡聚化成更高级的蛋白质。因此,在嵌合蛋白中,二硫键似乎对于控制高级寡聚化是很重要的。
为了进一步证实这一点,构建了缺乏Fc结构域的嵌合蛋白,例如“PD-1-No Fc-OX40L”。此类嵌合蛋白不会具有在前述嵌合蛋白中的Fc结构域之间出现的二硫键。如图27所示,当缺乏Fc结构域的嵌合蛋白在天然PAGE上分离时,基本上没有一种蛋白质从其加样孔中迁移出来;再次表明“无Fc”嵌合蛋白已经形成了包含许多蛋白质的多联体样复合物。因此,在嵌合蛋白中省略Fc结构域导致蛋白质聚集体的形成。这些数据指示,例如,在不同嵌合蛋白上的Fc结构域之间的二硫键使嵌合蛋白稳定并确保它们各自作为六聚体存在而不是作为更高级的蛋白质/多联体存在。换句话说,Fc结构域令人惊讶地将次序置于嵌合蛋白复合物上。泳道#1至#4分别包括2.5μg的 PD-1-No Fc-OX40L、5μg的PD-1-No Fc-OX40L、2.5μg的PD-1-No Fc-OX40L和5μg的PD-1-No Fc-OX40L
图28中示出的是总结上述数据的模型,并且示出了如何由本发明的嵌合蛋白形成六聚体和多联体。例示性嵌合蛋白(PD-1-Fc-OX40L) 天然形成六聚体(由于OX40L结构域之间的静电相互作用和Fc结构域的二聚化)。然而,在不存在对Fc结构域之间的二硫键的控制作用的情况下,在PD-1-Fc-OX40L蛋白的还原条件下并且由于PD-1-No Fc-OX40L中不存在Fc结构域,这些后者的嵌合蛋白形成多联体。
另外,构建嵌合蛋白,其中Fc结构域(如本文所述)被纤维胶凝蛋白(Ficolin)(其缺乏嵌合蛋白之间的二硫键必需的半胱氨酸残基)替换。与无Fc嵌合蛋白和包含Fc的嵌合蛋白一样,并且在天然PAGE 上分离且在还原剂的存在下(其两者都形成不迁移到凝胶中的聚集体),包含Ficolin的嵌合蛋白似乎也形成更高级的晶格,其不会迁移到凝胶中。这些数据强化了以下结论,即二硫键对于本发明的嵌合蛋白的正确折叠和功能是很重要的。
最后,使用卷曲的Fc结构域(CCDFc)制备嵌合蛋白。在功能性评估下递送非常少的纯化蛋白。
因此,在嵌合蛋白的接头中包含Fc结构域(其能够在嵌合蛋白之间形成二硫键),有助于避免形成不可溶的并且可能是非功能性的蛋白质多联体和/或聚集体。
实施例8:嵌合蛋白的不同连接接头序列的表征
鉴定了具有不同特征(长度、溶解度、电荷和柔性)的不同的独特连接接头序列(17个接头)。然后将这17个连接接头序列中的每一个并入“接头2”位置来合成构建体,其中嵌合蛋白的构型:
ECD 1–连接接头1–Fc–连接接头2–ECD 2
在CHO细胞中测试了这17种构建体的产生水平。下表提供了不同连接接头序列、这些连接接头的特征、产生水平(通过A280)以及基于对PD-L1或OX40的FACS分析的结合值(EC50)的总结。确定了某些连接接头序列之间的产生水平和活性的一些变化。
表2:任选的连接接头序列的总结
图29A至图29Q中示出通过蛋白质印迹分析进行的具有不同连接接头序列(17个接头)的PD-1-IgG4-OX40L嵌合蛋白的表征。具体地,使用抗PD-1、抗Fc或抗OX40L抗体探测融合构建体的每个个体结构域。结果显示每种嵌合蛋白具有相似的性能,从而表明所有的候选连接接头序列是功能性的。
另外,具有不同接头序列的每种纯化蛋白还通过在ELISA测定中结合PD-L1或OX40(图30)以及基于细胞的流式细胞术测定(图 31A至图31P)来表征。
实施例9:包含其他II型蛋白的细胞外结构域的另外的含有TIGIT 的嵌合蛋白的产生
在此实施例中,描述了本发明的另外的嵌合蛋白。以与制备 TIGIT-Fc-OX40L、TIGIT-Fc-CD40L或TIGIT-Fc-LIGHT嵌合蛋白相似的方式制备此类另外的嵌合蛋白,例如,如以上具体实施方式和本申请的优先权文献:U.S.62/464,002中所述。
这些另外的嵌合蛋白将具有以下通式:ECD 1–连接接头1–Fc 结构域–连接接头2–ECD 2,其中ECD 1是TIGIT的细胞外结构域,并且ECD 2是除了CD40L、OX40L或LIGHT以外的II型蛋白的细胞外结构域。示例性II型蛋白包括4-1BBL、CD30L、FasL、 GITRL、TL1A和TRAIL。这些嵌合蛋白可能缺乏连接接头中的一个或两个。示例性连接接头1、Fc结构域和连接接头2在以上表1中描述;用于形成嵌合蛋白并包含特异性连接接头1、Fc结构域和连接接头2的模块接头在图32中示出。
可替代地,另外的嵌合蛋白是具有以下通式的融合蛋白:N末端–(a)–(b)–(c)–C末端,其中(a)是TIGIT,(b)是包含Fc结构域的至少一部分的接头,并且(c)是除了CD40L、OX40L或LIGHT以外的 II型蛋白的细胞外结构域。示例性II型蛋白包括4-1BBL、CD30L、FasL、GITRL、TL1A和TRAIL。示例性接头在以上表1中描述;用于形成嵌合蛋白并包含特异性连接接头1、Fc结构域和连接接头2的模块接头在图32中示出。
4-1BBL、CD30L、FasL、GITRL、TL1A和TRAIL的氨基酸序列分别包括SEQ ID NO:12、26、30、15、18和40。4-1BBL、CD30L、 FasL、GITRL、TL1A和TRAIL的细胞外结构域的氨基酸序列分别包括SEQ ID NO:13、27、31、16、19和41。TIGIT的氨基酸序列包括 SEQ ID NO:9,并且TIGIT的细胞外结构域包括SEQ ID NO:10。嵌合蛋白可以包含以上提及的序列的变体,例如与以上提及的序列具有至少约95%同一性。
因此,本发明还包括以下另外的嵌合蛋白和使用另外的嵌合蛋白的方法(例如,在治疗癌症和/或治疗炎性疾病中):TIGIT-Fc-4-1BBL、 TIGIT-Fc-CD30L、TIGIT-Fc-FasL、TIGIT-Fc-GITRL、TIGIT-Fc-TL1A 和TIGIT-Fc-TRAIL。
另外的嵌合蛋白将如上所述在实施例1至8中针对 TIGIT-Fc-OX40L、TIGIT-Fc-CD40L或TIGIT-Fc-LIGHT进行表征,不同的是用对另外的嵌合蛋白特异性的并非对于表征TIGIT-Fc-OX40L、TIGIT-Fc-CD40L或TIGIT-Fc-LIGHT所需要的试剂(例如,结合配偶体、重组靶细胞和癌细胞/肿瘤类型)。因此,使用 TIGIT-Fc-4-1BBL和TIGIT-Fc-CD40L作为实例,可以使用除了对于 TIGIT-Fc-CD40L所需要的抗TIGIT、抗Fc和抗CD40L抗体以外的抗TIGIT、抗Fc和抗4-1BBL抗体进行类似于实施例1的 TIGIT-Fc-4-1BBL的表征。
与TIGIT-Fc-OX40L、TIGIT-Fc-CD40L或TIGIT-Fc-LIGHT嵌合蛋白一样,另外的嵌合蛋白通过阻断TIGIT(其抑制免疫抑制信号的传递)并且通过活化4-1BBL、CD30L、FasL、GITRL、TL1A和TRAIL 中的一个的受体/配体增强、增加和/或刺激免疫抑制信号的传递来有效治疗癌症和/或治疗炎性疾病。此外,另外的嵌合蛋白有效治疗癌症和/或炎性疾病,但是没有由包括多种抗体(例如,阻断抗体以及 4-1BBL、CD30L、FasL、GITRL和TRAIL中的一个的受体/配体的激动剂抗体)的治疗引起的毒性和不想要的副作用,例如GI并发症。
实施例10:包含其他I型蛋白的细胞外结构域的另外的含有 LIGHT的嵌合蛋白的产生
在此实施例中,描述了本发明的另外的嵌合蛋白。以与制备 CD172a(SIRPα)-Fc-LIGHT、TIGIT-Fc-LIGHT或PD-1-Fc-LIGHT嵌合蛋白相似的方式制备此类另外的嵌合蛋白,例如,如以上具体实施方式和本申请的优先权文献:U.S.62/464,002中所述。
这些另外的嵌合蛋白将具有以下通式:ECD 1–连接接头1–Fc 结构域–连接接头2–ECD 2,其中ECD 1是除了CD172a(SIRPα)、 TIGIT或PD-1以外的I型蛋白的细胞外结构域,并且ECD 2是LIGHT 的细胞外结构域。示例性I型蛋白包括TIM3和BTLA。这些嵌合蛋白可能缺乏连接接头中的一个或两个。示例性连接接头1、Fc结构域和连接接头2在以上表1中描述;用于形成嵌合蛋白并包含特异性连接接头1、Fc结构域和连接接头2的模块接头在图32中示出。
可替代地,另外的嵌合蛋白是具有以下通式的融合蛋白:N末端–(a)–(b)–(c)–C末端,其中(a)是除了CD172a(SIRPα)、TIGIT或 PD-1以外的I型蛋白的细胞外结构域,(b)是包含Fc结构域的至少一部分的接头,并且(c)是LIGHT的细胞外结构域。示例性I型蛋白包括TIM3和BTLA。示例性接头在以上表1中描述;用于形成嵌合蛋白并包含特异性连接接头1、Fc结构域和连接接头2的模块接头在图 32中示出。
TIM3和BTLA的氨基酸序列分别包括SEQ ID NO:36和24。 TIM3和BTLA的细胞外结构域的氨基酸序列分别包括SEQ ID NO: 37和25。LIGHT的氨基酸序列包括SEQ ID NO:1,并且LIGHT的细胞外结构域包括SEQ ID NO:2。嵌合蛋白可以包含以上提及的序列的变体,例如与以上提及的序列具有至少约95%同一性。
因此,本发明还包括以下另外的嵌合蛋白和使用另外的嵌合蛋白的方法(例如,在治疗癌症和/或治疗炎性疾病中):IM3-Fc-LIGHT和 BTLA-Fc-LIGHT。另外的嵌合蛋白将如上所述在实施例1至8中针对CD172a(SIRPα)-Fc-LIGHT、TIGIT-Fc-LIGHT或PD-1-Fc-LIGHT进行表征,不同的是用对另外的嵌合蛋白特异性的并非对于表征 TIM3-Fc-LIGHT和BTLA-Fc-LIGHT所需要的试剂(例如,结合配偶体、重组靶细胞和癌细胞/肿瘤类型);作为实例,可以使用除了对于 CD172a(SIRPα)-Fc-LIGHT所需要的抗TIGIT、抗Fc和抗 CD172a(SIRPα)抗体以外的抗TIGIT、抗Fc和抗TIM3抗体进行类似于实施例2的TIM3-Fc-LIGHT的表征。
与CD172a(SIRPα)-Fc-LIGHT、TIGIT-Fc-LIGHT或 PD-1-Fc-LIGHT嵌合蛋白一样,另外的嵌合蛋白通过阻断TIM3和 LIGHT(其抑制免疫抑制信号的传递)并且通过LIGHT活化受体/配体增强、增加和/或刺激免疫抑制信号的传递来有效治疗癌症和/或治疗炎性疾病。此外,另外的嵌合蛋白有效治疗癌症和/或炎性疾病,但是没有由包括多种抗体(例如,阻断抗体以及TIM3和LIGHT中的一个的受体/配体的激动剂抗体)的治疗引起的毒性和不想要的副作用,例如GI并发症。
等效物
尽管本发明已结合其具体实施方案进行描述,但应了解可对其进行进一步修改并且本申请旨在涵盖任何通常根据本发明的原理而对本发明进行的任何变动、使用或适应性调整,并且包括虽然不属于本公开内容但属于本发明所属领域的已知或习用实施手段的和属于上文所述的实质特征的以及符合所附权利要求范围的变更。
仅使用常规实验,本领域技术人员将认识到或能够确定本文确切描述的具体实施方案的许多等效方案。这些等效方案意图涵盖在以下权利要求书的范围中。
以引用的方式并入
本文引用的所有专利和出版物以引用的方式整体并入本文。
本文中讨论的公布仅仅提供它们在本申请的提交日期之前的公开内容。本文中的任何内容均不应解释为承认由于先前发明而使本发明无权先于这些出版物。
如本文所用的,所有标题仅用于组织,并不意图以任何方式限制本公开。任何单个部分的内容可同样适用于所有部分。
等效物
尽管本发明已结合其具体实施方案进行描述,但应了解可对其进行进一步修改并且本申请旨在涵盖任何通常根据本发明的原理而对本发明进行的任何变动、使用或适应性调整,并且包括虽然不属于本公开内容但属于本发明所属领域的已知或习用实施手段的和属于上文所述的实质特征的以及符合所附权利要求范围的变更。
仅使用常规实验,本领域技术人员将认识到或能够确定本文确切描述的具体实施方案的许多等效方案。这些等效方案意图涵盖在以下权利要求书的范围中。
序列表
<110> 夏塔克实验室公司(SHATTUCK LABS, INC.)
<120> 基于TIGIT和LIGHT的嵌合蛋白
<130> SHK-001PC1
<150> US 62/464,002
<151> 2017-02-27
<160> 101
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50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln
165
<210> 4
<211> 147
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 4
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln
145
<210> 5
<211> 559
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 5
Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe Ser Pro Ala
1 5 10 15
Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr Cys Ser Phe
20 25 30
Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro
35 40 45
Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp Arg Ser Gln
50 55 60
Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro Asn Gly Arg
65 70 75 80
Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp Ser Gly Thr
85 90 95
Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln Ile Lys Glu
100 105 110
Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala Glu Val Pro
115 120 125
Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly Gln Phe Gln Ser
130 135 140
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
145 150 155 160
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met
165 170 175
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
180 185 190
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
195 200 205
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
210 215 220
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ser Gly
225 230 235 240
Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser Ile
245 250 255
Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln Val
260 265 270
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
275 280 285
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
290 295 300
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
305 310 315 320
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
325 330 335
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu
340 345 350
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
355 360 365
Leu Gly Lys Ile Glu Gly Arg Met Asp Leu Gln Leu His Trp Arg Leu
370 375 380
Gly Glu Met Val Thr Arg Leu Pro Asp Gly Pro Ala Gly Ser Trp Glu
385 390 395 400
Gln Leu Ile Gln Glu Arg Arg Ser His Glu Val Asn Pro Ala Ala His
405 410 415
Leu Thr Gly Ala Asn Ser Ser Leu Thr Gly Ser Gly Gly Pro Leu Leu
420 425 430
Trp Glu Thr Gln Leu Gly Leu Ala Phe Leu Arg Gly Leu Ser Tyr His
435 440 445
Asp Gly Ala Leu Val Val Thr Lys Ala Gly Tyr Tyr Tyr Ile Tyr Ser
450 455 460
Lys Val Gln Leu Gly Gly Val Gly Cys Pro Leu Gly Leu Ala Ser Thr
465 470 475 480
Ile Thr His Gly Leu Tyr Lys Arg Thr Pro Arg Tyr Pro Glu Glu Leu
485 490 495
Glu Leu Leu Val Ser Gln Gln Ser Pro Cys Gly Arg Ala Thr Ser Ser
500 505 510
Ser Arg Val Trp Trp Asp Ser Ser Phe Leu Gly Gly Val Val His Leu
515 520 525
Glu Ala Gly Glu Lys Val Val Val Arg Val Leu Asp Glu Arg Leu Val
530 535 540
Arg Leu Arg Asp Gly Thr Arg Ser Tyr Phe Gly Ala Phe Met Val
545 550 555
<210> 6
<211> 373
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 6
Met Glu Pro Ala Gly Pro Ala Pro Gly Arg Leu Gly Pro Leu Leu Cys
1 5 10 15
Leu Leu Leu Ala Ala Ser Cys Ala Trp Ser Gly Val Ala Gly Glu Glu
20 25 30
Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala Ala Gly
35 40 45
Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Ile Pro Val Gly
50 55 60
Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu Ile Tyr
65 70 75 80
Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
85 90 95
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn Ile Thr
100 105 110
Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
115 120 125
Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser Val
130 135 140
Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg Ala
145 150 155 160
Thr Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser
165 170 175
Pro Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser
180 185 190
Asp Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr Ser
195 200 205
Ile His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val His Ser
210 215 220
Gln Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp Pro Leu
225 230 235 240
Arg Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro Thr Leu
245 250 255
Glu Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn Val Thr
260 265 270
Cys Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr Trp Leu
275 280 285
Glu Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val Thr Glu
290 295 300
Asn Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val Asn Val
305 310 315 320
Ser Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu His Asp
325 330 335
Gly Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser Ala His
340 345 350
Pro Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly Ser Asn
355 360 365
Glu Arg Asn Ile Tyr
370
<210> 7
<211> 343
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 7
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala
115 120 125
Arg Ala Thr Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly
130 135 140
Phe Ser Pro Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu
145 150 155 160
Leu Ser Asp Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser
165 170 175
Tyr Ser Ile His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val
180 185 190
His Ser Gln Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp
195 200 205
Pro Leu Arg Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro
210 215 220
Thr Leu Glu Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn
225 230 235 240
Val Thr Cys Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr
245 250 255
Trp Leu Glu Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val
260 265 270
Thr Glu Asn Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val
275 280 285
Asn Val Ser Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu
290 295 300
His Asp Gly Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser
305 310 315 320
Ala His Pro Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly
325 330 335
Ser Asn Glu Arg Asn Ile Tyr
340
<210> 8
<211> 759
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 8
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala
115 120 125
Arg Ala Thr Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly
130 135 140
Phe Ser Pro Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu
145 150 155 160
Leu Ser Asp Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser
165 170 175
Tyr Ser Ile His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val
180 185 190
His Ser Gln Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp
195 200 205
Pro Leu Arg Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro
210 215 220
Thr Leu Glu Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn
225 230 235 240
Val Thr Cys Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr
245 250 255
Trp Leu Glu Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val
260 265 270
Thr Glu Asn Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val
275 280 285
Asn Val Ser Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu
290 295 300
His Asp Gly Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser
305 310 315 320
Ala His Pro Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly
325 330 335
Ser Asn Glu Arg Asn Ile Tyr Ser Lys Tyr Gly Pro Pro Cys Pro Pro
340 345 350
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
355 360 365
Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr
370 375 380
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
405 410 415
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
420 425 430
Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val Ser
435 440 445
Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala Thr
450 455 460
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
465 470 475 480
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
485 490 495
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
515 520 525
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
530 535 540
Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr
545 550 555 560
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg Met
565 570 575
Asp Leu Gln Leu His Trp Arg Leu Gly Glu Met Val Thr Arg Leu Pro
580 585 590
Asp Gly Pro Ala Gly Ser Trp Glu Gln Leu Ile Gln Glu Arg Arg Ser
595 600 605
His Glu Val Asn Pro Ala Ala His Leu Thr Gly Ala Asn Ser Ser Leu
610 615 620
Thr Gly Ser Gly Gly Pro Leu Leu Trp Glu Thr Gln Leu Gly Leu Ala
625 630 635 640
Phe Leu Arg Gly Leu Ser Tyr His Asp Gly Ala Leu Val Val Thr Lys
645 650 655
Ala Gly Tyr Tyr Tyr Ile Tyr Ser Lys Val Gln Leu Gly Gly Val Gly
660 665 670
Cys Pro Leu Gly Leu Ala Ser Thr Ile Thr His Gly Leu Tyr Lys Arg
675 680 685
Thr Pro Arg Tyr Pro Glu Glu Leu Glu Leu Leu Val Ser Gln Gln Ser
690 695 700
Pro Cys Gly Arg Ala Thr Ser Ser Ser Arg Val Trp Trp Asp Ser Ser
705 710 715 720
Phe Leu Gly Gly Val Val His Leu Glu Ala Gly Glu Lys Val Val Val
725 730 735
Arg Val Leu Asp Glu Arg Leu Val Arg Leu Arg Asp Gly Thr Arg Ser
740 745 750
Tyr Phe Gly Ala Phe Met Val
755
<210> 9
<211> 141
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 9
Met Arg Trp Cys Leu Leu Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala
1 5 10 15
Pro Leu Ala Ser Gly Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn
20 25 30
Ile Ser Ala Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser
35 40 45
Ser Thr Thr Ala Gln Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln
50 55 60
Leu Leu Ala Ile Cys Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser
65 70 75 80
Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln
85 90 95
Ser Leu Thr Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr
100 105 110
Tyr Pro Asp Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu
115 120 125
Ser Ser Val Ala Glu His Gly Ala Arg Phe Gln Ile Pro
130 135 140
<210> 10
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 10
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro
115 120
<210> 11
<211> 536
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 11
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala
225 230 235 240
Thr Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg
340 345 350
Met Asp Leu Gln Leu His Trp Arg Leu Gly Glu Met Val Thr Arg Leu
355 360 365
Pro Asp Gly Pro Ala Gly Ser Trp Glu Gln Leu Ile Gln Glu Arg Arg
370 375 380
Ser His Glu Val Asn Pro Ala Ala His Leu Thr Gly Ala Asn Ser Ser
385 390 395 400
Leu Thr Gly Ser Gly Gly Pro Leu Leu Trp Glu Thr Gln Leu Gly Leu
405 410 415
Ala Phe Leu Arg Gly Leu Ser Tyr His Asp Gly Ala Leu Val Val Thr
420 425 430
Lys Ala Gly Tyr Tyr Tyr Ile Tyr Ser Lys Val Gln Leu Gly Gly Val
435 440 445
Gly Cys Pro Leu Gly Leu Ala Ser Thr Ile Thr His Gly Leu Tyr Lys
450 455 460
Arg Thr Pro Arg Tyr Pro Glu Glu Leu Glu Leu Leu Val Ser Gln Gln
465 470 475 480
Ser Pro Cys Gly Arg Ala Thr Ser Ser Ser Arg Val Trp Trp Asp Ser
485 490 495
Ser Phe Leu Gly Gly Val Val His Leu Glu Ala Gly Glu Lys Val Val
500 505 510
Val Arg Val Leu Asp Glu Arg Leu Val Arg Leu Arg Asp Gly Thr Arg
515 520 525
Ser Tyr Phe Gly Ala Phe Met Val
530 535
<210> 12
<211> 254
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 12
Met Glu Tyr Ala Ser Asp Ala Ser Leu Asp Pro Glu Ala Pro Trp Pro
1 5 10 15
Pro Ala Pro Arg Ala Arg Ala Cys Arg Val Leu Pro Trp Ala Leu Val
20 25 30
Ala Gly Leu Leu Leu Leu Leu Leu Leu Ala Ala Ala Cys Ala Val Phe
35 40 45
Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser
50 55 60
Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp
65 70 75 80
Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val
85 90 95
Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp
100 105 110
Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu
115 120 125
Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe
130 135 140
Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser
145 150 155 160
Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala
165 170 175
Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala
180 185 190
Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala
195 200 205
Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His
210 215 220
Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val
225 230 235 240
Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
245 250
<210> 13
<211> 205
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 13
Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser Ala
1 5 10 15
Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp Pro
20 25 30
Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala
35 40 45
Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro
50 55 60
Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp
65 70 75 80
Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe
85 90 95
Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val
100 105 110
Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala
115 120 125
Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg
130 135 140
Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly
145 150 155 160
Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala
165 170 175
Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Thr
180 185 190
Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
195 200 205
<210> 14
<211> 559
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 14
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala
225 230 235 240
Thr Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg
340 345 350
Met Asp Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly
355 360 365
Ser Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp
370 375 380
Asp Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
385 390 395 400
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
405 410 415
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
420 425 430
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
435 440 445
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
450 455 460
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
465 470 475 480
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
485 490 495
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
500 505 510
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
515 520 525
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
530 535 540
Val Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
545 550 555
<210> 15
<211> 199
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 15
Met Thr Leu His Pro Ser Pro Ile Thr Cys Glu Phe Leu Phe Ser Thr
1 5 10 15
Ala Leu Ile Ser Pro Lys Met Cys Leu Ser His Leu Glu Asn Met Pro
20 25 30
Leu Ser His Ser Arg Thr Gln Gly Ala Gln Arg Ser Ser Trp Lys Leu
35 40 45
Trp Leu Phe Cys Ser Ile Val Met Leu Leu Phe Leu Cys Ser Phe Ser
50 55 60
Trp Leu Ile Phe Ile Phe Leu Gln Leu Glu Thr Ala Lys Glu Pro Cys
65 70 75 80
Met Ala Lys Phe Gly Pro Leu Pro Ser Lys Trp Gln Met Ala Ser Ser
85 90 95
Glu Pro Pro Cys Val Asn Lys Val Ser Asp Trp Lys Leu Glu Ile Leu
100 105 110
Gln Asn Gly Leu Tyr Leu Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn
115 120 125
Tyr Asn Asp Val Ala Pro Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp
130 135 140
Met Ile Gln Thr Leu Thr Asn Lys Ser Lys Ile Gln Asn Val Gly Gly
145 150 155 160
Thr Tyr Glu Leu His Val Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser
165 170 175
Glu His Gln Val Leu Lys Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu
180 185 190
Ala Asn Pro Gln Phe Ile Ser
195
<210> 16
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 16
Gln Leu Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro Leu
1 5 10 15
Pro Ser Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn Lys
20 25 30
Val Ser Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu Ile
35 40 45
Tyr Gly Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro Phe
50 55 60
Glu Val Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr Asn
65 70 75 80
Lys Ser Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val Gly
85 90 95
Asp Thr Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys Asn
100 105 110
Asn Thr Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile Ser
115 120 125
<210> 17
<211> 482
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 17
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala
225 230 235 240
Thr Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg
340 345 350
Met Asp Gln Leu Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly
355 360 365
Pro Leu Pro Ser Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val
370 375 380
Asn Lys Val Ser Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr
385 390 395 400
Leu Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala
405 410 415
Pro Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu
420 425 430
Thr Asp Lys Ser Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His
435 440 445
Val Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu
450 455 460
Lys Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe
465 470 475 480
Ile Ser
<210> 18
<211> 251
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 18
Met Ala Glu Asp Leu Gly Leu Ser Phe Gly Glu Thr Ala Ser Val Glu
1 5 10 15
Met Leu Pro Glu His Gly Ser Cys Arg Pro Lys Ala Arg Ser Ser Ser
20 25 30
Ala Arg Trp Ala Leu Thr Cys Cys Leu Val Leu Leu Pro Phe Leu Ala
35 40 45
Gly Leu Thr Thr Tyr Leu Leu Val Ser Gln Leu Arg Ala Gln Gly Glu
50 55 60
Ala Cys Val Gln Phe Gln Ala Leu Lys Gly Gln Glu Phe Ala Pro Ser
65 70 75 80
His Gln Gln Val Tyr Ala Pro Leu Arg Ala Asp Gly Asp Lys Pro Arg
85 90 95
Ala His Leu Thr Val Val Arg Gln Thr Pro Thr Gln His Phe Lys Asn
100 105 110
Gln Phe Pro Ala Leu His Trp Glu His Glu Leu Gly Leu Ala Phe Thr
115 120 125
Lys Asn Arg Met Asn Tyr Thr Asn Lys Phe Leu Leu Ile Pro Glu Ser
130 135 140
Gly Asp Tyr Phe Ile Tyr Ser Gln Val Thr Phe Arg Gly Met Thr Ser
145 150 155 160
Glu Cys Ser Glu Ile Arg Gln Ala Gly Arg Pro Asn Lys Pro Asp Ser
165 170 175
Ile Thr Val Val Ile Thr Lys Val Thr Asp Ser Tyr Pro Glu Pro Thr
180 185 190
Gln Leu Leu Met Gly Thr Lys Ser Val Cys Glu Val Gly Ser Asn Trp
195 200 205
Phe Gln Pro Ile Tyr Leu Gly Ala Met Phe Ser Leu Gln Glu Gly Asp
210 215 220
Lys Leu Met Val Asn Val Ser Asp Ile Ser Leu Val Asp Tyr Thr Lys
225 230 235 240
Glu Asp Lys Thr Phe Phe Gly Ala Phe Leu Leu
245 250
<210> 19
<211> 192
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 19
Arg Ala Gln Gly Glu Ala Cys Val Gln Phe Gln Ala Leu Lys Gly Gln
1 5 10 15
Glu Phe Ala Pro Ser His Gln Gln Val Tyr Ala Pro Leu Arg Ala Asp
20 25 30
Gly Asp Lys Pro Arg Ala His Leu Thr Val Val Arg Gln Thr Pro Thr
35 40 45
Gln His Phe Lys Asn Gln Phe Pro Ala Leu His Trp Glu His Glu Leu
50 55 60
Gly Leu Ala Phe Thr Lys Asn Arg Met Asn Tyr Thr Asn Lys Phe Leu
65 70 75 80
Leu Ile Pro Glu Ser Gly Asp Tyr Phe Ile Tyr Ser Gln Val Thr Phe
85 90 95
Arg Gly Met Thr Ser Glu Cys Ser Glu Ile Arg Gln Ala Gly Arg Pro
100 105 110
Asn Lys Pro Asp Ser Ile Thr Val Val Ile Thr Lys Val Thr Asp Ser
115 120 125
Tyr Pro Glu Pro Thr Gln Leu Leu Met Gly Thr Lys Ser Val Cys Glu
130 135 140
Val Gly Ser Asn Trp Phe Gln Pro Ile Tyr Leu Gly Ala Met Phe Ser
145 150 155 160
Leu Gln Glu Gly Asp Lys Leu Met Val Asn Val Ser Asp Ile Ser Leu
165 170 175
Val Asp Tyr Thr Lys Glu Asp Lys Thr Phe Phe Gly Ala Phe Leu Leu
180 185 190
<210> 20
<211> 549
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 20
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala
225 230 235 240
Thr Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg
340 345 350
Met Asp Ser Gln Leu Arg Ala Gln Gly Glu Ala Cys Val Gln Phe Gln
355 360 365
Ala Leu Lys Gly Gln Glu Phe Ala Pro Ser His Gln Gln Val Tyr Ala
370 375 380
Pro Leu Arg Ala Asp Gly Asp Lys Pro Arg Ala His Leu Thr Val Val
385 390 395 400
Arg Gln Thr Pro Thr Gln His Phe Lys Asn Gln Phe Pro Ala Leu His
405 410 415
Trp Glu His Glu Leu Gly Leu Ala Phe Thr Lys Asn Arg Met Asn Tyr
420 425 430
Thr Asn Lys Phe Leu Leu Ile Pro Glu Ser Gly Asp Tyr Phe Ile Tyr
435 440 445
Ser Gln Val Thr Phe Arg Gly Met Thr Ser Glu Cys Ser Glu Ile Arg
450 455 460
Gln Ala Gly Arg Pro Asn Lys Pro Asp Ser Ile Thr Val Val Ile Thr
465 470 475 480
Lys Val Thr Asp Ser Tyr Pro Glu Pro Thr Gln Leu Leu Met Gly Thr
485 490 495
Lys Ser Val Cys Glu Val Gly Ser Asn Trp Phe Gln Pro Ile Tyr Leu
500 505 510
Gly Ala Met Phe Ser Leu Gln Glu Gly Asp Lys Leu Met Val Asn Val
515 520 525
Ser Asp Ile Ser Leu Val Asp Tyr Thr Lys Glu Asp Lys Thr Phe Phe
530 535 540
Gly Ala Phe Leu Leu
545
<210> 21
<211> 183
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 21
Met Glu Arg Val Gln Pro Leu Glu Glu Asn Val Gly Asn Ala Ala Arg
1 5 10 15
Pro Arg Phe Glu Arg Asn Lys Leu Leu Leu Val Ala Ser Val Ile Gln
20 25 30
Gly Leu Gly Leu Leu Leu Cys Phe Thr Tyr Ile Cys Leu His Phe Ser
35 40 45
Ala Leu Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val
50 55 60
Gln Phe Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln
65 70 75 80
Lys Glu Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn
85 90 95
Cys Asp Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu
100 105 110
Val Asn Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln
115 120 125
Leu Lys Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr
130 135 140
Tyr Lys Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu
145 150 155 160
Asp Asp Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn
165 170 175
Pro Gly Glu Phe Cys Val Leu
180
<210> 22
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 22
Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val Gln Phe
1 5 10 15
Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln Lys Glu
20 25 30
Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn Cys Asp
35 40 45
Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu Val Asn
50 55 60
Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln Leu Lys
65 70 75 80
Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr Tyr Lys
85 90 95
Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu Asp Asp
100 105 110
Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn Pro Gly
115 120 125
Glu Phe Cys Val Leu
130
<210> 23
<211> 487
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 23
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala
225 230 235 240
Thr Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg
340 345 350
Met Asp Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val
355 360 365
Gln Phe Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln
370 375 380
Lys Glu Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn
385 390 395 400
Cys Asp Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu
405 410 415
Val Asn Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln
420 425 430
Leu Lys Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr
435 440 445
Tyr Lys Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu
450 455 460
Asp Asp Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn
465 470 475 480
Pro Gly Glu Phe Cys Val Leu
485
<210> 24
<211> 150
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 24
Met Lys Thr Leu Pro Ala Met Leu Gly Thr Gly Lys Leu Phe Trp Val
1 5 10 15
Phe Phe Leu Ile Pro Tyr Leu Asp Ile Trp Asn Ile His Gly Lys Glu
20 25 30
Ser Cys Asp Val Gln Leu Tyr Ile Lys Arg Gln Ser Glu His Ser Ile
35 40 45
Leu Ala Gly Asp Pro Phe Glu Leu Glu Cys Pro Val Lys Tyr Cys Ala
50 55 60
Asn Arg Pro His Val Thr Trp Cys Lys Leu Asn Gly Thr Thr Cys Val
65 70 75 80
Lys Leu Glu Asp Arg Gln Thr Ser Trp Lys Glu Glu Lys Asn Ile Ser
85 90 95
Phe Phe Ile Leu His Phe Glu Pro Val Leu Pro Asn Asp Asn Gly Ser
100 105 110
Tyr Arg Cys Ser Ala Asn Phe Gln Ser Asn Leu Ile Glu Ser His Ser
115 120 125
Thr Thr Leu Tyr Val Thr Asp Val Lys Ser Ala Ser Glu Arg Pro Ser
130 135 140
Lys Asp Glu Met Ala Ser
145 150
<210> 25
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 25
Lys Glu Ser Cys Asp Val Gln Leu Tyr Ile Lys Arg Gln Ser Glu His
1 5 10 15
Ser Ile Leu Ala Gly Asp Pro Phe Glu Leu Glu Cys Pro Val Lys Tyr
20 25 30
Cys Ala Asn Arg Pro His Val Thr Trp Cys Lys Leu Asn Gly Thr Thr
35 40 45
Cys Val Lys Leu Glu Asp Arg Gln Thr Ser Trp Lys Glu Glu Lys Asn
50 55 60
Ile Ser Phe Phe Ile Leu His Phe Glu Pro Val Leu Pro Asn Asp Asn
65 70 75 80
Gly Ser Tyr Arg Cys Ser Ala Asn Phe Gln Ser Asn Leu Ile Glu Ser
85 90 95
His Ser Thr Thr Leu Tyr Val Thr Asp Val Lys Ser Ala Ser Glu Arg
100 105 110
Pro Ser Lys Asp Glu Met Ala Ser Arg Pro Trp Leu Leu Tyr Arg
115 120 125
<210> 26
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 26
Met Asp Pro Gly Leu Gln Gln Ala Leu Asn Gly Met Ala Pro Pro Gly
1 5 10 15
Asp Thr Ala Met His Val Pro Ala Gly Ser Val Ala Ser His Leu Gly
20 25 30
Thr Thr Ser Arg Ser Tyr Phe Tyr Leu Thr Thr Ala Thr Leu Ala Leu
35 40 45
Cys Leu Val Phe Thr Val Ala Thr Ile Met Val Leu Val Val Gln Arg
50 55 60
Thr Asp Ser Ile Pro Asn Ser Pro Asp Asn Val Pro Leu Lys Gly Gly
65 70 75 80
Asn Cys Ser Glu Asp Leu Leu Cys Ile Leu Lys Arg Ala Pro Phe Lys
85 90 95
Lys Ser Trp Ala Tyr Leu Gln Val Ala Lys His Leu Asn Lys Thr Lys
100 105 110
Leu Ser Trp Asn Lys Asp Gly Ile Leu His Gly Val Arg Tyr Gln Asp
115 120 125
Gly Asn Leu Val Ile Gln Phe Pro Gly Leu Tyr Phe Ile Ile Cys Gln
130 135 140
Leu Gln Phe Leu Val Gln Cys Pro Asn Asn Ser Val Asp Leu Lys Leu
145 150 155 160
Glu Leu Leu Ile Asn Lys His Ile Lys Lys Gln Ala Leu Val Thr Val
165 170 175
Cys Glu Ser Gly Met Gln Thr Lys His Val Tyr Gln Asn Leu Ser Gln
180 185 190
Phe Leu Leu Asp Tyr Leu Gln Val Asn Thr Thr Ile Ser Val Asn Val
195 200 205
Asp Thr Phe Gln Tyr Ile Asp Thr Ser Thr Phe Pro Leu Glu Asn Val
210 215 220
Leu Ser Ile Phe Leu Tyr Ser Asn Ser Asp
225 230
<210> 27
<211> 172
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 27
Gln Arg Thr Asp Ser Ile Pro Asn Ser Pro Asp Asn Val Pro Leu Lys
1 5 10 15
Gly Gly Asn Cys Ser Glu Asp Leu Leu Cys Ile Leu Lys Arg Ala Pro
20 25 30
Phe Lys Lys Ser Trp Ala Tyr Leu Gln Val Ala Lys His Leu Asn Lys
35 40 45
Thr Lys Leu Ser Trp Asn Lys Asp Gly Ile Leu His Gly Val Arg Tyr
50 55 60
Gln Asp Gly Asn Leu Val Ile Gln Phe Pro Gly Leu Tyr Phe Ile Ile
65 70 75 80
Cys Gln Leu Gln Phe Leu Val Gln Cys Pro Asn Asn Ser Val Asp Leu
85 90 95
Lys Leu Glu Leu Leu Ile Asn Lys His Ile Lys Lys Gln Ala Leu Val
100 105 110
Thr Val Cys Glu Ser Gly Met Gln Thr Lys His Val Tyr Gln Asn Leu
115 120 125
Ser Gln Phe Leu Leu Asp Tyr Leu Gln Val Asn Thr Thr Ile Ser Val
130 135 140
Asn Val Asp Thr Phe Gln Tyr Ile Asp Thr Ser Thr Phe Pro Leu Glu
145 150 155 160
Asn Val Leu Ser Ile Phe Leu Tyr Ser Asn Ser Asp
165 170
<210> 28
<211> 261
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 28
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 29
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 29
His Arg Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp
1 5 10 15
Phe Val Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser
20 25 30
Leu Ser Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe
35 40 45
Val Lys Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser
50 55 60
Phe Glu Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val
65 70 75 80
Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu
85 90 95
Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly
100 105 110
Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln
115 120 125
Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile
130 135 140
Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu
145 150 155 160
Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser
165 170 175
Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe
180 185 190
Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr
195 200 205
Ser Phe Gly Leu Leu Lys Leu
210 215
<210> 30
<211> 281
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 30
Met Gln Gln Pro Phe Asn Tyr Pro Tyr Pro Gln Ile Tyr Trp Val Asp
1 5 10 15
Ser Ser Ala Ser Ser Pro Trp Ala Pro Pro Gly Thr Val Leu Pro Cys
20 25 30
Pro Thr Ser Val Pro Arg Arg Pro Gly Gln Arg Arg Pro Pro Pro Pro
35 40 45
Pro Pro Pro Pro Pro Leu Pro Pro Pro Pro Pro Pro Pro Pro Leu Pro
50 55 60
Pro Leu Pro Leu Pro Pro Leu Lys Lys Arg Gly Asn His Ser Thr Gly
65 70 75 80
Leu Cys Leu Leu Val Met Phe Phe Met Val Leu Val Ala Leu Val Gly
85 90 95
Leu Gly Leu Gly Met Phe Gln Leu Phe His Leu Gln Lys Glu Leu Ala
100 105 110
Glu Leu Arg Glu Ser Thr Ser Gln Met His Thr Ala Ser Ser Leu Glu
115 120 125
Lys Gln Ile Gly His Pro Ser Pro Pro Pro Glu Lys Lys Glu Leu Arg
130 135 140
Lys Val Ala His Leu Thr Gly Lys Ser Asn Ser Arg Ser Met Pro Leu
145 150 155 160
Glu Trp Glu Asp Thr Tyr Gly Ile Val Leu Leu Ser Gly Val Lys Tyr
165 170 175
Lys Lys Gly Gly Leu Val Ile Asn Glu Thr Gly Leu Tyr Phe Val Tyr
180 185 190
Ser Lys Val Tyr Phe Arg Gly Gln Ser Cys Asn Asn Leu Pro Leu Ser
195 200 205
His Lys Val Tyr Met Arg Asn Ser Lys Tyr Pro Gln Asp Leu Val Met
210 215 220
Met Glu Gly Lys Met Met Ser Tyr Cys Thr Thr Gly Gln Met Trp Ala
225 230 235 240
Arg Ser Ser Tyr Leu Gly Ala Val Phe Asn Leu Thr Ser Ala Asp His
245 250 255
Leu Tyr Val Asn Val Ser Glu Leu Ser Leu Val Asn Phe Glu Glu Ser
260 265 270
Gln Thr Phe Phe Gly Leu Tyr Lys Leu
275 280
<210> 31
<211> 179
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 31
Gln Leu Phe His Leu Gln Lys Glu Leu Ala Glu Leu Arg Glu Ser Thr
1 5 10 15
Ser Gln Met His Thr Ala Ser Ser Leu Glu Lys Gln Ile Gly His Pro
20 25 30
Ser Pro Pro Pro Glu Lys Lys Glu Leu Arg Lys Val Ala His Leu Thr
35 40 45
Gly Lys Ser Asn Ser Arg Ser Met Pro Leu Glu Trp Glu Asp Thr Tyr
50 55 60
Gly Ile Val Leu Leu Ser Gly Val Lys Tyr Lys Lys Gly Gly Leu Val
65 70 75 80
Ile Asn Glu Thr Gly Leu Tyr Phe Val Tyr Ser Lys Val Tyr Phe Arg
85 90 95
Gly Gln Ser Cys Asn Asn Leu Pro Leu Ser His Lys Val Tyr Met Arg
100 105 110
Asn Ser Lys Tyr Pro Gln Asp Leu Val Met Met Glu Gly Lys Met Met
115 120 125
Ser Tyr Cys Thr Thr Gly Gln Met Trp Ala Arg Ser Ser Tyr Leu Gly
130 135 140
Ala Val Phe Asn Leu Thr Ser Ala Asp His Leu Tyr Val Asn Val Ser
145 150 155 160
Glu Leu Ser Leu Val Asn Phe Glu Glu Ser Gln Thr Phe Phe Gly Leu
165 170 175
Tyr Lys Leu
<210> 32
<400> 32
000
<210> 33
<400> 33
000
<210> 34
<400> 34
000
<210> 35
<400> 35
000
<210> 36
<211> 202
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 36
Met Phe Ser His Leu Pro Phe Asp Cys Val Leu Leu Leu Leu Leu Leu
1 5 10 15
Leu Leu Thr Arg Ser Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln
20 25 30
Asn Ala Tyr Leu Pro Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu
35 40 45
Val Pro Val Cys Trp Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly
50 55 60
Asn Val Val Leu Arg Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser
65 70 75 80
Arg Tyr Trp Leu Asn Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr
85 90 95
Ile Glu Asn Val Thr Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile
100 105 110
Gln Ile Pro Gly Ile Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val
115 120 125
Ile Lys Pro Ala Lys Val Thr Pro Ala Pro Thr Arg Gln Arg Asp Phe
130 135 140
Thr Ala Ala Phe Pro Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala
145 150 155 160
Glu Thr Gln Thr Leu Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile
165 170 175
Ser Thr Leu Ala Asn Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu
180 185 190
Arg Asp Ser Gly Ala Thr Ile Arg Ile Gly
195 200
<210> 37
<211> 181
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 37
Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln Asn Ala Tyr Leu Pro
1 5 10 15
Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu Val Pro Val Cys Trp
20 25 30
Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly Asn Val Val Leu Arg
35 40 45
Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser Arg Tyr Trp Leu Asn
50 55 60
Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr Ile Glu Asn Val Thr
65 70 75 80
Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile Gln Ile Pro Gly Ile
85 90 95
Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val Ile Lys Pro Ala Lys
100 105 110
Val Thr Pro Ala Pro Thr Arg Gln Arg Asp Phe Thr Ala Ala Phe Pro
115 120 125
Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala Glu Thr Gln Thr Leu
130 135 140
Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile Ser Thr Leu Ala Asn
145 150 155 160
Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu Arg Asp Ser Gly Ala
165 170 175
Thr Ile Arg Ile Gly
180
<210> 38
<211> 150
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 38
Met Gly Ser Pro Gly Met Val Leu Gly Leu Leu Val Gln Ile Trp Ala
1 5 10 15
Leu Gln Glu Ala Ser Ser Leu Ser Val Gln Gln Gly Pro Asn Leu Leu
20 25 30
Gln Val Arg Gln Gly Ser Gln Ala Thr Leu Val Cys Gln Val Asp Gln
35 40 45
Ala Thr Ala Trp Glu Arg Leu Arg Val Lys Trp Thr Lys Asp Gly Ala
50 55 60
Ile Leu Cys Gln Pro Tyr Ile Thr Asn Gly Ser Leu Ser Leu Gly Val
65 70 75 80
Cys Gly Pro Gln Gly Arg Leu Ser Trp Gln Ala Pro Ser His Leu Thr
85 90 95
Leu Gln Leu Asp Pro Val Ser Leu Asn His Ser Gly Ala Tyr Val Cys
100 105 110
Trp Ala Ala Val Glu Ile Pro Glu Leu Glu Glu Ala Glu Gly Asn Ile
115 120 125
Thr Arg Leu Phe Val Asp Pro Asp Asp Pro Thr Gln Asn Arg Asn Arg
130 135 140
Ile Ala Ser Phe Pro Gly
145 150
<210> 39
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 39
Leu Ser Val Gln Gln Gly Pro Asn Leu Leu Gln Val Arg Gln Gly Ser
1 5 10 15
Gln Ala Thr Leu Val Cys Gln Val Asp Gln Ala Thr Ala Trp Glu Arg
20 25 30
Leu Arg Val Lys Trp Thr Lys Asp Gly Ala Ile Leu Cys Gln Pro Tyr
35 40 45
Ile Thr Asn Gly Ser Leu Ser Leu Gly Val Cys Gly Pro Gln Gly Arg
50 55 60
Leu Ser Trp Gln Ala Pro Ser His Leu Thr Leu Gln Leu Asp Pro Val
65 70 75 80
Ser Leu Asn His Ser Gly Ala Tyr Val Cys Trp Ala Ala Val Glu Ile
85 90 95
Pro Glu Leu Glu Glu Ala Glu Gly Asn Ile Thr Arg Leu Phe Val Asp
100 105 110
Pro Asp Asp Pro Thr Gln Asn Arg Asn Arg Ile Ala Ser Phe Pro Gly
115 120 125
<210> 40
<211> 281
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 40
Met Ala Met Met Glu Val Gln Gly Gly Pro Ser Leu Gly Gln Thr Cys
1 5 10 15
Val Leu Ile Val Ile Phe Thr Val Leu Leu Gln Ser Leu Cys Val Ala
20 25 30
Val Thr Tyr Val Tyr Phe Thr Asn Glu Leu Lys Gln Met Gln Asp Lys
35 40 45
Tyr Ser Lys Ser Gly Ile Ala Cys Phe Leu Lys Glu Asp Asp Ser Tyr
50 55 60
Trp Asp Pro Asn Asp Glu Glu Ser Met Asn Ser Pro Cys Trp Gln Val
65 70 75 80
Lys Trp Gln Leu Arg Gln Leu Val Arg Lys Met Ile Leu Arg Thr Ser
85 90 95
Glu Glu Thr Ile Ser Thr Val Gln Glu Lys Gln Gln Asn Ile Ser Pro
100 105 110
Leu Val Arg Glu Arg Gly Pro Gln Arg Val Ala Ala His Ile Thr Gly
115 120 125
Thr Arg Gly Arg Ser Asn Thr Leu Ser Ser Pro Asn Ser Lys Asn Glu
130 135 140
Lys Ala Leu Gly Arg Lys Ile Asn Ser Trp Glu Ser Ser Arg Ser Gly
145 150 155 160
His Ser Phe Leu Ser Asn Leu His Leu Arg Asn Gly Glu Leu Val Ile
165 170 175
His Glu Lys Gly Phe Tyr Tyr Ile Tyr Ser Gln Thr Tyr Phe Arg Phe
180 185 190
Gln Glu Glu Ile Lys Glu Asn Thr Lys Asn Asp Lys Gln Met Val Gln
195 200 205
Tyr Ile Tyr Lys Tyr Thr Ser Tyr Pro Asp Pro Ile Leu Leu Met Lys
210 215 220
Ser Ala Arg Asn Ser Cys Trp Ser Lys Asp Ala Glu Tyr Gly Leu Tyr
225 230 235 240
Ser Ile Tyr Gln Gly Gly Ile Phe Glu Leu Lys Glu Asn Asp Arg Ile
245 250 255
Phe Val Ser Val Thr Asn Glu His Leu Ile Asp Met Asp His Glu Ala
260 265 270
Ser Phe Phe Gly Ala Phe Leu Val Gly
275 280
<210> 41
<211> 243
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 41
Thr Asn Glu Leu Lys Gln Met Gln Asp Lys Tyr Ser Lys Ser Gly Ile
1 5 10 15
Ala Cys Phe Leu Lys Glu Asp Asp Ser Tyr Trp Asp Pro Asn Asp Glu
20 25 30
Glu Ser Met Asn Ser Pro Cys Trp Gln Val Lys Trp Gln Leu Arg Gln
35 40 45
Leu Val Arg Lys Met Ile Leu Arg Thr Ser Glu Glu Thr Ile Ser Thr
50 55 60
Val Gln Glu Lys Gln Gln Asn Ile Ser Pro Leu Val Arg Glu Arg Gly
65 70 75 80
Pro Gln Arg Val Ala Ala His Ile Thr Gly Thr Arg Gly Arg Ser Asn
85 90 95
Thr Leu Ser Ser Pro Asn Ser Lys Asn Glu Lys Ala Leu Gly Arg Lys
100 105 110
Ile Asn Ser Trp Glu Ser Ser Arg Ser Gly His Ser Phe Leu Ser Asn
115 120 125
Leu His Leu Arg Asn Gly Glu Leu Val Ile His Glu Lys Gly Phe Tyr
130 135 140
Tyr Ile Tyr Ser Gln Thr Tyr Phe Arg Phe Gln Glu Glu Ile Lys Glu
145 150 155 160
Asn Thr Lys Asn Asp Lys Gln Met Val Gln Tyr Ile Tyr Lys Tyr Thr
165 170 175
Ser Tyr Pro Asp Pro Ile Leu Leu Met Lys Ser Ala Arg Asn Ser Cys
180 185 190
Trp Ser Lys Asp Ala Glu Tyr Gly Leu Tyr Ser Ile Tyr Gln Gly Gly
195 200 205
Ile Phe Glu Leu Lys Glu Asn Asp Arg Ile Phe Val Ser Val Thr Asn
210 215 220
Glu His Leu Ile Asp Met Asp His Glu Ala Ser Phe Phe Gly Ala Phe
225 230 235 240
Leu Val Gly
<210> 42
<211> 543
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 42
Lys Glu Ser Cys Asp Val Gln Leu Tyr Ile Lys Arg Gln Ser Glu His
1 5 10 15
Ser Ile Leu Ala Gly Asp Pro Phe Glu Leu Glu Cys Pro Val Lys Tyr
20 25 30
Cys Ala Asn Arg Pro His Val Thr Trp Cys Lys Leu Asn Gly Thr Thr
35 40 45
Cys Val Lys Leu Glu Asp Arg Gln Thr Ser Trp Lys Glu Glu Lys Asn
50 55 60
Ile Ser Phe Phe Ile Leu His Phe Glu Pro Val Leu Pro Asn Asp Asn
65 70 75 80
Gly Ser Tyr Arg Cys Ser Ala Asn Phe Gln Ser Asn Leu Ile Glu Ser
85 90 95
His Ser Thr Thr Leu Tyr Val Thr Asp Val Lys Ser Ala Ser Glu Arg
100 105 110
Pro Ser Lys Asp Glu Met Ala Ser Arg Pro Trp Leu Leu Tyr Arg Ser
115 120 125
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
130 135 140
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met
145 150 155 160
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
165 170 175
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
180 185 190
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
195 200 205
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ser Gly
210 215 220
Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser Ile
225 230 235 240
Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln Val
245 250 255
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
260 265 270
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
275 280 285
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
290 295 300
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
305 310 315 320
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu
325 330 335
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
340 345 350
Leu Gly Lys Ile Glu Gly Arg Met Asp Leu Gln Leu His Trp Arg Leu
355 360 365
Gly Glu Met Val Thr Arg Leu Pro Asp Gly Pro Ala Gly Ser Trp Glu
370 375 380
Gln Leu Ile Gln Glu Arg Arg Ser His Glu Val Asn Pro Ala Ala His
385 390 395 400
Leu Thr Gly Ala Asn Ser Ser Leu Thr Gly Ser Gly Gly Pro Leu Leu
405 410 415
Trp Glu Thr Gln Leu Gly Leu Ala Phe Leu Arg Gly Leu Ser Tyr His
420 425 430
Asp Gly Ala Leu Val Val Thr Lys Ala Gly Tyr Tyr Tyr Ile Tyr Ser
435 440 445
Lys Val Gln Leu Gly Gly Val Gly Cys Pro Leu Gly Leu Ala Ser Thr
450 455 460
Ile Thr His Gly Leu Tyr Lys Arg Thr Pro Arg Tyr Pro Glu Glu Leu
465 470 475 480
Glu Leu Leu Val Ser Gln Gln Ser Pro Cys Gly Arg Ala Thr Ser Ser
485 490 495
Ser Arg Val Trp Trp Asp Ser Ser Phe Leu Gly Gly Val Val His Leu
500 505 510
Glu Ala Gly Glu Lys Val Val Val Arg Val Leu Asp Glu Arg Leu Val
515 520 525
Arg Leu Arg Asp Gly Thr Arg Ser Tyr Phe Gly Ala Phe Met Val
530 535 540
<210> 43
<211> 838
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 43
Val Pro Val Val Trp Ala Gln Glu Gly Ala Pro Ala Gln Leu Pro Cys
1 5 10 15
Ser Pro Thr Ile Pro Leu Gln Asp Leu Ser Leu Leu Arg Arg Ala Gly
20 25 30
Val Thr Trp Gln His Gln Pro Asp Ser Gly Pro Pro Ala Ala Ala Pro
35 40 45
Gly His Pro Leu Ala Pro Gly Pro His Pro Ala Ala Pro Ser Ser Trp
50 55 60
Gly Pro Arg Pro Arg Arg Tyr Thr Val Leu Ser Val Gly Pro Gly Gly
65 70 75 80
Leu Arg Ser Gly Arg Leu Pro Leu Gln Pro Arg Val Gln Leu Asp Glu
85 90 95
Arg Gly Arg Gln Arg Gly Asp Phe Ser Leu Trp Leu Arg Pro Ala Arg
100 105 110
Arg Ala Asp Ala Gly Glu Tyr Arg Ala Ala Val His Leu Arg Asp Arg
115 120 125
Ala Leu Ser Cys Arg Leu Arg Leu Arg Leu Gly Gln Ala Ser Met Thr
130 135 140
Ala Ser Pro Pro Gly Ser Leu Arg Ala Ser Asp Trp Val Ile Leu Asn
145 150 155 160
Cys Ser Phe Ser Arg Pro Asp Arg Pro Ala Ser Val His Trp Phe Arg
165 170 175
Asn Arg Gly Gln Gly Arg Val Pro Val Arg Glu Ser Pro His His His
180 185 190
Leu Ala Glu Ser Phe Leu Phe Leu Pro Gln Val Ser Pro Met Asp Ser
195 200 205
Gly Pro Trp Gly Cys Ile Leu Thr Tyr Arg Asp Gly Phe Asn Val Ser
210 215 220
Ile Met Tyr Asn Leu Thr Val Leu Gly Leu Glu Pro Pro Thr Pro Leu
225 230 235 240
Thr Val Tyr Ala Gly Ala Gly Ser Arg Val Gly Leu Pro Cys Arg Leu
245 250 255
Pro Ala Gly Val Gly Thr Arg Ser Phe Leu Thr Ala Lys Trp Thr Pro
260 265 270
Pro Gly Gly Gly Pro Asp Leu Leu Val Thr Gly Asp Asn Gly Asp Phe
275 280 285
Thr Leu Arg Leu Glu Asp Val Ser Gln Ala Gln Ala Gly Thr Tyr Thr
290 295 300
Cys His Ile His Leu Gln Glu Gln Gln Leu Asn Ala Thr Val Thr Leu
305 310 315 320
Ala Ile Ile Thr Val Thr Pro Lys Ser Phe Gly Ser Pro Gly Ser Leu
325 330 335
Gly Lys Leu Leu Cys Glu Val Thr Pro Val Ser Gly Gln Glu Arg Phe
340 345 350
Val Trp Ser Ser Leu Asp Thr Pro Ser Gln Arg Ser Phe Ser Gly Pro
355 360 365
Trp Leu Glu Ala Gln Glu Ala Gln Leu Leu Ser Gln Pro Trp Gln Cys
370 375 380
Gln Leu Tyr Gln Gly Glu Arg Leu Leu Gly Ala Ala Val Tyr Phe Thr
385 390 395 400
Glu Leu Ser Ser Pro Gly Ala Gln Arg Ser Gly Arg Ala Pro Gly Ala
405 410 415
Leu Pro Ala Gly His Leu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
420 425 430
Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
435 440 445
Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
450 455 460
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
465 470 475 480
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
485 490 495
Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
500 505 510
His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser
515 520 525
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly
530 535 540
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
545 550 555 560
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
565 570 575
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
580 585 590
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
595 600 605
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
610 615 620
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr
625 630 635 640
Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
645 650 655
Leu Gln Leu His Trp Arg Leu Gly Glu Met Val Thr Arg Leu Pro Asp
660 665 670
Gly Pro Ala Gly Ser Trp Glu Gln Leu Ile Gln Glu Arg Arg Ser His
675 680 685
Glu Val Asn Pro Ala Ala His Leu Thr Gly Ala Asn Ser Ser Leu Thr
690 695 700
Gly Ser Gly Gly Pro Leu Leu Trp Glu Thr Gln Leu Gly Leu Ala Phe
705 710 715 720
Leu Arg Gly Leu Ser Tyr His Asp Gly Ala Leu Val Val Thr Lys Ala
725 730 735
Gly Tyr Tyr Tyr Ile Tyr Ser Lys Val Gln Leu Gly Gly Val Gly Cys
740 745 750
Pro Leu Gly Leu Ala Ser Thr Ile Thr His Gly Leu Tyr Lys Arg Thr
755 760 765
Pro Arg Tyr Pro Glu Glu Leu Glu Leu Leu Val Ser Gln Gln Ser Pro
770 775 780
Cys Gly Arg Ala Thr Ser Ser Ser Arg Val Trp Trp Asp Ser Ser Phe
785 790 795 800
Leu Gly Gly Val Val His Leu Glu Ala Gly Glu Lys Val Val Val Arg
805 810 815
Val Leu Asp Glu Arg Leu Val Arg Leu Arg Asp Gly Thr Arg Ser Tyr
820 825 830
Phe Gly Ala Phe Met Val
835
<210> 44
<211> 597
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 44
Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln Asn Ala Tyr Leu Pro
1 5 10 15
Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu Val Pro Val Cys Trp
20 25 30
Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly Asn Val Val Leu Arg
35 40 45
Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser Arg Tyr Trp Leu Asn
50 55 60
Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr Ile Glu Asn Val Thr
65 70 75 80
Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile Gln Ile Pro Gly Ile
85 90 95
Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val Ile Lys Pro Ala Lys
100 105 110
Val Thr Pro Ala Pro Thr Arg Gln Arg Asp Phe Thr Ala Ala Phe Pro
115 120 125
Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala Glu Thr Gln Thr Leu
130 135 140
Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile Ser Thr Leu Ala Asn
145 150 155 160
Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu Arg Asp Ser Gly Ala
165 170 175
Thr Ile Arg Ile Gly Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
180 185 190
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
195 200 205
Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
210 215 220
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
225 230 235 240
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
245 250 255
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
260 265 270
Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys
275 280 285
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln
290 295 300
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
305 310 315 320
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
325 330 335
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
340 345 350
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
355 360 365
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg Met Asp Leu
405 410 415
Gln Leu His Trp Arg Leu Gly Glu Met Val Thr Arg Leu Pro Asp Gly
420 425 430
Pro Ala Gly Ser Trp Glu Gln Leu Ile Gln Glu Arg Arg Ser His Glu
435 440 445
Val Asn Pro Ala Ala His Leu Thr Gly Ala Asn Ser Ser Leu Thr Gly
450 455 460
Ser Gly Gly Pro Leu Leu Trp Glu Thr Gln Leu Gly Leu Ala Phe Leu
465 470 475 480
Arg Gly Leu Ser Tyr His Asp Gly Ala Leu Val Val Thr Lys Ala Gly
485 490 495
Tyr Tyr Tyr Ile Tyr Ser Lys Val Gln Leu Gly Gly Val Gly Cys Pro
500 505 510
Leu Gly Leu Ala Ser Thr Ile Thr His Gly Leu Tyr Lys Arg Thr Pro
515 520 525
Arg Tyr Pro Glu Glu Leu Glu Leu Leu Val Ser Gln Gln Ser Pro Cys
530 535 540
Gly Arg Ala Thr Ser Ser Ser Arg Val Trp Trp Asp Ser Ser Phe Leu
545 550 555 560
Gly Gly Val Val His Leu Glu Ala Gly Glu Lys Val Val Val Arg Val
565 570 575
Leu Asp Glu Arg Leu Val Arg Leu Arg Asp Gly Thr Arg Ser Tyr Phe
580 585 590
Gly Ala Phe Met Val
595
<210> 45
<211> 569
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 45
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Ser Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala
225 230 235 240
Thr Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ile Glu Gly Arg
340 345 350
Met Asp His Arg Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His
355 360 365
Glu Asp Phe Val Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu
370 375 380
Arg Ser Leu Ser Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu
385 390 395 400
Gly Phe Val Lys Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu
405 410 415
Asn Ser Phe Glu Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala
420 425 430
His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp
435 440 445
Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu
450 455 460
Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr
465 470 475 480
Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro
485 490 495
Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile
500 505 510
Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln
515 520 525
Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser
530 535 540
Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly
545 550 555 560
Phe Thr Ser Phe Gly Leu Leu Lys Leu
565
<210> 46
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 46
Ala Pro Glu Phe 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 Gln Glu Asp Pro Glu Val Gln 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 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
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 Arg Leu Thr Val Asp Lys Ser Ser Trp Gln Glu 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 Leu Gly Lys
210 215
<210> 47
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 47
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 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 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Thr Pro His
65 70 75 80
Ser Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
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 Arg Leu Thr Val Asp Lys Ser Ser Trp Gln Glu Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 48
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 48
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 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 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Ser Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
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 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 49
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 49
Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro
1 5 10
<210> 50
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 50
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 51
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 51
Ser Lys Tyr Gly Pro Pro
1 5
<210> 52
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 52
Ile Glu Gly Arg Met Asp
1 5
<210> 53
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 53
Gly Gly Gly Val Pro Arg Asp Cys Gly
1 5
<210> 54
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 54
Ile Glu Gly Arg Met Asp Gly Gly Gly Gly Ala Gly Gly Gly Gly
1 5 10 15
<210> 55
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 55
Gly Gly Gly Ser Gly Gly Gly Ser
1 5
<210> 56
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 56
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10
<210> 57
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 57
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr
1 5 10
<210> 58
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 58
Gly Gly Ser Gly
1
<210> 59
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 59
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
1 5 10
<210> 60
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 60
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
<210> 61
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 61
Glu Ala Ala Ala Arg Glu Ala Ala Ala Arg Glu Ala Ala Ala Arg Glu
1 5 10 15
Ala Ala Ala Arg
20
<210> 62
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 62
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1 5 10 15
Ser
<210> 63
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 63
Gly Gly Gly Gly Ala Gly Gly Gly Gly
1 5
<210> 64
<400> 64
000
<210> 65
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 65
Gly Ser Gly Ser Gly Ser
1 5
<210> 66
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 66
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10
<210> 67
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 67
Gly Gly Gly Gly Ser Ala Ser
1 5
<210> 68
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 68
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10 15
Ala Pro Ala Pro
20
<210> 69
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 69
Cys Pro Pro Cys
1
<210> 70
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 70
Gly Gly Gly Gly Ser
1 5
<210> 71
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 71
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 72
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 72
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 73
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 73
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 74
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 74
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 Gly Gly Gly Ser
20 25
<210> 75
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 75
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 Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
<210> 76
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 76
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 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser
35
<210> 77
<211> 40
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 77
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 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser
35 40
<210> 78
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 78
Gly Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 79
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 79
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 80
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 80
Gly Gly Gly Gly Gly Gly
1 5
<210> 81
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 81
Glu Ala Ala Ala Lys
1 5
<210> 82
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 82
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10
<210> 83
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 83
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
<210> 84
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 84
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
1 5 10
<210> 85
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 85
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Ala
<210> 86
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 86
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala
20
<210> 87
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 87
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
20 25
<210> 88
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 88
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
35 40 45
<210> 89
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 89
Pro Ala Pro Ala Pro
1 5
<210> 90
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 90
Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser
1 5 10 15
Leu Asp
<210> 91
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 91
Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe
1 5 10
<210> 92
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 92
Gly Gly Gly Ser Glu
1 5
<210> 93
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 93
Gly Ser Glu Ser Gly
1 5
<210> 94
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 94
Gly Ser Glu Gly Ser
1 5
<210> 95
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 95
Gly Glu Gly Gly Ser Gly Glu Gly Ser Ser Gly Glu Gly Ser Ser Ser
1 5 10 15
Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu
20 25 30
Gly Gly Ser
35
<210> 96
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 96
Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu
1 5 10 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ser
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Ser Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
225 230
<210> 97
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 97
Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu
1 5 10 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Thr Pro His Ser Asp Trp Leu Ser
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Ser Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
225 230
<210> 98
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 98
Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu
1 5 10 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ser
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
225 230
<210> 99
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 99
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
1 5 10 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ser
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Ser Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
225 230
<210> 100
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 100
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
1 5 10 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Thr Pro His Ser Asp Trp Leu Ser
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Ser Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
225 230
<210> 101
<211> 234
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 101
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
1 5 10 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Ser
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Ser Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Asn Ala Thr Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Leu Gly Lys Ile Glu Gly Arg Met Asp
225 230
Claims (47)
1.一种嵌合蛋白,其具有以下一般结构:
N末端–(a)–(b)–(c)–C末端,
其中:
(a)是第一结构域,其包含I型跨膜蛋白的细胞外结构域,所述跨膜蛋白是TIGIT,
(b)是接头,其包含至少一个能够形成二硫键的半胱氨酸残基,并且
(c)是第二结构域,其包含II型跨膜蛋白的细胞外结构域,所述跨膜蛋白选自4-1BBL、GITRL、TL1A和LIGHT,其中:
所述接头连接所述第一结构域和所述第二结构域,并且任选地包含一个或多个连接接头,此类连接接头选自SEQ ID NO:49-95。
2.如权利要求1所述的嵌合蛋白,其中所述第二结构域是4-1BBL。
3.如权利要求1所述的嵌合蛋白,其中所述第二结构域是GITRL。
4.如权利要求1所述的嵌合蛋白,其中所述第二结构域是TL1A。
5.如权利要求1所述的嵌合蛋白,其中所述第二结构域是LIGHT。
6.一种嵌合蛋白,其具有以下一般结构:
N末端–(a)–(b)–(c)–C末端,
其中:
(a)是第一结构域,其包含I型跨膜蛋白的细胞外结构域,所述跨膜蛋白选自PD-1、CD172a(SIRPα)和TIGIT,
(b)是接头,其包含至少一个能够形成二硫键的半胱氨酸残基,并且
(c)是第二结构域,其包含II型跨膜蛋白的细胞外结构域,所述跨膜蛋白是LIGHT,其中:
所述接头连接所述第一结构域和所述第二结构域,并且任选地包含一个或多个连接接头,此类连接接头选自SEQ ID NO:49-95。
7.如权利要求6所述的嵌合蛋白,其中所述第一结构域是PD-1。
8.如权利要求6所述的嵌合蛋白,其中所述第一结构域是CD172a(SIRPα)。
9.如权利要求6所述的嵌合蛋白,其中所述第一结构域是TIGIT。
10.如权利要求1至9中任一项所述的嵌合蛋白,其中所述接头是选自柔性氨基酸序列、IgG铰链区或抗体序列的多肽。
11.如权利要求1至10中任一项所述的嵌合蛋白,其中所述接头包含衍生自IgG4的铰链-CH2-CH3 Fc结构域。
12.如权利要求11所述的嵌合蛋白,其中所述铰链-CH2-CH3 Fc结构域衍生自人IgG4。
13.如权利要求11或权利要求12所述的嵌合蛋白,其中所述接头包含与SEQ ID NO:46或SEQ ID NO:47的氨基酸序列具有至少95%同一性的氨基酸序列。
14.如权利要求11或权利要求12所述的嵌合蛋白,其中所述接头包含与SEQ ID NO:48的氨基酸序列具有至少95%同一性的氨基酸序列。
15.如权利要求10至14中任一项所述的嵌合蛋白,其中所述接头包含一个或多个连接接头,此类连接接头独立地选自SEQ ID NO:49-95。
16.如权利要求15所述的嵌合蛋白,其中所述接头包含两个或更多个连接接头,每个连接接头独立地选自SEQ ID NO:49-95;其中一个连接接头在所述铰链-CH2-CH3 Fc结构域的N末端,并且另一个连接接头在所述铰链-CH2-CH3 Fc结构域的C末端。
17.如权利要求1至16中任一项所述的嵌合蛋白,其中所述嵌合蛋白是重组融合蛋白。
18.如权利要求1至17中任一项所述的嵌合蛋白,其中所述嵌合蛋白能够在细胞之间形成稳定突触。
19.如权利要求18所述的嵌合蛋白,其中所述细胞之间的稳定突触提供有利于肿瘤减少的空间取向。
20.如权利要求18或权利要求19所述的嵌合蛋白,其中所述空间取向定位T细胞以攻击肿瘤细胞和/或在空间上防止肿瘤细胞递送负信号,包括超出本发明的嵌合蛋白掩蔽的那些信号的负信号。
21.如权利要求1至20中任一项所述的嵌合蛋白,其中所述细胞外结构域中的一者或两者与其各自的结合配偶体的结合以低解离速率(Koff)发生,其提供受体与其配体的长相互作用。
22.如权利要求21所述的嵌合蛋白,其中所述长相互作用提供持续的负信号掩蔽效果。
23.如权利要求21或权利要求22所述的嵌合蛋白,其中所述长相互作用递送更长的正信号效果。
24.如权利要求23所述的嵌合蛋白,其中所述更长的正信号效果允许效应细胞被足够地刺激以用于抗肿瘤效果。
25.如权利要求21至24中任一项所述的嵌合蛋白,其中所述长相互作用提供T细胞增殖并允许抗肿瘤攻击。
26.如权利要求21至25中任一项所述的嵌合蛋白,其中所述长相互作用允许足够的信号传递以提供刺激信号的释放。
27.如权利要求26所述的嵌合蛋白,其中所述刺激信号是细胞因子。
28.如权利要求1所述的嵌合蛋白,其中所述嵌合蛋白具有与SEQ ID NO:14、17或20的氨基酸序列具有至少95%同一性的氨基酸序列。
29.如权利要求6所述的嵌合蛋白,其中所述嵌合蛋白具有与SEQ ID NO:5、8或11的氨基酸序列具有至少95%同一性的氨基酸序列。
30.一种表达载体,其包含编码如权利要求1至29中任一项所述的嵌合蛋白的核酸。
31.一种宿主细胞,其包含如权利要求30所述的表达载体。
32.一种药物组合物,其包含治疗有效量的如权利要求1至29中任一项所述的嵌合蛋白。
33.一种治疗癌症或炎性疾病的方法,其包括向有需要的受试者施用有效量的如权利要求32所述的药物组合物。
34.一种调节患者的免疫应答的方法,其包括向有需要的受试者施用有效量的如权利要求32所述的药物组合物。
35.如权利要求33或权利要求34所述的方法,其中所述患者的T细胞被活化。
36.如权利要求33至35中任一项所述的方法,其中所述患者具有肿瘤,并且预防一种或多种肿瘤细胞传递免疫抑制信号。
37.一种用于治疗癌症或炎性疾病的方法,其包括向有需要的受试者施用有效量的药物组合物,所述药物组合物包含嵌合蛋白,所述嵌合蛋白包含:
(a)第一结构域,其包含I型跨膜蛋白的细胞外结构域,所述跨膜蛋白是TIGIT,
(b)接头,其包含至少一个能够形成二硫键的半胱氨酸残基,以及
(c)第二结构域,其包含II型跨膜蛋白的细胞外结构域,所述跨膜蛋白选自4-1BBL、GITRL、TL1A和LIGHT。
38.一种用于治疗癌症或炎性疾病的方法,其包括向有需要的受试者施用有效量的药物组合物,所述药物组合物包含嵌合蛋白,所述嵌合蛋白包含:
(a)第一结构域,其包含I型跨膜蛋白的细胞外结构域,所述跨膜蛋白选自PD-1、CD172a(SIRPα)和TIGIT,
(b)接头,其包含至少一个能够形成二硫键的半胱氨酸残基,以及
(c)第二结构域,其包含II型跨膜蛋白的细胞外结构域,所述跨膜蛋白是LIGHT。
39.如权利要求37或38所述的方法,其中当与所述嵌合蛋白的所述第二结构域结合时,所述受试者的T细胞被活化,并且:
(a)当与所述嵌合蛋白的所述第一结构域结合时,预防一种或多种肿瘤细胞传递免疫抑制信号,
(b)所述受试者的外周血中的可定量的细胞因子应答被活化,并且/或者
(c)与用针对所述I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述有需要的受试者中的肿瘤生长减少。
40.如权利要求33至39中任一项所述的方法,其中所述方法刺激LIGHT、4-1BBL、GITRL和TL1A中的一种或多种的信号传导,并且活化抗原呈递细胞。
41.如权利要求33至40中任一项所述的方法,其中与未治疗的受试者或用针对所述I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述方法减少调节T细胞(Treg)的量或活性。
42.如权利要求33至41中任一项所述的方法,其中与未治疗的受试者或用针对所述I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述方法增加所述受试者的引流淋巴结中效应T细胞的引发。
43.如权利要求33至42中任一项所述的方法,其中与未治疗的受试者或用针对所述I型或II型蛋白的抗体或其各自的配体或受体治疗的受试者相比,所述方法引起免疫抑制细胞的总体降低和朝向更具炎性的肿瘤环境的转移。
44.如权利要求1至29中任一项所述的嵌合蛋白,其用作药物。
45.如权利要求1至29中任一项所述的嵌合蛋白,其用于治疗癌症。
46.如权利要求1至29中任一项所述的嵌合蛋白,其用于治疗炎性疾病。
47.如权利要求1至29中任一项所述的嵌合蛋白在制造药物中的用途。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114209815A (zh) * | 2021-11-22 | 2022-03-22 | 山东大学 | 一种药物组合物及其制备方法和应用 |
WO2022179567A1 (zh) * | 2021-02-24 | 2022-09-01 | 克莱格医学有限公司 | Tigit工程化细胞及其组合物 |
CN115260312A (zh) * | 2021-04-30 | 2022-11-01 | 保诺科技(北京)有限公司 | 结合ox40的抗体或抗原结合片段 |
WO2024046394A1 (zh) * | 2022-08-30 | 2024-03-07 | 北京卡替医疗技术有限公司 | 增强受体、表达增强受体的免疫细胞及其用途 |
WO2024119768A1 (zh) * | 2022-12-06 | 2024-06-13 | 上海恩凯细胞技术有限公司 | 逆转肿瘤微环境抑制性信号的nk细胞制备方法及应用 |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110234345A (zh) * | 2017-02-27 | 2019-09-13 | 沙塔克实验室有限公司 | 制备和使用基于细胞外结构域的嵌合蛋白的方法 |
AU2019290192A1 (en) * | 2018-06-21 | 2021-01-07 | Shattuck Labs, Inc. | Heterodimeric proteins and uses thereof |
WO2020047322A1 (en) * | 2018-08-29 | 2020-03-05 | Shattuck Labs, Inc. | Combination therapies comprising tim-3-based chimeric proteins |
CA3109354A1 (en) | 2018-08-29 | 2020-03-05 | Shattuck Labs, Inc. | Combination therapies comprising pd-1-based chimeric proteins |
US20210324041A1 (en) * | 2018-08-29 | 2021-10-21 | Shattuck Labs, Inc. | Combination therapies |
US20220119782A1 (en) * | 2018-08-31 | 2022-04-21 | Yale University | ENPP1 Polypeptides and Methods of Using Same |
JP2022524173A (ja) * | 2018-09-05 | 2022-04-28 | アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・アリゾナ・ステイト・ユニバーシティー | 血液癌を処置するための腫瘍溶解性ウイルスプラットフォーム |
KR20210093303A (ko) | 2018-11-21 | 2021-07-27 | 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 | 아데노바이러스 및 아데노바이러스의 사용 방법 |
AU2020228053A1 (en) * | 2019-02-28 | 2021-09-23 | Shattuck Labs, Inc. | Combination therapies |
KR20210144818A (ko) * | 2019-04-29 | 2021-11-30 | 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 | 암을 치료하기 위한 다가 pd-l1 결합 화합물 |
CN112111437B (zh) * | 2020-05-25 | 2023-09-05 | 江南大学 | 2’-岩藻糖基乳糖产量提高的重组枯草芽孢杆菌及其构建方法 |
BR112022025801A2 (pt) | 2020-06-18 | 2023-10-03 | Hoffmann La Roche | Métodos para tratar um paciente e para tratar um paciente com escc avançado, kit, anticorpo, uso de um anticorpo e uso de um antagonista de ligação |
TW202216778A (zh) | 2020-07-15 | 2022-05-01 | 美商安進公司 | Tigit及cd112r阻斷 |
CN111808800B (zh) * | 2020-07-20 | 2022-08-26 | 中南大学湘雅二医院 | 一种体外诱导免疫抑制性髓系抑制细胞及其制备和应用 |
IL301454A (en) * | 2020-09-17 | 2023-05-01 | Shattuck Labs Inc | Clinical dosing of SIRP1A chimeric protein |
EP4377350A2 (en) | 2021-07-28 | 2024-06-05 | Genentech, Inc. | Methods and compositions for treating cancer |
WO2023056403A1 (en) | 2021-09-30 | 2023-04-06 | Genentech, Inc. | Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists |
WO2023077152A2 (en) * | 2021-11-01 | 2023-05-04 | Shattuck Labs, Inc. | Chimeric proteins for treating cutaneous inflammation |
WO2023105281A1 (en) * | 2021-12-11 | 2023-06-15 | Fundaciò Privada Institut De Recerca De La Sida-Caixa | Soluble tigit recombinant proteins |
CN114196691B (zh) * | 2021-12-28 | 2023-08-11 | 重庆澳龙生物制品有限公司 | 一种制备防治牛、羊棘球蚴病多表位重组疫苗的基因、蛋白质、疫苗和应用 |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
CN116350748A (zh) * | 2022-11-01 | 2023-06-30 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | Tigit融合蛋白在制备用于治疗系统性红斑狼疮药物中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102850458A (zh) * | 2011-06-28 | 2013-01-02 | 华博生物医药技术(上海)有限公司 | 新型重组双功能融合蛋白及其制法和用途 |
US20160340430A1 (en) * | 2010-03-05 | 2016-11-24 | The Johns Hopkins University | Compositions and methods for targeted immunomodulatory antibodies and fusion proteins |
Family Cites Families (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5844095A (en) | 1991-06-27 | 1998-12-01 | Bristol-Myers Squibb Company | CTLA4 Ig fusion proteins |
DK0822199T3 (da) | 1991-10-25 | 2004-12-27 | Amgen Inc | N-terminalt monopegylerede polypeptider og fremgangsmåder til fremstilling heraf |
US20110041190A1 (en) | 2002-10-31 | 2011-02-17 | Tykocinski Mark L | Novel chimeric proteins |
CA2395945C (en) | 2000-01-03 | 2013-12-24 | Tr Associates, L.L.C. | Novel chimeric proteins and methods for using the same |
US7696168B2 (en) * | 2000-04-21 | 2010-04-13 | Tufts Medical Center, Inc. | G protein coupled receptor agonists and antagonists and methods of activating and inhibiting G protein coupled receptors using the same |
CA2466279A1 (en) | 2001-11-13 | 2003-05-22 | Dana-Farber Cancer Institute, Inc. | Agents that modulate immune cell activation and methods of use thereof |
EP1685159B1 (en) | 2003-10-03 | 2012-08-01 | Brigham & Women's Hospital | Tim-3 polypeptides |
AU2004282984B2 (en) | 2003-11-13 | 2011-07-14 | Hanmi Science Co., Ltd. | Protein complex using immunoglobulin fragment andmethod for the preparation thereof |
JP2006345852A (ja) | 2005-06-16 | 2006-12-28 | Virxsys Corp | 抗体複合体 |
US20080131431A1 (en) | 2006-05-15 | 2008-06-05 | Viral Logic Systems Technology Corp. | CD47 related compositions and methods for treating immunological diseases and disorders |
NZ573646A (en) | 2006-06-12 | 2012-04-27 | Wyeth Llc | Single-chain multivalent binding proteins with effector function |
US20110028688A1 (en) | 2006-06-21 | 2011-02-03 | Genentech, Inc. | Crystal structure of ox40l and ox40l complexed with ox40 receptor |
US20100150931A1 (en) | 2006-11-22 | 2010-06-17 | Centre Hospitalier De L'universite De Montreal | Novel receptor for cd40l and uses thereof |
EP2650018A3 (en) | 2007-05-14 | 2014-09-03 | The University of Chicago | Antibody-LIGHT fusion products for cancer therapeutics |
CA3170329A1 (en) | 2008-01-15 | 2009-07-23 | Siddhartha Jaiswal | Methods for manilpulating phagocytosis mediated by cd47 |
WO2009114110A1 (en) | 2008-03-08 | 2009-09-17 | Immungene, Inc. | Engineered fusion molecules immunotherapy in cancer and inflammatory diseases |
EP2111869A1 (en) | 2008-04-23 | 2009-10-28 | Stichting Sanquin Bloedvoorziening | Compositions and methods to enhance the immune system |
AU2009269141B2 (en) | 2008-06-30 | 2013-04-04 | University Of Pennsylvania | Fn14/TRAIL fusion proteins |
EA201170031A1 (ru) | 2008-07-02 | 2011-08-30 | Эмерджент Продакт Дивелопмент Сиэтл, Ллс | СВЯЗЫВАЮЩИЕ НЕСКОЛЬКО МИШЕНЕЙ БЕЛКИ, ОБЛАДАЮЩИЕ АНТАГОНИСТИЧЕСКИМ ДЕЙСТВИЕМ ПО ОТНОШЕНИЮ К TGF-β |
DK2310509T3 (en) | 2008-07-21 | 2015-04-27 | Apogenix Gmbh | Single chain molecules TNFSF |
WO2010062399A2 (en) | 2008-11-26 | 2010-06-03 | Five Prime Therapeutics, Inc. | Csf1r extracellular domain fusion molecules and treatments using same |
WO2010062401A2 (en) | 2008-11-26 | 2010-06-03 | Five Prime Therapeutics, Inc. | Treatment of osteolytic disorders and cancer using csf1r extracellular domain fusion molecules |
US20110237498A1 (en) * | 2008-12-19 | 2011-09-29 | Novartis Ag | Soluble polypeptides for use in treating autoimmune and inflammatory disorders |
CN102421913A (zh) | 2009-03-13 | 2012-04-18 | 宾夕法尼亚大学董事会 | Ox40/trail融合蛋白 |
CA2812057A1 (en) | 2010-09-28 | 2012-04-05 | Kahr Medical Ltd. | Compositions and methods for treatment of hematological malignancies |
US9029315B2 (en) | 2010-11-11 | 2015-05-12 | The University Of Hong Kong | Soluble PD-1 variants, fusion constructs, and uses thereof |
EP3144320B9 (en) | 2011-04-13 | 2018-08-22 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
WO2012162565A2 (en) | 2011-05-25 | 2012-11-29 | Cel-Sci Corporation | Method for inducing an immune response for treatment of cancer and autoimmune diseases or conditions |
EP3915588A1 (en) | 2011-07-29 | 2021-12-01 | The Trustees of the University of Pennsylvania | Switch costimulatory receptors |
WO2013119202A1 (en) | 2012-02-06 | 2013-08-15 | Providence Health & Services - Oregon | Cancer treatment and monitoring methods using ox40 agonists |
NZ714549A (en) | 2012-04-30 | 2016-10-28 | Biocon Ltd | Targeted/immunomodulatory fusion proteins and methods for making same |
PT2850106T (pt) | 2012-05-18 | 2022-07-18 | Aptevo Res & Development Llc | Imunofusão biespecífica (bif) de scfv de ligação a cd123 e cd3 |
CN112587671A (zh) | 2012-07-18 | 2021-04-02 | 博笛生物科技有限公司 | 癌症的靶向免疫治疗 |
ES2755156T3 (es) | 2012-12-17 | 2020-04-21 | Trillium Therapeutics Inc | Tratamiento de células enfermas CD47+ con fusiones SIRP alfa-Fc |
AU2013371826A1 (en) | 2013-01-01 | 2015-08-13 | Kahr Medical Ltd. | Stable form of signal converting protein fusion proteins, and methods of use and preparation thereof |
US20140242077A1 (en) | 2013-01-23 | 2014-08-28 | Abbvie, Inc. | Methods and compositions for modulating an immune response |
EP2950814A4 (en) | 2013-01-31 | 2016-06-08 | Univ Jefferson | PD-L1 AND PD-L2 BASED FUSION PROTEINS AND USES THEREOF |
WO2015116178A1 (en) | 2014-01-31 | 2015-08-06 | Thomas Jefferson University | Fusion proteins for modulating regulatory and effector t cells |
WO2014121093A1 (en) | 2013-01-31 | 2014-08-07 | Thomas Jefferson University | Fusion proteins that facilitate cancer cell destruction |
EP2951199A4 (en) | 2013-01-31 | 2016-07-20 | Univ Jefferson | Fusion proteins for the modulation of regulatory and effector T cells |
WO2014121099A1 (en) | 2013-01-31 | 2014-08-07 | Thomas Jefferson University | Agonist fusion protein for cd40 ox40 and uses thereof |
AU2014223601B9 (en) | 2013-02-26 | 2020-04-23 | Memorial Sloan-Kettering Cancer Center | Compositions and methods for immunotherapy |
CA2902830C (en) | 2013-03-12 | 2023-09-19 | Biocon Ltd. | Fusion immunomodulatory proteins and methods for making same |
IL296026B1 (en) | 2013-09-13 | 2024-06-01 | Beigene Switzerland Gmbh | Anti-PD1 antibodies and their uses as drugs and for diagnosis |
US10144770B2 (en) * | 2013-10-17 | 2018-12-04 | National University Of Singapore | Chimeric receptors and uses thereof in immune therapy |
US10196435B2 (en) | 2013-11-18 | 2019-02-05 | University Of Southern California | OX40L fusion protein for the immunotherapy of tumors of veterinary animals |
US20150190506A1 (en) | 2013-12-17 | 2015-07-09 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
US10927154B2 (en) | 2014-01-13 | 2021-02-23 | Pieris Pharmaceuticals Gmbh | Multi-specific polypeptide useful for localized tumor immunomodulation |
EP3094651B1 (en) | 2014-01-14 | 2020-03-11 | Kymab Limited | Anti-light antibodies |
US20170015758A1 (en) | 2014-01-21 | 2017-01-19 | Medimmune, Llc | Compositions And Methods For Modulating And Redirecting Immune Responses |
US9527901B2 (en) | 2014-03-24 | 2016-12-27 | Macroimmune Inc | Recombinant bi-functional fusion proteins, preparations and methods for treating disease |
BR112016027845A2 (pt) | 2014-05-29 | 2017-10-31 | Medimmune Llc | proteínas de fusão de ox40l e usos das mesmas |
WO2015200828A1 (en) | 2014-06-27 | 2015-12-30 | H. Lee Moffit Cancer Center And Research Institute, Inc. | Conjugates for immunotherapy |
TWI759810B (zh) | 2014-08-08 | 2022-04-01 | 美商Alx腫瘤技術股份有限公司 | 信號調節蛋白α(signal-regulatory proteinα, SIRP-α)變體構築物及其用途 |
CN113234138A (zh) | 2014-08-11 | 2021-08-10 | 德里尼亚公司 | 选择性地活化调节性t细胞用于治疗自身免疫病的修饰的il-2变体 |
KR20170036796A (ko) | 2014-08-15 | 2017-04-03 | 메르크 파텐트 게엠베하 | Sirp-알파 면역글로불린 융합 단백질 |
SG10201807625PA (en) | 2014-11-17 | 2018-10-30 | Genentech Inc | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
AU2015357463B2 (en) | 2014-12-05 | 2021-10-07 | Immunext, Inc. | Identification of VSIG8 as the putative vista receptor and its use thereof to produce vista/VSIG8 modulators |
WO2016112983A1 (en) * | 2015-01-15 | 2016-07-21 | Biontech Ag | Cytokine fusion proteins |
US11161907B2 (en) | 2015-02-02 | 2021-11-02 | Novartis Ag | Car-expressing cells against multiple tumor antigens and uses thereof |
MA41460A (fr) | 2015-02-03 | 2017-12-12 | Oncomed Pharm Inc | Agents de liaison à la tnfrsf et leurs utilisations |
RU2714157C2 (ru) | 2015-02-06 | 2020-02-12 | Хит Байолоджикс, Инк. | Вектор, коэкспрессирующий молекулы для вакцинации и костимулирующие молекулы |
WO2016166139A1 (en) | 2015-04-14 | 2016-10-20 | Eberhard Karls Universität Tübingen | Bispecific fusion proteins for enhancing immune responses of lymphocytes against tumor cells |
WO2016187226A1 (en) | 2015-05-18 | 2016-11-24 | Ab Initio Biotherapeutics, Inc. | Sirp polypeptide compositions and methods of use |
CN108350048B (zh) * | 2015-08-07 | 2024-02-09 | Alx肿瘤生物技术公司 | 具有SIRP-α结构域或其变体的构建体 |
SG10201913576RA (en) | 2015-10-01 | 2020-02-27 | Heat Biologics Inc | Compositions and methods for adjoining type i and type ii extracellular domains as heterologous chimeric proteins |
EP3529276A4 (en) | 2016-10-21 | 2020-06-17 | Arch Oncology, Inc. | CD47 THERAPEUTIC ANTIBODIES |
CN110234345A (zh) * | 2017-02-27 | 2019-09-13 | 沙塔克实验室有限公司 | 制备和使用基于细胞外结构域的嵌合蛋白的方法 |
-
2018
- 2018-02-27 CN CN201880009524.3A patent/CN110234345A/zh active Pending
- 2018-02-27 EP EP18756868.8A patent/EP3585418A4/en active Pending
- 2018-02-27 CA CA3054133A patent/CA3054133A1/en active Pending
- 2018-02-27 SG SG11201906465YA patent/SG11201906465YA/en unknown
- 2018-02-27 KR KR1020197023430A patent/KR20190122667A/ko active IP Right Grant
- 2018-02-27 US US16/484,850 patent/US20190367579A1/en not_active Abandoned
- 2018-02-27 BR BR112019017298A patent/BR112019017298A2/pt unknown
- 2018-02-27 MX MX2019009812A patent/MX2019009812A/es unknown
- 2018-02-27 EP EP18757341.5A patent/EP3585425A4/en not_active Withdrawn
- 2018-02-27 WO PCT/US2018/020037 patent/WO2018157162A1/en active Application Filing
- 2018-02-27 CN CN201880013956.1A patent/CN110381983A/zh active Pending
- 2018-02-27 IL IL268198A patent/IL268198B1/en unknown
- 2018-02-27 AU AU2018223821A patent/AU2018223821B2/en active Active
- 2018-02-27 CA CA3054127A patent/CA3054127A1/en active Pending
- 2018-02-27 WO PCT/US2018/020040 patent/WO2018157165A1/en active Application Filing
- 2018-02-27 JP JP2019546149A patent/JP7260477B2/ja active Active
- 2018-02-27 US US16/484,852 patent/US11332509B2/en active Active
- 2018-02-27 JP JP2019546144A patent/JP7128195B2/ja active Active
-
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- 2019-06-28 PH PH12019501533A patent/PH12019501533A1/en unknown
- 2019-08-20 ZA ZA2019/05488A patent/ZA201905488B/en unknown
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- 2020-04-24 US US16/857,787 patent/US10899817B2/en active Active
- 2020-09-10 US US17/017,108 patent/US10927159B2/en active Active
-
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- 2022-04-06 US US17/714,912 patent/US20220227831A1/en active Pending
- 2022-04-11 US US17/717,740 patent/US20220315637A1/en active Pending
- 2022-08-18 AU AU2022218575A patent/AU2022218575A1/en not_active Abandoned
- 2022-08-18 JP JP2022130749A patent/JP2022159510A/ja active Pending
-
2023
- 2023-04-06 JP JP2023062366A patent/JP2023076695A/ja active Pending
-
2024
- 2024-03-04 US US18/594,400 patent/US20240190939A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160340430A1 (en) * | 2010-03-05 | 2016-11-24 | The Johns Hopkins University | Compositions and methods for targeted immunomodulatory antibodies and fusion proteins |
CN102850458A (zh) * | 2011-06-28 | 2013-01-02 | 华博生物医药技术(上海)有限公司 | 新型重组双功能融合蛋白及其制法和用途 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022179567A1 (zh) * | 2021-02-24 | 2022-09-01 | 克莱格医学有限公司 | Tigit工程化细胞及其组合物 |
CN115260312A (zh) * | 2021-04-30 | 2022-11-01 | 保诺科技(北京)有限公司 | 结合ox40的抗体或抗原结合片段 |
CN114209815A (zh) * | 2021-11-22 | 2022-03-22 | 山东大学 | 一种药物组合物及其制备方法和应用 |
CN114209815B (zh) * | 2021-11-22 | 2024-04-26 | 山东大学 | 一种药物组合物及其制备方法和应用 |
WO2024046394A1 (zh) * | 2022-08-30 | 2024-03-07 | 北京卡替医疗技术有限公司 | 增强受体、表达增强受体的免疫细胞及其用途 |
WO2024119768A1 (zh) * | 2022-12-06 | 2024-06-13 | 上海恩凯细胞技术有限公司 | 逆转肿瘤微环境抑制性信号的nk细胞制备方法及应用 |
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