CN116033926A - 针对ace2靶向病毒可用的结合蛋白 - Google Patents
针对ace2靶向病毒可用的结合蛋白 Download PDFInfo
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Abstract
本文描述了可用于针对ACE2靶向病毒(例如SARS‑CoV和SARS‑CoV‑2等)的结合蛋白以及它们的使用方法。这些结合蛋白可包含不包括collectrin结构域的血管紧张素转换酶2(ACE2)的细胞外部分,以及将所述ACE2部分偶联至片段结晶化(Fc)结构域的柔性多肽柔性接头。这些结合蛋白二聚化,并且所述柔性接头可选择为足够长以允许与所述ACE2靶向病毒上的多个刺突(S)蛋白同时相互作用。
Description
相关申请的交叉引用
本申请要求名称为“针对ACE2靶向病毒可用的结合蛋白”且于2020年4月3日提交的美国临时专利申请号63/004,823的优先权,该专利申请以引用的方式整体并入本文。
援引并入
本说明书中提及的所有公布和专利申请均以引用的方式整体并入本文,其引用程度如同特别且单独地指示将每个单独的公布或专利申请以引用的方式并入一般。
技术领域
本文涉及结合严重急性呼吸综合征冠状病毒(SARS-CoV和SARS-CoV-2)的结合蛋白。这些结合蛋白可以是柔性连接的ACE2诱饵,其可用于治疗罹患SARS-CoV和/或SARS-CoV-2感染的受试者的药物组合物,以及它们的使用方法。
背景技术
SARS-CoV-2大流行对全球社会和经济造成了前所未有的破坏性影响,并且标志着高致病性冠状病毒向人群中的第三次已知的动物源性引入。尽管先前的冠状病毒SARS-CoV和MERS-CoV流行病提高了对于临床上可用的治疗或预防干预的需求的认识,但迄今为止,还没有证实有效的治疗可供使用。有效的干预策略的开发依赖于对冠状病毒感染的分子和细胞机制的了解,这突出了在分子水平上研究病毒-宿主相互作用以识别抗病毒干预的靶标并阐明对于严重疾病的发展具有决定性的关键的病毒和宿主决定因素的重要性。
粘膜屏障作为防止外来物进入体内的屏障,起着重要的潜在保护作用。粘膜屏障可以通过局部免疫来进一步增强,使得在肠、泌尿生殖道和呼吸系统的粘膜(即,与外部环境接触的表面)处发生强大的免疫系统反应。粘膜免疫系统可以提供病原体防护,但对无害的共生微生物和良性环境物质维持耐受。因为粘膜是宿主与其环境之间的主要接触点,所以此处存在大量的次级淋巴组织。粘膜相关淋巴组织或MALT提供了粘膜免疫反应的关键要素。粘膜免疫系统提供三种主要功能:充当身体抵御抗原和感染的第一道防线;防止对共生细菌和食物抗原(主要是肠相关淋巴组织中的食物蛋白)的全身免疫反应(所谓的口服耐受);以及调节对每天遇到的病原体的适当免疫反应。
不幸的是,粘膜免疫反应可能不充分,并且通常难以引发必要的免疫反应持续足够的时间。参见例如美国专利公开号2015/0284451。尽管已经显示一些抗体与粘蛋白相互作用以将单独的抗体包被的病原体与粘蛋白粘接性地交联,从而将它们固定在粘液中(通常称为粘液捕获的过程),但是提供更有效地防止外来物(包括病毒)渗透通过粘液以到达靶细胞的能力进一步改良的抗体或抗体构建体将是有益的。特别地,提供可有助于以限制外来物有效渗透通过粘液的方式将外来物凝集和/或束缚在一起的结合蛋白(诸如抗体)将是有帮助的。
发明内容
本文描述了用于增强一种或多种ACE2靶向病毒(例如SARS-CoV和SARS-CoV-2等)的凝集、束缚和/或粘液捕获,降低可渗透通过粘液的ACE2靶向病毒的分数的方法和组合物。具体而言,本文描述了针对ACE2靶向病毒可用的工程化结合蛋白。这些结合蛋白对于ACE2靶向病毒可以是多价的,并且可以包括两个冠状病毒结合区,每个冠状病毒结合区通过柔性多肽接头柔性地连接至Fc结构域。接头可以足够长和柔性,使得两个冠状病毒结合区可以同时结合靶标(例如刺突蛋白)。
例如,本文描述了血管紧张素转换酶2(ACE2)-免疫球蛋白(IgG)杂合结合蛋白(本文称为柔性连接的ACE2诱饵),其二聚化并对ACE2靶向病毒(特别包括SARS-CoV-2)具有皮摩尔亲和力。这些蛋白质可被工程化以实现“粘液捕获”,并且可以用于治疗或预防SARS-CoV(例如SARS-CoV-2)感染,例如,用于针对ACE2靶向病毒(包括SARS-CoV-2)的局部免疫疗法。这些分子通常可以通过使用柔性接头(诸如但不限于(GGGGS)n、(EAAAK)n等)将ACE2的两个或更多个细胞外部分(例如,可溶性血管紧张素转换酶2的一部分)与Fc部分偶联来形成。
在本文所述的一些示例中,ACE2的细胞外部分可以对应于ACE2的野生型细胞外片段;然而,通过一种或多种修饰(突变)修饰的ACE2的细胞外片段可以用作细胞外ACE2片段,包括被设计成改善与病毒(例如,SARS-CoV-2)的结合或消除ACE2酶的先天催化活性的突变。ACE2的细胞外片段可以不包括collectrin结构域(对应于野生型人ACE2的氨基酸615-740)。此外,可以使用任何适当的Fc结构域,包括来自不同IgG同种型(例如,IgG3、IgG4)的抗体Fc,以及被工程化成具有不同效应功能的Fc(例如,抑制Fcg-R结合的LALA-PG,或改善FcRn结合的YTE或LS突变等)。可以使用任何适当的接头区。例如,对于一个或两个接头区,接头区可以是(GGGGS)n(其将两个或更多个冠状病毒结合/诱饵结构域中的每一个连接至Fc结构域)。在一些示例中,每个柔性接头的n在1与26之间,并且特别地,其中n在2-25之间、3-24之间、4-22之间、5-20之间、6-20之间、3-10之间、4-15之间等,或(EAAK)n(其中n在0与26之间,并且特别地,其中n在2-25之间、3-24之间、4-22之间、5-20之间、6-20之间、3-10之间、4-15之间等)。可选择柔性接头的长度,使得两个(或更多个)冠状病毒结合/诱饵结构域之间的平均间距总共大于约14nm(例如,每个接头可为约5nm或更长)。
可溶性血管紧张素转换酶2(ACE2)可充当诱饵分子,其可以通过阻断病毒的刺突(S)蛋白与宿主细胞上的ACE2结合来中和严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。基于ACE2和S蛋白的结构,ACE2-Fc缀合物如本文所述进行工程化并且包括ACE2的细胞外片段,在一些示例中,不具有C末端collectrin结构域,并且经由可实现分子与病毒上的S蛋白的二价结合改善的延长的柔性接头连接至人Ig结构域(例如,IgG1-Fc)。
此分子家族在本文中称为二价且柔性连接的ACE2-Fc诱饵(或简称为“柔性连接的ACE2诱饵”)表现出比预期结合亲和力和这种结合亲和力大得多的结合亲和力和中和效力。有趣的是,这些柔性连接的ACE2诱饵的中和效力高于不包括柔性接头区或包括短接头区的全长ACE2-Fc诱饵。这些柔性连接的ACE2诱饵表现出皮摩尔结合亲和力(250pM)和中和效力(IC50:50ng/mL)。柔性连接的ACE2诱饵还能有效捕获新鲜人呼吸道粘液中的荧光SARS-CoV-2病毒样颗粒,并且可以使用商业振动筛网雾化器进行稳定雾化。最迟在感染后2天,在仓鼠中鼻内给药柔性连接的ACE2诱饵,到第4天提供鼻甲组织中病毒载量减少10倍。这些结果强烈支持使用柔性连接的ACE2诱饵用于对COVID-19以及其他使用ACE2作为进入受体的新兴病毒的吸入免疫疗法。
灵活连接的ACE2诱饵的一个非限制性示例称为ACE2-(G4S)6-Fc,其包括两个ACE2胞外结构域(每个均不包括C末端collectrin结构域),所述结构域经由(GGGGS)6柔性连接至Fc结构域。尽管在本文使用的许多示例和说明中描述了此特定的ACE2-(G4S)6-Fc示例,但应该理解其他柔性连接的ACE2诱饵已被识别并显示具有相似的特性。一般来讲,柔性连接的ACE2诱饵包含两个具有一个或多个突变的ACE2细胞外结构域(参见如表1,更详细地描述于下文),它们各自通过长度为大于约5nm的柔性接头连接至Fc结构域,所述ACE2诱饵可如本文所述起作用并且可具有与ACE2-(G4S)6-Fc类似的亲和力和性质。
本文还描述了针对ACE2靶向病毒的工程化柔性连接的多价(例如双特异性)结合蛋白,其仅包含单个ACE2,但代之以使用一种或多种冠状病毒结合蛋白,诸如具有针对ACE2靶向病毒的结合活性的抗体屁啊按断。
本文所述的任一种结合蛋白(例如柔性连接的ACE2诱饵)可被糖基化(或被选择用于富集糖基化),其G0F糖基化可以增强其粘液捕获效力。增加G0F含量可以提高捕获效力,例如,通过将G0F含量增加到至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少80%、至少90%、至少95%等。
例如,本文描述了分离的结合蛋白,其结合ACE2靶向病毒,所述分离的结合蛋白具有包含以下的氨基酸序列:
A-(B)n-C (式I)
其中:A为不包括collectrin结构域的血管紧张素转换酶2(ACE2)的细胞外部分或其变体;n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;B为多肽柔性接头;C为片段结晶化(Fc)结构域,其中所述分离的结合蛋白为二聚体。
ACE2靶向病毒包括冠状病毒,诸如SARS样冠状病毒(例如,SARS-CoV和SARS-CoV-2、SARS-CoV-1、NL63季节性冠状病毒)。
本文所述的结合蛋白可以包含柔性接头,其长度足以使得二聚体的A结构域之间的距离大于约14nm(例如大于约15nm、大于约16nm、大于约17nm、大于约18nm、大于约19nm、大于约20nm等)。二聚体中接头的距离可以以推测方式和/或以计算方式确定;距离可以指平均距离,如本领域技术人员将理解的。尽管柔性接头的长度可以随着分子构型的空间变化而有所不同,但是低于最小长度(例如14nm、15nm、16nm等),能够二价地在靶标(例如ACE2靶向病毒上的刺突蛋白)上的结合蛋白的百分比可能低于功效的阈值。
例如,柔性多肽接头的长度可以基于多肽的残基数目来确定。例如,残基的数目可以是24个或更多、25个或更多、26个或更多、27个或更多、28个或更多、20个或更多、30个或更多、31个或更多、32个或更多、33个或更多、34个或更多、35个或更多、36个或更多、37个或更多、38个或更多等。
一般来讲,本文所述的结合蛋白可以包含任何适当的Fc结构域,例如,权利要求1-2中所述的任一种的Fc结构域,其中Fc结构域为人IgA、IgM或IgG Fc结构域。Fc结构域可以是人IgG1 Fc结构域。Fc结构域可以包含YTE突变、LS突变或LALA-PG突变,或者改善功能的其他修饰。
一般来讲,ACE2的细胞外部分可以为人ACE2的细胞外部分,不包括collectrin结构域。细胞外序列一般可以对应于野生型人ACE2细胞外结构域的序列,例如至少40%(至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%等)的来自残基18-614的氨基酸序列的一段。在一些示例中,ACE2的细胞外部分与氨基酸序列SEQ ID NO:11具有80%或更大的氨基酸序列同一性。例如,ACE2的细胞外部分可以具有在SEQ ID NO:11的氨基酸内具有至多10个氨基酸差异的氨基酸序列。例如,ACE2的细胞外部分可以包含至少一个突变,或者在一些例子中,包含两个或更多个突变。突变可以在图16A-16B的表1中识别的任何位置。
多肽柔性接头可以具有任何适当的序列。例如,柔性接头可以是序列GGS、GGGS、GGGGS等。基于接头区的长度,序列长度(n)可以最小为例如2、3、4、5、6、7、8、9、10等,如上文所述。例如,如果柔性接头具有序列GGGGS,则n可为5或更大(例如,6或更大、7或更大等)。在一些示例中,结合蛋白包含序列SEQ ID NO:2和SEQ ID NO:4。在一些示例中,结合蛋白包含序列SEQ ID NO:11和SEQ ID NO:4。在一些示例中,结合蛋白包含SEQ ID NO:2或SEQ IDNO:11、柔性接头诸如(GGGS)n以及SEQ ID NO:12或SEQ ID NO:13,其中n在5与10之间(例如,n=6)。这些结合蛋白中的任一种可包含在柔性接头与Fc结构域之间的铰链。
一般来讲,这些结合蛋白中的任一种可以包含在Fc结构域上具有G0糖基化模式的寡糖。例如,Fc结构域可以包含具有G0糖基化模式的寡糖,所述寡糖包含在每个分枝具有末端N-乙酰基葡糖胺的双触角核心聚糖结构Manα1-6(Manα1-3)Manβ1-4GlcNAcβl-4G1cNAcβ1,以增强粘液中结合蛋白的捕捉效力。
一般来讲,结合蛋白可以是混合物的一部分,在混合物中,所有或一些(例如,20%或更多、30%或更多、40%或更多、50%或更多、60%或更多、70%或更多、80%或更多、90%或更多等)结合蛋白被糖基化并且包含在Fc结构域上的G0糖基化模式。
因此,描述了药物组合物,其包含任一结合蛋白和药学上可接受的赋形剂。例如,赋形剂、稀释剂或载体可以被配置用于吸入。组合物可以被配置用于口服、肠胃外、腹膜内、经粘膜、经皮、直肠、吸入和局部施用中的一种或多种。
本文还描述了治疗罹患SARS-CoV-2的受试者的方法,所述方法包括施用药学上可接受量的这些结合蛋白中任一种的药物组合物。施用可以包括将药物组合物全身应用于患者。在一些示例中,施用包括将药物组合物应用于患者的粘膜。应用可以包括雾化药物组合物。
例如,本文描述了治疗或抑制ACE2靶向病毒的病毒感染的方法,所述方法包括经由通过吸入途径向受试者施用任一结合蛋白的结合蛋白(例如,本文所述的任一柔性连接的ACE2诱饵)。如所提及的,ACE2靶向病毒可以是SARS-CoV-2。
本文还描述了分离的结合蛋白,其结合ACE2靶向病毒,所述分离的结合蛋白具有包含以下的氨基酸序列:
A-(B)n-C (式I)
其中:A为不包括collectrin结构域的血管紧张素转换酶2(ACE2)的细胞外部分,其与氨基酸序列SEQ ID NO:11具有80%或更大的氨基酸序列同一性;n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;B为多肽柔性接头;C为片段结晶化(Fc)结构域,其中所述分离的结合蛋白为二聚体,进一步地,其中n选择为使得二聚体的A结构域之间的距离大于14nm。
附图说明
通过参考以下对说明性实施方案阐述的详细描述和附图,将会获得对本文所述的方法和设备的特征和优点的更好的理解,在附图中:
图1A显示针对SARS样冠状病毒的结合蛋白的一个示例的3D分子结构的一个示例,所述结合蛋白包含ACE2-Fc二聚体,每个单体具有柔性接头,在此示例中显示为(GGGGS)n。
图1B显示不具有柔性接头的ACE2-Fc二聚体的示例。
图2A-2B说明不同ACE2-Fc构建体(二聚体)在S蛋白三聚体上的对接,显示与S蛋白的“刺突内(intra-spike)”结合的差异。图2A显示不具有柔性接头的ACE2-Fc仅可单价结合同一S蛋白刺突,因为ACE2-Fc的这种示例的几何结构不允许第二Fab弯曲并到达S蛋白三聚体上两个剩余可用的S蛋白中任一个的周围。图2B显示具有柔性接头的ACE2-Fc的示例(柔性连接的ACE2诱饵),其允许单个ACE2-Fc分子在S蛋白三聚体上的二价结合,例如当接头为至少5.7nm时。
图3显示不具有柔性接头的ACE2-Fc二聚体的示例,说明它可以潜在地结合两个不同刺突(即“刺突间”结合),但频率有限。ACE2结构域的结合界面之间的距离为约14.6nm,大致等于当S蛋白垂直对齐时,COVID19病毒表面上的刺突间距离(约14至15nm)。由于在ACE2Fab上缺乏旋转柔韧性,所以有可能的是,两个S三聚体刺突可能需要基本上比15nm近的距离,以便不具有柔性接头的ACE2-Fc二价结合。
图4说明具有柔性接头的ACE2-Fc二聚体(柔性连接的ACE2诱饵),其可以更容易地实现与两种不同的S蛋白三聚体二价结合。两个接头的接头长度为5.6nm,使得两个ACE2结构域有可能结合相隔15nm的S蛋白,即使两个S-三聚体垂直对齐时亦如此,就像在病毒表面上天然存在的那样。
图5显示提出的双特异性单克隆抗体的示例,其衍生自CR3022 IgG(针对人冠状病毒SARS-CoV-2刺突糖蛋白S的抗体)和ACE2,其可以实现二价结合COVID19的每个S-蛋白刺突上的三个三聚体S蛋白中的仅一个,而不彼此阻碍。RC3022的N末端和C末端相隔9.8nm,这可以用(GGGGS)6接头桥联。
图6A-6C说明不同ACE2融合蛋白的二聚体的假设结构的计算预测。图6A显示一示例,其中由整个细胞外ACE2分子(包含collectrin结构域)构成的ACE2-Fc融合物连接至IgG1-Fc(本文称为ACE2(740)-Fc)。如图所示,在此示例中,即使当通过Fc结构域连接时,ACE2结构域也聚集。图6B显示一示例,其中ACE2-Fc融合物包含不具有collectrin结构域的ACE2的细胞外结构域,但是其在没有柔性接头的情况下连接至Fc结构域。此示例被称为ACE2-Fc。图6C显示柔性连接的ACE2诱饵的示例,其中两个不具有collectrin结构域的ACE2片段通过30个氨基酸的甘氨酸-丝氨酸柔性接头(例如,ACE2-(G4S)6-Fc)连接至人IgG1-Fc。
图7A说明针对图6B(ACE2-Fc,不具有柔性接头)和图6C(ACE2-(G4S)6-Fc)中所示的结合蛋白的计算预测的示例。如图7A所示,针对ACE2-Fc的计算预测显示ACE2-Fc将与仅单个RBD结构域一起对接至S蛋白上。相比之下,如图7B所示,预测ACE2-(G4S)6-Fc(柔性连接的ACE2诱饵)以“向上”的位置与三个RBD结构域中的两个一起对接在S蛋白上。图7C显示ACE2-Fc(泳道2)和ACE2-(G4S)6-Fc(泳道3)的Native-PAGE。图7D是ACE2-(G4S)6-Fc和ACE2-Fc的尺寸排阻色谱法。洗脱时间和大小均符合预期。针对略微较大的ACE2-(G4S)6-Fc柔性连接的ACE2诱饵。
图8A-8D说明图6所示的示例性ACE融合蛋白的显著不同的结合亲和力,如通过SARS-CoV-2S-蛋白ELISA所评估。图8A显示ACE2-(G4S)6-Fc(黑色圆形)、ACE2-Fc(淡灰色方形)和全长ACE2诱饵ACE2(740)-Fc(灰色三角形)的代表性浓度依赖性结合曲线。图8B显示不同独特批次的图6的ACE2融合蛋白的ELISA来源EC50值(应用与图8A相同的标记)。CH表示CHO细胞中产生的ACE2-(G4S)6-Fc。图8C显示针对来源于不同病毒毒株(包括WT(USA-WA1/2020)、UK(B.1.1.7)和SA(B.1.351)毒株)的S蛋白的ACE2-(G4S)6-Fc的代表性浓度依赖性结合曲线;图8D显示来自同一组毒株的EC50数据。
图9A-9C说明上文图6A-6C所示的三种不同的ACE2融合蛋白的基于假病毒的中和效力。在图9A中,显示在不同浓度的ACE2诱饵内,假型SARS-CoV-2病毒的代表性感染性曲线。图9B显示三类ACE2二价融合蛋白中每一种的IC50数据,并且图9C显示根据结合曲线估计的IC90值。每个数据点代表独立的实验。灵活连接的ACE2诱饵与其他融合蛋白之间有显著差异。
图10A-10B说明柔性连接的ACE2诱饵在粘液诱捕中的有效性。图10A显示快速移动SARS-CoV-2VLP百分比的比较,显示ACE2-(G4S)6-Fc在人AM中有效捕获SARS-2VLP,其效力比ACE2-Fc或CR3022(CR3022为对照抗SARS-CoV-2mAb)大得多。图10B显示通过SARS-CoV-2S蛋白ELISA评估的雾化ACE2-(G4S)6-Fc的结合亲和力。将从上部腔室(完整圆形)和下部腔室(灰色方形)收集的ACE2-(G4S)6-Fc与未雾化蛋白(三角形)相比较。
图11说明针对感染后4天时收集的SARS-CoV-2感染仓鼠的鼻甲组织中病毒载量的基于PCR的测定。
图12A-12B说明雾化ACE2-(G4S)6-Fc的生物物理特征。图12C显示雾化ACE2-(G4S)6-Fc的native-PAGE的示例。样品收集自雾化装置的上部腔室(泳道2、5、8)、下部腔室(泳道3、6、9)和雾化后的剩余液体(“死体积”)(泳道4、7、10)。显示3次重复的数据。图12B是ACE2-(G4S)6-Fc的尺寸排阻色谱法,包括雾化之前的样品、收集自雾化设备的上部腔室、下部腔室或剩余液体的样品。显示代表3次重复的数据。
图13显示在蛋白A亲和色谱法之后ACE2-Fc融合蛋白的产率与ACE2-(G4S)6-Fc(柔性连接的ACE2诱饵)相比的示例。蛋白是从500mL Expi293T细胞培养物纯化的。
图14是显示ACE2-(G4S)6-Fc的差示扫描荧光测定法的示例。图中显示三个独立重复的数据。
图15显示全长ACE2(人)的序列。
图16A-16B显示表1,说明了可在本文所述的任何柔性连接的ACE2诱饵中产生的全长ACE2多肽的突变。
具体实施方式
一般地,本文描述了用于结合一种或多种ACE2靶向病毒(例如SARS-CoV和SARS-CoV-2)的方法和组合物(例如,工程化结合蛋白)。这些结合蛋白可用于治疗、预防和/或减少SARS样冠状病毒的感染。在一些示例中,这些结合蛋白可用于增强ACE2靶向病毒的凝集、束缚和/或粘液捕获,包括降低可渗透通过粘液的ACE2靶向病毒的分数。
例如,本文描述了血管紧张素转换酶2(ACE2)-免疫球蛋白(IgG)杂合结合蛋白(本文称为柔性连接的ACE2诱饵),其二聚化并对SARS样冠状病毒(特别包括,SARS-CoV-2)具有皮摩尔亲和力。这些蛋白质可以被工程化以用于“粘液捕获”,包括通过特异性选择在结合蛋白的Fc结构域上糖基化的结合蛋白的粘液捕获增强。这些结合蛋白可用于治疗或预防SARS-CoV(例如,SARS-CoV-2)感染,例如,用于针对ACE2靶向病毒(包括SARS-CoV-2)的局部免疫疗法。这些分子通常可以是使用柔性接头(诸如但不限于(GGGGS)n、(EAAAK)n等)的ACE2的细胞外部分(例如,不包括collectrin结构域的可溶性血管紧张素转换酶2的一部分)与Fc部分的融合物。
本文还描述了结合蛋白,其对于ACE2靶向病毒是多价的,并且可以包括两个(或在一些示例中,更多个)冠状病毒结合区,每个冠状病毒结合区通过柔性多肽接头柔性地连接至Fc结构域。接头可以足够长和柔性,使得两个冠状病毒结合区可以同时结合靶标(例如,刺突蛋白)。
本文所述的结合蛋白可以增强ACE2靶向病毒(例如,SARS-CoV-2)的凝集,促进其束缚生长和/或改善其粘液捕获,如本文所述。这些结合蛋白可以通过提高凝集效力、促进靶标的束缚生长和/或实现粘液捕获来阻止SARS样CoV渗透通过粘液,并且可以预防、限制和/或治疗感染。
定义
除非另有说明,否则根据常规用法使用技术术语。分子生物学中常用术语的定义可见于Benjamin Lewin,Genes X,由Jones&Bartlett Publishers出版,2009;以及Meyers等人(编),The Encyclopedia of Cell Biology and Molecular Medicine,由Wiley-VCH以16卷出版,2008;以及其他类似参考文献。
除非上下文另外明确指出,否则如本文所用,单数形式“一个”、“一种”和“所述”是指单数和复数两种例如,术语“一种抗原”包括单种或多种抗原,并且可以被认为等同于短语“至少一种抗原”。如本文所用,术语“包含”意指“包括”。应进一步理解,除非另外指出,否则针对核酸或多肽给出的任何和所有碱基大小或氨基酸大小、以及所有分子重量或分子质量值均为近似值,并且处于描述目的而提供。虽然可以使用与本文所述的那些类似或等效的许多方法和材料,但是本文描述了特定合适的方法和材料。如发生矛盾,则将以本说明书(包括术语的解释)为准。此外,材料、方法和示例仅为说明性的并且不意图为限制性的。
如本文所用,如本文所用的术语“施用”是指通过选择的途径将组合物引入至受试者中。施用可为局部或全身性的。例如,如果选择的途径是静脉内,则通过将组合物引入至受试者的静脉中来施用组合物(诸如包括所公开的抗体的组合物)。示例性施用途径包括但不限于口服、注射(诸如皮下、肌肉内、皮内、腹膜内和静脉内)、舌下、直肠、经皮(例如,局部)、鼻内、阴道和吸入途径。
除非上下文另外指出,否则明确地意图可以以任何组合使用本文所述的各种特征。此外,本发明还设想,在本发明的一些示例中,可以不包括或省略本文中阐述的任何特征或特征组合。为了说明,如果说明书陈述了复合物包含组分A、B和C,则明确地意图可以省略A、B或C中的任一种或其组合,并且可以单独地或以任何组合方式放弃。
如本文所用的术语“约”当提及可测量值(诸如本发明的化合物或剂的量、剂量、时间、温度等)时,意指涵盖指定量的±10%、±5%、±1%、±0.5%或甚至±0.1%的变化。
除非另外指出,否则在说明书和权利要求中使用的表示成分的量、性质诸如反应条件等的所有数字应理解为在所有情况下均由术语“约”修饰。因此,除非有相反的指示,否则本说明书和权利要求书中阐述的数值参数为近似值,其可根据通过本发明公开的主题寻求获得的所需性质而变化。
如本文所用,范围可以表示为从“约”一个特定值和/或至“约”另一个特定值。还应理解,本文公开了多个值,并且每个值在本文中除所述值本身之外也公开为“约”所述特定值。例如,如果公开了值“10”,则还公开了“约10”。还应理解,还公开了两个特定单位之间的每个单位。例如,如果公开了10和15,则还公开了11、12、13和14。
过渡短语“基本上由……组成”意指将权利要求的范围解读为涵盖权利要求中所列举的指定材料或步骤以及实质上不影响所要求保护的发明的一个或多个基本特征和新颖特征的那些材料或步骤。本文所述的任何方法和组合物可以部分或完全不包括其他组分(例如,可以“由……组成”或可以“基本上由……组成”)。一般而言,本文所述的任何设备和方法应被理解为是包括性的,但组分和/或步骤的全部或子集可以替代地为排他性的,并且可以表示为“由各种组分、步骤、子组分或子步骤组成”或替代地“基本上由各种组分、步骤、子组分或子步骤组成”。
如本文所用,术语“氨基酸取代”是指用不同的氨基酸或不用氨基酸(即,缺失)替代多肽中的一个氨基酸。在一些示例中,多肽中的氨基酸被例如来自同源多肽的氨基酸取代,并且重组SARS-CoV或SARS-CoV-2多肽中的氨基酸可以被来自不同SARS-CoV或SARS-CoV-2毒株的对应氨基酸取代。
如本文所用,术语“抗体”是指特异性结合并识别抗原诸如SARS-CoV或SARS-CoV-2S蛋白的结合蛋白或其抗原结合片段。术语“抗体”在本文中以最广义使用并且涵盖各种抗体结构,包括但不限于单克隆抗体、多克隆抗体、双特异性抗体、多特异性抗体、嵌合抗体、重组抗体及其抗原结合片段,只要它们表现出所需的抗原结合活性即可。
如本文所用,术语“单克隆抗体”是指从大体上同源的抗体群体获得的抗体,即除了可能以少量存在的可能天然发生的突变之外,包含群体的各个抗体是相同的。单克隆抗体是高度特异性的,针对单一抗原表位。修饰语“单克隆”指示,抗体的特性是获自抗体的基本同质群体,而并不应当被解释为需要通过任何特定方法来生产抗体。在一些示例中,单克隆抗体是由B淋巴细胞的单一克隆或由编码单一抗体(或其抗原结合片段)的抗体轻链和重链可变区的核酸所转染的细胞或者其后代产生的抗体。在一些示例中,单克隆抗体是从受试者分离的。单克隆抗体可以具有对抗原结合或其他免疫球蛋白功能基本上没有影响的保守氨基酸取代。产生单克隆抗体的示例性方法是已知的,例如,参见Harlow和Lane,Antibodies,A Laboratory Manual,第2版,Cold Spring Harbor Publications,New York(2013)。
通常,免疫球蛋白具有通过二硫键相互连接的重(H)链和轻(L)链。免疫球蛋白基因包括κ、λ、α、γ、δ、ε和μ恒定区基因,以及无数的免疫球蛋白可变结构域基因。有两种类型的轻链,即λ和κ。有五种主要的重链类别(或同种型):IgM、IgD、IgG、IgA和IgE,它们决定了抗体分子的功能活性。
每条重链和轻链含有一个恒定区(或恒定结构域)和一个可变区(或可变结构域;参见例如Kindt等人,Kuby Immunology,第6版,W.H.Freeman and Co.,第91页(2007))。在若干示例中,重链可变区和轻链可变区组合以特异性结合抗原。在其他示例中,仅需要重链可变区。例如,仅由重链组成的天然存在的骆驼抗体在不存在轻链的情况下是功能性的并且稳定的(参见例如Hamers-Casterman等人,Nature,363:446-448,1993;Sheriff等人,Nat.Struct.Biol.,3:733-736,1996)。提及“VH”或“VH”是指抗体重链的可变区,包括抗原结合片段(诸如Fv、scFv、dsFv或Fab)的可变区。提及“VL”或“VL”是指抗体轻链的可变结构域,包括Fv、scFv、dsFv或Fab的可变结构域。
轻链和重链可变区含有被三个高变区(也称为“互补决定区”或“CDR”)间断的“框架”区(参见例如Kabat等人,Sequences of Proteins of Immunological Interest,U.S.Department of Health and Human Services,1991)。不同轻链或重链的框架区的序列在物种内相对保守。抗体的框架区,即组成型轻链和重链的组合框架区,用于在三维空间中定位和对齐CDR。
CDR主要负责与抗原表位的结合。给定CDR的氨基酸序列边界可以容易地使用许多熟知的方案中的任何一种来确定,方案包括以下描述的那些:Kabat等人(“Sequences ofProteins of Immunological Interest”,第5版,Public Health Service,NationalInstitutes of Health,Bethesda,Md.,1991;“Kabat”编号方案)、Al-Lazikani等人(JMB273,927-948,1997;“Chothia”编号方案)和Lefranc等人(“IMGT unique numbering forimmunoglobulin and T cell receptor variable domains and Ig superfamily V-likedomains”,Dev.Comp.Immunol.,27:55-77,2003;“IMGT”编号方案)。每条链的CDR通常称为CDR1、CDR2和CDR3(从N末端至C末端),并且通常还通过其中定位特定CDR的链来识别。因此,VH CDR3是来自发现它的抗体的重链的可变结构域的CDR3,而VL CDR1是来自发现它所在的抗体的轻链的可变结构域的CDR1。轻链CDR有时称为LCDR1、LCDR2和LCDR3。重链CDR有时称为HCDR1、HCDR2和HCDR3。
如本文所用,短语“抗原结合片段”是指全长抗体中保留特异性识别同源抗原的能力的部分以及此类部分的各种组合。抗原结合片段的非限制性示例包括Fv、Fab、Fab'、Fab'-SH、F(ab)2;双抗体;线性抗体;单链抗体分子(例如,scFv);以及由抗体片段形成的双特异性和多特异性抗体。抗体片段包括通过全抗体的修饰产生的或使用重组DNA方法从头合成的抗原结合片段(参见例如Kontermann和Dubel(编),Antibody Engineering,第1-2卷,第2版,Springer Press,2010)。
单链抗体(scFv)是基因工程化的分子,其含有一种或多种抗体的VH和VL结构域,所述结构域通过合适的多肽接头连接为遗传融合的单链分子(参见例如Bird等人,Science,242:423-426,1988;Huston等人,Proc.Natl.Acad.Sci.,85:5879-5883,1988;Ahmad等人,Clin.Dev.Immunol.,2012,doi:10.1155/2012/980250;Marbry,IDrugs,13:543-549,2010)。scFv中VH结构域和VL结构域的分子内取向通常对于scFv来说不是决定性的。因此,可以使用具有两种可能排列(VH结构域-接头结构域-VL结构域;VL结构域-接头结构域-VH结构域)的scFv。
在dsFv中,重链和轻链可变链突变以引入二硫键从而使链的缔合稳定。还包括双抗体,其为二价双特异性抗体,其中VH和VL结构域表达于单一多肽链上,但使用过短而不允许同一链上的两个结构域之间配对的接头,从而迫使结构域与另一链的互补结构域配对且产生两个抗原结合位点(参见例如Holliger等人,Proc.Natl.Acad.Sci.,90:6444-6448,1993;Poljak等人,Structure,2:1121-1123,1994)。
抗体还包括基因工程化形式,诸如嵌合抗体(诸如,人源化鼠抗体)和异源缀合抗体(诸如双特异性抗体)。还参见Pierce Catalog and Handbook,1994-1995(PierceChemical Co.,Rockford,Ill.);Kuby,J.,Immunology,第3版,W.H.Freeman&Co.,NewYork,1997。
非天然存在的抗体可以使用固相肽合成来构建,可以重组产生,或者可以例如通过筛选由可变重链和可变轻链组成的组合文库获得,如Huse等人,Science246:1275-1281(1989)所述,其以引用方式并入本文。这些和其他制备例如嵌合抗体、人源化抗体、CDR接枝抗体、单链抗体和双功能抗体的方法是本领域技术人员熟知的(Winter和Harris,Immunol.Today 14:243-246(1993);Ward等人,Nature 341:544-546(1989);Harlow和Lane,同前,1988;Hilyard等人,Protein Engineering:A practical approach(IRL Press1992);Borrabeck,Antibody Engineering,第2版(Oxford University Press 1995);其各自以引用的方式并入本文)。
如本文所用,术语“人源化”抗体或抗原结合片段是指人框架区和来自非人(诸如小鼠、大鼠或合成)抗体或抗原结合片段的一个或多个CDR。提供CDR的非人抗体或抗原结合片段称为“供体”,并且提供框架的人抗体或抗原结合片段称为“受体”。在一个示例中,所有CDR都来自人源化免疫球蛋白中的供体免疫球蛋白。恒定区不需要存在,但是如果它们存在,则它们应与人免疫球蛋白恒定区基本上相同,诸如具有至少约85%-90%或约95%或更多同一性。因此,人源化抗体或抗原结合片段的所有部分(可能除了CDR)都与天然人抗体序列的对应基本上基本相同。
如本文所用,如本文所用的短语“嵌合抗体”是指包含衍生自两种不同抗体(其通常属于不同种物种)的序列的抗体。在一些示例中,嵌合抗体包含来自一种人抗体的一个或多个CDR和/或框架区和来自另一人抗体的CDR和/或框架区。
“完全人抗体”或“人抗体”是包含来自(或衍生自)人基因组的序列,并且不包括来自另一物种的序列的抗体。在一些示例中,人抗体包含来自(或源自)人基因组的CDR、框架区和(如果存在的话)Fc区。可以使用基于来源于人基因组的序列产生抗体的技术,例如通过噬菌体展示或使用转基因动物来识别和分离人抗体(参见例如Barbas等人,Phagedisplay:A Laboratory Manuel.1”版New York:Cold Spring Harbor Laboratory Press,2004.Print.;Lonberg,Nat.Biotech.,23:1117-1125,2005;Lonenberg,Curr.Opin.Immunol.,20:450-459,2008)。
抗体可以具有一个或多个结合位点。如果有多于一个结合位点,则结合位点可彼此相同或可不同。例如,天然存在的免疫球蛋白具有两个相同的结合位点,单链抗体或Fab片段具有一个结合位点,而双特异性或双功能抗体具有两个不同的结合位点。
在如本文所用,术语或“抗原”是指可刺激动物的抗体产生或T细胞反应的化合物、组合物或物质,包括注射或吸收至动物中的组合物。抗原与特定体液或细胞免疫的产物反应,包括由异源抗原诱导的产物,例如所公开的SARS-CoV或SARS-CoV-2抗原。抗原的示例包括但不限于多肽、肽、脂质、多糖、其组合(诸如糖肽)和含有抗原决定簇的核酸,诸如被免疫细胞识别的那些。
如本文所用,术语“结合蛋白”是指至少一种包含与确定的靶标的结合能力的蛋白。靶标可以是一种或多种分析物、抗原、自身抗原、蛋白、多肽等。在一些方面,结合蛋白可以包括融合蛋白。除此之外并且在其他方面,本公开的结合蛋白还可以包括一种或多种其他分子,例如一种或多种免疫球蛋白或免疫球蛋白片段。在一些方面,结合蛋白是抗体或其抗体结合片段。
如本文所用的术语“融合蛋白”涉及包含基因接合的至少一第一蛋白质和至少一第二蛋白质的蛋白质。融合蛋白是通过接合两个或更多个最初编码单独蛋白质的基因而产生的。因此,融合蛋白可以包含不同或相同结合蛋白的多聚体,所述结合蛋白被表达为单个线性多肽。此类融合蛋白可以还包含不参与靶标的结合的额外结构域,诸如但不限于例如多聚化部分、多肽标签、多肽接头。
如本文所用,术语“保守的”当与氨基酸取代结合使用时,是指那些基本上不影响或降低蛋白的功能(诸如蛋白在向受试者施用时诱导免疫反应的能力)的那些取代。例如,在一些示例中,重组SARS-CoV或SARS-CoV-2S蛋白或S1片段可包含与对应的天然SARS-CoV或SARS-CoV-2蛋白序列相比,至多1、2、3、4、5、6、7、8、9或至多10个保守取代,并且诱导受试者的对SARS-CoV或SARS-CoV-2S蛋白的免疫反应。术语保守变异还包括使用取代的氨基酸代替未取代的亲本氨基酸。
此外,本领域技术人员将认识到,在编码序列中改变、添加或缺失单个氨基酸或小百分比(例如小于5%,在一些示例中小于1%)的氨基酸的个别取代、缺失或添加是保守变异,其中改变导致氨基酸被化学上相似的氨基酸取代。
提供功能相似的氨基酸的保守氨基酸取代表是本领域普通技术人员熟知的。以下六组是被认为是彼此保守取代的氨基酸的示例:
1)丙氨酸(A)、丝氨酸(S)、苏氨酸(T);
2)天冬氨酸(D)、谷氨酸(E);
3)天冬酰胺(N)、谷氨酰胺(Q);
4)精氨酸(R)、赖氨酸(K);
5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);以及
6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。
非保守取代是降低蛋白(例如,SARS-CoV或SARS-CoV-2S蛋白)的活性或功能(诸如当施用至受试者时,诱导免疫反应的能力)的那些。例如,如果一个氨基酸残基对于蛋白的功能是必不可少的,那么即使是另外保守取代也可能破坏该活性。因此,保守取代不改变感兴趣的蛋白的基本功能。
如本文所用,术语“表达”是指核酸序列的转录或翻译。例如,当基因的DNA被转录成RNA或RNA片段(在一些示例中,其被加工成mRNA)时,基因被表达。当基因的mRNA被翻译成氨基酸序列,诸如蛋白或蛋白片段时,基因也可以被表达。在一个具体示例中,当异源基因被转录成RNA时,所述异源基因被表达。在另一示例中,当异源基因的RNA被翻译成氨基酸序列时,所述异源基因被表达。术语“表达”在本文中用于表示转录或翻译。表达的调节可以包括对转录、翻译、RNA转运和加工、中间分子(诸如mRNA)的降解的控制,或者通过特定蛋白分子产生之后的活化、失活、区室化或降解进行控制。
如本文所用,短语“表达控制序列”是指调节其可操作地连接的异源核酸序列的表达的核酸序列。当表达控制序列控制并调节核酸序列的转录和(适当时)翻译时,表达控制序列可操作地连接至核酸序列。因此,表达控制序列可以包括适当的启动子、增强子、转录终止子、蛋白编码基因前面的起始密码子(ATG)、内含子的剪接信号、维持该基因正确翻译mRNA的正确阅读框和终止密码子。术语“控制序列”旨在至少包括其存在可以影响表达的组分,并且还可以包括其存在是有利的额外组分,例如前导序列和融合配偶体序列。表达控制序列可以包括启动子。
启动子是足以指导转录的最小序列。还包括那些足以使启动子依赖性基因表达可控以实现细胞类型特异性、组织特异性或可被外部信号或可由外部信号或剂诱导的那些启动子元件;此类元件可位于基因的5'或3'区。包括组成型和诱导型启动子(参见例如Bitter等人,Methods in Enzymology 153:516-544,1987)。例如,当在细菌系统中克隆时,可以使用诱导型启动子诸如噬菌体λ的pL、plac、ptrp、ptac(ptrp-lac杂合启动子)等。在一个示例中,当在哺乳动物细胞系统中克隆时,可以使用来源于哺乳动物细胞的基因组(诸如金属硫蛋白启动子)或来源于哺乳动物病毒(诸如逆转录病毒长末端重复;腺病毒晚期启动子;牛痘病毒7.5K启动子)的启动子。通过重组DNA或合成技术产生的启动子也可以用于提供核酸序列的转录。
可以将多核苷酸插入到含有启动子序列的表达载体中,所述启动子序列促进插入的宿主基因序列的有效转录。表达载体通常含有复制起点、启动子以及允许对转化细胞进行表型选择的特定核酸序列。
如本文所用,短语“表达载体”是指包含重组多核苷酸的载体,该重组多核苷酸包含与要表达的核苷酸序列可操作地连接的表达控制序列。表达载体包含足够的用于表达的顺式作用元件;其他用于表达的元件可以由宿主细胞或在体外表达系统中提供。表达载体包括本领域中所有已知的表达载体,诸如粘粒、质粒(例如,裸露或包含在脂质体中)和病毒(例如,慢病毒、逆转录病毒、腺病毒和腺相关病毒),所述表达载体并入有重组多核苷酸。
如本文所用,术语“异源”是指源自不同的遗传来源。与细胞西苑的核酸分子源自除其所表达的细胞之外的遗传来源。在一个具体的非限制性示例中,编码重组SARS-CoV或SARS-CoV-2多肽或特异性抗体的异源核酸分子在细胞诸如哺乳动物细胞中表达。用于将异源核酸分子引入细胞或生物体中的方法是本领域熟知的,例如用核酸转化,包括电穿孔、脂质转染、粒子枪加速和同源重组。
如本文所用,短语“宿主细胞”是指载体可在其中繁殖并表达DNA的细胞。所述细胞可以是原核的或真核的。所述术语还包括主题宿主细胞的任何后代。应当理解,所有后代可能与亲代细胞不同,因为在复制期间可能发生突变。然而,当使用术语“宿主细胞”时,包括此类后代。
如本文所用,“IgA”是指属于基本上通过识别的免疫球蛋白α基因编码的抗体类别的多肽。在人类中,此类或同种型包括IgA1和IgA2。IgA抗体可以以单体、主要为二聚体形式的聚合物(称为pIgA)和分泌型IgA的形式存在。野生型IgA的恒定链在其C末端含有18个氨基酸的延伸,称为尾段(tp)。聚合物IgA由浆细胞分泌,其中称为J链的15kDa肽通过尾段中的保守半胱氨酸残基连接两个IgA单体。
如本文所用,“IgG”是指属于基本上通过识别的免疫球蛋白γ基因编码的抗体类别或同种型的多肽。在人类中,此类包括IgG1、IgG2、IgG3和IgG4。
如本文所用,术语“分离的”是指生物组分(诸如蛋白质,例如公开的编码这种抗原的核酸)已与其他生物组分(诸如天然存在所述组分的其他生物组分,诸如其他染色体和染色体外DNA、RNA和蛋白质)基本分离或纯化。已“分离”的蛋白质、肽和核酸包括通过标准纯化方法纯化的蛋白质。所述术语还涵盖通过在宿主细胞中重组表达所制备的蛋白质或肽以及化学合成的蛋白质、肽和核酸分子。分离的不需要绝对纯度,并且可以包括至少50%分离,诸如至少75%、80%、90%、95%、98%、99%或甚至99.9%分离的核酸分子。
如本文所用,“接头”是可用于将两个分子连接成一个连续分子,例如将载体分子连接至多肽的双功能分子。肽接头的非限制性示例包括甘氨酸-丝氨酸接头,诸如(GGGGS)n接头(其中n为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25)。
如本文所用,术语“缀合”、“接合”、“结合”或“连接”可以指使两个分子成为一个连续的分子;例如,将两个多肽连接成一个连续的多肽,或将载体分子或其他分子共价连接至多肽。键联可以通过化学或重组手段进行。“化学手段”是指例如在多肽部分与载体分子之间的反应,使得在两个分子之间形成共价键以形成一个分子。
如本文所用,“严重急性呼吸病毒综合征冠状病毒”或“SARS-CoV”是指β-冠状病毒,其为属于冠状病毒亚科(subfamily Coronavirinae)的正义单链RNA病毒并且导致人严重呼吸综合征。SARS-CoV具有与已知的其他三组冠状病毒相同的结构蛋白:刺突糖蛋白(S)、膜蛋白(M)、包膜蛋白(E)和核衣壳蛋白(N)。冠状病毒N蛋白是冠状病毒RNA合成所需的并且具有可能参与模板转换的RNA伴侣活性。
SARS-CoV刺突糖蛋白的长度为1255个氨基酸,与其他冠状病毒的氨基酸相似性较低(20-27%)。它的羧基末端(C末端)由跨膜区和细胞质尾构成。SARS-CoV刺突糖蛋白的细胞外结构域由两个七肽重复区构成,所述七肽重复区被称为七肽重复区1(HR1)和七肽重复区2。
SARS-CoV刺突糖蛋白具有两个功能结构域:S1和S2。S1负责与宿主细胞上的受体血管紧张素转换酶2(ACE2)结合,并限定病毒的宿主范围。S2是促进病毒和细胞膜融合的跨膜亚基。当HR中发生构象变化以形成融合核心时,发生膜融合。蛋白质的HR折叠成卷曲螺旋结构(称为基因融合状态),导致S蛋白的HR结构域折叠成发夹样结构。这种发夹结构导致细胞膜和病毒膜被拉在一起并最终融合。
其他已知的β-冠状病毒包括SARS-CoV-2和MERS-CoV,它们均导致严重且可能致命的呼吸道感染。SARS-CoV-2的基因组序列与蝙蝠CoV RaTG13具有96.2%同一性且与SARS-CoV具有79.5%同一性。许多不同样品的SARS-CoV-2的序列已在多个出版物中进行了描述,诸如Lu等人,Lancet,395:565-574(2020年2月)和https://www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs/,其各自的内容以引用的方式并入本文。
如本文所用,短语“中和抗体”是指通过结合感染原上的具体抗原来降低感染因子的感染效价的抗体。在一些示例中,感染原是病毒。在一些示例中,对SARS-CoV或SARS-CoV-2S蛋白具有特异性的抗体中和SARS-CoV或SARS-CoV-2的感染效价。“广泛中和抗体”是结合并抑制相关抗原的功能的抗体,诸如具有至少85%、90%、95%、96%、97%、98%或99%同一性抗原表面的抗原。关于来自病原体(诸如病毒)的抗原,抗体可以结合并抑制来自多于一类和/或亚类病原体的抗原的功能。例如,对于SARS-CoV或SARS-CoV-2,抗体可以结合并抑制抗原的功能,诸如来自SARS-CoV或SARS-CoV-2的多于一种毒株的SARS-CoV或SARS-CoV-2S蛋白。在一个示例中,针对SARS-CoV或SARS-CoV-2S蛋白的广泛中和抗体与针对SARS-CoV或SARS-CoV-2S蛋白的其他抗体的不同之处在于,它们在循环中中和高百分比的许多类型SARS-CoV或SARS-CoV-2。
如本文所用,短语“核酸”是指由经由磷酸二酯键连接的核苷酸单元(核糖核苷酸、脱氧核糖核苷酸、相关天然存在的结构变体以及其合成的非天然存在的类似物)构成的聚合物、相关天然存在的结构变体以及其合成的非天然存在的类似物。因此,所述术语包括核苷酸聚合物,在核苷酸聚合物中,核苷酸和它们之间的键联包括非天然存在的合成类似物,例如但不限于硫代磷酸酯、氨基磷酸酯、甲基膦酸酯、手性甲基膦酸酯、2-O-甲基核糖核苷酸、肽-核酸(PNA)等。例如,可以使用自动化DNA合成仪合成此类多核苷酸。术语“寡核苷酸”通常是指短多核苷酸,通常不超过约50个核苷酸。应当理解,当核苷酸序列由DNA序列(即,A、T、G、C)表示时,这还包括其中“U”替代“T”的RNA序列(即,A、U、G、C)。
如本文所用,术语“核苷酸”是指但不限于包括与糖连接的碱基的单体,例如嘧啶、嘌呤或其合成类似物,或与氨基酸连接的碱基,如在肽核酸(PNA)中。核苷酸是多核苷酸中的一种单体。核苷酸序列是指多核苷酸中的碱基序列。
本文使用常规符号描述核苷酸序列:单链核苷酸序列的左手端是5'端;双链核苷酸序列的左手方向被称为5'方向。将核苷酸5'至3'添加至新生RNA转录物的方向被称为转录方向。与mRNA具有相同序列的DNA链被称为“编码链”;DNA链上与从该DNA转录的mRNA具有相同序列并且位于RNA转录物的5'端的5'的序列被称为“上游序列”;DNA链上与RNA具有相同序列并且位于编码RNA转录物的3'端的3'的序列被称为“下游序列”。
“cDNA”是指与单链或双链形式的mRNA互补或相同的DNA。
如本文所用,术语“编码”是指多核苷酸(例如基因、cDNA或mRNA)中核苷酸的特定序列用作生物过程中合成其他聚合物和大分子的模板的固有特性,该聚合物和大分子具有确定的核苷酸序列(即,rRNA、tRNA和mRNA)或确定的氨基酸序列以及由此产生的生物学特性。因此,如果由基因产生的mRNA的转录和翻译在细胞或其他生物系统中产生蛋白质,则所述基因编码所述蛋白质。编码链(其核苷酸序列与mRNA序列相同,且通常在序列表中提供)和非编码链(用作基因或cDNA转录的模板)都可以称为编码所述基因或cDNA的蛋白质或其他产物。除非另外说明,否则“编码氨基酸序列的核苷酸序列”包括彼此呈简并形式且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质和RNA的核苷酸序列可包含内含子。
如果序列为第一序列的多核苷酸与序列为第二序列的多核苷酸特异性杂交,则第一序列相对于第二序列为“反义”。
如本文所用,短语“可操作地连接”是指当第一核酸序列被放置成与第二核酸序列有功能关系时,所述第一核酸序列与所述第二核酸序列可操作地连接。例如,如果启动子(诸如CMV启动子)影响编码序列的转录或表达,则所述启动子与编码序列可操作地连接。一般来讲,可操作连接的DNA序列是连续的,并且在需要接合两个蛋白质编码区域的情况下在相同阅读框中。
如本文所用,短语“药学上可接受的载剂”是指本领域已知的惯用和常规载剂,例如Remington's Pharmaceutical Sciences,E.W.Martin,Mack Publishing Co.,Easton,Pa.,第19版,1995中所述。通常,载体的性质取决于所采用的特定施用方式。例如,肠胃外制剂通常包含可注射的流体,其包括药学上和生理学上可接受的流体如水、生理盐水、平衡盐溶液、葡萄糖水溶液、甘油等作为媒介物。对于固体组合物(例如,粉剂、丸剂、片剂或胶囊形式),常规的无毒固体载体可包括例如药物级的甘露醇、乳糖、淀粉或硬脂酸镁。除生物学中性载体外,待施用的药物组合物还可含有少量无毒辅助物质,诸如润湿剂或乳化剂、防腐剂和pH缓冲剂等,例如,乙酸钠或失水山梨糖醇单月桂酸酯。在特定方面,适合于向受试者施用的载剂可以是无菌的,和/或悬浮或以其他方式包含在单位剂型中,所述单位剂型含有一个或多个测量剂量的适合诱导所需抗SARS-CoV或SARS-CoV-2免疫反应的组合物。它也可能伴随用于治疗目的的药物。例如,单位剂型可以在含有无菌内容物的密封小瓶中或用于注射至受试者体内的注射器中,或被冻干以用于随后溶解和投与,或者呈固体或控释剂量。
如本文所用,术语“多肽”是指任何氨基酸链,不管长度或翻译后修饰(例如糖基化或磷酸化)。“多肽”适用于氨基酸聚合物,包括天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物,以及其中一个或多个氨基酸残基是非天然氨基酸的氨基酸聚合物,例如对应的天然存在的氨基酸的人工化学模拟物。“残基”是指通过酰胺键或酰胺键模拟物掺入多肽中的氨基酸或氨基酸模拟物。多肽具有氨基末端(N-末端)端和羧基末端(C-末端)端。“多肽”与肽或蛋白质可互换使用,并且在本文中用于指氨基酸残基的聚合物。
肽、多肽或蛋白质中的氨基酸通常经由酰胺键联(CONH)化学结合在一起。此外,氨基酸可以通过其他化学键结合在一起。例如,氨基酸或氨基酸类似物的键联可以包括CH2NH--、--CH2S--、--CH2--CH2–CH=CH--(顺式和反式)、--COCH2--CH(OH)CH2--和--CHH2SO--(这些和其他键联可见于Spatola,Chemistry and Biochemistry of AminoAcids,Peptides,and Proteins,B.Weinstein编,Marcel Dekker,New York,第267页(1983);Spatola,A.F.,Vega Data(1983年3月),第1卷,第3期,Peptide BackboneModifications(一般综述);Morley,Trends Pharm Sci第463-468页,1980;Hudson等人,Int J Pept Prot Res 14:177-185,1979;Spatola等人,Life Sci 38:1243-1249,1986;Harm J.Chem.Soc Perkin Trans.1307-314,1982;Almquist等人,J.Med.Chem.23:1392-1398,1980;Jennings-White等人,Tetrahedron Lett 23:2533,1982;Holladay等人,Tetrahedron.Lett24:4401-4404,1983;以及Hruby Life Sci 31:189-199,1982。
如本文所用,术语“样品”或“生物样品”是指获自受试者的含有基因组DNA、RNA(包括mRNA)、蛋白质或其组合的生物试样。示例包括但不限于外周血、组织、细胞、尿液、唾液、组织活检、细针抽吸物、手术试样和尸检材料。
如本文所用,术语“序列同一性”是指氨基酸序列之间的相似性,关于序列之间的相似性表示,否则称为序列同一性。序列同一性以同一性百分(或相似性或同源性)频繁测量;百分比越高,两个序列越相似。当使用标准方法比对时,多肽的同源物、直系同源物或变体将具有相对高度的序列同一性。
用于比较的序列比对方法是本领域熟知的。各种程序和比对算法描述于:Smith和Waterman,Adv.Appl.Math.2:482,1981;Needleman和Wunsch,J.Mol.Biol.48:443,1970;Pearson和Lipman,Proc.Natl.Acad.Sci.USA 85:2444,1988;Higgins和Sharp,Gene,73:237-44,1988;Higgins和Sharp,CABIOS 5:151-3,1989;Corpet等人,Nuc.Acids Res.16:10881-90,1988;Huang等人,Computer Appls.the Biosciences 8,155-65,1992;以及Pearson等人,Meth.Mol.Bio.24:307-31,1994。Altschul等人,J.Mol.Biol.215:403-10,1990提出了序列比对方法和同源性计算的详细考虑因素。
一旦进行了比对,便通过计算两个序列中存在相同核苷酸或氨基酸残基的位置的数量来确定匹配的数量。序列同一性百分比通过将匹配数除以所识别的序列中示出的序列长度除以铰接长度(诸如所识别的序列中示出的100个连续核苷酸或氨基酸残基),接着将所得值乘以100来确定。例如,当与具有1554个氨基酸的测试序列比对时,具有1166个匹配的肽序列与测试序列具有75.0%同一性(1166/1554*100=75.0)。序列同一性百分比值被四舍五入至最近的十分位。例如,75.11、75.12、75.13以及75.14向下舍入至75.1,而75.15、75.16、75.17、75.18以及75.19向上舍入至75.2。长度值将总是整数。
NCBI基本局部比对研究工具(BLAST)(Altschul等人,J.Mol.Biol.215:403,1990)来自若干来源,包括国家生物信息中心(NCBI,Bethesda,Md.)和在因特网上获得以与序列分析程序blastp、blastn、blastx、tblastn和tblastx关联使用。如何使用此程序确定序列同一性的描述可在因特网上的NCBI网站上找到。
多肽的同源物和变体通常特征在于具有在与感兴趣的氨基酸序列的全长比对中计数的至少约75%,例如至少约80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的序列同一性。通过此方法评估时,与参考序列具有甚至更高相似性的蛋白质将显示出更高的同一性百分比,如至少80%、至少85%、至少90%、至少95%、至少98%或至少99%序列同一性。当小于完整序列的序列进行序列同一性的比较时,同源物和变体将通常在10-20个氨基酸的短窗口上具有至少80%的序列同一性,并且根据其与参考序列的相似性可以具有至少85%或至少90%或95%的序列同一性。用于确定在此类短窗口上的序列同一性的方法可在网上的NCBI网站处获得。本领域技术人员将理解,提供这些序列同一性范围仅用于指导;可以获得超出所提供范围的非常重要的同源物是完全有可能的。
对于核酸序列的序列比较,通常一个序列充当参考序列,将测试序列与参考序列比较。当使用序列比较算法时,将测试序列和参考序列输入至计算机中,必要时指定子序列坐标,并且指定序列算法程序参数。使用默认程序参数。用于比较的序列比对方法是本领域熟知的。用于比较的序列的最佳比对可例如通过以下进行:Smith和Waterman,Adv.Appl.Math.2:482,1981的局部同源算法;Needleman和Wunsch,J.Mol.Biol.48:443,1970的同源比对算法;Pearson和Lipman,Proc.Nat'l.Acad.Sci.USA 85:2444,1988的相似性研究方法;这些算法的计算机化实施(Wisconsin Genetics软件包中的GAP、BESTFIT、FASTA和TFASTA,Genetics Computer Group,575Science Dr.,Madison,Wis.);或人工比对和目视检查(参见例如,Sambrook等人(Molecular Cloning:A Laboratory Manual,第4版,Cold Spring Harbor,N.Y.,2012)和Ausubel等人(In Current Protocols in MolecularBiology,John Wiley&Sons,New York,至增刊104,2013)。有用算法的一个示例是PILEUP。PILEUP使用Feng和Doolittle,J.Mol.Evol.35:351-360,1987的渐进式比对方法的简单化。使用的方法类似于Higgins和Sharp,CABIOS5:151-153,1989描述的方法。使用PILEUP,将参考序列与其他测试序列进行比较,以确定使用以下参数的序列同一性百分比关系:默认空位权重(3.00)、默认空位长度权重(0.10)和加权末端空位。PILEUP可以获自GCG序列分析软件包中,例如,7.0版(Devereaux等人,Nuc.Acids Res.12:387-395,1984)。
适用于确定序列同一性百分比和序列相似性的算法的另一示例是BLAST和BLAST2.0算法,它们描述于Altschul等人,J.Mol.Biol.215:403-410,1990以及Altschul等人,Nucleic Acids Res.25:3389-3402,1977中。用于执行BLAST分析的软件可通过国家生物技术信息中心公开获得(ncbi.nlm.nih.gov)。BLAST程序(对于核苷酸序列)使用字长(W)11、比对(B)50、期望值(E)10、M=5、N=-4和两条链的比较作为默认值。BLASTP程序(对于氨基酸序列)使用字长(W)3和期望(E)10作为默认值以及BLOSUM62计分矩阵(参见Henikoff和Henikoff,Proc.Natl.Acad.Sci.USA 89:10915,1989)。寡核苷酸是长度至多约100个核苷酸碱基的线性多核苷酸序列。
如本文所用,提及“至少80%同一性”是指与指定参考序列具有“至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或甚至100%同一性”。
如本文所用,短语“信号肽”是指引导新合成的分泌或膜蛋白到达和穿过膜(例如,内质网膜)的短氨基酸序列(例如,长度约10-35个氨基酸)。信号肽通常位于多肽的N末端并被信号肽酶去除。信号肽序列通常含有三个常见的结构特征:N末端极性碱性区(n区)、疏水核心和亲水c区。示例性信号肽序列如SEQ ID NO.:1和6所示。
如本文所用,当提及抗体:抗原蛋白质复合物或蛋白质:蛋白质复合物的形成时,短语“特异性结合”是指在蛋白质和其他生物制剂的异质群体存在的情况下,确定靶蛋白、肽或多糖(例如糖蛋白)的存在的结合反应。因此,在指定条件下,特定的抗体或蛋白质优先结合特定的靶蛋白、肽或多糖(例如存在于病原体表面的抗原,例如SARS-CoV或SARS-CoV-2S蛋白),并且不与样品或受试者中存在的其他蛋白质或多糖大量结合。可以通过本领域已知的方法确定特异性结合。当相互作用的KD小于约10-6摩尔,例如小于约10-7摩尔、小于约10-8摩尔、小于约10-9摩尔、小于约10-10等时,第一蛋白质或抗体“特异性结合”靶蛋白。
多种免疫测定形式适用于选择与特定蛋白质特异性免疫反应的抗体或其他配体。例如,固相ELISA免疫测定常规地用于选择与蛋白质特异性免疫反应的单克隆抗体。关于可以用来确定特异性免疫反应的免疫测定形式和条件的描述,参见Harlow和Lane,Antibodies,A Laboratory Manual,第2版,Cold Spring Harbor Publications,New York(2013)。
如本文所用,术语“受试者”是指活的多细胞脊椎动物生物体,包括人和非人哺乳动物的类别。在一示例中,受试者是人。在特定示例中,受试者是人或骆驼或蝙蝠。在另一示例中,选择需要抑制SARS-CoV或SARS-CoV-2感染的受试者。例如,受试者未被感染并且处于感染SARS-CoV或SARS-CoV-2的风险中,或者已感染且需要治疗。
如本文所用,短语“治疗有效量”是指足以预防、治疗(包括防治)、减少和/或改善病症或疾病的症状和/或根本原因,如预防、抑制和/或治疗SARS-CoV或SARS-CoV-2感染的剂(诸如所公开的抗体)的量。在一些示例中,治疗有效量足以减轻或消除疾病(诸如SARS-CoV或SARS-CoV-2感染)的症状。例如,这可能是抑制或预防病毒复制或显著改变病毒感染的外在症状所必需的量。通常,此量足可测量地抑制病毒复制或感染性。
此描述不旨在详细列出可实施本发明的所有不同方式或可添加到本发明的所有特征。例如,关于一个示例说明的特征可以并入其他示例中,并且关于特定示例说明的特征可以从所述示例删除。此外,根据不背离本发明的本公开内容,对本文提出的各种示例的许多变化和添加对于本领域技术人员来说将是显而易见的。因此,以下说明书旨在说明本发明的一些特定特定,但不是详尽地指定其所有排列、组合和变化。
在一个示例中,期望的反应是抑制或减少或预防SARS-CoV或SARS-CoV-2感染。SARS-CoV或SARS-CoV-2感染的细胞不需要被完全消除或减少或防止以实现组合物有效。例如,与不存在组合物的情况下SARS-CoV或SARS-CoV-2感染的细胞的数目相比,施用治疗有效量的剂可以减少SARS-CoV或SARS-CoV-2感染的细胞的数目(或预防细胞感染)所需的量,例如至少10%、至少20%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或甚至至少100%(消除或预防可检测的SARS-CoV或SARS-CoV-2感染的细胞)。
所公开的抗体的治疗有效量可以取决于被治疗的受试者、被治疗的病症的严重性和类型以及施用方式。单位剂型的抗体可以以治疗量或者以多倍治疗量包装于例如具有无菌组件的小瓶(例如,具有可刺穿的盖子)或注射器中。
治疗或预防疾病:抑制处于例如诸如SARS-CoV或SARS-CoV-2感染的风险中的受试者的疾病或病状的全面发展。“治疗”是指在疾病或病理病状开始发展后改善其体征或症状的治疗干预。关于疾病或病理病状的术语“改善”是指对治疗的任何可观察到的有益效果。例如,可以通过在易感受试者中疾病的临床症状的延迟发作、疾病的一些或所有临床症状的严重性降低、疾病的进展缓慢、病毒负载减少、受试者整体健康或幸福的改善或对特定疾病特异的本领域公知的其他参数来证明有益效果。“防治性”治疗是出于降低发生病理学的风险而对没有表现出疾病体征或仅表现出早期体征的受试者施用的治疗。
术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment of)”(或语法上等同的术语)意指受试者病状的严重性降低或至少部分减轻或改善和/或实现至少一种临床症状的一些华安和、缓解或减少和/或病症进展延迟。
如本文所用,术语“预防(prevent)”、“预防(prevents)”或“预防(prevention)”和“抑制(inhibit)”、“抑制(inhibits)”或“抑制(inhibition)”(及其语法等价物)不抑制完全消除疾病且涵盖任何类型的防治性治疗,所述治疗降低病状的发生率、延迟病状的发作和/或减少与发作后病状相关的症状。
本文所用的“有效”、“防治有效”或“治疗有效”的量是足以为受试者提供一些改善或益处的量换句话说,“有效的”、“防治有效的”或“治疗有效的”量是将在受试者的至少一种临床症状中提供一些延迟、减轻、缓解或减少的量。本领域技术人员将理解,效果不必是完全的或治愈性的,只要为受试者提供一些益处即可。
如本文所用,术语“减少(reduces)”或“减少(reduction)”是相对术语,使得与参考剂相比,如果在施用剂之后反应或病状定量削弱,或如果在施用剂之后其削弱,则所述剂减少反应或病状。类似地,术语“预防”不一定意指剂完全消除反应或条件,只要消除了反应或条件的至少一个特征即可。因此,减少或预防感染或反应的组合物可以但不一定完全消除这种感染或反应,只要感染或反应被可测量的削弱例如不存在所述剂或相比于参考剂的感染或反应的至少约50%,诸如至少约70%、或约80%、或甚至约90%(即至10%或更低)。
如本文所用,术语“载体”是指引入宿主细胞中,从而产生转化的宿主细胞的核酸分子。重组DNA载体是具有重组DNA的载体。载体可以包括允许其在宿主细胞中复制的核酸序列,诸如复制起点。载体还可以包括一种或多种可选择标志物基因和本领域已知的其他遗传元件。病毒载体是具有至少一些源自一种或多种病毒的核酸序列的重组核酸载体。复制缺陷型病毒载体是由于至少一种复制必需基因功能的缺陷而需要与复制所需的病毒基因组的一个或多个区域互补的载体。例如,使得病毒载体不在典型宿主细胞中复制,尤其是在治疗方法过程中可能被病毒载体感染的人类患者中的那些细胞。
式I的分离的结合蛋白
在一个方面,本公开内容涉及一种分离的结合蛋白,其特异性结合SARS-CoV和/或SARS-CoV-2蛋白上的表位。具体而言,特异性结合SARS-CoV和/或SARS-CoV-2蛋白上的表位的分离的结合蛋白可以中和SARS-CoV和/或SARS-CoV-2感染。具体而言,分离的结合蛋白具有包含式I的氨基酸序列:
A-(B)n-C (式I)
其中A是SARS-CoV和/或SARS-CoV-2蛋白用于介导细胞进入的受体,例如血管紧张素转换酶2(ACE2)、DPP4或其变体;n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;B是多肽接头;并且C是片段结晶化(Fc)结构域。这些蛋白质通常二聚化(例如,通过Fc结构域)。
式I中使用的Fc结构域可以是任何人Fc结构域并且可以是人IgA、IgM或IgG Fc结构域。此外,Fc结构域可以是最优化的Fc结构域,诸如美国专利申请号2010/093979中描述的那些。在本公开的一个方面,Fc结构域是IgG1。此外,Fc结构域可以含有一个或多个氨基酸取代(例如,保守取代)或突变,例如,以实现新生儿Fc-受体(FcRn)结合增强。
式I中使用的ACE2可以是人ACE2。在式I中可以使用ACE2或其片段(此类片段的长度为至少10个氨基酸、至少15个氨基酸、至少20个氨基酸、至少25个氨基酸、至少30个氨基酸、至少40个氨基酸、至少45个氨基酸、至少50个氨基酸等)。在一些方面,使用人ACE2或其片段的细胞外结构域。特别地,不包括collectrin结构域的细胞外结构部。图15显示野生型人ACE2的注释序列表。此序列显示collectrin结构域,氨基酸615-740(加框)。可以使用ACE2蛋白或其一部分的细胞外结构域的一部分(例如,氨基酸17、19或19至氨基酸614)。参见SEQ ID NO:11。
一般来讲,本文针对式I描述的组合物和方法可以与肽一起使用,所述肽与ACE2或其一部分(不包括collectrin结构域)的细胞外区具有约80%同一性。此外,式I中使用的ACE2可以含有一个或多个氨基酸取代(例如,保守取代)或突变。在一个方面,突变消除ACE2分子的先天酶活性,同时保持/保留Fc结构域的二聚化结构域。可以在本公开中使用的ACE2序列的示例是SEQ ID NO.:2、4、11、15、17、19、21和23,它们提供含有两个取代或突变的ACE2的氨基酸序列,所述取代或突变可以用于本文所述的结合蛋白中。SEQ ID NO.2和4两者均含有H374N和H378N取代或突变。
图16的表1说明可以在细胞外ACE2多肽序列中单独或共同进行的氨基酸突变。具体而言,这些残基中的一个或多个(或所有)氨基酸可以被修饰并且本文所述的柔性连接的ACE2诱饵的活性可以被保留(并且在一些情况下,与由不具有collectrin结构域的野生型细胞外ACE2多肽形成的相比而增强)。例如,残基位置19、20、24、25、27、29、31、33、34、35、37、38、39、40、41、42、69、72、75、76、79、89、90、91、92、101、110、135-136、160、169、192、219、239、271、273、309、312、324、324、325、330、338-340、345、350、351、355、359、386、389、393、465-467、481、505、514、518和/或603的一个或多个氨基酸。这些残基的具体变化可以如表1中所指出,或者它们可以是不同的;在一些情况下,氨基酸变化可以是保守变化,例如,基于电荷和/或大小。例如,SEQ ID NO:15显示了不具有collectrin结构域的细胞外ACE2多肽的示例,其中五个残基被修饰:K31F、N33D、H34S、E35Q和H345L。ACE2的这种变体可以经由如本文所述的合适的柔性接头连接至Fc结构域以形成柔性连接的ACE2诱饵,其一个示例以SEQID NO:16显示。SEQ ID NO:17显示ACE2变体的另一示例(不包括collectrin结构域并且修饰残基T27Y、L79T、N330Y的细胞外ACE2),其可以经由合适的柔性接头连接至Fc结构域以形成柔性连接的ACE2诱饵,其一个示例以SEQ ID NO:18显示。SEQ ID NO:19显示ACE2变体的另一示例(不包括collectrin结构域并且修饰残基T20I、H34A、T92Q和Q101H的细胞外ACE2),其可以经由合适的柔性接头连接至Fc结构域以形成柔性连接的ACE2诱饵,其一个示例以SEQ ID NO:20显示。SEQ ID NO:21显示ACE2变体的另一示例(不包括collectrin结构域并且修饰残基A25V、K31N、E34K和L79F的细胞外ACE2),其可以经由合适的柔性接头连接至Fc结构域以形成柔性连接的ACE2诱饵,其一个示例以SEQ ID NO:22显示。SEQ ID NO:23显示ACE2变体的另一示例(修饰残基T27W的细胞外ACE2),其可以经由合适的柔性接头连接至Fc结构域以形成柔性连接的ACE2诱饵,其一个示例以SEQ ID NO:24显示。
任何多肽接头(且特别是柔性的)可用于式I中以将不包括collectrin结构域的细胞外ACE2连接至Fc结构域。在一些示例中,接头具有序列GGGGS(SEQ ID NO:11)。
在一些示例中,结合蛋白还可以包含在式I中的在多肽接头与Fc结构域之间的铰链。式I中铰链的位置并不是关键的。铰链区可以在柔性接头之前(例如,在柔性接头与细胞外ACE2结构域之间)、在柔性接头内(例如,(G4S)2-铰链-(G4S)4等)或在之后(例如,在柔性接头与Fc结构域之间)。
在一些其他示例中,式I的结合蛋白还可以包含信号肽。可以使用的信号肽的示例以SEQ ID NO.1和5显示。可以使用其他信号序列。式I中信号肽的位置并不是关键的。
在一些示例中,结合蛋白是抗体或其抗体结合片段。当结合蛋白是抗体时,抗体可以是单克隆抗体、人源化抗体、重组抗体、嵌合抗体、人抗体、双特异性抗体或多特异性抗体。当结合蛋白是抗体结合片段时,它可以是单链抗体、Fab片段、F(ab')2片段、Fab'片段、Fsc片段、Fv片段、scFv、sc(Fv)2或双抗体。用于制备抗体和抗体结合片段的方法是本领域熟知的。
在某些方面,考虑了本文提供的结合蛋白的氨基酸序列变体。例如,可能希望改善结合蛋白(例如,当结合蛋白是抗体时)的结合亲和力和/或其他生物特性。可以通过在编码结合蛋白(例如,抗体)的核苷酸序列中引入适当的修饰或通过肽合成来制备结合蛋白(例如,抗体)的氨基酸序列变体。此类修饰包括例如结合蛋白的氨基酸序列内的残基的缺失和/或插入和/或取代。可以进行缺失、插入和取代的任何组合以获得最终的构建体,条件是最终的构建体具有所需的特征(例如,抗原结合)。
本公开的式I的结合蛋白的示例包括图中所示的那些,并在下文的实施例中讨论。这些结合蛋白的氨基酸序列提供在序列表中。
式II的分离的特异性结合蛋白
本文还描述了特异性结合SARS-CoV和/或SARS-CoV-2蛋白上的至少一个表位的双特异性结合蛋白。具体而言,特异性结合SARS-CoV和/或SARS-CoV-2蛋白上的至少一个表位的分离的双特异性结合蛋白可以中和SARS-CoV和/或SARS-CoV-2感染。具体来讲,分离的特异性结合蛋白包含至少一个具有包含式II的氨基酸序列的重链可变区:
X-(Y)n-Z (式II)
其中X是(i)SARS-CoV和/或SARS-CoV-2蛋白用于介导细胞进入的受体,例如血管紧张素转换酶2(ACE2)、DPP4或其变体;(ii)来自结合SARS-CoV、SARS-CoV-2或其片段上的表位的抗体的可变重链区;n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;Y是多肽接头;并且Z是(i)SARS-CoV和/或SARS-CoV-2蛋白用于介导细胞进入的受体,例如血管紧张素转换酶2(ACE2)、DPP4或其变体;或(ii)来自结合SARS-CoV、SARS-CoV-2或其片段的抗体的可变重链区,条件是(a)当X是SARS-CoV和/或SARS-CoV-2蛋白用于介导细胞进入的受体时,Z是来自结合SARS-CoV、SARS-CoV-2或其片段的抗体的可变重链区;或(b)当X是来自结合SARS-CoV、SARS-CoV-2或其片段的抗体的可变重链区时,Z是SARS-CoV和/或SARS-CoV-2蛋白用于介导细胞进入的受体。在式II中,如果n为0,则不存在多肽接头。
式II中使用的ACE2可以是人ACE2或变体(如上所述)。在式II中可以使用全长ACE2或其片段(此类片段的长度为至少10个氨基酸、至少15个氨基酸、至少20个氨基酸、至少25个氨基酸、至少30个氨基酸、至少40个氨基酸、至少45个氨基酸、至少50个氨基酸等)。在一些方面,可以使用人ACE2或其片段的细胞外结构域。此外,式II中使用的ACE2可以含有一个或多个氨基酸取代(例如,保守取代)或突变。在一个方面,突变消除ACE2分子的先天酶活性,同时保持/保留Fc结构域的二聚化结构域。可以在本公开中使用的ACE2序列的示例是SEQ ID NO.:2、4、11、15、17、19、21和23,它们提供含有两个取代或突变的ACE2的氨基酸序列,所述取代或突变可以用于本文所述的结合蛋白中。SEQ ID NO.2和4两者均含有H374N和H378N取代或突变。
任何多肽接头可用于式II中以将式II中的X与Z连接。在一些示例中,接头具有序列GGGGS(SEQ ID NO:11)。替代地,在一些示例中,不存在接头并且X直接连接至Z(例如,当n为0时)。
在一些示例中,结合蛋白还可以包含在式II中在多肽接头与X和Z之间的铰链。式II中铰链的位置并不是关键的。
在一些其他示例中,式II的结合蛋白还可以包含信号肽。可以使用的信号肽的示例以SEQ ID NO.1和5显示。式II中单个肽的位置并不是关键的。
如先前所提及的,在式II中,如果X是ACE2,则Z是特异性结合SARS-CoV、SARS-CoV-2或其片段(例如SARS-CoV的片段或SARS-CoV-2的片段)上的至少一个表位的结合蛋白的重链可变区。替代地,如果X是特异性结合SARS-CoV、SARS-CoV-2或其片段上的至少一个表位的结合蛋白的重链可变区,则Z是ACE2。可在结合蛋白中使用的特异性结合SARS-CoV-2上的至少一个表位的结合蛋白的重链可变区的示例是单克隆抗体CR3014或CR3022,其描述于J.ter Meulen,PLoS Medicine,3(7):1071-1079(2006年7月),其内容以引用的方式并入本文。可以使用特异性结合SARS-CoV或SARS-CoV-2上的至少一个表位的结合蛋白(诸如CR3014或CR3022)的整个重链可变区或其片段(此类片段的长度为至少10个氨基酸、至少15个氨基酸、至少20个氨基酸、至少25个氨基酸、至少30个氨基酸、至少40个氨基酸、至少45个氨基酸、至少50个氨基酸、至少60个氨基酸、至少70个氨基酸、至少80个氨基酸、至少90个氨基酸、至少100个氨基酸等)。
在一些示例中,结合蛋白是抗体或其抗体结合片段。当结合蛋白是抗体时,抗体可以是双特异性抗体或多特异性抗体。在一些方面,双特异性抗体可以是scFv。用于制备抗体和抗体结合片段的方法是本领域熟知的。
在某些方面,考虑了本文提供的结合蛋白的氨基酸序列变体。例如,可能希望改善结合蛋白(例如当结合蛋白是抗体时)的结合亲和力和/或其他生物特性。可以通过在编码结合蛋白(例如抗体)的核苷酸序列中引入适当的修饰或通过肽合成来制备结合蛋白(例如抗体)的氨基酸序列变体。此类修饰包括例如结合蛋白的氨基酸序列内的残基的缺失和/或插入和/或取代。可以进行缺失、插入和取代的任何组合以获得最终的构建体,条件是最终的构建体具有所需的特征(例如抗原结合)。
式II的双特异性结合蛋白还可以包括其他蛋白质,诸如其他抗体的轻链可变区、其他抗体的重链可变区、其他结合蛋白的一个或多个CDR、一个或多个轻链和重链恒定区、框架区和Fc结构域。如果使用Fc结构域,则Fc结构域可以是任何人Fc结构域,诸如人IgA、IgM或IgG Fc结构域。此外,Fc结构域可以是最优化的Fc结构域,诸如美国专利申请号2010/093979中描述的那些。在本公开的一个方面,Fc结构域是IgG1。此外,Fc结构域可以含有一个或多个氨基酸取代(例如保守取代)或突变,例如,以实现新生儿Fc-受体(FcRn)结合增强。此类其他蛋白质的示例包括特异性结合SARS-CoV和/或SARS-CoV-2上的至少一个表位的抗体的一个或多个重链可变区。例如,具有SEQ ID NO:6中的氨基酸序列的CR3022的轻链可变区可以与式II的结合蛋白一起使用以制备双特异性抗体。
本公开的式II的双特异性结合蛋白的示例如图5所示。此双特异性结合蛋白的氨基酸序列提供在序列表中。
多核苷酸和表达
提供了编码式I或II的结合蛋白的多核苷酸,所述结合蛋白特异性结合SARS-CoV和/或SARS-CoV-2蛋白质上的表位。这些多核苷酸包括编码公开的式I或II的结合蛋白的DNA、cDNA和RNA序列。编码这些分子的核酸可由本领域技术人员使用本文提供的氨基酸序列(诸如用于产生抗体的CDR以及重链和轻链序列)、本领域可获得的序列(诸如框架序列)和遗传密码产生。本领域技术人员可以容易地使用遗传密码来构建多种功能等效的核酸,诸如序列不同但编码相同抗体序列的核酸,或者编码包括所述核酸序列的缀合物或融合蛋白。
编码公开的式I或II的结合蛋白的多核苷酸可以通过任何合适的方法制备,包括例如克隆适当的序列或通过由诸如以下的方法直接化学合成:Narang等人,Meth.Enzymol.68:90-99,1979的磷酸三酯法;Brown等人,Meth.Enzymol.68:109-151,1979的磷酸二酯法;Beaucage等人,Tetra.Lett.22:1859-1862,1981的二乙基亚磷酰胺法;Beaucage和Caruthers,Tetra.Letts.22(20):1859-1862,1981的固相亚磷酰胺三酯法,例如使用如例如Needham-VanDevanter等人,Nucl Acids Res.12:6159-6168,1984中所述的自动化合成仪;以及美国专利号4,458,066的固体支持法。化学合成产生单链寡核苷酸。这可以通过与互补序列杂交或通过使用单链作为模板与DNA聚合酶聚合来转化为双链DNA。技术人员会认识到,虽然DNA的化学合成通常限于约100个碱基的序列,但可以通过连接较短的序列来获得较长的序列。
适当的克隆和定序技术的示例以及足以引导技术人员通过许多克隆练习的说明书是已知的(参见例如,Sambrook等人(Molecular Cloning:A Laboratory Manual,第4版,Cold Spring Harbor,N.Y.,2012)和Ausubel等人(In Current Protocols in MolecularBiology,John Wiley&Sons,New York,增刊104,2013)。来自生物试剂和实验设备制造商的产品信息也提供了有用的信息。此类制造商包括SIGMAChemical Company(Saint Louis,Mo.)、R&D Systems(Minneapolis,Minn.)、Pharmacia Amersham(Piscataway,N.J.)、CLONTECH Laboratories,Inc.(Palo Alto,Calif.)、Chem Genes Corp.,AldrichChemical Company(Milwaukee,Wis.)、Glen Research,Inc.、GIBCO BRL LifeTechnologies,Inc.(Gaithersburg,Md.)、Fluka Chemica-Biochemika Analytika(FlukaChemie AG,Buchs,Switzerland)、Invitrogen(Carlsbad,Calif.)和Applied Biosystems(Foster City,Calif.)以及技术人员已知的许多其他商业来源。
核酸也可以通过扩增方法制备。扩增方法包括聚合酶链式反应(PCR)、连接酶链式反应(LCR)、基于转录的扩增系统(TAS)、自动维持序列复制系统(3SR)。多种克隆方法、宿主细胞和体外扩增方法是本领域技术人员熟知的。
核酸分子可以在重组工程化细胞诸如细菌、植物、酵母、昆虫和哺乳动物细胞中表达。在原核生物中表达具有真核或病毒序列的DNA序列的方法是本领域熟知的。合适的宿主细胞的非限制性示例包括细菌、古菌、昆虫、真菌(例如,酵母)、植物和动物细胞(例如,哺乳动物细胞,诸如人)。使用的示例性细胞包括大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillus subtilis)、酿酒酵母(Saccharomyces cerevisiae)、鼠伤寒沙门氏菌(Salmonella typhimurium)、SF9细胞、C129细胞、293细胞、脉孢菌(Neurospora)和永生化的哺乳动物骨髓和淋巴细胞系。用于培养物中哺乳动物细胞的增殖的技术是熟知的(参见例如,Helgason和Miller(编),2012,Basic Cell Culture Protocols(Methods inMolecular Biology),第4版,Humana Press)。常用的哺乳动物宿主细胞系的示例包括VERO和HeLa细胞、CHO细胞以及WI38、BHK和COS细胞系,但是可以使用细胞系,诸如被设计用于提供更高表达、所需糖基化模式或其他特征的细胞。在一些示例中,宿主细胞包括HEK293细胞或其衍生物,如GnTI-/-细胞(编号CRL-3022)或HEK-293F细胞。
编码本文所述的蛋白质的核酸的表达可以通过将DNA或cDNA可操作地连接至启动子(其为组成型或诱导型),然后并入表达盒中来实现。启动子可以是任何感兴趣的启动子,包括细胞巨化病毒启动子和人嗜T淋巴细胞病毒启动子(HTLV)-1。任选地,构建体中包括增强子,诸如细胞巨化病毒增强子。盒可适用于原核生物或真核生物中的复制和整合。典型的表达盒含有可用于调节编码蛋白质的DNA的表达的特定序列。例如,表达盒可以包括适当的启动子、增强子、转录和翻译终止子、起始序列、蛋白质编码基因前面的起始密码子(即ATG)、内含子的剪接信号、维持所述基因的正确阅读框以允许mRNA适当翻译的序列和终止密码子。载体可以编码可选择标志物,诸如编码药物抗性(例如氨苄青霉素或四环素抗性)的标志物。
为了获得克隆基因的高水平表达,希望构建表达盒,其至少含有引导转录的强启动子、用于翻译起始的核糖体结合位点(内部核糖体结合序列)和转录/翻译终止子。对于大肠杆菌,这包括启动子(诸如T7、trp、lac或λ启动子)、核糖体结合位点和优选地转录终止信号。对于真核细胞,控制序列可以包括源自例如免疫球蛋白基因、HTLV、SV40或细胞巨化病毒的启动子和/或增强子,以及多腺苷酸化序列,并且可以还包括剪接供体和/或受体序列(例如,CMV和/或HTLV剪接受体和供体序列)。可以通过熟知的方法将盒转移至选定的宿主细胞中,诸如大肠杆菌的转化或电穿孔以及哺乳动物细胞的磷酸钙处理、电穿孔或脂质体转染。被盒转化的细胞可以通过对盒中包含的基因(诸如amp、gpt、neo和hyg基因)赋予的抗生素抗性来选择。
当宿主是真核宿主时,可使用以下DNA转染方法,如磷酸钙共沉淀、常规机械程序(如微弹轰击、电穿孔、插入包裹在脂质体中的质粒或病毒载体)。真核细胞还可以与编码SARS-CoV或SARS-CoV-2S、M、N或E结合蛋白或其片段的多核苷酸序列,或特异性结合SARS-CoV或SARS-CoV-2S、M、N或E蛋白的抗体、抗体结合片段或缀合物,以及编码可选择表型的第二外来DNA分子(诸如单纯疱疹胸苷激酶基因)一起共同转化。另一种方法是使用真核病毒载体,诸如猿猴病毒40(SV40)或牛乳头瘤病毒,以瞬时感染或转化真核细胞并表达蛋白质(参见例如,Viral Expression Vectors,Springer press,Muzyczka编,2011)。本领域技术人员可以容易地使用表达系统,诸如质粒和载体,用于在细胞中产生蛋白质,包括高等真核细胞,诸如COS、CHO、HeLa和骨髓瘤细胞系。
当结合蛋白是抗体或抗原结合片段时,此类抗体和抗原结合片段可表达为单独的VH和/或VL链(按需与效应分子或可检测标志物连接),或可以表达为融合蛋白。表达和纯化抗体和抗原结合片段的方法是已知的并在本文中进一步描述(参见例如,Al-Rubeai(编),Antibody Expression and Production,Springer Press,2011)。核酸序列可以任选地编码前导序列。
为了产生scFv,可以将VH和VL编码DNA片段可操作地连接至编码柔性接头(例如,编码氨基酸序列(Gly4-Ser)3)的另一片段,使得VH和VL序列可以表达为邻接单链蛋白质,其中VH和VL结构域通过柔性接头结合(参见例如,Bird等人,Science 242:423-426,1988;Huston等人,Proc.Natl.Acad.Sci.USA85:5879-5883,1988;McCafferty等人,Nature 348:552-554,1990;Kontermann和Dubel(编),Antibody Engineering,第1-2卷,第2版,SpringerPress,2010;Harlow和Lane,Antibodies:A Laboratory Manual,第2版,Cold SpringHarbor Laboratory,New York,2013)。任选地,裂解位点可以包括在接头中,例如弗林蛋白酶裂解位点。
编码VH和/或VL的核酸可任选地编码Fc结构域(免疫粘附素)。Fc结构域可以是IgA、IgM或IgG Fc域。Fc结构域可以是优化的Fc结构域,如美国公开专利申请号20100/093979中所述,其以引用方式并入本文。在一个示例中,免疫粘附素是IgG1 Fc。
如果仅使用VH和VL,则单链抗体可以是单价的,如果使用两个VH和VL,则是二价的,或者如果使用多于两个VH和VL,则是多价的。可以产生特异性结合SARS-CoV S、M、N和/或E蛋白和/或另一种抗原的双特异性或多价抗体。
从哺乳动物细胞和诸如大肠杆菌的细菌表达结合蛋白(诸如抗体和抗原结合片段)和/或重折叠成适当活性形式的方法已经被描述并且是熟知的并且适用于本文公开的抗体。参见例如,Harlow和Lane,Antibodies:A Laboratory Manual,第2版,Cold SpringHarbor Laboratory,New York,2013;Simpson编,Basic methods in ProteinPurification and Analysis:A laboratory Manual,Cold Harbor Press,2008;以及Ward等人,Nature 341:544,1989。
还提供了包含至少一种本文所述宿主细胞的细胞群。细胞群可以是异质群,其包含有包含本文所述的重组表达载体中任一种的宿主细胞以及至少一种不包含任何重组表达载体的细胞,例如宿主细胞(例如T细胞),或除T细胞意外的细胞,例如B细胞、巨噬细胞、中性粒细胞、红细胞、肝细胞、内皮细胞、上皮细胞、肌肉细胞、脑细胞等。替代地,细胞群可以是基本上同质的群体,其中群体主要包含有包含重组表达载体的宿主细胞(例如基本上由其组成)。群体还可以是细胞的克隆群体,其中群体的所有细胞都是包含重组表达载体的单个宿主细胞的克隆,使得群体的所有细胞都包含重组表达载体。在本公开的一个示例中,细胞群是包含宿主细胞的克隆群,所述宿主细胞包含如本文所述的重组表达载体。
可以对编码本文所述多肽的核酸进行修饰而不降低其生物活性。可以进行一些修饰以促进靶向分子的克隆、表达或向融合蛋白中的并入。此类修饰是本领域技术人员熟知的并且包括例如终止密码子、在氨基末端添加以提供起始位点的甲硫氨酸、放置于任一末端以产生方便定位的限制性位点的额外氨基酸或帮助纯化步骤的额外氨基酸(诸如polyHis)。除了重组方法之外,本公开的免疫缀合物、效应部分和抗体还可以整体或部分使用本领域熟知的标准肽合成来构建。
在若干示例中,核酸分子编码本公开的结合蛋白的前体,当在适当的细胞中表达时,其可以被加工成SARS-CoV或SARS-CoV-2蛋白或其片段。例如,核酸分子可以编码本公开的结合蛋白,其包含用于进入细胞分泌系统中的N末端信号序列,所述信号序列在SARS-CoV或SARS-CoV-2蛋白或其片段在细胞中加工期间中被蛋白水解裂解。
编码本公开的结合蛋白的多核苷酸可以包括重组DNA,其被并入至载体、自主复制质粒或病毒或者原核生物或真核生物的基因组DNA中,或者其作为独立于其他序列的单独分子(诸如mRNA或cDNA)而存在。核苷酸可以是核糖核苷酸、脱氧核糖核苷酸或任一核苷酸的修饰形式。所述术语包括单链和双链形式的DNA。在一个非限制性示例中,使用pVRC8400载体表达所公开的免疫原(描述于Barouch等人,J.Virol,79,8828-8834,2005中,其以引用的方式并入本文)。
一旦被表达,本公开的结合蛋白或者特异性结合SARS-CoV或SARS-CoV-2蛋白上的表位的抗体或抗体结合片段可以根据本领域中的标准程序来纯化,包括硫酸铵沉淀、亲和柱、柱层析等(大体上参见,Simpson编,Basic methods in Protein Purification andAnalysis:A laboratory Manual,Cold Harbor Press,2008)。SARS-CoV或SARS-CoV-2蛋白或其片段或者特异性结合SARS-CoV或SARS-CoV-2上的表位的抗体或抗体结合片段不必是100%纯的。
通常,来自大肠杆菌或其他细菌的功能性异源蛋白质分离自包涵体并且需要使用强变性剂进行溶解以及后续的再折叠。在溶解步骤期间,如本领域所熟知的,必须存在还原剂以分离二硫键。具有还原剂的示例性缓冲液是:0.1M Tris pH 8、6M胍、2mM EDTA、0.3MDTE(二硫赤藓糖醇)。二硫键的再氧化可以在存在呈还原和氧化形式的低分子量硫醇试剂的情况下发生,如Saxena等人,Biochemistry 9:5015-5021,1970中所述,并且尤其如Buchner等人,同前所述。
除重组方法之外,结合蛋白,包括任何抗体或抗原结合片段,还可以整体或部分使用标准肽合成来构建。多肽的固相合成可以通过将序列的C末端氨基酸连接至不溶性支持物,然后顺序添加序列中的剩余氨基酸来完成。用于固相合成的技术由以下描述:Barany和Merrifield,The Peptides:Analysis,Synthesis,Biology.第2卷:Special Methods inPeptide Synthesis,部分A.第3-284页;Merrifield等人,J.Am.Chem.Soc.85:2149-2156,1963;以及Stewart等人,Solid Phase Peptide Synthesis,第2版,Pierce Chem.Co.,Rockford,Ill.,1984。长度较长的蛋白质可以通过缩合较短片段的氨基和羧基末端来合成。通过活化羧基末端(诸如,通过使用偶联试剂N,N'-二环己基碳二亚胺)来形成肽键的方法是本领域中熟知的。
组合物和施用
式I或II的结合蛋白可以包含在药物组合物(包括治疗性和预防性制剂)中,常常与一种或多种药学上可接受的媒介物和任选地其他治疗性成分(里,抗生素或抗病毒药物)组合在一起。组合物可用于例如治疗或检测受试者的SARS-CoV或SARS-CoV-2感染或者诱导其对SARS-CoV或SARS-CoV-2感染的免疫反应。
可以将组合物制备成单位剂型以用于施用于至受试者。施用的量和时间由治疗医师决定以实现所需目的。公开的结合蛋白或编码此类分子的多核苷酸可被配制用于全身或局部施用。在一个示例中,公开的特异性结合SARS-CoV或SARS-CoV-2上的表位的结合蛋白或编码此类分子的多核苷酸被配制用于肠胃外施用,诸如静脉内施用。
公开的结合蛋白、或编码此类分子的多核苷酸、或包含此类分子的组合物、以及额外剂可以以各种方式向受试者施用,包括局部和全身施用,诸如像通过皮下、静脉内、动脉内、鼻内、腹膜内、肌肉内、皮内或鞘内注射。在一个示例中,通过每天一次的单次皮下、静脉内、动脉内、腹膜内、肌肉内、皮内或鞘内注射来施用治疗剂。治疗剂还可以通过在疾病部位处或附近直接注射来施用。
在一些方面,组合物通过吸入(例如通过气溶胶递送),诸如通过与雾化器(诸如振动筛网雾化器)一起使用来施用。在其他方面,组合物可以与干粉吸入剂或计量剂量的吸入剂一起使用。
另一种施用方法是通过渗透泵(例如Alzet泵)或微型泵(例如Alzet微型渗透泵),其允许治疗剂或药物组合物在预定时间段内受控、连续和/或缓释递送。渗透泵或微型泵可以皮下植入或植入在目标部位附近。
治疗剂或其组合物还可以通过其他方式施用。确定治疗剂或其组合物的最有效的施用方式在技术人员的技能内。治疗剂可以作为适合于例如口服(包括口腔和舌下)、直肠、鼻、局部、肺部、阴道或肠胃外施用的药物制剂施用,或以适合于通过吸入或吹入施用的形式施用。取决于预期的施用方式,药物制剂可以呈固体、半固体或液体剂型的形式,诸如片剂、栓剂、丸剂、胶囊、散剂、液体、混悬液、乳液、乳膏、软膏、洗剂等等。
在一些方面,组合物可以以单位剂型提供,用于诱导受试者的免疫反应,以例如预防、抑制或治疗受试者的SARS-CoV或SARS-CoV-2感染。单位剂型含有合适于向受试者施用的单个预选剂量,或两个或更多个预选单位剂量的合适的标记或测量倍数,和/或用于施用单位剂量或其倍数的计量机制。在其他示例中,组合物还包含佐剂。
用于静脉内施用式I或II的结合蛋白的典型组合物包括每名受试者每天约0.01至约30mg/kg。用于制备可施用的组合物的实际方法将是本领域技术人员已知的或显而易见的且更详细地在此类公布如Remington's Pharmaceutical Science,第19版,MackPublishing Company,Easton,Pa.(1995)中描述。
为了配制药物组合物,公开的特异性结合SARS-CoV或SARS-CoV-2蛋白上的表位的结合蛋白,或编码此类分子的多核苷酸,可以与各种药学上可接受的添加剂以及用于缀合物的分散的基料或媒介物组合。所需添加剂包括但不限于pH控制剂,诸如精氨酸、氢氧化钠、甘氨酸、盐酸、柠檬酸等等。此外,可以包含局部麻醉剂(例如苯甲醇)、等渗剂(例如氯化钠、甘露醇、山梨糖醇)、吸附抑制剂(例如80)、溶解度增强剂(例如环糊精及其衍生物)、稳定剂(例如血清白蛋白)和还原剂(例如谷胱甘肽)。
用于施用的组合物可以包含公开的结合蛋白或编码此类分子的多核苷酸溶解于药学上可接受的载剂(诸如水性载剂)中的溶液可以使用多种水性载剂,例如缓冲盐水等。组合物可以含有如接近生理条件所需要的药学上可接受的辅助物质或赋形剂,如pH调节剂和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。公开的特异性结合SARS-CoV或SARS-CoV-2蛋白上的表位的结合蛋白或编码此类分子的多核苷酸在这些制剂中的浓度可以广泛变化,并且将主要根据所选择的特定施用方式和患者的需要,基于流体体积、粘度、体重等来选择。
可以以冻干形式提供公开的结合蛋白或编码此类分子的多核苷酸,并在给药之前用无菌水再水合,但是它们也提供于已知浓度的系列溶液中。
柔性接头
在本文所述的任何柔性连接的ACE2诱饵中,可以包括柔性接头。在每个ACE2区与Fc区之间可以使用任何适当的柔性接头,特别是那些长度大于5nm(两个ACE2区之间的总长度大于约14nm或更大)的接头。如本文所用,柔性接头可以在每个ACE2区与Fc区之间提供一定程度的运动。柔性接头通常可以由小的非极性(例如Gly)或极性(例如Ser或Thr)氨基酸构成。这些氨基酸的小尺寸可以提供柔性,并且可以允许连接区的迁移率。Ser或Thr的并入可通过与水分子形成氢键来维持接头在水溶液中的稳定性,并且可以减少接头与蛋白质部分之间的不利的相互作用。
柔性接头可具有主要由Gly和Ser残基的延伸组成的序列(“GS”接头)。柔性接头的一个示例具有序列(Gly-Gly-Gly-Gly-Ser)n。通过调整拷贝数“n”,可调整此GS接头的长度以实现功能区(例如,ACE2区或其他结合区)的适当分离。其他柔性接头可能富含小的或极性氨基酸如Gly和Ser,但可含有额外氨基酸如Thr和Ala,以维持柔性,以及极性氨基酸如Lys和Glu,以提高溶解度。其他类型的柔性接头包括KESGSVSSEQLAQFRSLD和EGKSSGSGSESKST。这些接头可以是重复的(KESGSVSSEQLAQFRSLD)n或(EGKSSGSGSESKST)n。另一柔性接头是GSAGSAAGSGEF或(GSAGSAAGSGEF)n。在这些接头中的任一个中,接头的长度可以通过选择重复的数目n来调整(例如,n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25等)。可以选择每个接头的长度,例如在ACE2区与Fc区之间的接头长度,以使得ACE2结构域(或在一些示例中,ACE2结构域和另一COV)的总分离
粘液捕获
如本文所用,术语“捕获效力”是指特异性结合靶标病原体的结合蛋白(例如,本文所述的结合蛋白)抑制病原体移动穿过粘液的能力。可以通过本领域已知并且如本文所述的方法测量捕获效力。捕获效力可以被定量为例如将至少50%(例如,至少55%、至少60%、至少65%、至少70%、至少75%等)的病原体在粘液凝胶中的迁移率降低至其在溶液(例如,盐水)和/或粘液中的天然迁移率的至少一半(例如,四分之一、十分之一等)所需的结合蛋白的量(例如,结合蛋白在粘液中的浓度)。可以使用本领域熟知和本文所述的技术测量在粘液中的迁移率。替代地,捕获效力可以定量为穿透粘液的病原体百分比的减少。
术语“增强捕获效力”是指与蛋白质(例如与本文所述的柔性连接的ACE2诱饵中的Fc结构域)相比的增强。此外,可以选择或进一步配置本文所述的任何结合蛋白,以通过包括包含在每个分枝具有末端N-乙酰基葡糖胺的双触角核心聚糖结构Manα1-6(Manα1-3)Manβ1-4GlcNAcβl-4G1cNAcβ1的糖基化模式来增强粘蛋白铰链。这种糖基化模式可以在蛋白质(例如,柔性连接的ACE2诱饵)的Fc区上。替代地或另外地,可以选择或配置本文所述的构建体的组合物,以使得至少x%的构建体(例如二聚化的柔性连接的ACE2诱饵结合蛋白)具有包含在每个分枝具有末端N-乙酰基葡糖胺的双触角核心聚糖结构Manα1-6(Manα1-3)Manβ1-4GlcNAcβl-4G1cNAcβ1的糖基化模式,其中x%为20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或基本上全部。在其中例如大于20%(大于25%、大于30%、大于35%、大于40%、大于45%、大于50%等)的本文所述的构建体包含提供增加的粘蛋白交联(例如G0)的寡糖的组合物可能在与靶标(例如SARS样CoV)结合后对靶标的粘液捕获特别有益。
本文所述的结合蛋白(包含柔性连接的ACE2诱饵)、组合和方法可以包括用于抑制和/或治疗SARS样CoV(并且特别是SARS-CoV-2)的感染和/或消除粘膜表面的病原体的方法。具体来说,本发明公开的主题涉及这些的构建体和组合物,它们能够促进病原体(例如SARS-CoV)的聚集和/或束缚生长,和/或捕获粘液中的病原体,从而抑制病原体跨越或穿过粘液分泌的运输,从而可以导致这些病原体的破坏和/或自然消除。
本文所述的结合蛋白构建体(包括柔性连接的ACE2诱饵)通常可以通过粘液快速扩散,仅因与粘液内的粘蛋白的微弱、短暂的粘附相互作用而略微减慢。这种快速扩散允许构建体积累病原体。当多个构建体与病原体偶联时,多个构建体与粘液之间的粘附相互作用可能变得足以将结合的病原体捕获在粘液中,从而预防或减少感染。捕获在粘液中的病原体无法到达体内的靶细胞,而是将通过自发的热降解以及粘液中的额外保护因子(例如防御素)而脱落和/或灭活。如本文所公开,这种病原体凝集和/或捕获活性在没有中和的情况下提供保护,并且即使在相对低的剂量下也可以有效地抑制感染。本文所述的构建体可与粘蛋白形成的低亲和力相互作用也可能受到糖基化的影响。
因此,本文所述的构建体可以包括在糖基化位点(特别是在Fc结构域上)的寡糖,所述寡糖包含关于(提供)粘液中结合蛋白的捕获效力增强的模式或由其组成(或在一些示例中,基本上由其组成)。结合蛋白特异性结合靶标(例如SARS样CoV靶标,例如SARS-CoV-2)。一旦结合蛋白与一个或多个靶标(例如病原体,诸如SARS-CoV-2)形成复合物,结合蛋白(例如柔性连接的ACE2诱饵蛋白)的糖基化模式/寡糖组分可最大化结合蛋白的捕获效力,而不会过度阻碍未结合的构建体容易地通过粘液扩散以快速结合靶标的能力。在某些示例中,本文所述的构建体展现出相对于其在溶液(例如粘液、盐水或水)中的天然迁移率,在粘液中的迁移率减小不超过约50%,例如不超过约40%、30%、20%、10%或5%,并且在与一个或多个靶标复合之后,有效捕获粘液中的靶病原体(例如至少50%的靶标减慢至少一般)。在一些示例中,本文所述的构建体使至少50%的靶标(例如至少50%、60%、70%、80%或90%或更多的靶标)的迁移率减小至少50%(例如60%、70%、75%、80%、85%、90%、95%、96%、97%、98%或99%等)或更多。在其他示例中,本文所述的构建体将可以穿透粘液的靶标(例如病原体)的百分比减小至少10%,例如,至少20%、30%、40%、50%、60%、70%、80%、90%或更多。例如,本文所述的构建体与靶标的表位的结合速率足以在粘液中小于10mg/ml(例如,小于5mg/ml、小于1mg/ml、小于0.1mg/ml、小于50μg/ml、小于30μg/ml、小于20μg/ml、小于10μg/ml、小于5μg/ml、小于2.5μg/ml、小于1μg/ml、小于0.5μg/ml、小于0.1μg/ml等)的构建体浓度下在一小时内(例如在30分钟或15分钟内)捕获粘液中的靶病原体。
在一些示例中,本文所述的构建体可以包括与构建体的Fc区中的N-连接的糖基化位点结合的寡糖组分。N-连接的糖基化位点可以是Fc区上的天冬酰胺残基,例如Asn 297天冬酰胺残基。氨基酸编号是关于人/人源化IgG分子的标准氨基酸结构。如所提及的,可以使用来自IgM、IgD、IgG、IgA和IgE的Fc区或其修饰的变体。
N-聚糖结构可以是G0/G0F形式,或纯GnGn形式(例如,在每个分枝上具有末端N-乙酰基葡糖胺而没有末端半乳糖或唾液酸)在一些示例中,与构建体连接的寡糖组分(即聚糖)包含没有任何岩藻糖残基的核心结构,基本上由其组成或由其组成。在一些示例中,寡糖组分在侧链上包含岩藻糖。在其他示例中,聚糖不含有任何半乳糖残基。在一些示例中,聚糖不包括半乳糖。
本文所述的构建体可以包括具有不同寡糖组分的构建体的混合物。在一些示例中,混合物包含至少约30%的具有G0/G0F核心聚糖结构(例如具有或不具有岩藻糖残基)的构建体,例如,至少约40%、50%、60%、70%、80%、90%或更多。
在一些实施例中,本文所述的构建体在人细胞系(例如293细胞系,例如293T细胞系)、其他哺乳动物细胞系(例如CHO)、植物(例如烟草)或其他微生物(例如木霉)中产生。
本文所述的构建体可用于结合靶标以将靶标捕获在粘液中以抑制靶标的感染。本文所述的构建体可用于治疗、预防或减少任何与ACE2结合的病毒的感染,诸如可通过粘膜感染受试者的冠状病毒(例如SARS-CoV-2)。
术语病毒、病原体和病毒病原体在本文中可以互换使用,并且进一步指与ACE2结合的任何病毒,例如冠状病毒(例如SARS-CoV-2)。
组合物
如本领域技术人员将认识到的,本文所述的构建体还可以形成为合适的组合物,例如用于施用于受试者以治疗或预防由靶病原体(例如,结合ACE2的病毒,诸如冠状病毒,诸如SARS-CoV-2)所致的感染或由靶病原体感染所致的疾病或病症的药物组合物。组合物可以包含预防或治疗有效量的如本文所述的构建体和药学上可接受的载剂、基本上由其组成或由其组成。
含有本文所述的构建体的药物组合物可与本领域常用的任何合适的药物媒介物、赋形剂或载剂组合配制,包括出于此目的的此类常规材料,例如,盐水、右旋糖、水、甘油、乙醇及其组合。如本领域技术人员将认识到的,所使用的特定媒介物、赋形剂或载剂将根据受试者和受试者的状况而变化,并且多种施用方式将适用于本文所述的组合物。本申请中公开的任何药物组合物的合适施用方法包括但不限于局部、口服、鼻内、口腔、吸入、肛门和阴道施用,其中此类施用实现了将结合蛋白递送至感兴趣的粘膜。
组合物可以是适合将本文所述的构建体递送至粘膜表面的任何类型的组合物,并且可以是本领域已知的各种形式,包括固体、半固体或液体形式或是在水性凝胶组合物中的洗剂形式(水包油或油包水乳液)。组合物包括但不限于凝胶、糊剂、栓剂、冲洗剂、胚珠(ovule)、泡沫、膜、喷雾剂、软膏、阴道栓、胶囊、片剂、果冻、乳膏、牛奶、分散液、脂质体、散剂/滑石粉或其他固体、混悬液、溶液、乳液、微乳液、纳米乳液、液体、气溶胶、微胶囊、时间-释放胶囊、控释制剂、缓释制剂或生物粘附凝胶(例如,粘膜粘附热凝胶组合物)或嵌入基质中用于组合物向已施加或接触的表面缓释或控释的其他形式。
如果需要局部施用,则可以根据需要将组合物配制成合适的形式,例如软膏、乳膏、凝胶、洗剂、滴剂(例如滴眼剂和滴耳剂)或溶液(如漱口水)。组合物可含有常规添加剂,诸如防腐剂、促进渗透的溶剂和润肤剂。局部制剂还可包含常规载剂,诸如乳膏或软膏基料、乙醇或油醇。其他用于施用(包括鼻内施用等)的制剂被考虑用于与本发明公开的主题结合使用。本领域技术人员已知的适用于将本文所述的构建体或含有本文所述的构建体的组合物递送至受试者的一种或多种粘膜的所有制剂、装置和方法都可以与本发明公开的主题结合使用。
本文所述的任何组合物可包括本文所述的构建体的混合物。
在本文所述的方法中使用的组合物可以包括不会负面影响或以其他方式影响组合物组分的抑制有效性的其他剂,包括抗体和抗病毒剂。例如,固体、液体或固体和液体的混合物的药学上可接受的载剂、稀释剂、媒介物或赋形剂可用于药物组合物中。合适的生理上可接受的、基本上惰性的载剂包括水、聚乙二醇、矿物油或矿脂、丙二醇、羟乙基纤维素、羧甲基纤维素、纤维素衍生物、聚羧酸、连接的聚丙烯酸,例如卡波姆;和其他聚合物,例如聚(赖氨酸)、聚(谷氨酸)、聚(马来酸)、聚乳酸、热聚天冬氨酸盐和脂肪族-芳香族树脂;甘油、淀粉、乳糖、硫酸钙二水合物、白土、蔗糖、滑石、明胶、果胶、阿拉伯胶、硬脂酸镁、硬脂酸、糖浆、花生油、橄榄油、盐水溶液等。
本文所述的可用于本发明方法的药物组合物还可以包含稀释剂、填充剂、粘合剂、着色剂、稳定剂、香料、胶凝剂、抗氧化剂、保湿剂、防腐剂、酸和本领域技术人员已知的其他要素。例如,合适的防腐剂是本领域熟知的,并且包括例如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、苯甲酸和苯甲醇。
对于口服施用,本文所述的构建体可以以固体剂型施用,例如胶囊、片剂和散剂,或以液体剂型施用,例如酏剂、糖浆和混悬液。组合物可与非活性成分和粉末载剂(如葡萄糖、乳糖、蔗糖、甘露醇、淀粉、纤维素或纤维素衍生物、硬脂酸镁、硬脂酸、糖精钠、滑石粉、碳酸镁等等)一起包封在明胶胶囊中。可加入以提供所希望颜色、味道、稳定性、缓冲能力、分散或其他已知所希望特征的另外非活性成分的示例是氧化铁红、硅胶、十二烷基硫酸钠、二氧化钛、可食用白色油墨等等。类似的稀释剂可用于制备压缩片剂。片剂和胶囊两者均可制成持续释放产品,以在数小时内提供连续释放药物。压缩片剂可以是糖包衣或膜包衣以掩盖任何令人不愉快的味道并保护片剂免受大气影响,或肠溶包衣以在胃肠道中选择性崩解。用于口服施用的液体剂型可含有着色剂和调味剂以增加患者的接受度。
适用于口腔(舌下)施用的组合物包括在调味基料(通常是蔗糖和阿拉伯胶或黄蓍胶)中包含结合蛋白的片剂或锭剂;以及在惰性基料(诸如明胶和甘油或蔗糖和阿拉伯胶)中包含结合蛋白的香锭。组合物可以包括口腔可溶解或可降解的组合物。替代地,组合物可包含含有结合蛋白的散剂或烟雾化或雾化溶液或混悬液。此类粉末状、烟雾化或雾化组合物在分散时优选具有在约0.1至约200纳米范围内的平均颗粒或液滴尺寸。
适用于肠胃外施用的本文所述构建体的组合物包括本文所述构建体的无菌水性和非水性注射溶液,所述制剂优选与预期接受者的血液等渗。这些制剂可以含有抗氧化剂、缓冲剂、抑菌剂和溶质,它们使组合物与预期接受者的血液等渗。水性和非水性无菌混悬液可以包含悬浮剂和增稠剂。组合物可以呈现在单位剂量或多剂量容器例如密封的安瓿和小瓶中,并且可以储存在冷冻干燥(冻干)的条件下,从而仅需紧临使用前添加无菌液体载体(例如,盐水或注射用水)。
即时注射溶液和混悬液可以从先前所述种类的无菌粉剂、颗粒剂和片剂制备。例如,在一个方面,提供了一种在密封的容器中以单位剂型的包含本文所述构建体的可注射、稳定、无菌的组合物。本文所述的构建体可以冻干物的形式提供,所述冻干物能够用合适的药学上可接受的载剂复原以形成适合将其注射至受试者中的液体组合物。
适用于直肠施用的组合物可以呈现为单位剂量栓剂。这些可以通过将本文所述的构建体与一种或多种常规固体载剂(例如可可脂混合),然后将所得混合物成形来制备。
具体来说,本文所述的构建体可以替代地被配制用于经鼻施用或另外通过任何合适的方式施用至受试者的肺,例如,通过受试者吸入的包含本文所述构建体的可吸入颗粒的气溶胶悬浮液来施用。可吸入颗粒可以是液体或固体。术语“气溶胶”包括能够被吸入细支气管或鼻道的任何气载悬浮相。具体而言,气溶胶包括气载液滴悬浮液,如可以在计量剂量的吸入器或雾化器中或在喷雾器中产生的那样。气溶胶还包括悬浮在空气或其他载气中的干粉组合物,其可以通过例如从吸入器装置吹入来递送。参见Ganderton和Jones,DrugDelivery to the Respiratory Tract,Ellis Harwood(1987);Gonda(1990)CriticalReviews in Therapeutic Drug Carrier Systems 6:273-313;以及Raeburn等人,J.Pharmacol.Toxicol.Meth.27:143(1992)。包含本文所述构建体的液体颗粒的气溶胶可通过本领域技术人员已知的任何合适的方式产生,诸如使用压力驱动的气溶胶雾化器或超声雾化器。参见例如美国专利号4,501,729。包含本文所述构建体的固体颗粒的气溶胶同样可以通过制药领域已知的技术,用任何固体颗粒药物气雾剂发生器生产。
可替代地,可以以局部而非全身的方式(例如,以长效制剂或缓释制剂)施用本文所述的构建体。
本文所述的构建体可以被涂覆或浸渍在装置上(或者可以涂覆或浸渍包含本文所述的构建体的组合物)。所述装置可用于将本文所述的构建体和合成结合剂的组合物递送至粘膜(包括肺、鼻、口等)。
如上所述,本文所述的构建体能够在未结合时通过粘液扩散,以允许构建体以期望的速率结合靶标(例如病原体)。还希望,当本文所述的构建体与靶标结合时,结合蛋白-粘蛋白相互作用的累积效应有效地将病原体捕获在粘液中和/或凝集靶标。
在一些示例中,药物组合物可以还包含额外活性剂,例如预防剂或治疗剂。合适的抗病毒剂包括例如病毒灭活剂诸如非离子、阴离子和阳离子表面活性剂和C31 G(氧化胺和烷基甜菜碱)、聚双胍、二十二烷醇、酰基肉碱类似物、辛基甘油和抗微生物肽(诸如蛙皮素(magainin)、短杆菌肽、protegrin和retrocyclin)。温和的表面活性剂(例如,山梨醇酐月桂酸酯)可有利地用作本文所述组合物中的抗病毒剂。可有利地用于本文所述组合物中的其他抗病毒剂包括核苷酸或核苷类似物,诸如替诺福韦(tenofovir)、阿昔洛韦(acyclovir)、金刚烷胺(amantadine)、去羟肌苷(didanosine)、膦甲酸(foscarnet)、更昔洛韦(ganciclovir)、利巴韦林(ribavirin)、阿糖腺苷(vidarabine)、扎西他滨(zalcitabine)和齐多夫定(zidovudine)。可以使用的其他抗病毒剂包括非核苷逆转录酶抑制剂,柱UC-781(硫代羧苯胺(thiocarboxanilide))、吡啶酮、TIBO、奈瓦利平(nevaripine)、地拉韦定(delavirdine)、calanolide A、卡普韦林(capravirine)和依法韦仑(efavirenz)。从这些逆转录酶抑制剂中,口服生物利用度差的剂和它们的类似物特别适合施用于粘膜组织。
本发明公开的主题还包括:试剂盒,其包括本文所述的构建体或包含如本文所述的构建体的组合物;和任选地,用于施用构建体或组合物的装置。
实施例
结合ACE2的病毒家族包括SARS-CoV-2、SARS-CoV-1和NL63-CoV。当这些病毒的刺突蛋白(S)的受体结合结构域(RBD)结合靶细胞表面上的血管紧张素转换酶2(ACE2)时,这些病毒进入细胞。这种ACE2趋向性可用于开发可以中和病毒的ACE2-Fc诱饵。一种策略是将整个ACE2分子(残基18-740,其包括自二聚化collectrin结构域)连接至人IgG1-Fc,或简单地将不具有C末端collectrin结构域(残基18-614)的ACE2的细胞外区段连接至人IgG1-Fc。参见图6A和6B。然而,S蛋白仅以适度的亲和力结合ACE2,因此基于野生型ACE2的此类ACE2诱饵的对应中和效力有限;典型的结合亲和力(EC50)和中和效力(IC50)在数百ng/mL至数十ug/mL范围的范围内。此类效力至少比已经接受EUA或正处于积极临床开发中的单克隆抗体弱大约1至2log。参见例如图1B和2A,其显示ACE-Fc二聚体。
为了克服野生型ACE2对S蛋白的有限亲和力,已通过随机诱变和使用酵母表面展示的选择来工程化更高亲和力的ACE2变体(参见例如表1、图16A-16B)。定向进化策略揭开了结合野生型ACE2但不结合突变ACE2的逃逸病毒的可能性。因此,可以提高结合亲和力但利用天然存在的ACE2的另一种方法可能是有益的。SARS-CoV-1的冷冻电子显微镜显示,病毒表面上存在约50-100个S蛋白,平均间距为约15nm。S蛋白刺突的三聚体形式还导致单个刺突上的3个S蛋白中的任何2个之间的距离很大。在这两种情况下,距离限制抗体上的两个Fab结构域同时结合两个不同的S蛋白。鉴于结合ACE2的病毒(例如,SARS-CoV-1和SARS-CoV-2)之间的高度序列同源性,S蛋白在此类病毒上的呈现可能相似。因此,本文所述的方法和组合物可以通过调整两个ACE2结构域的呈递以最大化实现病毒表面行的二价结合的可能性来提高ACE2诱饵的效力。
Cryo-EM分析表明,大多数刺突蛋白具有1或2个“向上”构象的RBD,并且极少数具有全部3个假设“向上”构象的RBD。天然ACE2是同二聚体,其中collectrin结构域用作主要的二聚化结构域。本文进行的工作表明,此几何结构可阻止分子实现最佳的刺突内结合。为了客服此缺点,可以将Fc结构域(诸如但不限于标准IgG1 Fab的VH-CH1结构域)与不包括collectrin结构域(残基18-614)的ACE2的细胞外结构域组合,并且还包括在ACE2片段与Fc结构域(Fc重链恒定结构域,CH2)之间的延长的(例如,22个或更多个、23个或更多个、24个或更多个、25个或更多个、26个或更多个、27个或更多个、28个或更多个、29个或更多个、30个或更多个、31个或更多个、32个或更多个、33个或更多个、34个或更多个、35个或更多个等)氨基酸的柔性接头,其被设计成增加分子的范围并因此增大结合亲和力。参见例如图6C(以及图1A和2B)。
如本文所述,柔性连接的ACE2诱饵构建体(例如ACE2-(G4S)6-Fc,如图6C中所示)结合SARS-CoV-2S蛋白的不同变体,以皮摩尔效力中和SARS-CoV-2假病毒,有效捕获人气道粘液中的SARS-CoV-2病毒样颗粒,可以稳定地雾化并且有效减少在仓鼠中的SARS-CoV-2感染。
为了确定结合同一S蛋白的ACE分子之间的距离,由7A98产生“三个向上”RBD构象的报告刺突蛋白结构。此模型用于确定是否ACE2-Fc(例如,图1B和2A)可结合同一S蛋白三聚体上的两个RBD。参见例如图7A。如图7A所示,当ACE2-Fc上的两个ACE2结构域之一接合三个RBD中的任一个时,由于将ACE2连接至Fc的IgG1的铰链中缺乏柔性和长度,所以剩余的ACE2结构域变得向上远离S蛋白取向。因此,不可能ACE2-Fc可以有效地二价结合至同一刺突蛋白上的任两个RBD或者病毒上两个不同刺突蛋白之间的RBD。相同的限制适用于包含collectrin结构域的常规ACE2-Fc,因为collectrin结构域二聚化直接限制了相邻ACE2片段的范围,如图6A所示。
当这三个RBD处于“三个向上”构象时,同一刺突蛋白上的RBD之间的估计距离的范围为60至为了桥联距离并增加分子的柔性,在细胞外ACE2片段与Fc区(例如IgG1-Fc)之间添加了长度为约10nm的柔性接头(如但不限于(GGGGS)6柔性接头),如针对柔性连接的ACE2诱饵结构域(例如,在图6C中,ACE2-(G4S)6-F)的一个示例所示。由于两条重链中的每一条都存在柔性接头,所以柔性连接的ACE2诱饵(例如,ACE2-(G4S)6-Fc)上的两个ACE2片段理论上可以跨越几乎两倍长度(即约20nm)的距离。建模表明,柔性接头足够长的柔性连接的ACE2诱饵(例如,ACE2-(G4S)6-Fc只是一个示例)具有必要的柔性并且当任何两个RBD以“向上”构象取向时,实现二价结合,如图7B中所示。
在哺乳动物培养物中针对ACE2-Fc和ACE2-(G4S)6-Fc检查了此关系,并且使用标准蛋白质A色谱法纯化了两种分子。在Native-PAGE中检查了分子(参见图7C);两者的单条带证实它们作为单体存在,但是它们以约350kDa的分子量跑胶。使用尺寸排阻色谱法/多角度光散射(SEC/MALS)检查它们的分子量。ACE2-Fc和ACE2-(G4S)6-Fc的MW分别为约208kDa和约212kDa,与理论MW非常吻合,如图7D中所示。两种分子主要以单体形式存在:ACE2-Fc和ACE2-(G4S)6-Fc在简单的蛋白质A纯化之后分别为约85%和约91%,剩余的流份对应于蛋白质和聚集体的低聚物。在ACE2-(G4S)6-Fc产生的情况下持续获得明显较大的产率,平均量为每500mL培养物约86mg,是在相同条件下产生ACE2-Fc的情况下实现的典型产率的两倍多,后者产率为每500mL培养物约36mg蛋白质。例如,参见图13。
方法
从含有不具有CD结构域与单体Fc结构域的融合物的ACE2(pAce2-mFc)的质粒克隆本文所述的ACE2诱饵(包括柔性连接的ACE2诱饵)。含有(GGGGS)6-Fc融合物的双链DNA链购自IDT DNA。为了产生ACE2-(G4S)6-Fc(pAce2-LdFc)的质粒,用BamH和XhoI消化pAce2-mFc,并且通过Gibson组装插入(GGGGS)6-Fc。将反应物转化为化学感受态(Thermo Fisher)并铺板于LB+羧苄青霉素板上。使用Sanger定序来确认组装。为了产生ACE2-Fc(pAce2-dFc)的质粒,使用引物pF1和pR1,使用高保真Phusion聚合酶,从(GGGGS)6-Fc扩增Fc。然后通过Gibson组装,将PCR产物克隆至用BamH和XhoI消化的pAce2-mFc中,如先前所述。
针对可溶性表达克隆SARS-CoV-2野生型和突变体S蛋白是从质粒nCov-2.sol进行,其编码具有2P突变、突变弗林蛋白酶位点、C末端折叠子和六组氨酸标签的SARS-CoV-2野生型S蛋白。这用于S蛋白的可溶性表达。为了在nCov2.sol中产生编码SARS-CoV-2SA的南非毒株中的突变的S蛋白,用AgeI和NheI消化质粒。PCR引物Pf2、Pr2、Pf3、pR3被设计用于扩增具有突变K417N、E484K和N501Y的S蛋白的2个片段。通过Gibson组装将这两个片段克隆至消化的nCov2.sol中以产生具有SA突变的全长S蛋白。通过Sanger定序(Genewiz)确认蛋白质的正确组装。通过用引物Pf5和Pr5(其扩增载体和S蛋白1-816和943-1208)扩增nCov2.sol,并且通过Gibson组装与hexa-pro突变一起插入编码S蛋白残基817-942的DNA片段,来将旨在使可溶性蛋白质稳定的hexapro突变插入至野生型和SA-nCov2.sol中。所得载体此后被称为WT-hexapro-nCov2.sol和SA-hexapro-nCov2.sol。从质粒UK-hexapro-nCoV2.xdna扩增具有hexa-pro突变的片段。此质粒编码具有hexa-pro突变的UK毒株的S蛋白并且购自Twist Bioscience。
如下产生得到SARS-CoV-2假型感染性慢病毒所需的质粒。含有人密码子优化刺突DNA的质粒pUC57-2019-nCoV-S购自Genscript Molecular Cloud。使用引物(P6,P6)扩增此DNA以产生C末端截短,并且将其克隆至哺乳动物表达载体pAH中以产生pAH-S-CoV-2-ΔCt。为了产生具有SA突变的pAH-S-Cov2-ΔCt,使用引物Pf7和Pr7,从SA-nCov1.sol扩增pAH-SA-CoV-2-ΔCt.vlp(SA S蛋白的一个片段)。用Pf8和Pr8,从WT pAH-S-CoV-2-ΔCt扩增WTS蛋白的另一片段。然后通过Gibson组装,将所述片段克隆至用KpnI和XhoI消化的pAH克隆载体中。使用第三代包装系统,使用4种质粒pMDLg/pRRE(Addgene)+pRSV-Rev(Addgene)+pAH-S-CoV-2-ΔCt和含有用于示踪感染的EGFPgen的转移质粒(pLL7.0 EGFP)制备慢病毒。
如下产生得到非复制SARS-Cov-2野生型和SA VLPS所需的质粒。编码SARS-CoV-1的C末端结构域的购自IDT DNA。用BamHI和XhoI消化WT-hexapro-nCov2.sol、SA-hexapro-nCov2.sol和UK-hexapro-nCov2.sol,以除去折叠子结构域和his标签,然后通过Gibson组装引入含有SARS-CoV-1的C末端的
使用NucleoBond Xtra Midi Plus EF试剂盒(Macherey-Nagel)纯化用于转染的无内毒素pAce2-dFc和pAce2-LdFc。使用ExpiFectamineTM转染试剂盒(Thermo Fisher),通过瞬时转染,在Expi293TTM细胞中产生ACE2-Fc和ACE2-(G4S)6-Fc。使用500mL培养物,并且在活力降低至低于约75%之前,收获细胞。使用切向流(使用醚砜膜的具有100,000MWCO盒的Sartorius Vivaflow 50交叉流盒系统)浓缩细胞培养物上清液,以通过蛋白质A色谱法进行纯化。将三个5mL HiTrap蛋白质A柱(Cytivia)串联地连接至NGC Quest 10FPLC(BioRad)。用5个柱体积(CV)的pH 7.0的10mM磷酸钠缓冲液平衡柱。将蛋白质以0.5mL/min上样至柱中,接着用磷酸盐缓冲液进行10CV洗涤步骤,并且随后通过5CV等渗洗脱步骤,用100%pH 2.0的0.2M甘氨酸缓冲液进行洗脱。将3mL流份收集于填充有300uL pH 8的具有0.2%聚山梨醇酯80的1M Tris缓冲液的管中。通过SDS-PAGE评估每种流份的纯度,并且将没有额外条带的流份合并,并且使用Spin-UF50k MWCO PES离心柱(Corning)将其缓冲液交换至20mM His、mg/mL蔗糖、0.2%聚山梨醇酯80、130mM NaCl,pH 6.2(标准缓冲液)中。缓冲液交换之后,用0.22μm过滤器过滤蛋白质,并且在液氮中快速冷冻,之后在-80℃下储存。
使用NucleoBond Xtra Midi Plus EF试剂盒纯化无内毒素的ncov2.sol、WT-hexapro-nCov2.sol、SA-hexapro-nCov2.sol和UK-hexapro-nCov2.sol。使用ExpiFectamineTM转染试剂盒,将质粒转染至Expi293TTM中。使用500mL培养物,并且在活力降低至低于约45%之前,收获细胞。通过切向流(使用醚砜膜的具有100,000MWCO盒的Sartorius Vivaflow 50交叉流盒系统)十倍浓缩细胞培养物上清液。将浓缩的上清液与1mL Ni-Nta琼脂糖树脂(Qiagen)一起孵育过夜,之后用重力流柱(Bio-Rad)回收。然后将树脂用若干柱体积的具有20mM咪唑的PBS洗涤,然后用具有500mM咪唑的PBS洗脱。然后使用Spin-UF 50k MWCO PES离心柱,将蛋白质缓冲液交换至pH 7的具有120mM蔗糖和20mM氯化钠的PBS或20mM tris中。缓冲液交换之后,将在tris-蔗糖缓冲液中的蛋白质在液氮中快速冷冻,之后在-80℃下储存。
通过以1:1比率共转染pGAG-mcherry质粒(来自Gummuluru lab的赠礼)和Cov2 S蛋白质粒来制备荧光VLP。使用以下质粒,以1:1:1:2比率产生用SARS-CoV-2UK刺突蛋白假型的非复制慢病毒:pMDLg/pRRE、pRSV-REV、SARS-CoV-2UK刺突和pLL7 GFP。使用与上文相同的质粒/比率,用SARS Cov2UK刺突替代SARS Cov2南非刺突,产生用SARS-CoV-2南非刺突假型的非复制慢病毒。使用NucleoBond Xtra Midi Plus EF试剂盒纯化所有质粒。使用LVMaxx转染试剂盒将质粒转染至LVMaxx中。每个VLP在60mL培养物中制备,并且在48小时之后收获。使用25%蔗糖(在25mM Hepes/130mM NaCl中)垫旋转方案纯化VLP。将3mL 25%蔗糖溶液添加至每个Beckman Coulter超速离心管中,然后将7mL细胞培养上清液轻轻加在顶层。然后将管在4℃下以36,000rpm旋转2.5小时。然后吸出蔗糖/上清液,并且将20μL 10%蔗糖溶液放在VLP沉淀顶部。在4℃下24小时之后,然后将VLP等分并在-80℃下储存。
使用UCSF Chimera 1.14生成本文所述的3D模型,以生成所有蛋白质模型,并且使用UCSF Chimera X 1.1呈现模型以用于发表。针对ACE2使用模型6M17,针对人IgG使用模型1HZH,并且针对GGGGS接头使用模型1EIB,构建ACE2-Fc和ACE2-(G4S)6-Fc。通过将ACE2-Fc和ACE2-(G4S)6-Fc的ACE2与RBD结合的ACE2在“全部向上”S蛋白模型7A98中进行匹配,来产生结合S蛋白的ACE2-Fc和ACE2-(G4S)6-Fc。具有collectrin结构域的ACE2-Fc的预测3D模型被修饰。
使用在标准缓冲液中制备的含有1.0mg/mL ACE2-(G4S)6-Fc或Ace2-Fc的溶液进行纯化蛋白和天然PAGE的SEC-MALS测量。然后将100uL这些溶液装载至安装在NGC Quest10FPLC(BioRad)上的Superdex 200Increase 10/300GL(Cytivia)中。将柱用PBS预平衡,并且以0.5mL/min进行全部运行。使用Mini Dawn多角度光散射检测器及其伴随软件Astra8(Wyatt)确定从柱洗脱的蛋白质的分子量,假定延伸系数为1.92。计算了两批独立的ACE2-(G4S)6-Fc和两批Ace2-Fc的分子量。对于天然PAGE,将5μg蛋白质装载至3-12% Bis-Tris凝胶(Invitrogen)上,并如制造商的方案所述进行跑胶。
对于差示扫描荧光法,通过nanoDSF,使用Promethius NT.48(NanotemperTechnologies)确定ACE2-LFC的解链温度。以1℃/min的速率,将样品从25℃加热至95℃。一式三份测量样品。报告的数据是3次独立重复的平均值。
使用96孔半区板(Fisher Scientific,Costar 3690)进行ELISA结合测定,该板涂覆0.5ug/mL S蛋白并在4℃下孵育过夜。第二天用5%(w/v)牛奶(LabScientific MSPP-M0841)和Tween 20(Fisher Scientific BP337-100)在室温下以1:2000的稀释度封闭ELISA板一小时。将样品以1:10,000稀释度稀释于具有Tween 20的1%(w/v)牛奶中,并且一旦开始封闭并且丢弃5%牛奶,便进行铺板。将样品在室温下孵育1小时,并且在1小时孵育之后丢弃溶液。然后以1:2000稀释度用含有Tween 20的PBS洗涤板四次。将过氧化物酶缀合的抗人IgG Fc抗体(Rockland 709-1317)以1:5000稀释度稀释于具有Tween 20的1%牛奶中,铺板并且在室温下孵育1小时。然后将溶液丢弃并用具有Tween 20的PBS洗涤两次,接着仅用PBS再洗涤两次。将板用TMB溶液(ThermoFisher 34029)显影,并且通过添加2N HCl(Sigma-Aldrich 320331)停止显影。然后用微孔板光电检测器(Fisher Scientific,accuSkan Fc)测量在450nm和595nm处的吸光度。
对于本文所述的中和测定,在OptiMEM中以20ug/ml开始,由ACE2-接头-Fc或ACE2-Fc或IgG制成一系列十个4倍系列稀释液。将10ul的每种稀释液一式三份添加至96孔板的孔中。向这些稀释液中的每种添加0.5ul SARS-CoV-2假型慢病毒(在OptiMEM中稀释至10ul,MOI 1,使用HEK293-ACE2细胞感染估计的效价)并在室温下孵育30分钟。3个孔含有20ulOptiMEM,并且3个孔含有19.5ul OptiMEM+0.5ul假病毒作为对照以归一化和计算IC50。30分钟后,将在100ul DMEM+10% FBS中的5000个HEK-ACE2细胞添加到板的每个孔中,并在37℃5% CO2下孵育72小时。72小时后,在不破坏细胞的情况下小心去除培养基,并且将细胞胰蛋白酶化并通过流式细胞术(Attune NxT,ThermoFisher)分析,并记录每个孔的EGFP荧光。
将一式三份的孔的EGFP荧光的MFI取平均值并且针对ACE2/mAb的浓度作图,并且使用四参数非线性回归估计中和的IC50。
对于粘膜捕获,对人气道粘膜(AM)中的荧光SARS-CoV-2VLP进行多颗粒示踪分析。简言之,将荧光VLP和ACE2-Fc或ACE2-(G4S)6-Fc的溶液添加至定制的玻璃腔室中的约10μL新鲜、未稀释的气道粘液中。然后将样品在37℃下孵育约30分钟,之后进行显微镜法。将PBS和抗体CR3022(最终浓度10μg/ml)分别用作阴性和阳性对照。所有运行都使用相同的AM,以便在样品之间进行直接比较。使用MetaMorph软件(Molecular Devices,Sunnyvale,CA)以66.7ms的时间分辨率记录VLP在AM中扩散的视频。使用AI Tracking Solutions的NetTracker分析视频,以将视频原始数据转换为颗粒轨迹。时间平均均方位移(MSD)和有效扩散率通过将颗粒质心坐标转换为时间MSD来计算,公式为<Δr2(τ)>=[x(t+τ)–x(t)]2+[y(t+τ)–y(t)]2,其中τ=时间尺度或时间。
本文提及的用于评估ACE2-(G4S)6-Fc的仓鼠研究在金色叙利亚仓鼠SARS-CoV-2感染模型中进行,如前所述,有一些修改。将四个组(n=8/组)鼻内给药ACE2-(G4S)6-Fc作为预防剂(暴露前4小时)或作为治疗剂(激发后4、24或48小时)。给药PBS的一个组用作阴性对照。通过用在Dubelcco改良的Eagle培养基中稀释的100uL SARS-CoV-2鼻内接种小鼠来进行病毒激发。然后每天将仓鼠给药ACE2-(G4S)6-Fc,直到病毒暴露之后4天将它们处死。通过qRT-PCR定量鼻甲中的病毒载量,并通过β-肌动蛋白(内部基因对照)归一化。
对于雾化研究,使用Phillips Innospire Go振动筛网雾化器将以10mg/mL于标准缓冲液中的ACE2-(G4S)6-Fc雾化。按照欧洲药典5.0中的方案指导,将气溶胶收集到具有上部和下部腔室的玻璃冲击器装置中。运行雾化器直至其看起来是干的。然后,将缓冲液添加至玻璃冲击器的不同腔室中以回收沉积的抗体。通过SEC,使用安装在NGC Quest 10FPLC(BioRad)上的EN-Rich 650尺寸排阻柱(Bio-Rad),并且通过native PAGE评估上部腔室、下部腔室和剩余(“死体积”)样品中的聚集体形成,如先前所述。通过S蛋白ELISA评估雾化分子的结合亲和力,如上文所述。
结果
使用差示扫描量热法检查了分子的稳定性。ACE2-(G4S)6-Fc的解链温度TM为约52±0.6℃(参见例如,图14)。
通过首先使用ELISA测量不同ACE2诱饵对WT毒株USA-WA1/2020的刺突蛋白的结合亲和力来确定不同ACE2诱饵的效力。除了ACE2-Fc和ACE2-(G4S)6-Fc之外,还检查了全长ACE2诱饵(即,ACE2(740)-Fc,缩写为208)。在三种ACE2诱饵中,ACE2-(G4S)6-Fc始终显示出最高的结合亲和力,如图8A所示。在多个独立产生的批次中,ACE2-(G4S)6-Fc始终展现出皮摩尔EC50(平均值:490pM或96ng/mL,参见例如图8B);最有效批次ACE2-(G4S)6-Fc的中值EC50低至136pM或27ng/mL。相比之下,在3.6nM(680ng/mL)和1.6nM(370ng/mL)下,ACE2-Fc和ACE2(740)-Fc的平均EC50与ACE2-(G4S)6-Fc相比低约7.3倍和约3.3倍。
ACE2-(G4S)6-Fc在中国仓鼠卵巢(CHO)细胞中产生,所述细胞是大规模生物制剂生产中最常用的细胞,其EC50(参见例如图8C)与在Expi293细胞中产生的ACE2-(G4S)6-Fc相当。
一般来讲,本文所述的柔性连接的ACE2诱饵可能比常规单克隆抗体(mAb)更可能结合不同SARS-CoV-2变体。结合亲和力实验确认,使用ELISA,使用B.1.1.7(UK)和B.1.351(SA)刺突蛋白,ACE2-(G4S)6-Fc可以实际上结合不同的SARS-CoV-2变体,如图8C所示。在5个独立产生的ACE2-(G4S)6-Fc批次中,它们对WT和U.K.和S.A.变体的结合亲和力是高度可比的(图8D)。为了比较,还检查了RGN10989的结合,其为Regeneron开发的mAb,是从FDA接受EUA的mAb混合物的一部分。虽然RGN10989能够以可比的结合亲和力结合WT和UK S蛋白,但mAb未能实现针对SA S蛋白的可检测结合。这些结果强调本文所述的柔性连接的ACE2诱饵(包括但不限于ACE2-(G4S)6-Fc)在结合ACE2的所有病毒(诸如SARS-CoV-2病毒)中的实用性。
ACE2-(G4S)6-Fc的表观结合亲和力增加还与较大的中和活性相关。经由假病毒测定测量了ACE2-(G4S)6-Fc、ACE2-Fc和ACE2(740)-Fc的中和效力,其中过表达ACE2的HEK细胞用编码以SARS-CoV-2刺突蛋白的D614G变体假型的eGFP转基因的慢病毒感染。不同ACE2诱饵浓度下假病毒的感染性可以通过使用测量与不同量的ACE2诱饵一起孵育的细胞的eGFP荧光的流式细胞仪来确定。在此测定设置中,ACE2-(G4S)6-Fc以皮摩尔亲和力中和SARS-CoV-2假病毒,其中平均IC50为52ng/mL。相比之下,ACE2-Fc和ACE2(740)-Fc的中和效力分别降低接近5倍及6倍,IC50为约240ng/mL和约310ng/mL。ACE2-(G4S)6-Fc的IC90是ACE2-Fc的约2倍(约2.3μg/ml相对于约4.2μg/ml)。这些结果确认,ACE2-(G4S)6-Fc实际上具有比常规ACE2诱饵大的结合亲和力和中和效力。
本文所述的柔性连接的ACE2诱饵(诸如ACE2-(G4S)6-Fc)有效地捕获结合ACE2的病毒,诸如SARS-CoV-2,人气道粘膜中的VLP,且可以被稳定中和。与SARS-CoV-1、NL63和HKU1冠状病毒一样,SARS-CoV-2严格经由气道上皮(即气道腔)的顶端感染,并且主要将子代病毒脱落回气道粘液(AM),因为感染从上呼吸道蔓延至下呼吸道,没有明显的脱落或细胞间蔓延。这种病毒蔓延机制意味着病毒必须在AM中扩散,使得感染在气道内传播。反过来,通过将病毒与AM的粘蛋白基质交联来防止病毒在AM中扩散可能有助于阻止感染的蔓延,并且经由自然粘膜纤毛清除机制促进从气道中快速清除。这可能允许在人类AM中有效地捕获病毒,导致VLP从气道快速清除。
为了评估本文所述的柔性连接的ACE2诱饵(诸如但不限于ACE2-(G4S)6-Fc)是否可以在人AM中捕获SARS-CoV-2,通过与GAG-mCherry融合构建体共表达S蛋白制备荧光SARS-2VLP,并且将其在从拔出的气管内导管分离的新鲜人AM中的迁移率可视化。如图10A和10B所示,ACE2-(G4S)6-Fc有效捕获AM中的SARS-2VLP,与盐水对照相比,即使在AM中仅1ug/mL浓度下,也将快速移动病毒群体(定义为具有足够的扩散性以在约1小时内跨约50um层扩散)减少约14倍。相比之下,ACE2-Fc和CR3022(针对来自JNJ/Crucell的S蛋白的高亲和力mAb)即使在10倍以上的浓度下也无法将病毒迁移率降低到相同程度。
在呼吸道,特别是肺气道中实现mAb的治疗性浓度的最直接方法是经由吸入直接递送mAb。振动筛网雾化器能够雾化蛋白质治疗剂,而不产生可降解蛋白质的局部加热和剪切。本文所述的柔性连接的ACE2诱饵可以被稳定地雾化。例如,使用Philip的Innospire Go振动筛网雾化器雾化ACE2-(G4S)6-Fc,在双室玻璃冲击器装置中收集所得气溶胶(所述装置按照欧洲药典5.0捕获>6μm(上部腔室)和<6μm(下部腔室)的气溶胶),并且经由S蛋白ELISA测量回收的雾化ACE2-(G4S)6-Fc的结合亲和力。结果示出于图11。与未雾化ACE2-(G4S)6-Fc相比,观察到从上部或下部腔室回收的ACE2-(G4S)6-Fc的结合亲和力没有明显损失。NativePAGE还确认没有重链分离或可检测的聚集(参见例如图12A-12B)。这些结果强调了稳定雾化柔性连接的ACE2诱饵以便直接吸入递送至呼吸道中的能力。
此外,柔性连接的ACE2诱饵的鼻内递送减少了鼻甲中的病毒载量。例如,感染SARS-CoV-2的仓鼠显示了在用柔性连接的ACE2诱饵治疗之后病毒载量的减少。作为体内概念验证,测定了ACE2-(G4S)6-Fc在感染SARS-CoV-2的金色叙利亚仓鼠中的经鼻递送的功效。仓鼠呈现出体重减轻的临床征象,以及肺部病毒载量高的组织病理学变化,使得它们成为测试基于mAb的方法的合适模型,尽管呼吸道的解剖结构存在差异。大多数先前的研究评估了在感染后2-6小时内给药的针对SARS-CoV-2的mAb。在此,在感染前或者感染后4小时、24小时和48小时评估起始每日给药ACE2-(G4S)6-Fc。ACE2-(G4S)6-Fc治疗,即使延迟到感染后48小时,也在96小时内减少鼻甲组织中的病毒载量约10倍。这翻译为仅在2天的时间段内体重减轻显著减小(p=.03)。
尽管进入临床研究的许多mAb具有显著的效力,但病毒逃逸突变体可以容易地对抗任何单个mAb,而逃逸突变体仍保留ACE2结合。为了防止逃逸突变体,许多小组专注于结合两种针对不同结构表位的抗体。尽管通过使用此类mAb混合物可以大大降低病毒逃逸的风险,但病毒逃逸突变体仍有可能同时从混合物中的两种mAb中逃逸。鉴于对病毒逃逸突变体的担忧,以及通过3期临床研究推进mAb分子所需的巨大成本和时间,开发一种没有病毒逃逸风险的结合蛋白是非常有利的。此外,鉴于已有至少3种靶向ACE2作为主要宿主进入受体的人冠状病毒,包括两种大流行潜力的冠状病毒(SARS-CoV-1、SARS-CoV-2),另一种同样靶向ACE2的具有大流行潜力的呼吸道病毒出现可能只是时间问题。出于这些原因,本文所述的柔性连接的ACE2可以实现针对所有ACE2靶向病毒的免疫疗法。实际上,本文所述的可溶性柔性连接的ACE2诱饵可以阻断SARS-CoV-1和SARS-CoV2的感染,并且能够以可比的亲和力结合SARS-CoV-2的WT、UK和SA毒株的S蛋白(参见例如图8C和8D)。
尽管本文所述的柔性连接的ACE2诱饵可以使用野生型(WT)ACE2片段,所述片段可以降低结合WT ACE2但不可被ACE2突变体捕获的逃逸病毒突变体的潜在风险,但是在一些情况下,可以使用突变的ACE2,如本文所述。此外,Fc结构域可以是野生型的(例如,IgG1-Fc)或修饰的。一般来讲,可以省略collectrin结构域,并且可以优化ACE2的细胞外片段与Fc(例如,IgG1-Fc)结构域之间的键联,以使得接头区的长度允许多价结合。与具有collectrin结构域的全长ACE2或不具有柔性接头的ACE2-Fc缀合物相比,这些结合分子的结合亲和力和中和效果实质上更好,其具有皮摩尔结合亲和力和抑制浓度(IC50约52ng/mL),比得上或超越缺乏足够长度的柔性接头的ACE2诱饵,如本文所述。
ACE2经由细胞表面上的其collectrin结构域二聚化。本文所述的柔性连接的ACE2诱饵特异性去除了ACE2的collectrin结构域,其使得ACE2的细胞外片段能够用明确定义的接头接枝至野生型Fc,如本文所述。在使用野生型Fc的本文所述的柔性连接的ACE2诱饵(诸如ACE2-(G4S)6-Fc)的实施例中,构建体还可以促进其他细胞介导的免疫。令人惊讶的是,本文所述的柔性连接的ACE2诱饵还得到了更大的产率和稳定性;例如ACE2-(G4S)6-Fc的产率与在相似条件下产生的其他高表达IgG相当,单体分布可再现(相比于容易聚集的其他ACE2诱饵)。
ACE2仅可以结合其RBD为“向上”构象的S蛋白。因此,两个RBD结构域需要为“向上”构象以实现二价结合。在对SARS-CoV-2S蛋白成像期间未观察到RBD结构域为“2个向上”构象的S蛋白;然而,已被提出,与RBD结合可以触发S蛋白向“3个向上”状态的转变,这是在冠状病毒科中保守的机制。S蛋白的不同区中的突变可以增加RBD结构域为“2个向上”或“3个向上”构象的S蛋白的比例。例如,具有D614G的S蛋白显示“2个向上”和“3个向上”构象的分子的比例比D614高。hexa-pro突变还增加了两个RBD为向上取向的S蛋白的数目。已经报道了增加“2个向上”与“1个向上”S蛋白的比率的其他突变。因此,可以实现与SARS-CoV-2的刺突内结合,并且我们预计对具有增加RBD暴露的突变(诸如D614G)的SARS-CoV-2的中和更高。
局部吸入递送有重要的优点。首先,与全身递送相比,吸入递送最大化所需剂(例如mAb)在肺中的局部浓度并且最小化其总剂量,因为通常仅一小部分全身给药的Ab实际分布至气道中。对于相同量的剂(例如结合剂,如mAb),与全身递送相比,局部递送可能治疗是其4-10倍的患者,同时仍然在肺部中实现较大浓度。这降低了成本负担,并且更重要的是,使我们能够潜在地治疗更多患者,鉴于COVID-19的规模几乎前所未有,这是一个必不可少的考虑因素。其次,早期治疗是非常可取的,这是所有抗病毒药的普遍事实。不幸的是,对于全身给药的剂或小分子药物,即使在诊断后迅速给药,在剂可在肺部中到达Cmax之前也存在显著延迟。例如,每天两次给药奥司他韦需要3天实现肺部中的稳态浓度。相比之下,雾化将本文所述的ACE2-(G4S)6-Fc柔性连接的ACE2诱饵直接递送至气道中,因此使局部Cmax快速到达。雾化还绕过了对输液椅和输液后监测的需要,并且使治疗能够直接在患者舒适的家中进行。与IV递送相比,这大大减少了实施治疗的医疗保健基础设施的负担,后者通常需要1-2小时输注,然后是相当长的输液后观察时间。
AM每天被持续分泌至肺部气道中,通过自然粘膜纤毛或咳嗽驱使的清除从下部气道(细支气管)被运输至气管,之后在食道潜意识地吞咽来通过酸性和降解性胃环境进行杀菌。自然粘液清除可快速除去沿肺部气道沉积的任何外来颗粒。呼吸道病毒必须通过AM扩散进行蔓延,并且经过特定进化来有效地蔓延。通过使用结合蛋白将病毒与粘蛋白交联,我们不仅确保病毒不会通过粘液扩散以蔓延感染,而且还可以直接从气道中去除病毒和相关抗原。这继而又最小化可渗入肺部的巨噬细胞和中性粒细胞可能引起的潜在炎症和抗原导向免疫反应。本文所述的柔性连接的ACE2诱饵可与仅单个剂量一起使用,例如每天一次。
序列表
<110> 北卡罗来纳大学教堂山分校
<120> 针对ACE2靶向病毒可用的结合蛋白
<130> UNC2-38409.601
<150> US 63/004,823
<151> 2020-04-03
<160> 28
<170> PatentIn version 3.5
<210> 1
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 1
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
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Ala
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<213> 人工序列
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<223> 合成
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Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn
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His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
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Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
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Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
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Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
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Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
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Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
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Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
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Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
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Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
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Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
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Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
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Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
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Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
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Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
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Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
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Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
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Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
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Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
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Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
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Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
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Leu Thr Ala His Asn Glu Met Gly Asn Ile Gln Tyr Asp Met Ala Tyr
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Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
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Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
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Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
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Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
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Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
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Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp
595
<210> 3
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 3
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 Glu Pro
20 25 30
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
35 40 45
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
50 55 60
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
65 70 75 80
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
85 90 95
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
100 105 110
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
115 120 125
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
130 135 140
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
145 150 155 160
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
165 170 175
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
180 185 190
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
195 200 205
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
210 215 220
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
225 230 235 240
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
245 250 255
Ser Leu Ser Pro Gly Lys
260
<210> 4
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 4
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 5
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 5
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Gly Ser
20
<210> 6
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 6
Asp Ile Gln Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Ile Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 7
<211> 631
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 7
Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn
1 5 10 15
His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
595 600 605
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser
625 630
<210> 8
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 8
Gln Met Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Gly Phe Ile Thr Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Asn Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Gly Gly Ser Gly Ile Ser Thr Pro Met Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 9
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 9
Gln Met Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Gly Phe Ile Thr Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Asn Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Gly Gly Ser Gly Ile Ser Thr Pro Met Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
<210> 10
<211> 633
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 10
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Glu Phe Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp
35 40 45
Lys Phe Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala
50 55 60
Ser Trp Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met
65 70 75 80
Asn Asn Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr
85 90 95
Leu Ala Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys
100 105 110
Leu Gln Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu
115 120 125
Asp Lys Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile
130 135 140
Tyr Ser Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu
145 150 155 160
Leu Leu Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr
165 170 175
Asn Glu Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys
180 185 190
Gln Leu Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met
195 200 205
Ala Arg Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp
210 215 220
Tyr Glu Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu
225 230 235 240
Ile Glu Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu
245 250 255
His Leu His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser
260 265 270
Tyr Ile Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met
275 280 285
Trp Gly Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly
290 295 300
Gln Lys Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp
305 310 315 320
Asp Ala Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val
325 330 335
Gly Leu Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr
340 345 350
Asp Pro Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp
355 360 365
Leu Gly Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met
370 375 380
Asp Asp Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp
385 390 395 400
Met Ala Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu
405 410 415
Gly Phe His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr
420 425 430
Pro Lys His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu
435 440 445
Asp Asn Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile
450 455 460
Val Gly Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met
465 470 475 480
Val Phe Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp
485 490 495
Glu Met Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp
500 505 510
Glu Thr Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr
515 520 525
Ser Phe Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln
530 535 540
Glu Ala Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys
545 550 555 560
Asp Ile Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu
565 570 575
Arg Leu Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val
580 585 590
Gly Ala Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro
595 600 605
Leu Phe Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp
610 615 620
Ser Thr Asp Trp Ser Pro Tyr Ala Asp
625 630
<210> 11
<211> 597
<212> PRT
<213> 智人(Homo sapiens)
<400> 11
Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn His
1 5 10 15
Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn Tyr
20 25 30
Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala Gly
35 40 45
Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln Met
50 55 60
Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu Gln
65 70 75 80
Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser Lys
85 90 95
Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr Gly
100 105 110
Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu Pro
115 120 125
Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg Leu
130 135 140
Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg Pro
145 150 155 160
Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala Asn
165 170 175
His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val Asn
180 185 190
Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp Val
195 200 205
Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His Ala
210 215 220
Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser Pro
225 230 235 240
Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg Phe
245 250 255
Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro Asn
260 265 270
Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln Arg
275 280 285
Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro Asn
290 295 300
Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly Asn
305 310 315 320
Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys Gly
325 330 335
Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe Leu
340 345 350
Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr Ala
355 360 365
Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His Glu
370 375 380
Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His Leu
385 390 395 400
Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu Thr
405 410 415
Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr Leu
420 425 430
Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys Gly
435 440 445
Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys Arg
450 455 460
Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr Cys
465 470 475 480
Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile Arg
485 490 495
Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu Cys
500 505 510
Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser Asn
515 520 525
Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly Lys
530 535 540
Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys Asn
545 550 555 560
Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr Trp
565 570 575
Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp Trp
580 585 590
Ser Pro Tyr Ala Asp
595
<210> 12
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 12
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
1 5 10 15
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
20 25 30
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
35 40 45
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
50 55 60
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
65 70 75 80
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
85 90 95
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
100 105 110
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
115 120 125
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
130 135 140
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
145 150 155 160
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
165 170 175
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
180 185 190
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
195 200 205
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 13
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 13
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
1 5 10 15
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
20 25 30
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
35 40 45
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
50 55 60
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
65 70 75 80
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
85 90 95
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
100 105 110
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
115 120 125
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
130 135 140
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
145 150 155 160
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
165 170 175
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
180 185 190
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
195 200 205
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 14
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 14
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
1 5 10
<210> 15
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 15
Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Phe Phe Asp
1 5 10 15
Ser Gln Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys Leu Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp
595
<210> 16
<211> 859
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 16
Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Phe Phe Asp
1 5 10 15
Ser Gln Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys Leu Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
595 600 605
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
610 615 620
Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
625 630 635 640
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
645 650 655
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
660 665 670
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
675 680 685
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
690 695 700
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
705 710 715 720
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
725 730 735
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
740 745 750
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
755 760 765
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
770 775 780
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
785 790 795 800
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
805 810 815
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
820 825 830
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
835 840 845
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
850 855
<210> 17
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 17
Gln Ser Thr Ile Glu Glu Gln Ala Lys Tyr Phe Leu Asp Lys Phe Asn
1 5 10 15
His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Thr Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Tyr Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp
595
<210> 18
<211> 859
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 18
Gln Ser Thr Ile Glu Glu Gln Ala Lys Tyr Phe Leu Asp Lys Phe Asn
1 5 10 15
His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Thr Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Tyr Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
595 600 605
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
610 615 620
Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
625 630 635 640
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
645 650 655
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
660 665 670
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
675 680 685
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
690 695 700
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
705 710 715 720
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
725 730 735
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
740 745 750
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
755 760 765
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
770 775 780
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
785 790 795 800
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
805 810 815
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
820 825 830
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
835 840 845
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
850 855
<210> 19
<211> 597
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 19
Gln Ser Ile Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn
1 5 10 15
Ala Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Gln Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu His Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala
595
<210> 20
<211> 858
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 20
Gln Ser Ile Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe Asn
1 5 10 15
Ala Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Gln Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu His Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
595 600 605
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
610 615 620
Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
625 630 635 640
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
645 650 655
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
660 665 670
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
675 680 685
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
690 695 700
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
705 710 715 720
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
725 730 735
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
740 745 750
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
755 760 765
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
770 775 780
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
785 790 795 800
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
805 810 815
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
820 825 830
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
835 840 845
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
850 855
<210> 21
<211> 597
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 21
Gln Ser Thr Ile Glu Glu Gln Val Lys Thr Phe Leu Asp Asn Phe Asn
1 5 10 15
His Lys Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Phe Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala
595
<210> 22
<211> 858
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 22
Gln Ser Thr Ile Glu Glu Gln Val Lys Thr Phe Leu Asp Asn Phe Asn
1 5 10 15
His Lys Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Phe Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
595 600 605
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
610 615 620
Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
625 630 635 640
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
645 650 655
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
660 665 670
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
675 680 685
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
690 695 700
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
705 710 715 720
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
725 730 735
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
740 745 750
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
755 760 765
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
770 775 780
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
785 790 795 800
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
805 810 815
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
820 825 830
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
835 840 845
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
850 855
<210> 23
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 23
Gln Ser Thr Ile Glu Glu Gln Ala Lys Trp Phe Leu Asp Lys Phe Asn
1 5 10 15
His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp
595
<210> 24
<211> 859
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 24
Gln Ser Thr Ile Glu Glu Gln Ala Lys Trp Phe Leu Asp Lys Phe Asn
1 5 10 15
His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp Asn
20 25 30
Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn Ala
35 40 45
Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala Gln
50 55 60
Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln Leu
65 70 75 80
Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys Ser
85 90 95
Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser Thr
100 105 110
Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu Glu
115 120 125
Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu Arg
130 135 140
Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu Arg
145 150 155 160
Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg Ala
165 170 175
Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu Val
180 185 190
Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu Asp
195 200 205
Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu His
210 215 220
Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile Ser
225 230 235 240
Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly Arg
245 250 255
Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys Pro
260 265 270
Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala Gln
275 280 285
Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu Pro
290 295 300
Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro Gly
305 310 315 320
Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly Lys
325 330 335
Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp Phe
340 345 350
Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala Tyr
355 360 365
Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe His
370 375 380
Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys His
385 390 395 400
Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn Glu
405 410 415
Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly Thr
420 425 430
Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe Lys
435 440 445
Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met Lys
450 455 460
Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr Tyr
465 470 475 480
Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe Ile
485 490 495
Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala Leu
500 505 510
Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile Ser
515 520 525
Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu Gly
530 535 540
Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala Lys
545 550 555 560
Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe Thr
565 570 575
Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr Asp
580 585 590
Trp Ser Pro Tyr Ala Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
595 600 605
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
610 615 620
Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
625 630 635 640
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
645 650 655
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
660 665 670
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
675 680 685
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
690 695 700
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
705 710 715 720
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
725 730 735
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
740 745 750
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
755 760 765
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
770 775 780
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
785 790 795 800
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
805 810 815
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
820 825 830
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
835 840 845
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
850 855
<210> 25
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 25
Asp Lys Glu Trp Ile Leu Gln Lys Ile Tyr Glu Ile Met Arg Leu Leu
1 5 10 15
Asp Glu Leu Gly His Ala Glu Ala Ser Met Arg Val Ser Asp Leu Ile
20 25 30
Tyr Glu Phe Met Lys Lys Gly Asp Glu Arg Leu Leu Glu Glu Ala Glu
35 40 45
Arg Leu Leu Glu Glu Val Glu Arg
50 55
<210> 26
<211> 317
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 26
Asp Lys Glu Trp Ile Leu Gln Lys Ile Tyr Glu Ile Met Arg Leu Leu
1 5 10 15
Asp Glu Leu Gly His Ala Glu Ala Ser Met Arg Val Ser Asp Leu Ile
20 25 30
Tyr Glu Phe Met Lys Lys Gly Asp Glu Arg Leu Leu Glu Glu Ala Glu
35 40 45
Arg Leu Leu Glu Glu Val Glu Arg Gly Gly Gly Gly Ser Gly Gly Gly
50 55 60
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
65 70 75 80
Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr
85 90 95
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
100 105 110
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
115 120 125
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
130 135 140
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
145 150 155 160
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
165 170 175
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
180 185 190
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
195 200 205
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
210 215 220
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
225 230 235 240
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
245 250 255
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
260 265 270
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
275 280 285
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
290 295 300
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
305 310 315
<210> 27
<211> 64
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 27
Asn Asp Asp Glu Leu His Met Leu Met Thr Asp Leu Val Tyr Glu Ala
1 5 10 15
Leu His Phe Ala Lys Asp Glu Glu Ile Lys Lys Arg Val Phe Gln Leu
20 25 30
Phe Glu Leu Ala Asp Lys Ala Tyr Lys Asn Asn Asp Arg Gln Lys Leu
35 40 45
Glu Lys Val Val Glu Glu Leu Lys Glu Leu Leu Glu Arg Leu Leu Ser
50 55 60
<210> 28
<211> 325
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 28
Asn Asp Asp Glu Leu His Met Leu Met Thr Asp Leu Val Tyr Glu Ala
1 5 10 15
Leu His Phe Ala Lys Asp Glu Glu Ile Lys Lys Arg Val Phe Gln Leu
20 25 30
Phe Glu Leu Ala Asp Lys Ala Tyr Lys Asn Asn Asp Arg Gln Lys Leu
35 40 45
Glu Lys Val Val Glu Glu Leu Lys Glu Leu Leu Glu Arg Leu Leu Ser
50 55 60
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
65 70 75 80
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro
85 90 95
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
100 105 110
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
165 170 175
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly
325
Claims (37)
1.一种结合ACE2靶向病毒的分离的结合蛋白,其具有包含以下的氨基酸序列:
A-(B)n-C(式I)
其中,
A为不包括collectrin结构域的血管紧张素转换酶2(ACE2)的细胞外部分或其变体;
n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;
B为多肽柔性接头;
C为片段结晶化(Fc)结构域,
其中所述分离的结合蛋白为二聚体。
2.根据权利要求1所述的结合蛋白,其中n选择为使得所述二聚体的A结构域之间的距离大于14nm。
3.根据权利要求1-2中任一项所述的结合蛋白,其中所述Fc结构域为人IgA、IgM或IgGFc结构域。
4.根据权利要求2所述的结合蛋白,其中所述Fc结构域为人IgG1 Fc结构域。
5.根据权利要求1-3中任一项所述的结合蛋白,其中所述Fc结构域包含YTE突变、LS突变或LALA-PG突变。
6.根据权利要求1-5中任一项所述的结合蛋白,其中所述ACE2的细胞外部分为人ACE2的细胞外部分。
7.根据权利要求1-6中任一项所述的结合蛋白,其中所述ACE2的细胞外部分与氨基酸序列SEQ ID NO:11具有80%或更大的氨基酸序列同一性。
8.根据权利要求1-6中任一项所述的结合蛋白,其中所述ACE2的细胞外部分具有与氨基酸SEQ ID NO:11具有至多10个氨基酸差异的氨基酸序列。
9.根据权利要求1-6中任一项所述的结合蛋白,其中所述ACE2的细胞外部分包含至少一个突变。
10.根据权利要求9所述的结合蛋白,其中所述ACE2包含两个或更多个突变。
11.根据权利要求1-10中任一项所述的结合蛋白,其中所述多肽柔性接头具有序列GGGGS。
12.根据权利要求1-11中任一项所述的结合蛋白,其还包含在所述柔性接头与所述Fc结构域之间的铰链。
13.根据权利要求1-12中任一项所述的结合蛋白,其中所述Fc结构域包含具有G0糖基化模式的寡糖。
14.根据权利要求1-13中任一项所述的结合蛋白,其中所述Fc结构域包含具有G0糖基化模式的寡糖,所述寡糖包含在每个分枝具有末端N-乙酰基葡糖胺的双触角核心聚糖结构Manα1-6(Manα1-3)Manβ1-4GlcNAcβl-4G1cNAcβ1,以增强粘液中所述结合蛋白的捕捉效力。
15.一种药物组合物,其包含根据权利要求1-14中任一项所述的结合蛋白和药学上可接受的赋形剂。
16.根据权利要求15所述的药物组合物,其中所述赋形剂、稀释剂或载剂被配置用于吸入。
17.根据权利要求15所述的药物组合物,其中所述组合物被配置用于口服、肠胃外、腹膜内、经粘膜、经皮、直肠、吸入和局部施用中的一种或多种。
18.一种治疗罹患SARS-CoV-2的受试者的方法,所述方法包括施用药学上可接受量的根据权利要求15-17中任一项所述的药物组合物。
19.根据权利要求18所述的方法,其中施用包括将所述药物组合物全身应用于所述患者。
20.根据权利要求18所述的方法,其中施用包括将所述药物组合物应用于所述患者的粘膜。
21.根据权利要求18所述的方法,其中施用包括雾化所述药物组合物。
22.一种治疗或抑制ACE2靶向病毒的病毒感染的方法,所述方法包括经由吸入途径向所述受试者施用根据权利要求1-14中任一项所述的结合蛋白。
23.根据权利要求22所述的方法,其中所述ACE2靶向病毒是SARS-CoV-2。
24.一种结合ACE2靶向病毒的分离的结合蛋白,其具有包含以下的氨基酸序列:
A-(B)n-C(式I)
其中,
A为不包括collectrin结构域的血管紧张素转换酶2(ACE2)的细胞外部分,其与氨基酸序列SEQ ID NO:11具有80%或更大的氨基酸序列同一性;
n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;
B为多肽柔性接头;
C为片段结晶化(Fc)结构域,
其中所述分离的结合蛋白为二聚体,
进一步地,其中n选择为使得所述二聚体的所述A结构域之间的距离大于14nm。
25.一种结合严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的双特异性结合蛋白,其包含具有式II的至少一个重链可变区:
X-(Y)n-Z(式II)
其中,
X为(i)血管紧张素转换酶2(ACE2)或其变体;或(ii)结合SARS-CoV-2的抗体的重链可变区或其片段;
n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25;
Y为第一多肽柔性接头;
并且
Z为(i)ACE2或其变体;或(ii)结合SARS-CoV-2的抗体的重链可变区或其片段,条件是(a)当X为ACE2或其变体时,Z为结合SARS-CoV-2的抗体的重链可变区或其片段;或(b)当X为结合SARS-CoV-2的抗体的重链可变区或其片段时,Z为ACE2或其变体。
26.根据权利要求25所述的双特异性结合蛋白,其中X或Z还包含片段结晶化(Fc)结构域、结合SARS-CoV-2的抗体的至少一个重链恒定区、结合SARS-CoV-2的抗体的至少一个轻链恒定区、结合SARS-CoV-2的抗体的至少一个轻链可变区、或其任何组合。
27.根据权利要求26所述的双特异性结合蛋白,其中所述Fc结构域为人IgA、IgM或IgGFc结构域。
28.根据权利要求27所述的双特异性结合蛋白,其中所述Fc结构域为人IgG1 Fc结构域。
29.根据权利要求25-28中任一项所述的双特异性结合蛋白,其中所述ACE2为人ACE2。
30.根据权利要求25-29中任一项所述的双特异性结合蛋白,其中所述ACE2包含人ACE2的细胞外结构域。
31.根据权利要求25-30中任一项所述的双特异性结合蛋白,其中所述ACE2包含至少一个突变。
32.根据权利要求31所述的双特异性结合蛋白,其中所述ACE2包含两个或更多个突变。
33.根据权利要求25-32中任一项所述的双特异性结合蛋白,其中所述接头具有序列GGGGS。
34.根据权利要求25-33中任一项所述的双特异性结合蛋白,其中抗体的所述重链可变区来自单克隆抗体CR3014或CR3022。
35.根据权利要求25-34中任一项所述的双特异性结合蛋白,其中所述双特异性结合蛋白为双特异性抗体或其抗体结合片段。
36.一种药物组合物,其包含根据权利要求25-35中任一项所述的双特异性结合蛋白和药学上可接受的赋形剂。
37.一种治疗罹患SARS-CoV-2的受试者的方法,所述方法包括药学上可接受量的根据权利要求36所述的药物组合物。
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