CN116848242A - Ace2融合蛋白及其用途 - Google Patents

Abstract

本发明涉及ACE2与IgG Fc的融合蛋白，以及这些融合蛋白特别是在预防或治疗冠状病毒(如SARS‑CoV‑2)感染中的医学用途。

Description

ACE2融合蛋白及其用途

发明领域

本发明涉及ACE2与IgG Fc的融合蛋白，以及这些融合蛋白特别是在预防或治疗冠状病毒(如SARS-CoV-2)感染中的医学用途。

发明背景

ACE2(血管紧张素转化酶2)是肾素-血管紧张素系统的关键金属蛋白酶，在中心具有催化性锌原子(Donoghue等人(2002)Circ.Res.87:e1-e9)。全长ACE2由N端细胞外肽酶域、收集蛋白(collectrin)样域、单个跨膜螺旋以及短的细胞内区段组成。它用于切割血管紧张素II以产生血管紧张素(1-7)，以及切割血管紧张素I以产生血管紧张素(1-9)，然后由其它酶加工以变为血管紧张素(1-7)。ACE2用于降低血压并对抗ACE的活性，以维持Ras/MAS系统中的平衡。因此，它是用于治疗心血管疾病的有前景的靶标。

最近，ACE2作为冠状病毒并且特别是新型冠状病毒SARS-CoV-2的受体已经引起广泛关注。SARS-CoV-2是一种冠状病毒，导致了世界范围的大流行病。2020年5月22日，约翰霍普金斯大学(Johns Hopkins University)统计全世界超过5百万例确诊感染，致使超过330,000人死亡。这种大流行病导致许多国家实行封锁，产生了非常重大的经济和社会影响。

已显示ACE2作为SARS-CoV(Li等人(2003)Nature 426:450-454；Prakabaran等人(2004)Biochem.Biophys.Res.Comm.314:235-241)和SARS-CoV-2(Yan等人(2020)Science367:1444-1485)的受体起作用。另外，SARS-CoV-2进入呼吸道细胞取决于ACE2和丝氨酸蛋白酶TMPRSS2(Hoffmann等人(2020)Cell 181:1-10)。

鉴于ACE2对于病毒进入细胞的重要作用，提出使用可溶性ACE2来阻断SARS与细胞的结合(WO 2005/032487；WO 2006/122819)。相同的方法也被建议用于治疗SARS-CoV-2感染(Kruse(2020)F1000Res.9:72)。Apeiron公司已经启动用可溶形式的ACE2治疗SARS-CoV-2感染的临床试验(Pharmazeutische Zeitung，2020年4月10日)，并且最初结果显示一名患有由SARS-CoV-2所致的严重Covid-19的患者在用可溶性ACE2治疗后快速恢复(Zoufaly等人(2020)The Lancet Respiratory Medicine 8:1154-1158，可得自https://doi.org/ 10.1016/S2213-2600(20)30418-5)。

然而，分离的受体域的特征典型地在于低稳定性和血浆半衰期。对于ACE2的可溶形式，显示了10小时的剂量依赖性终末半衰期(Haschke等人(2013)Clin.Pharmacokinet.52:783-792)。鉴于这些结果，决定在后续研究中将可溶形式的ACE2以每日两次输注进行施用(Khan等人,(2017)Critical Care21:234)。然而，每天超过一次的施用对于患者和医务人员都不方便。

构建并测试了ACE2的融合蛋白，该ACE2的融合蛋白由与人IgG1的Fc域连接的酶促活性或酶促失活ACE2的胞外域组成。这显示出两种构建体均有力地中和SARS-CoV和SARS-CoV-2两者，并抑制S(刺突)蛋白介导的融合(Lei等人(2020)Nature Communications 11:2070)。另外，SorrentoTherapeutics公司开发出称为COVIDTRAP^TM或STI-4398的融合蛋白用于临床试验(参见https://www.globenewswire.com/news-release/2020/03/20/2003957/ 0/en/SORRENTO-DEVELOPS-STI-4398-COVIDTRAP-PROTEIN-FOR-POTENTIAL-PREVENTION- AND-TREATMENT-OF-SARS-COV-2-CORONAVIRUS-DISEASE-COVID-19.html)。Liu等人(2020)Int.J.Biol.Macromol.165:1626-1633(可得自https://www.biorxiv.org/content/ 10.1101/2020.08.13.248351v1.full.pdf)描述了野生型ACE2和影响ACE2的催化活性的九种ACE2突变体与人IgG1的Fc区的融合蛋白。然而，人IgG1的Fc域与免疫细胞上的Fcγ受体的相互作用可能增强病毒感染(Perlman和Dandekar(2005)Nat.Rev.Immunol.5(12):917-927；Chen等人(2020)Current Tropical Medicine Reports 3:1-4)。

Tada等人(2020)(可得自https://www.biorxiv.org/content/10.1101/ 2020.09.16.300319v1.full)公开了“ACE2微体”，其中无催化活性的ACE2的胞外域与免疫球蛋白重链的Fc域3融合。

Svilenov等人(2020)(可得自https://www.researchsquare.com/article/rs- 459941/v1)和PCT/EP2021/063692描述了具有IgG1和IgG4的Fc域的ACE2融合蛋白。

欧洲专利申请EP21188832.6公开了具有IgM和IgG2的Fc域的ACE2融合蛋白。

WO 2021/170113、WO 2021/183404、US2021/0284716和WO 2021/189772也公开了ACE2与不同免疫球蛋白的Fc部分的融合蛋白。

Zhang等人(2021)Cell Discovery 7:65描述了ACE2的胞外域与IgG1的Fc部分的融合蛋白保护小鼠免受SARS-CoV2感染，如由肺中减少的病毒复制、体重减轻、组织学变化和炎症所确定。另外，已显示与靶向SARS-CoV2的受体结合域的抗体不同，用融合蛋白治疗不会诱导逃逸突变体的发展。

因此，仍然需要可以用于治疗和/或预防冠状病毒(特别是SARS-CoV-2)感染的药剂。

发明内容

本发明提供了融合蛋白，该融合蛋白包含：第一部分，该第一部分包含人ACE2的片段或所述片段的变体，所述人ACE2具有根据SEQ ID No.1的氨基酸序列；以及第二部分，该第二部分包含人IgG1的Fc部分的变体，所述变体具有根据SEQ ID No.19的氨基酸序列。

在一个实施方案中，第一部分和第二部分通过根据SEQ ID No.15的氨基酸序列连接。

人ACE2的片段可以由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，或者可以是由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成的ACE2的胞外域。

在一个实施方案中，人ACE2片段的变体是人ACE2的酶促失活变体。

人ACE2的酶促失活变体可以包含H374N和H378N突变(编号参考SEQ ID No.1)，或者位置273处的突变，优选地R273A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的酶促失活变体由具有根据SEQ ID No.91或92的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的酶促失活变体由具有根据SEQ ID No.24或25的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2片段的变体包含S645C突变(编号参考SEQ ID No.1)。特别地，人ACE2片段的变体可以由具有根据SEQ ID No.28或29的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2片段的变体进一步包含H374N和H378N突变(编号参考SEQ ID No.1)。特别地，人ACE2片段的变体可以由具有根据SEQ ID No.32或33的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2片段的变体进一步包含位置273处的突变，优选地R273A突变(编号参考SEQ ID No.1)。特别地，人ACE2片段的变体可以由具有根据SEQ IDNo.36或37的氨基酸序列的蛋白质组成。

本发明进一步提供了融合蛋白，该融合蛋白包含：

(a)第一部分，该第一部分包含人ACE2的片段的变体，所述人ACE2具有根据SEQ IDNo.1的氨基酸序列，其中人ACE2片段的变体包含S645C突变(编号参考SEQ ID No.1)，以及(b)第二部分，该第二部分包含人IgG的Fc部分或人IgG的Fc部分的变体。

在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.28或29的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段的变体进一步包含H374N和H378N突变(编号参考SEQ ID No.1)。特别地，人ACE2片段的变体可以由具有根据SEQ ID No.32或33的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段的变体进一步包含位置273处的突变，优选地R273A突变(编号参考SEQ ID No.1)。特别地，人ACE2片段的变体可以由具有根据SEQ IDNo.36或37的氨基酸序列的蛋白质组成。

在一个实施方案中，第二部分包含人IgG1或IgG4的Fc部分或者人IgG1或IgG4的Fc部分的变体。

在一个实施方案中，第二部分包含根据SEQ ID No.16的人IgG1的Fc部分，优选地第一部分和第二部分通过根据SEQ ID No.15的氨基酸序列连接。

在另一个实施方案中，第二部分包含根据SEQ ID No.5的人IgG4的Fc部分，优选地第一部分和第二部分通过根据SEQ ID No.4的氨基酸序列连接。

在另一个实施方案中，第二部分包含具有根据SEQ ID No.44的序列的人IgG4的Fc部分的变体，优选地第一部分和第二部分通过根据SEQ ID No.4的氨基酸序列连接。

在另一个实施方案中，第二部分包含具有根据SEQ ID No.59的序列的人IgG1的Fc部分的变体或者具有根据SEQ ID No.60的序列的人IgG4的Fc部分的变体。

在一个实施方案中，第二部分包含具有根据SEQ ID No.59的序列的人IgG1的Fc部分的变体，并且第一部分和第二部分通过根据SEQ ID No.15的氨基酸序列连接。

在另一个实施方案中，第二部分包含具有根据SEQ ID No.60的序列的人IgG4的Fc部分的变体，并且第一部分和第二部分通过根据SEQ ID No.4的氨基酸序列连接。

本发明进一步提供了融合蛋白，该融合蛋白包含：第一部分，该第一部分包含人ACE2的片段或所述片段的变体，所述人ACE2具有根据SEQ IDNo.1的氨基酸序列；以及第二部分，该第二部分包含人IgG1的Fc部分的变体，所述变体具有根据SEQ ID No.59的序列，或人IgG4的Fc部分的变体，所述变体具有根据SEQ ID No.60的序列。

第二部分可以包含具有根据SEQ ID No.59的序列的人IgG1的Fc部分的变体，并且第一部分和第二部分通过根据SEQ ID No.15的氨基酸序列连接，或者第二部分可以包含具有根据SEQ ID No.60的序列的人IgG4的Fc部分的变体，并且第一部分和第二部分通过根据SEQ ID No.4的氨基酸序列连接。

人ACE2的片段可以由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，或者可为由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成的ACE2的胞外域。

在一个实施方案中，人ACE2片段的变体是人ACE2的酶促失活变体。

人ACE2的酶促失活变体可包含H374N和H378N突变(编号参考SEQ ID No.1)，或者位置273处的突变，优选地R273A突变(编号参考SEQ IDNo.1)。

本发明进一步提供了融合蛋白，该融合蛋白包含：

(a)第一部分，该第一部分包含人ACE2的片段的变体，所述人ACE2具有根据SEQ IDNo.1的氨基酸序列，其中人ACE2片段的变体包含R273A突变(编号参考SEQ ID No.1)，以及(b)第二部分，该第二部分包含人IgG的Fc部分或人IgG的Fc部分的变体。

在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.24或25的氨基酸序列的蛋白质组成。

第二部分可以包含人IgG1或IgG4的Fc部分。

在一个实施方案中，第二部分包含根据SEQ ID No.16的人IgG1的Fc部分，优选地第一部分和第二部分通过根据SEQ ID No.15的氨基酸序列连接。

在替代的实施方案中，第二部分包含根据SEQ ID No.5的人IgG4的Fc部分，优选地第一部分和第二部分通过根据SEQ ID No.4的氨基酸序列连接。

在替代的实施方案中，第二部分包含具有根据SEQ ID No.44的序列的人IgG4的Fc部分的变体。

本发明的融合蛋白可以具有选自根据SEQ ID No.20、21、22、23、26、27、30、31、34、35、38、39、40、41、42、43、45、46、47、48、49、50、51、52、53、54、55、56、57、58、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、93和94的氨基酸序列的氨基酸序列。

本发明还涉及包含编码所述融合蛋白的核酸序列的核酸分子、包含所述核酸分子的表达载体，以及包含所述核酸分子或所述表达载体的宿主细胞。

另外，本发明涉及用于产生所述融合蛋白的方法，该方法包括在合适的培养基中培养所述宿主细胞。

本发明还涉及所述融合蛋白用于医学用途，特别是用于预防和/或治疗结合ACE2的冠状病毒的感染。

在一个实施方案中，结合ACE2的冠状病毒选自SARS、SARS-CoV-2以及NL-63，优选地为SARS-CoV-2。

所述融合蛋白可以与抗病毒剂组合施用，该抗病毒剂可以选自瑞德西韦、盐酸阿比朵尔、利托那韦、洛匹那韦、地瑞那韦、利巴韦林、氯喹及其衍生物、硝唑尼特、甲磺酸卡莫司他、托珠单抗、司妥昔单抗、沙利鲁单抗(sarilumab)以及巴瑞克替尼磷酸盐。

所述融合蛋白也可以与抗体组合施用，该抗体可以选自巴尼韦单抗(bamlanivimab)、埃特司韦单抗(etesevimab)、卡斯瑞韦单抗(casirivimab)、依米得韦单抗(imdevimab)、索托韦单抗(sotrovimab)以及它们的混合物。

本发明还涉及所述融合蛋白，其用于治疗高血压病(包括高血压)、充血性心力衰竭、慢性心力衰竭、急性心力衰竭、收缩性心力衰竭、心肌梗死、动脉硬化、肾脏衰竭、肾衰竭、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、慢性阻塞性肺病(COPD)、肺动脉高压、肾纤维化、慢性肾衰竭、急性肾衰竭、急性肾损伤、炎性肠病以及多器官功能障碍综合征。

本发明还涉及药物组合物，该药物组合物包含所述融合蛋白以及药学上可接受的载剂或赋形剂。药物组合物可以进一步包含抗病毒剂。

附图简述

图1：蛋白A层析后不同融合蛋白的蛋白质产率，如由斜率光谱术所测定

图2：通过分析型尺寸排阻层析法对不同融合蛋白的高分子量种类的分析

图3：不同融合蛋白的O-糖基化分析

图4：不同融合蛋白对S1与ACE2结合的抑制，如由竞争性ELISA所测定

a)具有IgG4的Fc部分的构建体1-4

b)具有IgG1的Fc部分的构建体5-8

图5：构建体1、3、5和7对SARS-CoV-2(株Victoria/1/2020)的中和

图6：构建体1至8和两种参考蛋白质(Ref1、Ref2)的酶促活性的分析

a)来自六次单独实验的酶促活性的平均值与标准偏差

b)在六次单独实验中获得的每种构建体的单个值

图7：构建体1至8对不同冠状病毒的中和

a)SARS-CoV(株SARS-CoV-Fra-1(AY291315.1))的中和；来自三次独立实验的平均IC50值；误差线指示95％置信区间

b)SARS-CoV-2(SARS-CoV-2-Munich-TUM-1(EPI_ISL_582134))的中和；来自三次独立实验的平均IC50值；误差线指示95％置信区间

c)SARS-CoV-2D614G的中和；来自三次独立实验的平均IC50值；误差线指示95％置信区间

图8：根据SEQ ID NO.6的融合蛋白与ACE2的结合，如由结合ELISA所测定

图9：用根据SEQ ID No.6(构建体1，左手侧)和SEQ ID No.8(构建体3，右手侧)的融合蛋白对不同病毒分离株(A：SARS-CoV-2Munich-TUM-1；B：SARS-CoV-2D614G；C：SARS-CoV-2B.1.1.7；D：SARS-CoV-2B.1.351)的中和。虚线描绘了IC50值的测定。给出的数据是各三次独立实验的平均值±SEM。

图10：分析型尺寸排阻层析法对不同融合蛋白在储存不同时段后的高分子量种类的分析

a)构建体1至4(根据SEQ ID NO.6至9)的分析

b)构建体5至8(根据SEQ ID NO.10至13)的分析

发明详述

如以下示例性描述的本发明可以在不存在本文未具体公开的任何一个或多个要素、一个或多个限制的情况下适当地实践。

本发明将针对特定实施方案进行描述，但本发明并不限于此，而是仅由权利要求所限定。

在术语“包含”在本说明书和权利要求书中使用的情况下，它不排除其它要素。出于本发明的目的，术语“由……组成”被认为是术语“包含”的优选实施方案。如果组在下文中定义为包含至少特定数量的实施方案，则这也应理解为公开了优选地仅由这些实施方案组成的组。

出于本发明的目的，术语“获得的”被认为是术语“可获得的”的优选实施方案。如果在下文中例如细胞或生物体定义为通过特定方法可获得的，则这也应理解为公开了通过该方法获得的细胞或生物体。

在提及到单数名词时使用不定冠词或定冠词(例如，“一个”、“一种”或“该”)的情况下，这包括该名词的复数形式，除非另有特别说明。

如上所讨论，本发明提供了融合蛋白，该融合蛋白包含第一部分，该第一部分包含人ACE2的片段的某些变体，以及第二部分，该第二部分包含人IgG或IgG1的Fc部分或者人IgG或IgG1的Fc部分的变体。本发明还提供了融合蛋白，该融合蛋白包含第一部分，该第一部分包含人ACE2的某些片段或所述片段的变体，以及第二部分，该第二部分包含人IgG1或人IgG4的Fc部分的变体。已显示与包含氨基酸18至740的人ACE2的片段相比，包含氨基酸18至732的人ACE2的片段提供了更高的产率和更低量的高分子量种类，以及没有非天然O-糖基化，因为丝氨酸740缺失。另外，与包含氨基酸18至740的人ACE2的片段相比，包含氨基酸18至732的人ACE2的片段在储存后显示出更高的稳定性。然而，具有包含氨基酸18至732的人ACE2的片段的融合蛋白以与具有包含氨基酸18至740的人ACE2的片段的融合蛋白相似的效率中和了不同的SARS-CoV2变体。相比之下，其他人已发现，与包含ACE2的氨基酸18至740的融合蛋白相比，仅包含ACE2的氨基酸18至615的融合蛋白不太高效地阻断SARS-CoV2的感染(Li等人(2020)J.Virol.94(22):e01283-20)。鉴于文献(例如Tada等人(2020)，可得自https://www.biorxiv.org/content/10.1101/2020.09.16.300319v1.full)，假定与不具有Fc部分的可溶性ACE2二聚体相比，具有人IgG的Fc部分的融合蛋白对SARS-CoV-2的刺突蛋白具有更高的亲和力。还假定Fc部分之间的二硫桥稳定化融合蛋白与其靶标(如SARS-CoV-2的刺突蛋白)的结合。本发明的融合蛋白与FcRn结合，这导致比可溶性ACE2二聚体更长的半衰期。

已显示Fc介导的抗体功能如抗体依赖性细胞毒性(ADCC)和抗体依赖性吞噬作用(ADP)防御流感病毒和其它病毒病原体(Vanderven和Kent(2020)Immunology&CellBiology 98:253-263)。在SARS-CoV2治疗的上下文中，针对抗体卡斯瑞韦单抗和依米得韦单抗的混合物的EMA评估报告讨论这些抗体能够介导ADCC和ADP。另外，在任何治疗的动物中没有观察到抗体依赖性增强的证据。

“融合蛋白”是由至少两个彼此不天然连接的多肽部分形成的蛋白质。两个多肽部分通过肽键连接，并且任选地接头分子插入两个多肽部分之间。两个多肽部分作为单个分子被转录和翻译。融合蛋白典型地具有衍生自两个多肽部分的功能。在本发明的上下文中，融合蛋白保留了ACE2的结合特性，特别是病毒(如冠状病毒)的结合，以及人IgG的Fc部分所赋予的增加的半衰期和Fc受体结合。

术语“人ACE2”是指衍生自人受试者的血管紧张素转化酶2。人ACE2的全长序列具有805个氨基酸。它包含信号肽、N端细胞外肽酶域，继之以收集蛋白样域、单个跨膜螺旋以及短的细胞内区段。人ACE2的全长序列以SEQ ID No.1描绘。除非另外指明，否则本文使用的氨基酸编号是指根据SEQ ID No.1的人ACE2的全长序列的编号。人ACE2的胞外域由SEQID No.1的氨基酸18至740组成，并且以SEQ ID No.3描绘。

术语“人ACE2的片段”是指与根据SEQ ID No.1的人ACE2的全长序列相比缺乏一个或多个氨基酸的多肽。人ACE2的片段能够结合至少一种冠状病毒的S蛋白，特别是SARS-CoV-2的S蛋白。人ACE2的片段与至少一种冠状病毒的S蛋白的结合可以在ELISA测定中进行测定，其中S蛋白固定化在底物上并与人ACE2的片段接触，并且检测S蛋白与人ACE2的片段之间的相互作用。替代性地，人ACE2的片段与至少一种冠状病毒的S蛋白的结合可以通过表面等离子体共振进行测定，例如，如描述于Shang等人(2020)Nature doi:10.1038/s41586-020-2179-y；Wrapp等人(2020)Science 367(6483):1260-1263；Lei等人(2020)NatureCommunications 11(1):2070中。在进一步的替代物中，人ACE2的片段与至少一种冠状病毒的S蛋白的结合可以通过生物层干涉测量法进行测定，例如，如描述于Seydoux等人(2020)https://doi.org/10.1101/2020.05.12.091298中。用于测定与S蛋白的结合的合适方法也描述于本文的实施例部分中。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.1的序列内的360至723个连续氨基酸组成。优选地，人ACE2的片段由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸组成。优选地，人ACE2的片段由根据SEQ ID No.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸组成。更优选地，人ACE2的片段由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸组成。

在一个实施方案中，人ACE2的片段包含氨基酸残基K31和K353(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQID No.1)。在一个实施方案中，人ACE2的片段包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.1的序列内的360至723个连续氨基酸组成，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。优选地，人ACE2的片段由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸组成，并且包含氨基酸残基K31和K353(编号参考SEQ IDNo.1)。优选地，人ACE2的片段由根据SEQ ID No.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸组成，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。更优选地，人ACE2的片段由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸组成，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.1的序列内的360至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。优选地，人ACE2的片段由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。优选地，人ACE2的片段由根据SEQ IDNo.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。更优选地，人ACE2的片段由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.1的序列内的360至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ IDNo.1)。优选地，人ACE2的片段由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。优选地，人ACE2的片段由根据SEQID No.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。更优选地，人ACE2的片段由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸组成，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至380、18至400、18至420、18至440、18至460、18至480或18至500组成。优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至520、18至540、18至560、18至580或18至600组成。更优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至605、18至615、18至620、18至640、18至660、18至680或18至700组成。甚至更优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至710、18至720或18至730组成。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的氨基酸序列组成。根据SEQ ID No.2的氨基酸序列以根据SEQ ID No.1的序列中的氨基酸Q18起始且以氨基酸G732终止。在该片段的C端末端的氨基酸甘氨酸提供了高旋转自由度，这有利于两个蛋白质部分的融合并且增加融合蛋白的稳定性。另外，令人惊奇地发现，使用包含以根据SEQ ID No.1的序列中的氨基酸Q18起始且以氨基酸G732终止的氨基酸序列的ACE2片段提供相比较长的ACE2片段更好的产率以及更好的稳定性。此外，它缺乏非天然O糖基化并且以与较长ACE2片段相似的效率中和不同的SARS-CoV2变体。这与仅包含ACE2的氨基酸18至615的较短ACE2片段的发现形成对照，其抑制SARS-CoV2的感染的效率低于包含ACE2的氨基酸18至740的较长ACE2片段。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的人ACE2的完整胞外域组成。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.14的氨基酸序列组成。根据SEQ ID No.14的氨基酸序列以根据SEQ ID No.1的序列中的氨基酸Q18起始且以氨基酸G605终止。

在一个实施方案中，人ACE2的片段在选自N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)的至少一个氨基酸残基处被N-糖基化。在一个实施方案中，人ACE2的片段在氨基酸残基N53、N90和N322(编号参考SEQ ID No.1)处被N-糖基化。在一个实施方案中，人ACE2的片段在氨基酸残基N53、N90、N103、N322、N432、N546和N690(编号参考SEQ IDNo.1)处被N-糖基化。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的氨基酸序列组成，并且在选自N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)的至少一个氨基酸残基处被N-糖基化。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的氨基酸序列组成，并且在氨基酸残基N53、N90和N322(编号参考SEQ ID No.1)处被N-糖基化。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的氨基酸序列组成，并且在氨基酸残基N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)处被N-糖基化。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的氨基酸序列组成，并且在选自N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)的至少一个氨基酸残基处被N-糖基化。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的氨基酸序列组成，并且在氨基酸残基N53、N90和N322(编号参考SEQ ID No.1)处被N-糖基化。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的氨基酸序列组成，并且在氨基酸残基N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)处被N-糖基化。

在本发明的上下文中，术语“人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成”旨在意指该片段精确地具有如由序列表中的相应序列所定义的长度，并且不包含任何氨基酸添加和/或缺失。然而，该术语不排除在所定义片段的序列内存在的一个或多个氨基酸取代。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列内的360至723个连续氨基酸标识。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸标识。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸标识。更优选地，人ACE2的片段包含或由根据SEQ IDNo.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸标识。

在一个实施方案中，人ACE2的片段包含氨基酸残基K31和K353(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQID No.1)。在一个实施方案中，人ACE2的片段包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列内的360至723个连续氨基酸标识，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸标识，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸标识，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸标识，并且包含氨基酸残基K31和K353(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列内的360至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。优选地，人ACE2的片段包含或由根据SEQ IDNo.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ ID No.1)。更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、E35和Q42(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列内的360至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQID No.1)。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的380至723、400至723、420至723、440至723、460至723、480至723或500至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的520至723、540至723、560至723、580至723或600至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ IDNo.1)。更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列内的620至723、640至723、660至723、680至723、700至723或720至723个连续氨基酸标识，并且包含氨基酸残基Q24、D30、K31、E35、Q42和K353(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至380、18至400、18至420、18至440、18至460、18至480或18至500标识。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至520、18至540、18至560、18至580或18至600标识。更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至605、18至615、18至620、18至640、18至660、18至680或18至700标识。甚至更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至710、18至720或18至730标识。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的氨基酸序列标识。根据SEQ ID No.2的氨基酸序列以根据SEQ ID No.1的序列中的氨基酸Q18起始且以氨基酸G732终止。在该片段的C端末端的氨基酸甘氨酸提供了高旋转自由度，这有利于两个蛋白质部分的融合并且增加了融合蛋白的稳定性。另外，使用包含或由以根据SEQ ID No.1的序列中的氨基酸Q18起始且以氨基酸G732终止的氨基酸序列标识的ACE2片段提供了相比较长的ACE2片段更好的产率。

在一个实施方案中，人ACE2的片段包含或由具有根据SEQ ID No.3的氨基酸序列的人ACE2的完整胞外域标识。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.14的氨基酸序列标识。根据SEQ ID No.14的氨基酸序列以根据SEQ ID No.1的序列中的氨基酸Q18起始且以氨基酸G605终止。

在一个实施方案中，人ACE2的片段在选自N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)的至少一个氨基酸残基处被N-糖基化。在一个实施方案中，人ACE2的片段在氨基酸残基N53、N90和N322(编号参考SEQ ID No.1)处被N-糖基化。在一个实施方案中，人ACE2的片段在氨基酸残基N53、N90、N103、N322、N432、N546和N690(编号参考SEQ IDNo.1)处被N-糖基化。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的氨基酸序列标识，并且在选自N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)的至少一个氨基酸残基处被N-糖基化。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的氨基酸序列标识，并且在氨基酸残基N53、N90和N322(编号参考SEQ ID No.1)处被N-糖基化。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的氨基酸序列标识，并且在氨基酸残基N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)处被N-糖基化。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的氨基酸序列标识，并且在选自N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)的至少一个氨基酸残基处被N-糖基化。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的氨基酸序列标识，并且在氨基酸残基N53、N90和N322(编号参考SEQ ID No.1)处被N-糖基化。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的氨基酸序列标识，并且在氨基酸残基N53、N90、N103、N322、N432、N546和N690(编号参考SEQ ID No.1)处被N-糖基化。

术语“N-糖基化的(N-glycosylated)”或“N-糖基化(N-glycosylation)”意指聚糖结构附接到蛋白质的天冬酰胺残基的酰胺氮。聚糖是分支柔性的碳水化合物链，并且附接到蛋白质的天冬酰胺残基的聚糖的精确结构取决于用于产生糖蛋白的表达系统。

人ACE2的片段的“变体”是指如上所定义的片段，其中与根据SEQ IDNo.1的野生型全长人ACE2的氨基酸序列中的相应序列相比，至少一个氨基酸残基是不同的，或者至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少十个、至少十一个或至少十三个氨基酸是不同的。人ACE2的片段的“变体”包含人ACE2的片段的序列中的一个或多个氨基酸取代。与衍生该变体的序列相比，人ACE2的片段的“变体”不包含任何氨基酸添加或缺失。在一个实施方案中，人ACE2的片段的变体是根据SEQ ID No.2或3的人ACE2的片段的变体，并且与根据SEQ ID No.2或3的序列相比不包含任何氨基酸添加或缺失，即，它具有与根据SEQ ID No.2或3的序列相同的长度。在本发明的范围之内，人ACE2的片段的变体能够结合至少一种冠状病毒的S蛋白，特别是SARS-CoV-2的S蛋白。人ACE2的片段的变体与至少一种冠状病毒的S蛋白(特别是SARS-CoV-2的S蛋白)的结合如上针对人ACE2的片段所描述进行测定。

在一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差一个氨基酸。在另一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差两个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差三个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差四个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差五个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差六个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQID No.1的序列中的相应氨基酸序列相差七个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差八个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差九个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差十个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差十一个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差十二个氨基酸。在又一个实施方案中，人ACE2的片段的变体与根据SEQ ID No.1的序列中的相应氨基酸序列相差十三个氨基酸。

人ACE2的片段的一种变体可以是酶促失活变体。“人ACE2的片段的酶促失活变体”缺乏将血管紧张素II切割成Ang1-7的能力。人ACE2的酶促活性可以通过技术人员已知的方法进行测定。用于测定人ACE2的酶促活性的合适试剂盒可例如从BioVision或Anaspec公司商购获得。通过使用酶促失活ACE2变体，消除与ACE2的酶促活性相关联的任何副作用，如对心血管系统或血压调节的作用。另外，抗衡RAS-MAS平衡的风险下降。

人ACE2的片段的酶促失活变体可以包含ACE2催化中心内的一个或多个氨基酸突变。特别地，人ACE2的片段的酶促失活变体包含根据SEQ IDNo.1的序列的残基374处的野生型组氨酸的突变和/或根据SEQ ID No.1的序列的残基378处的野生型组氨酸的突变。野生型组氨酸可以突变为不同于组氨酸的任何氨基酸，并且特别地，野生型组氨酸突变为天冬酰胺。优选地，人ACE2的片段的酶促失活变体包含H374N和H378N突变(编号参考根据SEQ IDNo.1的序列)。

在另一个实施方案中，人ACE2的片段的酶促失活变体包含以下氨基酸残基中的一者或多者处的突变(编号参考根据SEQ ID No.1的序列)：残基345(野生型中为组氨酸)、273(野生型中为精氨酸)、402(野生型中为谷氨酸)和505(野生型中为组氨酸)。在一个实施方案中，人ACE2的片段的酶促失活变体包含残基345处的组氨酸突变为丙氨酸或亮氨酸、残基273处的精氨酸突变为丙氨酸、谷氨酰胺或赖氨酸、残基402处的谷氨酸突变为丙氨酸，和/或残基505处的组氨酸突变为丙氨酸或亮氨酸(编号参考根据SEQ ID No.1的序列)。在特定实施方案中，人ACE2的片段的酶促失活变体包含残基273处的精氨酸突变为丙氨酸(也称为R273A突变)。发现精氨酸273对于底物结合至关重要，并且其取代消除酶促活性(Guy等人(2005)FEBS J.272(14):3512-3520)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至380、18至400、18至420、18至440、18至460、18至480或18至500组成，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至520、18至540、18至560、18至580或18至600组成，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。更优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至615、18至620、18至640、18至660、18至680或18至700组成，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。甚至更优选地，人ACE2的片段由根据SEQID No.1的序列的氨基酸18至710、18至720或18至730组成，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含H374N和H378N突变。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.91的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含H374N和H378N突变。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.92的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至380、18至400、18至420、18至440、18至460、18至480或18至500标识，并且包含H374N和H378N突变(编号参考根据SEQ IDNo.1的序列)。优选地，人ACE2的片段包含或由根据SEQ IDNo.1的序列的氨基酸18至520、18至540、18至560、18至580或18至600标识，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至615、18至620、18至640、18至660、18至680或18至700标识，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。甚至更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至710、18至720或18至730标识，并且包含H374N和H378N突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N和H378N突变。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N和H378N突变。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至380、18至400、18至420、18至440、18至460、18至480或18至500标识，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至520、18至540、18至560、18至580或18至600组成，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。更优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至615、18至620、18至640、18至660、18至680或18至700组成，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。甚至更优选地，人ACE2的片段由根据SEQ ID No.1的序列的氨基酸18至710、18至720或18至730组成，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变。在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.24的氨基酸序列的蛋白质组成。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.25的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至380、18至400、18至420、18至440、18至460、18至480或18至500标识，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至520、18至540、18至560、18至580或18至600标识，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。更优选地，人ACE2的片段包含或由根据SEQ ID No.1的序列的氨基酸18至615、18至620、18至640、18至660、18至680或18至700标识，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。甚至更优选地，人ACE2的片段包含或由根据SEQID No.1的序列的氨基酸18至710、18至720或18至730标识，并且包含R273A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变。在一个实施方案中，人ACE2的片段的变体包含或由根据SEQ ID No.24或25的序列标识。

人ACE2的片段的另一种变体可以是抑制ACE2脱落的变体。已显示ACE2通过切割ACE2胞外域而从人气道上皮脱落，并且ADAM17调节ACE2切割。另外，位于ACE2胞外域中的全长ACE2的亮氨酸584处的点突变消除了脱落(Jia等人(2009)Am.J.Physiol.LungCell.Mol.Physiol.297(1):L84-96)。因此，在一个实施方案中，人ACE2的片段的变体包含亮氨酸584处的突变(编号参考根据SEQ ID No.1的序列)。在一个实施方案中，亮氨酸584处的突变为L584A突变。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段的变体包含H374N突变、H378N突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含H374N突变、H378N突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含H374N突变、H378N突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段的变体包含R273A突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变和L584A突变(编号参考根据SEQ ID No.1的序列)。

人ACE2的片段的另一种变体可以是抑制蛋白酶TMPRSS2对ACE2的切割的变体。已显示TMPRSS2的ACE2蛋白水解增强SARS-CoV的进入(Heurich等人(2014)J.Virol.88(2):1293-1307)。TMPRSS2也在SARS-CoV-2进入细胞中发挥着作用(Hoffmann等人(2020)Cell181:1-10)。为了消除TMPRSS2对ACE2的切割，可以使切割所必需的氨基酸残基突变。已显示跨越ACE2的氨基酸697至716的氨基酸区域内的精氨酸和赖氨酸残基对于TMPRSS2的ACE2切割是必需的(Heurich等人(2014)J.Virol.88(2):1293-1307)。因此，在一个实施方案中，人ACE2的片段的变体包含选自氨基酸697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ IDNo.1)。优选地，人ACE2的片段的变体包含选自氨基酸697、702、705、708、710和716的至少两个或三个残基处的突变(编号参考SEQ ID No.1)。更优选地，人ACE2的片段的变体包含选自氨基酸697、702、705、708、710和716的至少四个或五个残基处的突变(编号参考SEQ ID No.1)。最优选地，人ACE2的片段的变体包含残基697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。这些残基中的任一者处的野生型氨基酸残基可以突变为任何其它氨基酸，并且特别地野生型氨基酸残基突变为丙氨酸。

在一个实施方案中，人ACE2的片段的变体包含以下突变中的至少一者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。优选地，人ACE2的片段的变体包含以下突变中的至少两者或三者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。更优选地，人ACE2的片段的变体包含以下突变中的至少四者或五者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。最优选地，人ACE2的片段的变体包含以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

人ACE2的片段的变体可以进一步包含残基619、621和/或625处的突变(编号参考SEQ ID No.1)。特别地，人ACE2的片段的变体可以进一步包含以下突变：K619A、R621A和/或K625A(编号参考SEQ ID No.1)。

因此，在一个实施方案中，人ACE2的片段的变体包含以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含选自氨基酸697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含残基697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含以下突变中的至少一者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含选自氨基酸697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含残基697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含以下突变中的至少一者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含H374N突变、H378N突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含H374N突变、H378N突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含选自氨基酸619、621、625、697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含残基619、621、625、697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含以下突变中的至少一者：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含选自氨基酸619、621、625、697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含残基619、621、625、697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含以下突变中的至少一者：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含H374N突变、H378N突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含H374N突变、H378N突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含选自氨基酸697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含残基697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含以下突变中的至少一者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含选自氨基酸697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含残基697、702、705、708、710和716处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含以下突变中的至少一者：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变、L584A突变和以下突变：R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含选自氨基酸619、621、625、697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含残基619、621、625、697、702、705、708、710和716处的突变(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含以下突变中的至少一者：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含选自氨基酸619、621、625、697、702、705、708、710和716的至少一个残基处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含残基619、621、625、697、702、705、708、710和716处的突变(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含以下突变中的至少一者：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变、L584A突变和以下突变：K619A、R621A、K625A、R697A、K702A、R705A、R708A、R710A和R716A(编号参考根据SEQ ID No.1的序列)。

人ACE2的片段的另一种变体可以是为了在两个ACE2分子之间形成二硫桥而提供额外半胱氨酸的变体。二硫桥增加融合蛋白的内在稳定性，并且也可以对融合蛋白与其靶标的结合具有作用。可以通过用半胱氨酸取代SEQ ID NO.1的编号中的丝氨酸645来提供额外的半胱氨酸。

因此，在一个实施方案中，人ACE2的片段的变体包含S645C突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含S645C突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.28的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含S645C突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.29的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含H374N突变、H378N突变和S645C突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.32的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含H374N突变、H378N突变和S645C突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.33的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含H374N突变、H378N突变、L584A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含H374N突变、H378N突变、L584A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变和S645C突变(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.36的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变和S645C突变(编号参考SEQ IDNo.1)。在一个实施方案中，人ACE2的片段的变体由具有根据SEQ ID No.37的氨基酸序列的蛋白质组成。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变和S645C突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变和S645C突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变、L584A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变、L584A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A和S645C突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变、L584A突变和S645C突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变、L584A突变和S645C突变(编号参考SEQ IDNo.1)。

人ACE2的片段的另一种变体可以是抑制二聚化的变体。因此，在一个实施方案中，人ACE2的片段的变体包含氨基酸Q139处的突变(编号参考SEQ ID No.1)。在一个实施方案中，人ACE2的片段的变体包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含H374N突变、H378N突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含H374N突变、H378N突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.2的序列组成，并且包含H374N突变、H378N突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.3的序列组成，并且包含H374N突变、H378N突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变和Q139A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变和Q139A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.3的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.14的序列组成，并且包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由根据SEQ ID No.14的序列组成，并且包含H374N突变、H378N突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段由具有根据SEQ ID No.14的氨基酸序列的蛋白质组成，并且包含R273A突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变和Q139A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变和Q139A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含H374N突变、H378N突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含H374N突变、H378N突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.2的序列标识，并且包含R273A突变、L584A突变和Q139A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.3的序列标识，并且包含R273A突变、L584A突变和Q139A突变(编号参考SEQ IDNo.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.14的序列标识，并且包含Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.14的序列标识，并且包含H374N突变、H378N突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.14的序列标识，并且包含H374N突变、H378N突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.14的序列标识，并且包含R273A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，人ACE2的片段包含或由根据SEQ ID No.14的序列标识，并且包含R273A突变、L584A突变和Q139A突变(编号参考SEQ ID No.1)。

在一个实施方案中，本发明的融合蛋白的第二部分包含人IgG的Fc部分。人IgG的Fc部分可以是IgG1、IgG2、IgG3或IgG4的Fc部分。

在一个实施方案中，本发明的融合蛋白的第二部分包含人IgG4的Fc部分。人IgG4的Fc部分包含连接在一起形成Fc部分的人IgG4的CH2和CH3域。在全长人IgG4抗体中，Fc部分通过铰链区与Fab片段连接。Fab片段包含重链可变区和CH1域。优选地，本发明的融合蛋白中使用的人IgG4的Fc部分具有根据SEQ ID No.5的序列。

由于抗体的IgG4亚类仅对Fcγ受体具有部分亲和力并且不活化补体(参见Muhammed(2020)Immunome Res.16(1):173)，它不以与抗体的IgG1亚类相同的程度活化免疫系统。因此，细胞因子表达被刺激至较低的程度，并且细胞因子风暴的风险下降。抗体的IgG4亚类能够结合FcRn。

“人IgG4的Fc部分的变体”是指与根据SEQ ID No.5的人IgG4的野生型Fc部分相比具有一个或多个氨基酸取代的人IgG4的Fc部分。在一个实施方案中，与根据SEQ ID No.5的人IgG4的野生型Fc部分相比，人IgG4的Fc部分的变体具有一至十二个、一至十一个、一至十个、一至九个、一至八个、一至七个、一至六个、一至五个、一至四个、一至三个、一或两个氨基酸取代。在一个实施方案中，与根据SEQ ID No.5的人IgG4的野生型Fc部分相比，人IgG4的Fc部分的变体具有一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个或十二个氨基酸取代。在一个实施方案中，一个或多个氨基酸取代导致与根据SEQ ID No.5的人IgG4的野生型Fc部分相比降低的效应子功能。在一个实施方案中，一个或多个氨基酸取代导致与根据SEQ ID No.5的人IgG4的野生型Fc部分相比增加的半衰期。在一个实施方案中，一个或多个氨基酸取代导致与根据SEQ ID No.5的人IgG4的野生型Fc部分相比降低的效应子功能以及与根据SEQ ID No.5的人IgG4的野生型Fc部分相比增加的半衰期。

在一个实施方案中，一个或多个氨基酸取代不产生根据SEQ ID No.16的IgG1的野生型Fc部分。在一个实施方案中，一个或多个氨基酸取代不向改变的IgG4 Fc部分赋予野生型IgG1的效应子功能。

优选地，降低的效应子功能包括降低的补体依赖性细胞毒性(CDC)。更优选地，与根据SEQ ID No.5的人IgG4的野生型Fc部分的CDC相比，CDC降低至少两倍、至少三倍、至少四倍或至少五倍。用于测定和定量CDC的方法是技术人员公知的。一般来讲，CDC可以通过使与抗原结合部分融合的Fc部分与合适的靶细胞和补体一起温育并检测靶细胞的细胞死亡进行测定。补体募集可以使用ELISA板用C1q结合测定进行分析(参见例如Schlothauer等人(2016)Protein Eng.Des.Sel.29(10):457-466)。

在一个实施方案中，人IgG4的Fc部分的变体包含选自根据SEQ ID No.5的序列的F3、L4、G6、P7、F12、V33、N66和P98的氨基酸残基处的至少一个氨基酸取代。这些氨基酸残基对应于全长人IgG4的氨基酸残基F234、L235、G237、P238、F243、V264、N297和P329。已显示这些残基处的氨基酸取代导致降低的效应子功能(WO 94/28027；WO 94/29351；WO 95/26403；WO 2011/066501；WO 2011/149999；WO 2012/130831；Wang等人(2018)Protein Cell.9(1):63-73)。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代L4E/A，其对应于全长人IgG4的氨基酸序列中的氨基酸取代L235E/A。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代F3A和L4A，其对应于全长人IgG4的氨基酸序列中的氨基酸取代F234A和L235A。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代F3A、L4E、G6A和P7S，其对应于全长人IgG4的氨基酸序列中的氨基酸取代F234A、L235E、G237A和P238S。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代F12A和V33A，其对应于全长人IgG4的氨基酸序列中的氨基酸取代F243A和V264A。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代L4E和P98G，其对应于全长人IgG4的氨基酸序列中的氨基酸取代L235E和P329G。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代N66A/Q/G，其对应于全长人IgG4的氨基酸序列中的氨基酸取代N297A/Q/G。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG4的Fc部分的变体包含选自全长人IgG4的T250、M252、S254、T256、E258、K288、T307、V308、Q311、V427、M428、H433、N434和H435的氨基酸残基处的至少一个氨基酸取代。这些氨基酸残基对应于根据SEQ ID No.5的序列的氨基酸残基T19、M21、S23、T25、E27、K57、T76、V77、Q80、V196、M197、H202、N203和H204。已显示这些氨基酸取代导致含Fc蛋白的半衰期增加(WO 00/42072；WO 02/060919；WO 2004/035752；WO 2006/053301；WO 2009/058492；WO 2009/086320；US2010/0204454；GB 2013/02878；WO 2013/163630；US2019/0010243)。抗体或Fc融合蛋白的半衰期可以通过在施用抗体或Fc融合蛋白后的不同时间点测量血清中的抗体或Fc融合蛋白浓度并由此计算半衰期进行测定。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代M21Y、S23T和T25E，其对应于全长人IgG4的氨基酸序列中的氨基酸取代M252Y、S254T和T256E。在一个实施方案中，人IgG4的Fc部分的变体具有根据SEQ ID No.44的氨基酸序列。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代T25D和T76Q，其对应于全长人IgG4的氨基酸序列中的氨基酸取代T256D和T307Q。在一个实施方案中，人IgG4的Fc部分的变体具有根据SEQ ID No.60的氨基酸序列。该变体具有增加的半衰期以及增强的与FcRn的结合(Mackness等人(2019)MABS11(7):1276-1288)。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代T19Q/E和M197L/F，其对应于全长人IgG4的氨基酸序列中的氨基酸取代T250Q/E和M428L/F。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代N203S和V77W/Y/F，其对应于全长人IgG4的氨基酸序列中的氨基酸取代N434S和V308W/Y/F。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代M21Y和M197L，其对应于全长人IgG4的氨基酸序列中的氨基酸取代M252Y和M428L。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代T76Q和N203S，其对应于全长人IgG4的氨基酸序列中的氨基酸取代T307Q和N434S。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代M197L和V77F，其对应于全长人IgG4的氨基酸序列中的氨基酸取代M428L和V308F。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代Q80V和N203S，其对应于全长人IgG4的氨基酸序列中的氨基酸取代Q311V和N434S。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代H202K和N203F，其对应于全长人IgG4的氨基酸序列中的氨基酸取代H433K和N434F。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代E27F和V196T，其对应于全长人IgG4的氨基酸序列中的氨基酸取代E258F和V427T。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代K57E和H204K，其对应于全长人IgG4的氨基酸序列中的氨基酸取代K288E和H435K。该变体具有增加的半衰期。

在一个实施方案中，人IgG4的Fc部分的变体包含根据SEQ ID No.5的序列中的氨基酸取代R178K，其对应于全长人IgG4的氨基酸序列中的氨基酸取代R409K。该变体防止酸诱导的人IgG4聚集(参见Namisaki等人(2020)PloS ONE 15(3):e0229027)。

在一个实施方案中，人IgG4的Fc部分的变体不包含根据SEQ ID No.5的序列中的位置37、43、65、96、99、100、124、125、127、187和214中的一者或多者处的氨基酸取代。在一个实施方案中，人IgG4的Fc部分的变体不包含氨基酸取代Q37H、Q43K、F65Y、G96A、S99A、S100P、Q124R、E125D、M127L、R178K、E187Q和L214P中的一者或多者。在一个实施方案中，人IgG4的Fc部分的变体不包含根据SEQ ID No.5的序列中的位置37、43、65、96、99、100、124、125、127、187和214中任一者处的任何氨基酸取代。在一个实施方案中，人IgG4的Fc部分的变体不包含氨基酸取代Q37H、Q43K、F65Y、G96A、S99A、S100P、Q124R、E125D、M127L、R178K、E187Q和L214P中的任一者。

在一个实施方案中，本发明的融合蛋白的第二部分包含人IgG1的Fc部分或其变体。人IgG1的Fc部分包含连接在一起形成Fc部分的人IgG1的CH2和CH3域。在全长人IgG1抗体中，Fc部分通过铰链区与Fab片段连接。Fab片段包含重链可变区和CH1域。优选地，本发明的融合蛋白中使用的人IgG1的Fc部分具有根据SEQ ID No.16的序列。

“人IgG1的Fc部分的变体”是指与根据SEQ ID No.16的人IgG1的野生型Fc部分相比具有一个或多个氨基酸取代的人IgG1的Fc部分。在一个实施方案中，一个或多个氨基酸取代导致与根据SEQ ID No.16的人IgG1的野生型Fc部分相比降低的效应子功能。

优选地，降低的效应子功能包括降低的补体依赖性细胞毒性(CDC)。更优选地，与根据SEQ ID No.16的人IgG1的野生型Fc部分的CDC相比，CDC降低至少两倍、至少三倍、至少四倍或至少五倍。用于测定和定量CDC的方法是技术人员公知的并且已经在以上有所描述。

在一个实施方案中，人IgG1的Fc部分的变体包含选自根据SEQ ID No.16的序列的L3、L4和P98的氨基酸残基处的至少一个氨基酸取代。这些氨基酸残基对应于全长人IgG1的氨基酸残基L234、L235和P329。

在一个实施方案中，人IgG1的Fc部分的变体包含根据SEQ ID No.16的序列中的氨基酸取代L4E/A，其对应于全长人IgG1的氨基酸序列中的氨基酸取代L235E/A。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG1的Fc部分的变体包含根据SEQ ID No.16的序列中的氨基酸取代L3A和L4A，其对应于全长人IgG1的氨基酸序列中的氨基酸取代L234A和L235A。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG1的Fc部分的变体包含根据SEQ ID No.16的序列中的氨基酸取代L3A、L4A、P98G，其对应于全长人IgG1的氨基酸序列中的氨基酸取代L234A、L235A和P329G。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG1的Fc部分的变体包含根据SEQ ID No.16的序列中的氨基酸取代L4A和P98G，其对应于全长人IgG1的氨基酸序列中的氨基酸取代L235A和P329G。该变体具有降低的效应子功能，特别是降低的CDC。

在一个实施方案中，人IgG1的Fc部分的变体包含根据SEQ ID No.16的序列中的氨基酸取代M21Y、S23T和T25E，其对应于全长人IgG1的氨基酸序列中的氨基酸取代M252Y、S254T和T256E。在一个实施方案中，人IgG1的Fc部分的变体具有根据SEQ ID No.19的氨基酸序列。该变体具有增加的半衰期以及增强的与FcRn的结合。

在一个实施方案中，人IgG1的Fc部分的变体包含根据SEQ ID No.16的序列中的氨基酸取代T25D和T76Q，其对应于全长人IgG1的氨基酸序列中的氨基酸取代T256D和T307Q。在一个实施方案中，人IgG1的Fc部分的变体具有根据SEQ ID No.59的氨基酸序列。该变体具有增加的半衰期以及增强的与FcRn的结合(Mackness等人(2019)MABS11(7):1276-1288)。

在一个实施方案中，本发明的融合蛋白的第二部分包含人IgG2或IgG3的Fc部分或者人IgG1、IgG2或IgG3的Fc部分的变体，并且与包含相同的第一部分以及含有野生型人IgG1的Fc部分的第二部分的融合蛋白相比具有降低的与FcγRIIIa的结合。与包含相同的第一部分以及含有根据SEQ ID No.16的野生型人IgG1的Fc部分的第二部分的融合蛋白的结合相比，与FcγRIIIa的结合降低了至少两倍、至少三倍、至少四倍、至少五倍或至少10倍。

在一个实施方案中，本发明的融合蛋白的第二部分包含人IgG2或IgG3的Fc部分或者人IgG1、IgG2或IgG3的Fc部分的变体，并且与包含相同的第一部分以及含有野生型人IgG1的Fc部分的第二部分的融合蛋白相比与具有降低的FcγRIIIa的结合和基本上相同的与FcRn的结合。术语“基本上相同的与FcRn的结合”意味着包含人IgG2或IgG3的Fc部分或者人IgG1、IgG2或IgG3的Fc部分的变体的融合蛋白与FcRn的结合相对于包含相同的第一部分以及含有根据SEQ ID No.16的野生型人IgG1的Fc部分的第二部分的融合蛋白的结合相差不超过20％或不超过15％，优选地不超过10％或不超过5％，更优选地不超过3％或不超过2％，并且最优选地不超过1％。

融合蛋白与FcγRIIIa或FcRn的结合可以通过如本文的实施例中所述的表面等离子体共振进行测定。

在一个实施方案中，本发明的融合蛋白的第一和第二部分通过连接序列连接。连接序列是短氨基酸序列，其自身不具有功能并且不影响融合蛋白的折叠。在一个实施方案中，连接序列包含八至二十个氨基酸，优选地10至18个氨基酸，更优选地11至17个氨基酸或12至16个氨基酸，并且最优选地13个氨基酸。

在一个实施方案中，连接序列由选自甘氨酸和丝氨酸的小氨基酸组成。连接序列的综述提供于Chen等人(2013)Adv.Drug Deliv.Rev.65(10):1357-1369中。

在一个实施方案中，如果融合蛋白的第二部分是人IgG4的Fc部分或其变体，则连接序列由人IgG4的铰链区组成。在一个实施方案中，连接序列由根据SEQ ID No.4的序列组成。在根据SEQ ID No.4的序列中，IgG4的野生型铰链区的残基10处的丝氨酸(对应于全长IgG4的丝氨酸228)被脯氨酸替换，导致IgG半分子的交换减少。已知IgG4抗体可以经历Fab臂交换，导致两个不同的Fab臂的组合并产生新的双特异性抗体分子(参见例如Aalberse等人(2009)Clin.Exp.Allergy 39(4):469-477)。这种Fab臂交换可以通过使Fc区的丝氨酸228突变为脯氨酸(S228P；参见Silva等人(2015)J.Biol.Chem.290:5462-5469)来防止，该突变位于IgG4的铰链区中。另外，短接头序列的使用增加融合蛋白的稳定性并且降低融合蛋白对蛋白酶的可接近性。

在一个实施方案中，如果融合蛋白的第二部分是人IgG1的Fc部分或其变体，则连接序列由人IgG1的铰链区组成。在一个实施方案中，连接序列由根据SEQ ID No.15的序列组成。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.20的氨基酸序列，其包含人ACE2的氨基酸18至732(SEQ ID No.2)、根据SEQ IDNo.15的连接序列以及根据SEQID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.21的氨基酸序列，其包含人ACE2的氨基酸18至740(SEQ ID No.3)、根据SEQ IDNo.15的连接序列以及根据SEQID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.22的氨基酸序列，其包含具有H374N和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ IDNo.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.23的氨基酸序列，其包含具有H374N和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ IDNo.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.26的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.27的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.30的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.31的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.34的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.35的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.38的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.39的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.19的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.40的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.41的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.42的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.43的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.45的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.46的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.47的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.48的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.49的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.50的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.51的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.52的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.53的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.54的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.55的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.56的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.57的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.58的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.61的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.62的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.63的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.64的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.65的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.66的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.67的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.68的氨基酸序列，其包含具有S645C突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.69的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.70的氨基酸序列，其包含具有S645C突变、H374N突变和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.71的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.72的氨基酸序列，其包含具有S645C突变和R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.73的氨基酸序列，其包含人ACE2的氨基酸18至732(SEQ ID No.2)、根据SEQ IDNo.15的连接序列以及根据SEQID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.74的氨基酸序列，其包含人ACE2的氨基酸18至740(SEQ ID No.3)、根据SEQ IDNo.15的连接序列以及根据SEQID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.75的氨基酸序列，其包含人ACE2的氨基酸18至732(SEQ ID No.2)、根据SEQ IDNo.4的连接序列以及根据SEQ IDNo.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.76的氨基酸序列，其包含人ACE2的氨基酸18至740(SEQ ID No.3)、根据SEQ IDNo.4的连接序列以及根据SEQ IDNo.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.77的氨基酸序列，其包含具有H374N和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ IDNo.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.78的氨基酸序列，其包含具有H374N和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ IDNo.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.79的氨基酸序列，其包含具有H374N和H378N突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ IDNo.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.80的氨基酸序列，其包含具有H374N和H378N突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ IDNo.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.81的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.82的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.59的人IgG1的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.83的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.84的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.60的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.85的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.86的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.15的连接序列以及根据SEQ ID No.16的人IgG1的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.87的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.88的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.5的人IgG4的Fc部分。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.89的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.90的氨基酸序列，其包含具有R273A突变的人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ IDNo.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.93的氨基酸序列，其包含人ACE2的氨基酸18至732(SEQ ID No.2)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.44的人IgG4的Fc部分的变体。

在特定实施方案中，本发明的融合蛋白具有根据SEQ ID No.94的氨基酸序列，其包含人ACE2的氨基酸18至740(SEQ ID No.3)(编号参考SEQ ID No.1)、根据SEQ ID No.4的连接序列以及根据SEQ ID No.44的人IgG4的Fc部分的变体。

本发明还涉及包含编码本发明的融合蛋白的核酸序列的核酸分子。当已知蛋白质的氨基酸序列时，技术人员知道如何构建核酸分子。特别地，核酸分子的构建涉及使用三字母遗传密码将蛋白质的氨基酸序列回译为核酸序列，并任选地考虑使用该核酸分子表达蛋白质的宿主细胞的密码子使用。

在一个实施方案中，包含编码本发明的融合蛋白的核酸序列的核酸分子是分离的核酸分子。术语“分离的核酸分子”是指从至少一种污染物核酸分子中鉴定并分离出的核酸分子，该核酸分子通常在产生其的环境中与污染物核酸分子缔合。优选地，分离的核酸不与产生环境相关联的所有组分缔合。

如本文所用，术语“载体”是指能够增殖与之相连接的另一种核酸的核酸分子。该术语包括作为自我复制核酸结构的载体，以及掺入其所引入的宿主细胞的基因组中的载体。某些载体能够指导与它们可操作地连接的核酸的表达。此类载体在本文中称为“表达载体”。

表达载体含有用于表达核酸的元件，如合适的启动子和聚腺苷酸化信号。此外，表达载体典型地含有处于合适的启动子控制之下的选择标志物基因，以能够区分含有表达载体的细胞与不含表达载体的细胞。构建适用于表达重组蛋白(如本发明的融合蛋白)的表达载体所需的元件和方法是技术人员公知的，并且描述于例如Makrides等人(1999)ProteinExpr.Purif.17:183-202和Kaufman(2000)Mol.Biotechnol.16:151-161中。

使用表达载体以转化(即遗传修饰)合适的宿主细胞。

技术人员知道用于将表达载体引入到哺乳动物细胞中的方法。这些方法包括使用市售的转染试剂盒，如ThermoFisher的Polyplus Sciences的PEImax、293-Free转染试剂(Millipore)或Invitrogen的Freestyle Max。另外合适的方法包括电穿孔、磷酸钙介导的转染和DEAE葡聚糖转染。在转染后，通过用基于由一种或多种表达载体编码的一种或多种选择标志物的合适试剂进行处理而使细胞经受选择，以鉴定出含有重组核酸分子的稳定转染的细胞。

术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换地使用，并且是指其中已引入外源性核酸或表达载体的细胞，包括此类细胞的后代。宿主细胞包括“转化体”和“转化细胞”，其包括原代转化细胞及由其衍生的后代，而不考虑传代的次数。

本发明的融合蛋白优选地在哺乳动物宿主细胞中产生。用于表达本发明的融合蛋白的合适的哺乳动物宿主细胞包括中国仓鼠卵巢(Chinese Hamster Ovary，CHO)细胞(包括与DHFR选择性标志物一起使用的dhfr阴性CHO细胞)、NS0骨髓瘤细胞、COS细胞、SP2细胞、猴肾CV1、人胚胎肾系293、幼仓鼠肾细胞(BHK)、小鼠塞尔托利氏细胞(TM4)、非洲绿猴肾细胞(VERO-76)、人宫颈癌细胞(HELA)、犬肾细胞(MDC)、水牛鼠肝细胞(buffalo rat livercells)(BRL 3A)、人肺细胞(W138)、人肝细胞(Hep G2)、小鼠乳腺肿瘤细胞(MMT 060562)、TRI细胞、MRC 5细胞和FS4细胞。更优选地，宿主细胞衍生自啮齿动物。最优选地，哺乳动物细胞是中国仓鼠卵巢(CHO)细胞。

为了产生本发明的融合蛋白，使宿主细胞在合适的培养基中培养。

术语“培养基(medium)”、“细胞培养基”和“培养基(culture medium)”在本文中可互换使用，并且是指含有使哺乳动物细胞生长所需的营养物的溶液。典型地，细胞培养基提供细胞最低限度生长和/或存活所需的必需和非必需氨基酸、维生素、能量源、脂质和微量元素。细胞培养基还可以包含生长因子。优选地，培养基是化学定义的，因为所有其组分以及它们的浓度是已知的。还优选地，培养基是无血清和无水解产物的，并且不含有任何衍生自动物的组分。在更优选的实施方案中，培养基是无血清和无水解产物的，并且不含有任何衍生自动物的组分或胰岛素。

在一个实施方案中，用于本发明的方法中的培养基是市售培养基，如FreeStyle293表达培养基(Life Technologies)、PolCHO P Powder Base CD、ActiPro(均可得自GE)、PowerCHO-2、ProCHO-5(均可得自Lonza)或EX-Advanced CHO补料分批培养基(可得自Sigma)。

对于培养哺乳动物细胞，不同的策略是可用的，包括分批培养、灌流培养、连续培养和补料分批培养。优选地，使用补料分批培养过程。在补料分批培养中，培养过程以特定体积的基础培养基开始，并且在培养过程的一个或多个稍后时间点补料包含一种或多种营养物的一种或多种补料培养基以防止营养物耗尽，同时不从细胞培养肉汤中除去产物。因此，术语“补料”意指将至少一种组分添加到现有的细胞培养物中。

术语“基础培养基”旨在是指从细胞培养过程开始起使用的培养基。将哺乳动物细胞接种到基础培养基中，并在该培养基中生长特定时段，直到开始补料。基础培养基符合如上所提供的培养基的定义。如果使用市售的培养基，则可以向基础培养基中添加额外的组分。

在细胞已在基础培养基中培养特定时段后，向细胞培养物中添加补料培养基。补料培养基用于防止营养物耗尽，因此可以不具有与基础培养基相同的组成。特别地，一种或多种营养物的浓度在补料培养基中可能比在基础培养基中高。在一个实施方案中，补料培养基具有与基础培养基相同的组成。在另一个实施方案中，补料培养基具有与基础培养基不同的组成。补料培养基可以在限定的时间点连续地或以团注添加。

合适的补料培养基是技术人员已知的，并且包括PolCHO Feed-APowder Base CD、PolCHO Feed-B Powder Base CD、Cell Boost 7a和Cell Boost 7b(均可得自GE)、CHO Feed 3Medium(可得自Irvine Scientific)以及EX-/>AdvancedCHO feed 1(可得自Sigma)。

宿主细胞的培养可以在恒定温度下(例如，在37℃±0.2℃的温度下)执行。替代地，培养温度可以从第一温度降低至第二温度，即，主动下调温度。因此，第二温度低于第一温度。第一温度可以为37℃±0.2℃。第二温度可以在30℃至36℃的范围内。

通过在合适的培养基中培养宿主细胞来产生本发明的融合蛋白之后，从细胞培养物中收获融合蛋白。因为由哺乳动物细胞表达的Fc融合蛋白典型地在培育过程期间分泌到细胞培养液中，培育过程结束时的产物收获通过从细胞中分离出包含融合蛋白的细胞培养液而发生。细胞分离方法应当是温和的，以使细胞破碎最小化，从而避免细胞碎片的增加以及可能影响融合蛋白产物质量的蛋白酶及其它分子的释放。通常，包含融合蛋白的细胞培养液的收获涉及离心和/或过滤，由此融合蛋白分别存在于上清液和滤液中。扩张床吸附层析是避免离心/过滤方法的替代方法。

在收获包含融合蛋白的细胞培养液之后，必须将融合蛋白从细胞培养液中纯化出来。Fc融合蛋白的纯化通常通过一系列标准技术实现，这些技术可以包括层析步骤如阴离子交换层析、阳离子交换层析、亲和层析，特别是蛋白A亲和层析、疏水作用层析、羟磷灰石层析以及尺寸排阻层析。另外，纯化过程可以包括一个或多个超滤、纳滤或渗滤以及切向流过滤和/或错流过滤步骤。

在纯化融合蛋白之后，其可以用于制备药物组合物。药物组合物是旨在向患者递送以用于治疗或预防疾病或病况的组合物。除了活性剂(即本发明的融合蛋白)之外，药物组合物典型地含有至少一种药学上可接受的赋形剂。药学上可接受的赋形剂是不干扰融合蛋白的生理活性并且稳定化药物组合物并且/或者增强药物组合物的溶解度或者降低药物组合物的粘度的物质。用于重组蛋白的典型的药学上可接受的赋形剂包括缓冲剂、盐、糖或糖醇、氨基酸以及表面活性剂。

药物组合物包含治疗有效量的本发明的融合蛋白。术语“治疗有效量”是指足以治疗指定病症、病况或疾病(如改善、缓和、减轻和/或延缓其一种或多种症状)的本发明的融合蛋白的量。关于冠状病毒特别是SARS-CoV-2的感染，治疗有效量的本发明的融合蛋白改善、缓和、减轻和/或延缓选自咳嗽、呼吸短促、呼吸困难、发热、寒战、疲倦、肌肉酸痛、咽喉痛、头痛、胸痛以及嗅觉和/或味觉丧失的一种或多种症状。治疗有效量可以以一次或多次施用进行施用。

本发明的融合蛋白用于医学用途，即，其旨在用于预防和/或治疗疾病。

如本文所用，“治疗(treatment)”或“治疗(treating)”是用于获得有益的或者期望的结果(包括临床结果)的方法。出于本发明的目的，有益或期望的临床结果包括但不限于以下项中的一种或多种：缓解由疾病引起的一种或多种症状、减小疾病的程度、稳定化疾病(例如，预防或延缓疾病的恶化)、预防或延缓疾病的传播、预防或延缓疾病的复发、延缓或减缓疾病的进展、改善疾病状态、提供疾病的缓解(部分或全部)、减小治疗疾病所需的一种或多种其它药物的剂量、和/或延长生存。本发明的用途设想这些治疗方面中的任何一种或多种。

术语“预防(prevent)”和类似词语如“预防(prevented)”、“预防(preventing)”等指示用于预防、抑制疾病或病况，或者降低疾病或病况复发的可能性的方法。它还指延缓疾病或病况的复发，或者延缓疾病或病况的症状的复发。如本文所用，“预防”和类似术语还包括在疾病或病况复发之前降低疾病或病况的强度、效应、症状和/或负担。

在一个实施方案中，本发明的融合蛋白用于预防和/或治疗结合ACE2的冠状病毒的感染。冠状病毒是具有正义单链RNA基因组和二十面体蛋白质外壳的包膜病毒。由S1和S2亚基组成的刺突蛋白形成同源三聚体，其从包膜突出并通过结合ACE2来介导与靶细胞的相互作用。冠状病毒通常在人和其它哺乳动物以及鸟类中引起呼吸道疾病。在人中，已知七种冠状病毒株：HCoV-OC43、HCoV-HKU1、HCoV-229E、HCoV-NL63、MERS-CoV、SARS-CoV和SARS-CoV-2。前四种冠状病毒株(HCoV-OC43、HCoV-HKU1、HCoV-229E、HCoV-NL63)仅引起轻度症状，而MERS-CoV、SARS-CoV和SARS-CoV-2的感染可能导致严重的潜在危及生命的疾病。

已显示SARS-CoV、SARS-CoV-2和HCoV-NL63结合ACE2并利用这种结合进入靶细胞(Li等人(2003)Nature 426(6965):450-4；Hoffmann等人(2020)Cell 181:1-10；Hofmann等人(2005)Proc Natl Acad Sci U S A.102(22):7988-93)。因此，本发明的融合蛋白可以用于治疗和/或预防结合ACE2的冠状病毒的感染，特别是SARS-CoV、SARS-CoV-2或HCoV-NL63的感染。通过用表达冠状病毒刺突蛋白和报告蛋白的假型VSV(水泡性口炎病毒)瞬时或组成性接种表达ACE2的细胞，并在接种期后检测报告蛋白的活性，可以鉴定出结合ACE2的另外冠状病毒(参见Hoffmann等人(2020)Cell181:1-10中的方法)。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒不是SARS-CoV。

在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是SARS-CoV-2或者包含氨基酸取代D614G和/或氨基酸取代N439K的SARS-CoV-2的变体。包含氨基酸取代D614G的SARS-CoV-2的变体描述于Korber等人(2020)Cell 182(4):812-827，并且氨基酸取代N439K描述于Thomson等人(2021)Cell184(5):1171,1187.e20；可得自https://doi.org/10.1101/2020.11.04.355842。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G的SARS-CoV-2的变体。氨基酸取代D614G是由参考毒株NC_045512中位置23,403处的A至G的核苷酸突变引起的。变体中氨基酸的编号是指根据SEQ ID No.18的SARS-CoV-2的刺突蛋白中的编号。因此，具有根据SEQ ID No.18的刺突蛋白的SARS-CoV-2病毒被定义为衍生出任何变体的野生型SARS-CoV-2。

在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G和至少一个额外的氨基酸取代的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、N501Y、A570D、P681H、T716I、S982A和D1118H且包含氨基酸69、70和145缺失的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、Y453F、I692V和M1229I且包含氨基酸69和70缺失的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、S13I、W152C和L452R的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、E484K和V1176F的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、L18F、T20N、P26S、D138Y、R190S、K417T、E484K、N501Y、H655Y、T1027I和V1176F的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、D80A、D215G、K417N、E484K、N501Y和A701V且包含氨基酸242、243和244缺失的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、L18F、D80A、D215G、K417N、E484K、N501Y和A701V且包含氨基酸242、243和244缺失的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代D614G、D80A、R246I、K417N、E484K、N501Y和A701V且包含氨基酸242、243和244缺失的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代E484Q和L452R的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代E484K和D614G且包含氨基酸145和146缺失的SARS-CoV-2的变体。

变体中氨基酸的编号是指根据SEQ ID No.18的SARS-CoV-2的刺突蛋白中的编号。出于定义变体的目的，根据SEQ ID NO.18的氨基酸序列被视为SARS-CoV-2的刺突蛋白的野生型序列。

在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含SARS-CoV-2的刺突蛋白的受体结合域中的一个或多个氨基酸取代的SARS-CoV-2的变体。SARS-CoV-2的刺突蛋白的受体结合域包含SEQ IDNo.18的氨基酸331至524(参见Tai等人(2020)Cell.Mol.Immunol.17:613-620)。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代N501Y的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代E484K的SARS-CoV-2的变体。在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是包含氨基酸取代K417T/N的SARS-CoV-2的变体。

在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是与包含根据SEQ ID No.18的野生型刺突蛋白的SARS-CoV-2相比对ACE2具有更高的结合亲和力的SARS-CoV-2的变体。SARS-CoV-2的变体对ACE2的亲和力可以例如使用假病毒测定进行测定。假病毒测定使用慢病毒，该慢病毒经野生型SARS-CoV-2或其变体的S蛋白假型化，并且其含有报告基因，如萤光素酶基因。此类慢病毒可以获得自例如BPS Bioscience。将假型慢病毒与ACE2表达细胞一起温育，以允许病毒进入细胞并表达报告基因。如果从经变体SARS-CoV-2的S蛋白假型化的慢病毒的报告基因的表达高于从经野生型SARS-CoV-2的S蛋白假型化的慢病毒的报告基因的表达，则该变体对ACE2具有更高的结合亲和力。在本发明的上下文中，已发现本发明的融合蛋白对于对ACE2具有较高结合亲和力的那些变体(如变体B.1.1.7)具有较高的亲和力。

在一个实施方案中，本发明的融合蛋白用于治疗和/或预防结合ACE2的冠状病毒的感染，其中结合ACE2的冠状病毒是与包含根据SEQ ID No.18的野生型刺突蛋白的SARS-CoV-2相比具有更高的传播能力的SARS-CoV-2的变体。病毒传播能力可以使用基本传染数R₀进行确定，该基本传染数R₀为从一名传染性人员染病的平均人数。

施用途径根据已知和接受的方法，例如通过皮下、静脉内、腹膜内、肌内、动脉内、病灶内或关节内途径注射或输注。在另一个实施方案中，本发明的融合蛋白经鼻内施用，例如，借助于鼻喷雾剂、鼻软膏剂或滴鼻剂。在另一个实施方案中，本发明的融合蛋白通过局部施用或吸入施用。优选地，本发明的融合蛋白通过静脉内注射或输注施用。

本发明的药物组合物的剂量和期望药物浓度可以取决于所设想的具体用途而变化。适当的剂量或施用途径的确定完全在普通技术人员的技能范围内。动物实验为确定人疗法的有效剂量提供了可靠的指导。有效剂量的种间类推可以按照Mordenti,J.和Chappell,W.“The Use ofInterspecies Scaling in Toxicokinetics,”InToxicokinetics and New Drug Development,Yacobi等人编辑,Pergamon Press,NewYork 1989,第42-46页制定的原则来执行。

在一个实施方案中，本发明的融合蛋白以0.1mg/kg体重至4mg/kg体重的剂量，如0.1mg/kg体重、0.2mg/kg体重、0.3mg/kg体重、0.4mg/kg体重、0.5mg/kg体重、0.6mg/kg体重、0.7mg/kg体重、0.8mg/kg体重、0.9mg/kg体重、1.0mg/kg体重、1.1mg/kg体重、1.2mg/kg体重、1.3mg/kg体重、1.4mg/kg体重、1.5mg/kg体重、1.6mg/kg体重、1.7mg/kg体重、1.8mg/kg体重、1.9mg/kg体重、2.0mg/kg体重、2.1mg/kg体重、2.2mg/kg体重、2.3mg/kg体重、2.4mg/kg体重、2.5mg/kg体重、2.6mg/kg体重、2.7mg/kg体重、2.8mg/kg体重、2.9mg/kg体重、3.0mg/kg体重、3.1mg/kg体重、3.2mg/kg体重、3.3mg/kg体重、3.4mg/kg体重、3.5mg/kg体重、3.6mg/kg体重、3.7mg/kg体重、3.8mg/kg体重、3.9mg/kg体重或4.0mg/kg体重的剂量经静脉内施用。

在一个实施方案中，本发明的融合蛋白以10mg/kg体重至150mg/kg体重的剂量，如10mg/kg体重、15mg/kg体重、20mg/kg体重、25mg/kg体重、30mg/kg体重、35mg/kg体重、40mg/kg体重、45mg/kg体重、50mg/kg体重、55mg/kg体重、60mg/kg体重、65mg/kg体重、70mg/kg体重、75mg/kg体重、80mg/kg体重、85mg/kg体重、90mg/kg体重、95mg/kg体重、100mg/kg体重、105mg/kg体重、110mg/kg体重、115mg/kg体重、120mg/kg体重、125mg/kg体重、130mg/kg体重、135mg/kg体重、140mg/kg体重、145mg/kg体重或150mg/kg体重的剂量经静脉内施用。

融合蛋白可以每天一次、每天两次、每天三次、每隔一天、每周一次或每两周一次施用。

融合蛋白可以施用三天、四天、五天、六天、七天、八天、九天或十天的时段。

通过施用本发明的融合蛋白，冠状病毒并且特别是SARS-CoV-2的感染得到治疗，即，SARS-CoV-2感染的至少一种症状得到减轻或消除。SARS-CoV-2感染的症状包括咳嗽、呼吸短促、呼吸困难、发热、寒战、疲倦、肌肉酸痛、咽喉痛、头痛、胸痛以及嗅觉和/或味觉丧失。在一个实施方案中，通过施用本发明的融合蛋白，由SARS-CoV-2感染引起的发热减少。在一个实施方案中，向受试者施用本发明的融合蛋白降低受试者经历严重SARS-CoV-2感染过程的风险。在一个实施方案中，向受试者施用本发明的融合蛋白降低受试者经历多器官衰竭、急性呼吸窘迫综合征(ARDS)或肺炎的风险。在一个实施方案中，向受试者施用本发明的融合蛋白降低受试者经历SARS-CoV-2感染的长期效应如肺损伤、神经病症、皮肤病和心血管疾病的风险。在一个实施方案中，向受试者施用本发明的融合蛋白降低血液中细胞因子IL6和/或IL8的浓度。在一个实施方案中，向受试者施用本发明的融合蛋白降低血液中SARS-CoV-2病毒颗粒的浓度。在一个实施方案中，向受试者施用本发明的融合蛋白刺激抗病毒抗体的产生。在一个实施方案中，向受试者施用本发明的融合蛋白刺激抗病毒IgA和/或IgG抗体的产生。

在一个实施方案中，将本发明的融合蛋白施用于患有严重SARS-CoV-2感染的受试者。在一个实施方案中，将本发明的融合蛋白施用于感染SARS-CoV-2并需要人工通气的受试者。在一个实施方案中，将本发明的融合蛋白施用于感染SARS-CoV-2并需要体外膜氧合(ECMO)的受试者。

通过施用本发明的融合蛋白，冠状病毒并且特别是SARS-CoV-2的感染得到预防，即，所治疗的受试者不发展SARS-CoV-2感染的症状。

在一个实施方案中，将本发明的融合蛋白施用于已经与感染SARS-CoV-2的受试者接触过的受试者。已经与感染SARS-CoV-2的受试者接触过的受试者可以通过使用安装在智能电话上的“Corona警告应用程序”来鉴定。

在一个实施方案中，将本发明的融合蛋白施用于受试者，对于该受试者，用所述受试者的咽喉或鼻拭子进行的测试指示其感染有SARS-CoV-2，但是尚未发展出SARS-CoV-2感染的任何症状。

在治疗或预防结合ACE2的冠状病毒，并特别是SARS-CoV-2的感染中，本发明的融合蛋白可以与已知的抗病毒剂组合。抗病毒剂是用于治疗病毒感染的药物，并且包括特异性抗病毒剂和广谱性病毒剂两者。合适的抗病毒剂包括但不限于核苷类似物、病毒蛋白酶抑制剂、病毒聚合酶抑制剂、病毒进入细胞的阻断剂、Janus激酶抑制剂，而且有炎性介质抑制剂。

在具体的实施方案中，抗病毒剂选自瑞德西韦、盐酸阿比朵尔、利托那韦、洛匹那韦、地瑞那韦、利巴韦林、氯喹及其衍生物如羟氯喹、硝唑尼特、甲磺酸卡莫司他、抗IL6和抗IL6受体抗体如托珠单抗、司妥昔单抗以及沙利鲁单抗和巴瑞克替尼磷酸盐。

在SARS-CoV-2感染的治疗或预防中，本发明的融合蛋白可以与抗SARS-CoV-2单克隆抗体组合。抗SARS-CoV2单克隆抗体包括但不限于由Eli Lilly and Company开发的巴尼韦单抗(LY-CoV555 20；LY3819253；)、埃特司韦单抗(LY-3832479；LY-COV016；JS-016；NP-005)、REGN-COV2(其是REGN10933(卡斯瑞韦单抗)和REGN10987(依米得韦单抗)的混合物且由Regeneron开发)、由Vir Biotechnology和GlaxoSmithKline开发的索托韦单抗(VIR-7831；GSK4182136；)、由Celltrion开发的CT-P59、AZD 7442(其是抗体AZD8895和AZD1061的组合且由Astra Zeneca开发)、由Junshi Biosciences开发的JS016、由Tychan Pte Ltd开发的TY027 25、由Brii Biosciences开发的BRII-96和BRII-98、由Sinocelltech Ltd开发的SCTA01、由Ology Bioservices开发的ADM03820、由Boehringer Ingelheim等开发的BI767551以及由Corat Therapeutics开发的COR-101。

除了其在结合冠状病毒中的功能之外，ACE2还涉及若干病症和疾病，如高血压病(包括高血压)、充血性心力衰竭、慢性心力衰竭、急性心力衰竭、收缩性心力衰竭、心肌梗死、动脉硬化、肾脏衰竭、肾衰竭、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、慢性阻塞性肺病(COPD)、肺动脉高压、肾纤维化、慢性肾衰竭、急性肾衰竭、急性肾损伤、炎性肠病以及多器官功能障碍综合征。因此，本发明的融合蛋白也可以用于治疗这些病症和疾病。

虽然已经在附图和前述描述中详细说明和描述了本发明，但是此类说明和描述被认为是说明性或示例性的而非限制性的。本发明不限于所公开的实施方案。通过研究附图、公开内容和从属权利要求，本领域技术人员在实践所要求保护的发明时可以理解和实现所公开实施方案的其它变型。

详述本质上仅是示例性的，并且不旨在限制应用和用途。以下实施例进一步说明了本发明，但并没有将本发明的范围限制于此。本领域技术人员可以在本发明描述的基础上作出各种变化和修改，并且此类变化和修改也包括在本发明中。

实施例

A.材料和方法

1.融合蛋白的构建

构建了四种本发明的融合蛋白。此外，构建了四种包含人IgG1的Fc部分而非人IgG4的Fc部分的融合蛋白作为比较例。下表1显示了融合蛋白的各部分。

表1：所测试的融合蛋白的部分

使用HindIII/XhoI限制酶，将编码构建体的核酸序列插入表达载体pcDNA3.1(Invitrogen V860-20)的变体中。使根据SEQ ID No.17的白蛋白信号序列附接至构建体的N端。然后，使用FreeStyle表达系统(可得自ThermoFisher)，用表达载体瞬时转染293细胞。在第六天，分析样品的细胞存活力和细胞密度，并通过两步离心收获上清液并进行无菌过滤。将材料合并，并将其一半在-80℃下储存直至纯化。另一半经受蛋白A纯化。另外，从池中取出少量样品(～0.5mL)，以通过生物层干涉测量法(BLI)测定表达。

2.蛋白质纯化

瞬时材料的纯化通过蛋白A柱层析，继之以制备型SEC来执行。对于蛋白A纯化，在加载样品之后，清洗柱，并使用40mM NaAc(pH＝3.0)洗脱ACE2-Fc融合蛋白。在洗脱后，首先使用1M Tris(pH＝9.0)将样品中和至pH＝7.5，随后用50mM Tris(pH＝7.5)、300mM NaCl以1:1稀释，并使用旋转过滤器浓缩至10mg/mL。用经50mM Tris(pH＝7.5)、150NaCl平衡的Superdex 200increase(GE Healthcare)柱进一步纯化浓缩的蛋白质。合并主峰，将蛋白质浓度调节至1mg/mL，通过无菌过滤器并在4℃下储存直至进一步使用。

3.通过斜率光谱测定法测定蛋白质浓度(A280)

不同ACE2-Fc融合蛋白的纯化材料通过斜率光谱术进行分析，以测定蛋白质含量。检查了不存在缓冲液干扰的验证，并且通过使用可变的路径长度，精确地测量了蛋白质浓度，而无需在纯化过程期间的样品预稀释的任何先决条件。

4.通过分析型尺寸排阻层析对高分子量种类的测定

不同的纯化蛋白质构建体通过分析型尺寸排阻层析(SEC)进行分析。简而言之，在Waters H-Class bio UPLC系统上，使用Acquity UPLC Protein BEH SEC柱(4.6mm×150mm，1.7μm)来分析样品。检测是基于280nm处的UV吸光度。加载20μg的样品，流动相由20mM磷酸钠pH＝7.0、150mM NaCl组成，并且蛋白质以0.3mL/分钟的流速等度洗脱。

5.稳定性研究

对于所有八种纯化的Fc-融合蛋白，在紧密闭小瓶中使用740μL(300μL备用)等分试样以1mg/mL的浓度执行稳定性研究。首先，将每种Fc-融合蛋白的一个小瓶在37℃下温育3周。随后，将每个Fc-融合蛋白的第二小瓶添加到温育中。此外，再过2周之后，每个Fc-融合蛋白将第3小瓶添加到温育中。温育再持续一周，使得第1组小瓶温育6周，第2组小瓶温育3周且第3组小瓶温育1周。最后，与稳定性研究的最后一周平行，使第4组小瓶经历-80℃下的3x冻融(F/T)循环。使用以上对分析型SEC所解释的方法，分析来自测试间隔(即，6、3和1周)的所有样品以及F/T样品。对于T＝0，使用来自纯化后测试的数据。

6.通过Pepmap测定O-糖基化

使用UPLC-RP/MS，通过肽作图来分析纯化的ACE2-Fc融合蛋白。使蛋白质在盐酸胍中变性，然后在4℃下用DTT还原1小时，并在室温下于暗处用碘乙酰胺烷基化30分钟。使样品经受用胰蛋白酶和Lys-C酶的混合物的蛋白水解消化4小时。在60分钟的肽作图梯度中，使用于Milli-Q中的0.1％甲酸以及乙腈作为流动相，在C18反相UPLC(例如，Peptide BEHC18，2.1×300mm，1.7μm)柱上分离蛋白水解肽，初始保持时间为4.5分钟。应用两种不同的碰撞能量来改善糖肽的覆盖度(15-30eV的低碰撞能量和60-100eV的高碰撞能量)。肽的检测通过214nm处的UV且通过使用Xevo G2-XS QToF质谱仪(来自Waters)的质谱法来执行。分析以MS^E模式执行，以获得通过MS进行的质量验证之外的通过碎片化(MS/MS)进行的肽验证。使用Waters UNIFI 1.9软件(其包括用于去卷积的Waters MaxEnt3)来处理MS^E光谱。在运行期间，使用单独的参考探针输注Glu1-血纤维蛋白肽B，并用于锁定质量校正。去卷积的质量与理论序列相匹配，对于前体离子质量具有10ppm的离子容差，且对于碎片离子质量具有20ppm的离子容差。对于糖基化肽的鉴定，C-、N-和O-聚糖的有限文库包括在检索中。为了提高分配的置信度，检查糖基化肽的碎片光谱中标志物离子(例如在m/z 292和204处)的存在。此外，对于序列覆盖图，具有少于3个碎片离子的肽被排除在外。

7.融合蛋白与SARS-CoV-2的刺突蛋白的结合的测定

a)用SARS-CoV-2(野生型)的刺突蛋白进行的表面等离子体共振

使用市售的SARS-CoV-2刺突蛋白(ACROBiosystems,Newark,USA)，通过表面等离子体共振(Biacore)来分析融合蛋白与SARS-CoV-2的刺突蛋白的结合。

材料：

具有his标签和AviTag的SARS-CoV-2RBD来自Acrobiosystems(目录号SPD-C82E9，批号BV3541b-2043F1-RD)。根据制造商的建议重构蛋白质，等分，在液氮中休克冷冻并在-80℃下储存直至使用。每次测量使用新鲜的等分试样。

运行缓冲液是通过用MilliQ水以1:10稀释从10X HBS-EP+(Cytiva)制备的1XHBS-EP+。稀释的缓冲液通过0.1μm过滤器过滤。

使用Biotin CAPture试剂盒(Cytiva)和Biacore X-100系统进行测量。

方法：

用1X HBS-EP+缓冲液将ACE2-Fc稀释至200nM。使用1.84的A_280,0.1％，在10mm石英比色皿中通过UV光谱法验证浓度。用1X HBS-EP+将200nMACE2-Fc稀释至40、8、1.6和0.32nM。用1X HBS-EP+将解冻的SARS-CoV-2RBD域1:100稀释至2μg/mL的浓度。

使用单循环动力学方法。流速为30μL/分钟。在每次测量之前，使用再生溶液的三次注射来调节芯片。具有AviTag的SARS-CoV-2(Acrobiosystems)的固定化时间为30秒。在配体固定化后，在单循环动力学模式下，从低到高开始，将不同浓度的ACE2-Fc(0.32、1.6、8、40和200nM)注射到固定化配体上。基线获得自仅注射缓冲液的两个循环。

用产生K_D的1:1结合模型在Biacore软件中评价数据。

b)用SARS-CoV-2的δ变体的刺突蛋白进行的表面等离子体共振

用1×HBS-EP+缓冲液将ACE2-Fc构建体稀释至1nM。解冻的SARS COV-2刺突三聚体变体(获得自AcroBiosystems，目录号SPN-C82E7)用1×HBS-EP+缓冲液预稀释至200nM，并随后用1×HBS-EP+缓冲液稀释至20.00、6.67、2.22、0.74和0.25nM的最终测定浓度。在实验前，经由胺偶联试剂盒(NHS/EDC)，将芯片用抗人IgG Fc抗体固定化至1000RU的捕获水平。在每次实验之前，用配体ACE2-FC构建体以及分析物刺突三聚体运行6个启动循环，以便调节芯片。在每次样品注射之前，注射空白缓冲液样品用于后续的空白减去。使用单循环方法进行分析。流速设定为20μL/分钟，并将1×HBS-EP+用作运行缓冲液。ACE2-Fc构建体的固定化时间为80秒，而对于缔合的样品接触时间为600秒，且对于解离时段为900秒。在单循环动力学测定中，将刺突三聚体样品注射到固定化ACE2-Fc构建体上，以一式三份测量从低到高样品浓度开始。在每次样品循环之后，用3M的MgCl₂溶液再生芯片表面。经由Biacore T200Evaluation软件，通过传感图的双参考(参考流动池和参考的空白缓冲液)动力学筛选来获得动力学值。生成每个样品循环的基线图和捕获水平图以进行测定验证。

c)ELISA1

为了定量融合蛋白与SARS-CoV-2的刺突蛋白的结合，执行ELISA测定。用在包被缓冲液(15mM Na₂CO₃、35mM NAHCO₃、7.7mM NaN₃，pH9.6)中的0.2μg/孔的市售SARS-CoV-2刺突蛋白(ACROBiosystems,Newark,USA)来包被ELISA板。将孔用300μl/孔清洗缓冲液(0.05％Tween-20于TBS中，pH 7.4)清洗四次。将孔用300μl封闭缓冲液(2％BSA于清洗缓冲液中，pH7.4)在37℃下封闭90分钟，然后将孔用300μl/孔清洗缓冲液(0.05％Tween-20于TBS中，pH7.4)清洗四次。然后，向每个孔中添加100μl的连续稀释的融合蛋白，并将孔在37℃下温育一小时。将融合蛋白在样品稀释缓冲液(0.5％BSA于清洗缓冲液中，pH 7.4)中稀释。在温育后，将孔用300μl/孔清洗缓冲液(0.05％Tween-20于TBS中，pH 7.4)清洗四次。然后，将100μl的辣根过氧化物酶缀合抗人Fc抗体(在于清洗缓冲液中的0.5％BSA中稀释，pH 7.4)添加到每个孔中，并将孔在37℃下温育一小时。在温育后，将孔用300μl/孔清洗缓冲液(0.05％Tween-20于TBS中，pH 7.4)清洗四次，然后添加200μl的辣根过氧化物酶底物(8μl H₂O₂和100μl 10mg/ml TMB于10ml底物溶液A(50mM Na₂HPO₄ x 12H₂O，25mM柠檬酸，pH 5.5)中)，并将孔在37℃下于暗处温育二十分钟。通过向每个孔中添加50μl的1M硫酸终止反应。在ELISA读取器中，在OD450 nm处读取板。

根据制造商的说明书用调整的中和规程，使用ACE2:SARS-CoV-2Spike S1抑制剂筛选测定试剂盒(BPS Bioscience；目录#79945)来测试SARS-CoV-2刺突S1蛋白与ACE2的结合的抑制。简而言之，，将生物素化SARS-CoV-2刺突S1蛋白(25nM)与ACE2-Fc融合蛋白的连续稀释物在96孔中和板中在室温下缓慢摇动温育一小时(＝中和混合物)。

使ACE2蛋白以1μg/mL的浓度附着于镍包被的96孔板上，并在室温下缓慢摇动温育一小时。通过清洗步骤除去未结合的ACE2。随后，将中和混合物转移到ACE2包被的板上，并将板在室温下缓慢摇动温育一小时。在10分钟封闭步骤后，用链霉亲和素-HRP将板在室温下缓慢摇动温育1小时。在清洗和10分钟封闭后，添加HRP底物并在化学发光读取器上对板进行分析。

d)ELISA2

为了定量融合蛋白与SARS-CoV-2的刺突蛋白的结合，执行ELISA测定。使用100μL/孔用包被缓冲液(PBS)中的1.0μg/mL的市售SARS-CoV-2刺突蛋白(SPN-C52H9，ACROBiosystems)包被ELISA板(NUNC)。将孔在4℃下温育过夜。次日，除去包被并将孔用300μl/孔的清洗缓冲液(10mM磷酸钠，150mM NaCl，0.05％Tween-20，pH＝7.5)清洗三次。在室温下，将孔用200μl封闭缓冲液(补充有1％BSA的清洗缓冲液)封闭一小时，同时以150rpm摇动。然后除去封闭缓冲液，并将100μl的连续稀释的融合蛋白添加到每个孔中，并将孔在室温下以150rpm温育一小时。将融合蛋白在样品稀释缓冲液(含1％BSA的清洗缓冲液)中稀释。在温育后，将孔用300μl/孔清洗缓冲液清洗三次。接着，将100μl的辣根过氧化物酶缀合抗人IgG4Fc抗体(Southern Biotech，9200-05，在封闭缓冲液中以1:4000稀释)添加到每个孔中，并将孔在室温下温育一小时，同时摇动。在温育后，将孔用300μl/孔的清洗缓冲液清洗三次，然后添加100μl的TMB溶液(Invitrogen，SB02)并将孔在室温下温育两分钟。反应用100μl/孔的1M HCl终止，并在室温下避光温育30秒，同时摇动。在室温下于暗处进一步温育15分钟后，在酶标仪(Synergy HTX,BioTek)中OD450 nm处读取板，以OD655处为参考。使用4参数逻辑曲线拟合模型，将浓度(以μg/mL计)针对OD450(背景减去后)进行绘制。

8.在融合蛋白存在下SARS-CoV-2株Victoria/1/2020感染的分析

在不存在或存在融合蛋白的情况下，用Vero细胞执行SARS-CoV-2感染的分析。SARS-CoV-2的感染通过测定免疫空斑的数目进行检测。

将VeroE6细胞铺板于96孔板中并温育过夜。在一个或多个96孔转移板中制备ACE2-Fc融合蛋白样品的六个两倍连续稀释物。将Victoria/1/2020SARS-CoV-2野生型病毒以大约100空斑形成单位[PFU]/孔的目标工作浓度依次添加到稀释物中，并在37℃下温育60至90分钟。在温育期后，将中和混合物转移到含有VeroE6细胞的测定板中，随后在37℃和5％CO₂下温育。在60至90分钟温育期后，向孔中添加羧甲基纤维素(CMC)覆盖培养基，并将板再温育24小时。然后，将细胞固定并使用对SARS-CoV-2RBD S蛋白特异性的抗体对进行染色。使用TrueBlueTM底物使免疫空斑可视化，并使用Immunospot分析仪(CTL)计数。将免疫空斑计数输出到SoftMax Pro(Molecular Devices)，并将血清样品的中和滴度计算为对应于该特定样品的50％中和滴度(ID50)的倒数稀释度。

9.ACE2活性测定

使用来自Abcam的ACE2活性测定试剂盒(ab273297)来测量构建体的酶促活性。该测定根据制造商的手册执行。两种市售ACE2-Fc融合蛋白(来自Genscript(目录号Z03484-1)和Acrobiosystems(目录号AC2-H5257)用作参考蛋白(Ref1和Ref2)。该测定基于合成肽基-MCA衍生物的切割。该底物由活性ACE2切割以释放游离MCA荧光团，与肽基-MCA相比，该游离荧光团在420nm处具有增加的荧光强度(在320nm处激发)。从荧光强度增加的斜率和已知MCA浓度的标准曲线计算出由于从ACE2切割而释放的MCA的量。

10.病毒中和测定

病毒株

SARS-CoV-2-Munich-TUM-1(EPI_ISL_582134)是从慕尼黑(Munic)的COVID-19阳性患者的鼻咽拭子分离出来的(2020年1月)，并在DMEM培养基(5％FCS、1％青霉素/链霉素、200mmol/L L-谷氨酰胺、1％MEM-非必需氨基酸、1％丙酮酸钠(均来自Gibco))中的Vero E6细胞上生长和繁殖。

SARS-CoV-2D614G是从德国慕尼黑(Munich,Germany)的患者材料中分离出来的(2020年4月)，在Caco-2细胞上生长并在Vero E6细胞上繁殖。

使来自Frankfurt的SARS-CoV-Fra-1(AY291315.1)在DMEM培养基(10％胎牛血清(FCS)、100μg/ml链霉素、100IU/ml青霉素)(均来自Gibco)中的Vero E6细胞上生长和繁殖。

病毒中和测定，随后细胞内ELISA

将VeroE6细胞以1.6E04个细胞/孔铺板在96孔板的补充有5％FCS、1％青霉素-链霉素、200mmol/L L-谷氨酰胺、1％MEM-非必需氨基酸、1％丙酮酸钠(均来自Gibco)的DMEM培养基(Gibco)中，并在37℃和5％CO₂下温育过夜。将ACE2-Fc融合蛋白的连续稀释物与病毒在新鲜培养基中混合，并在37℃下预温育1小时。在37℃下，用中和的病毒溶液以0.3的MOI感染VeroE6细胞1小时。接着，除去中和混合物，添加培养基，并将细胞在37℃下温育24小时。模拟细胞代表用培养基温育的未感染Vero E6细胞。24小时后，将细胞用PBS清洗一次并用4％多聚甲醛(ChemCruz)在室温下固定10分钟。在PBS的清洗步骤后，用PBS中的0.5％皂苷(Roth)将固定的VeroE6细胞在室温下透化10分钟。接着，除去透化溶液，并将细胞用0.1％皂苷和10％山羊血清(Sigma)在PBS中的混合物在室温下封闭1小时，同时轻轻摇动。随后，将Vero E6细胞与抗dsRNA J2抗体(Jena Bioscience)在补充有1％FCS的PBS中的1:500稀释物在4℃下摇动温育过夜，继之以用清洗缓冲液(补充有0.05％Tween-20(Roth)的1X PBS)的四次清洗步骤。接着，将板与山羊抗小鼠IgG2a-HRP抗体(Southern Biotech)在补充有1％FCS的PBS中的1:2000稀释物一起温育，并在室温下轻轻摇动温育1小时。在四次清洗步骤之后，将3,3′,5,5′-四甲基联苯胺(TMB)底物(Invitrogen)添加到孔中并在暗处温育10分钟。在通过添加2N H₂SO₄(Roth)终止颜色反应后，执行Tecan infinite F200 pro读板器上450nm和560nm处的比色检测。在针对用未感染的Vero E6细胞获得的值进行归一化后，将光密度转化为百分比中和值，并计算半数最大抑制浓度(IC50值)(GraphpadPrism)。

11.使用表面等离子体共振(SPR)测定ACE2融合蛋白对Fc受体的结合亲和力

使用Biacore T200进行Fc-受体结合研究。对于FcγRI和FcγRIIIa实验，通过在CM5芯片上以5μL/分钟的流速将溶液注射在共价固定化的抗his标签抗体上90秒来捕获1.5nM浓度的His标签化FcγRI和FcγRIIIa。运行缓冲液是HBS-EP+pH 7.4(Cytiva)。以单循环动力学模式注射五种不同浓度的ACE2-Fc构建体(对于FcγRI的实验为3.7-300nM，且对于FcγRIIIa为25-2000nM)。将FcγRI-结合数据拟合至异质性配体模型，并报道第一结合常数。将FcγRIIIa-结合数据拟合至两态反应模型以导出结合常数。对于FcRn实验，将FcRn共价固定化在CM5芯片上至约50RU(响应单位)。样品缓冲液是HBS-EP+pH 6.0(Cytiva)。在单循环动力学模式下以205至8000nM的五种不同浓度注射ACE2-Fc构建体。用稳态亲和力拟合来评价FcRn结合。

12.用细胞存活力测定法来测定病毒中和

病毒株

SARS-CoV-2-Munich-TUM-1(EPI_ISL_582134)是从慕尼黑的COVID-19阳性患者的鼻咽拭子分离出来的(2020年1月)，并在DMEM培养基(5％FCS、1％青霉素/链霉素、200mmol/L L-谷氨酰胺、1％MEM-非必需氨基酸、1％丙酮酸钠(均来自Gibco))中的Vero E6细胞上生长和繁殖。

SARS-CoV-2D614G是从德国慕尼黑的患者材料中分离出来的(2020年4月)，在Caco-2细胞上生长并在Vero E6细胞上繁殖。

SARS-CoV-2B.1.1.7获得自德国联邦国防军微生物研究所(Institute forMicrobiology of the Bundeswehr)的Dr.Bugert(GISAID：EPI_ISL_755639)并在Vero E6细胞上增殖。

SARS-CoV-2B.1.351获得自LGL(Oberschleiβheim,Germany)。它是从德国的患者中分离出来的，在Caco-2细胞上生长并在Vero E6细胞上繁殖。变体的身份通过测序加以确认。

感染前24小时，将经工程化改造以过表达人血管紧张素转化酶2受体ACE2(A549-hACE2)的人肺上皮A549细胞(ATCC-CCL-185)以15,000个细胞/孔铺板在具有透明底的96孔白色孔半区板(Corning)中的含有2％胎牛血清、100U/mL青霉素-链霉素和1％NEAA的DMEM中。

使SARS-CoV-2-Munich-TUM-1和SARS-CoV-2变体D614G、B1.1.7和B.1.351在VeroE6细胞上生长。为此，在感染前一天将15×10⁶个Vero E6细胞接种在每个T150烧瓶中。通过在37℃、5％CO₂下以0.01的MOI添加病毒执行感染。在添加病毒后一小时，将培养基换成具有10％胎牛血清、100U/mL青霉素-链霉素以及1％NEAA、200mmol/l L-谷氨酰胺和1％丙酮酸钠(均来自Gibco)的DMEM。

感染使用病毒诱导的细胞毒性的发光读出进行测定。简而言之，感染后72小时，根据制造商的说明书处理细胞：将15μl CellTiter-Glo 2.0试剂(Promega,Wisconsin,USA)添加到每个孔中，在室温下于暗处温育10分钟，并使用Infinite F200酶标仪(Tecan)记录发光(0.5秒积分时间，无滤器)。通过将感染的细胞相对于未处理的对照细胞(设定为100％)进行归一化，计算出对于每种病毒分离株的细胞存活力和相应感染滴度。执行构建体的连续稀释，并与定义体积的指定SARS-CoV-2临床分离株的病毒原液混合，导致80％的细胞毒性。预温育1小时后，将构建体和相应的SARS-CoV-2分离株的混合物添加到A549-hACE2细胞中。感染后72小时，如上所述测定病毒诱导的细胞毒性。

13.通过空斑测定法来测定病毒滴度

病毒滴度如Baer等人(2014)J Vis Exp,e52065所述进行测定，具有一些修改。简而言之，将HepG2或Vero E6细胞以5E05个细胞/孔铺板在12孔板中的补充有5％FCS、1％P/S、200mmol/L L-谷氨酰胺、1％MEM-NEAA、1％丙酮酸钠(均来自Gibco)的DMEM培养基(Gibco)中，并在37℃和5％CO₂下温育过夜。在37℃下，将细胞用病毒样品在细胞培养基中的连续稀释物感染一小时。在弃去上清液后，每孔添加1mL的在最低基础培养基(Gibco)中稀释的5％羧甲基纤维素(Sigma)，并将板在37℃下温育，直至出现明显的空斑。在除去上清液后，将细胞用10％多聚甲醛(ChemCruz)在室温下固定30分钟。接着，用PBS执行清洗步骤，随后添加1％结晶紫(Sigma；在20％甲醇和水中稀释)。在室温下15分钟的温育时间后，用PBS洗去溶液，并将板干燥。样品的病毒滴度(PFU/mL)通过计数稀释物的平均空斑数和总稀释因子的倒数进行测定。

B.结果

图1显示，与包含ACE2的氨基酸18至740的融合蛋白(构建体2、4、6和8)相比，对于具有包含氨基酸18至732的较短ACE2片段的那些融合蛋白(构建体1、3、5和7)，获得了更高的产率。

另外，与包含ACE2的氨基酸18至740的融合蛋白(构建体2、4、6和8)相比，具有包含氨基酸18至732的较短ACE2片段的融合蛋白(构建体1、3、5和7)具有较低百分比的指示蛋白质聚集的高分子量种类(参见图2)。在储存三或六周后观察到相同的结果(参见图10)。

在表面等离子体共振中，所有构建体均显示出相当的与SARS-CoV-2的刺突蛋白的结合(参见表2)：

表2：

用SARS-CoV2的δ变体的刺突蛋白获得了相当的结果(参见表3)：

表3：

构建体	KD[M]	kon[1/Ms]	koff[1/s]
				构建体1	1.44E-09	1.52E+05	2.17E-04
构建体5	1.44E-09	1.36E+05	1.94E-04

图3显示，构建体1、3、5和7基本上没有O-糖基化，而构建体2、4、6和8具有不同量的单和双O-聚糖。

图4显示，如由ELISA1所测定，所有构建体1至8均抑制了SARS-CoV-2刺突S1蛋白与ACE2的结合。

构建体1、3、5和7几乎完全抑制了SARS-CoV-2株Victoria/1/2020对VeroE6细胞的感染(参见图5)。所有构建体均中和SARS-CoV-2株Victoria/1/2020，IC50值在0.5nM范围内。

构建体1、2、5和6在温育30分钟后切割相同量的合成肽基-MCA衍生物，而在活性ACE2位点具有突变的构建体已完全丧失酶促活性(参见图6a和6b)。

所有构建体1至8均中和了SARS-CoV(IC50值在150nM范围内)(参见图7a)、SARS-CoV-2(IC50值在10nM范围内)(参见图7b)以及SARS-CoV-2D614G(IC50值在1nM范围内)(参见图7c)。

当与IgG1对应物相比时，ACE2-IgG4-Fc融合蛋白显示出略低的对FcγRI的亲和力(参见表4)。ACE2-IgG4-Fc未显示出与FcγRII结合，这与ACE2-IgG1-Fc分子形成对照(参见表4)。所有四种构建体与FcRn具有相似的亲和力(参见表4)。

表4：ACE2-Fc构建体对Fc受体的结合亲和力

重复测量的平均值±SD

构建体1与野生型SARS-CoV-2的刺突蛋白结合，EC50值为25.9ng/ml，如由ELISA2所测定(参见图8)。

图9显示，根据SEQ ID No.6和8的ACE2-Fc融合蛋白(构建体1和3)中和所有受测试的SARS-CoV-2临床分离株。SARS-CoV-2变体的感染性越强，融合蛋白中和它的效果就越好，如由较低的IC50(50％抑制浓度)值所证实。特别地，融合蛋白针对SARS-CoV-2变体B.1.1.7和B.1.351是最有效的，这些变体已显示是难于由大多数针对刺突蛋白的N端域的单克隆抗体和针对受体结合基序的单克隆抗体中和的(Wang等人(2021)Nature)。此外，B.1.351变体显示对由来自已接种疫苗的个体的恢复期血浆和血清的中和的逃逸。

不同构建体和临床分离株的IC50值显示于表5中。

表5：不同构建体和临床分离株的IC50和95％置信区间

构建体	分离株	IC50(nM)	CI95
				1	SARS-CoV-2-Munich-TUM-1	4.7	3.9-5.8
1	SARS-CoV-2D14G	1.3	1.0-1.6
				1	SARS-CoV-2B.1.1.7	0.6	0.5-0.8
1	SARS-CoV-2B.1.351	0.4	0.3-0.5
				3	SARS-CoV-2-Munich-TUM-1	7.4	6.2-8.6
3	SARS-CoV-2D14G	1.6	1.3-2.0
				3	SARS-CoV-2B.1.1.7	0.6	0.4-0.8
3	SARS-CoV-2B.1.351	0.5	0.4-0.7

序列表

<110> 福迈康股份公司

<120> ACE2融合蛋白及其用途

<130> F09553WO2

<150> EP21170519.9

<151> 2021/4/26

<150> EP21164684.9

<151> 2021/3/24

<150> EP20210297.6

<151> 2020/11/27

<150> EP20204774.2

<151> 2020/10/29

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Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser

<210> 4

<211> 13

<212> PRT

<213> 人

<400> 4

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

1 5 10

<210> 5

<211> 216

<212> PRT

<213> 人

<400> 5

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

1 5 10 15

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

20 25 30

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

35 40 45

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

50 55 60

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

65 70 75 80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

85 90 95

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

100 105 110

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

130 135 140

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

145 150 155 160

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

165 170 175

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

180 185 190

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200 205

Ser Leu Ser Leu Ser Leu Gly Lys

210 215

<210> 6

<211> 944

<212> PRT

<213> 人工

<220>

<223> 融合蛋白1

<400> 6

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 7

<211> 952

<212> PRT

<213> 人工

<220>

<223> 融合蛋白2

<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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 8

<211> 944

<212> PRT

<213> 人工

<220>

<223> 融合蛋白3

<400> 8

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 9

<211> 952

<212> PRT

<213> 人工

<220>

<223> 融合蛋白4

<400> 9

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 10

<211> 942

<212> PRT

<213> 人工

<220>

<223> 融合蛋白5

<400> 10

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 11

<211> 950

<212> PRT

<213> 人工

<220>

<223> 融合蛋白6

<400> 11

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 12

<211> 942

<212> PRT

<213> 人工

<220>

<223> 融合蛋白7

<400> 12

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 13

<211> 950

<212> PRT

<213> 人工

<220>

<223> 融合蛋白8

<400> 13

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 14

<211> 588

<212> PRT

<213> 智人

<400> 14

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

580 585

<210> 15

<211> 11

<212> PRT

<213> 人

<400> 15

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10

<210> 16

<211> 216

<212> PRT

<213> 智人

<400> 16

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

1 5 10 15

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

20 25 30

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

35 40 45

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

50 55 60

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

65 70 75 80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

85 90 95

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

100 105 110

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

130 135 140

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

145 150 155 160

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

165 170 175

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

180 185 190

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200 205

Ser Leu Ser Leu Ser Pro Gly Lys

210 215

<210> 17

<211> 18

<212> PRT

<213> 智人

<400> 17

Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala

1 5 10 15

Tyr Ser

<210> 18

<211> 1273

<212> PRT

<213> SARS-CoV2

<400> 18

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr

145 150 155 160

Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu

165 170 175

Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe

180 185 190

Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr

195 200 205

Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu

210 215 220

Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr

225 230 235 240

Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser

245 250 255

Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro

260 265 270

Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala

275 280 285

Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys

290 295 300

Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val

305 310 315 320

Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys

325 330 335

Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala

340 345 350

Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu

355 360 365

Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro

370 375 380

Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe

385 390 395 400

Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly

405 410 415

Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys

420 425 430

Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn

435 440 445

Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe

450 455 460

Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys

465 470 475 480

Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly

485 490 495

Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val

500 505 510

Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys

515 520 525

Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn

530 535 540

Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu

545 550 555 560

Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val

565 570 575

Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe

580 585 590

Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val

595 600 605

Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile

610 615 620

His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser

625 630 635 640

Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val

645 650 655

Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala

660 665 670

Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala

675 680 685

Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser

690 695 700

Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile

705 710 715 720

Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val

725 730 735

Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu

740 745 750

Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr

755 760 765

Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln

770 775 780

Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe

785 790 795 800

Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser

805 810 815

Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly

820 825 830

Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp

835 840 845

Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu

850 855 860

Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly

865 870 875 880

Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile

885 890 895

Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr

900 905 910

Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn

915 920 925

Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala

930 935 940

Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn

945 950 955 960

Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val

965 970 975

Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln

980 985 990

Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val

995 1000 1005

Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

1010 1015 1020

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1025 1030 1035

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1040 1045 1050

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1055 1060 1065

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1070 1075 1080

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1085 1090 1095

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1100 1105 1110

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1115 1120 1125

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1130 1135 1140

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1145 1150 1155

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1160 1165 1170

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1175 1180 1185

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1190 1195 1200

Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu

1205 1210 1215

Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met

1220 1225 1230

Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys

1235 1240 1245

Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro

1250 1255 1260

Val Leu Lys Gly Val Lys Leu His Tyr Thr

1265 1270

<210> 19

<211> 216

<212> PRT

<213> 人工

<220>

<223> IgG1突变体

<400> 19

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

1 5 10 15

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

20 25 30

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

35 40 45

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

50 55 60

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

65 70 75 80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

85 90 95

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

100 105 110

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

130 135 140

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

145 150 155 160

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

165 170 175

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

180 185 190

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200 205

Ser Leu Ser Leu Ser Pro Gly Lys

210 215

<210> 20

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-732

<400> 20

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 21

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-740

<400> 21

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 22

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-732（H374N+H378N）

<400> 22

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 23

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-740 H374N+H378N

<400> 23

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 24

<211> 715

<212> PRT

<213> 人工

<220>

<223> ACE2 18-732 R273A

<400> 24

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly

705 710 715

<210> 25

<211> 723

<212> PRT

<213> 人工

<220>

<223> ACE2 18-740 R273A

<400> 25

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser

<210> 26

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-732 R273A

<400> 26

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 27

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-740 R273 A

<400> 27

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 28

<211> 715

<212> PRT

<213> 人工

<220>

<223> ACE2 18-732 S645C

<400> 28

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly

705 710 715

<210> 29

<211> 723

<212> PRT

<213> 人工

<220>

<223> ACE2 18-740 S645C

<400> 29

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser

<210> 30

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-732 S645C

<400> 30

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 31

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-740 S645C

<400> 31

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 32

<211> 715

<212> PRT

<213> 人工

<220>

<223> ACE2 18-732 S645C+H374N+H378N

<400> 32

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly

705 710 715

<210> 33

<211> 723

<212> PRT

<213> 人工

<220>

<223> ACE2 18-740 S645C+H374N+H378N

<400> 33

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser

<210> 34

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-732 S645C+H374N+H378N

<400> 34

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 35

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-740 S645C+H374N+H378N

<400> 35

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 36

<211> 715

<212> PRT

<213> 人工

<220>

<223> ACE2 18-732 S645C+R273A

<400> 36

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly

705 710 715

<210> 37

<211> 723

<212> PRT

<213> 人工

<220>

<223> ACE2 18-740 S645C+R273A

<400> 37

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser

<210> 38

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-732 S645C+R273A

<400> 38

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 39

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 YTE的ACE2 18-740 S645C+R273A

<400> 39

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 40

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-732 S645C

<400> 40

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 41

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-740 S645C

<400> 41

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 42

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-732 S645C

<400> 42

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 43

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-740 S645C

<400> 43

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 44

<211> 216

<212> PRT

<213> 人工

<220>

<223> 具有YTE突变的IgG4的Fc部分

<400> 44

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

1 5 10 15

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

20 25 30

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

35 40 45

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

50 55 60

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

65 70 75 80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

85 90 95

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

100 105 110

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

130 135 140

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

145 150 155 160

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

165 170 175

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

180 185 190

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200 205

Ser Leu Ser Leu Ser Leu Gly Lys

210 215

<210> 45

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-732 S645C

<400> 45

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg

740 745 750

Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 46

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-740 S645C

<400> 46

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 47

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-732 S645C H374N H378N

<400> 47

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 48

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-740 S645C H374N H378N

<400> 48

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 49

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-732 S645C R273A

<400> 49

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 50

<211> 950

<212> PRT

<213> 人工

<220>

<223> ACE2 18-740 S645C R273A IgG1 wt

<400> 50

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 51

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-732 S645C H374N H378N

<400> 51

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 52

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-740 S645C H374N H378N

<400> 52

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 53

<211> 944

<212> PRT

<213> 人工

<220>

<223> ACE2 18-732 S645C R273A IgG4 wt

<400> 53

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 54

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-740 S645C R273A

<400> 54

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 55

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-732 S645C H374N H378N

<400> 55

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg

740 745 750

Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 56

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-740 S645C H374N H378N

<400> 56

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 57

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-732 S645C R273 A

<400> 57

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg

740 745 750

Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 58

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-740 S645C R273A

<400> 58

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 59

<211> 216

<212> PRT

<213> 人工

<220>

<223> IgG1 T256D T307Q

<400> 59

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

1 5 10 15

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

20 25 30

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

35 40 45

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

50 55 60

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

65 70 75 80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

85 90 95

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

100 105 110

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

130 135 140

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

145 150 155 160

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

165 170 175

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

180 185 190

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200 205

Ser Leu Ser Leu Ser Pro Gly Lys

210 215

<210> 60

<211> 216

<212> PRT

<213> 人工

<220>

<223> IgG4 T256D T307Q

<400> 60

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

1 5 10 15

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

20 25 30

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

35 40 45

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

50 55 60

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

65 70 75 80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

85 90 95

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

100 105 110

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

130 135 140

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

145 150 155 160

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

165 170 175

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

180 185 190

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200 205

Ser Leu Ser Leu Ser Leu Gly Lys

210 215

<210> 61

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T 307Q的ACE2 18-732 S645C

<400> 61

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Asp Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 62

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-740 S645C

<400> 62

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 63

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-732 S645C H374N H378N

<400> 63

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Asp Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 64

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-740 S645C H374N H378N

<400> 64

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 65

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-732 S645C R273A

<400> 65

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Asp Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 66

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-740 S645C R273A

<400> 66

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 67

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-732 S645C

<400> 67

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Asp Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 68

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-740 S645C

<400> 68

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 69

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-732 S645C H374N H378N

<400> 69

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Asp Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 70

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-740 S645C H374N H378N

<400> 70

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 71

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-732 S645C R273A

<400> 71

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Asp Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 72

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-740 S645C R273A

<400> 72

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Cys Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 73

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-732

<400> 73

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Asp Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 74

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-740

<400> 74

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 75

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-732

<400> 75

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Asp Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 76

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-740

<400> 76

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 77

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-732 H374N H378N

<400> 77

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Asp Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 78

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-740 H374N H378N

<400> 78

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 79

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-732 H374N H378N

<400> 79

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Asp Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 80

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T 307Q的ACE2 18-740 H374N H378N

<400> 80

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 81

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-732 R273A

<400> 81

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Asp Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 82

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 T256D T307Q的ACE2 18-740 R273A

<400> 82

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 83

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-732 R273A

<400> 83

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Asp Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Gln Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 84

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 T256D T307Q的ACE2 18-740 R273A

<400> 84

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Asp Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Gln Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 85

<211> 942

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-732 R273A

<400> 85

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Asp Lys Thr His Thr

705 710 715 720

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

725 730 735

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

740 745 750

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

755 760 765

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

770 775 780

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

785 790 795 800

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

805 810 815

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

820 825 830

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

835 840 845

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

850 855 860

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

865 870 875 880

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

885 890 895

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

900 905 910

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

915 920 925

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

930 935 940

<210> 86

<211> 950

<212> PRT

<213> 人工

<220>

<223> 具有IgG1 wt的ACE2 18-740 R273A

<400> 86

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

725 730 735

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

740 745 750

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

755 760 765

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

770 775 780

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

785 790 795 800

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

805 810 815

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

820 825 830

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

835 840 845

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

850 855 860

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

865 870 875 880

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

885 890 895

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

900 905 910

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

915 920 925

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

930 935 940

Ser Leu Ser Pro Gly Lys

945 950

<210> 87

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-732 R273A

<400> 87

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

740 745 750

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 88

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 wt的ACE2 18-740 R273A

<400> 88

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 89

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-732 R273A

<400> 89

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg

740 745 750

Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 90

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-740 R273A

<400> 90

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 Ala

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

<210> 91

<211> 715

<212> PRT

<213> 人工

<220>

<223> ACE2 18-732 H374N H378N

<400> 91

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly

705 710 715

<210> 92

<211> 723

<212> PRT

<213> 人工

<220>

<223> ACE2 18-740 H374N H378N

<400> 92

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 Asn Glu Met Gly Asn 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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser

<210> 93

<211> 944

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-732

<400> 93

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Glu Ser Lys Tyr Gly

705 710 715 720

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

725 730 735

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg

740 745 750

Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

755 760 765

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

770 775 780

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

785 790 795 800

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

805 810 815

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

820 825 830

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

835 840 845

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

850 855 860

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

865 870 875 880

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

885 890 895

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

900 905 910

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

915 920 925

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

930 935 940

<210> 94

<211> 952

<212> PRT

<213> 人工

<220>

<223> 具有IgG4 YTE的ACE2 18-740

<400> 94

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 Gln Ser Ile Lys Val Arg Ile Ser Leu Lys

595 600 605

Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met Tyr

610 615 620

Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu Lys

625 630 635 640

Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val Ala

645 650 655

Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro Lys

660 665 670

Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile Arg

675 680 685

Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn Ser

690 695 700

Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln Pro

705 710 715 720

Pro Val Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

725 730 735

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

740 745 750

Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val

755 760 765

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

770 775 780

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

785 790 795 800

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

805 810 815

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

820 825 830

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

835 840 845

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

850 855 860

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

865 870 875 880

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

885 890 895

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

900 905 910

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

915 920 925

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

930 935 940

Ser Leu Ser Leu Ser Leu Gly Lys

945 950

Claims (96)

1.融合蛋白，其包含：第一部分，所述第一部分包含人ACE2的片段或所述片段的变体，所述人ACE2具有根据SEQ ID No.1的氨基酸序列；以及第二部分，所述第二部分包含人IgG1的Fc部分的变体，所述变体具有根据SEQ ID No.19的氨基酸序列。

2.根据权利要求1所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.15的氨基酸序列连接。

3.根据权利要求1或2所述的融合蛋白，其中所述人ACE2的片段由具有根据SEQ IDNo.2的氨基酸序列的蛋白质组成。

4.根据权利要求1或2所述的融合蛋白，其中所述人ACE2的片段是由具有根据SEQ IDNo.3的氨基酸序列的蛋白质组成的ACE2的胞外域。

5.根据权利要求1或2所述的融合蛋白，其具有根据SEQ ID No.20或21的氨基酸序列。

6.根据权利要求1至5中任一项所述的融合蛋白，其中所述人ACE2片段的变体是人ACE2的酶促失活变体。

7.根据权利要求6所述的融合蛋白，其中所述人ACE2的酶促失活变体包含H374N和H378N突变，编号参考SEQ ID No.1。

8.根据权利要求6或7所述的融合蛋白，其中所述人ACE2的酶促失活变体由具有根据SEQ ID No.91或92的氨基酸序列的蛋白质组成。

9.根据权利要求6至8中任一项所述的融合蛋白，其具有根据SEQ IDNo.22或23的氨基酸序列。

10.根据权利要求6所述的融合蛋白，其中所述人ACE2的酶促失活变体包含位置273处的突变，编号参考SEQ ID No.1。

11.根据权利要求10所述的融合蛋白，其中所述位置273处的突变是R273A突变。

12.根据权利要求10或11所述的融合蛋白，其中所述人ACE2的酶促失活变体由具有根据SEQ ID No.24或25的氨基酸序列的蛋白质组成。

13.根据权利要求10至12中任一项所述的融合蛋白，其具有根据SEQ ID No.26或27的氨基酸序列。

14.根据权利要求1至5中任一项所述的融合蛋白，其中所述人ACE2片段的变体包含S645C突变，编号参考SEQ ID No.1。

15.根据权利要求14所述的融合蛋白，其中所述人ACE2片段的变体由具有根据SEQ IDNo.28或29的氨基酸序列的蛋白质组成。

16.根据权利要求14或15所述的融合蛋白，其具有根据SEQ ID No.30或31的氨基酸序列。

17.根据权利要求14所述的融合蛋白，其中所述人ACE2片段的变体还包含H374N和H378N突变，编号参考SEQ ID No.1。

18.根据权利要求17所述的融合蛋白，其中所述人ACE2片段的变体由具有根据SEQ IDNo.32或33的氨基酸序列的蛋白质组成。

19.根据权利要求17或18所述的融合蛋白，其具有根据SEQ ID No.34或35的氨基酸序列。

20.根据权利要求14所述的融合蛋白，其中所述人ACE2片段的变体还包含位置273处的突变，编号参考SEQ ID No.1。

21.根据权利要求20所述的融合蛋白，其中所述位置273处的突变是R273A突变。

22.根据权利要求20或21所述的融合蛋白，其中所述人ACE2片段的变体由具有根据SEQID No.36或37的氨基酸序列的蛋白质组成。

23.根据权利要求20至22所述的融合蛋白，其具有根据SEQ ID No.38或39的氨基酸序列。

24.融合蛋白，其包含：

(a)第一部分，所述第一部分包含人ACE2的片段的变体，所述人ACE2具有根据SEQ IDNo.1的氨基酸序列，其中所述人ACE2片段的变体包含S645C突变，编号参考SEQ ID No.1，以及

(b)第二部分，所述第二部分包含人IgG的Fc部分或人IgG的Fc部分的变体。

25.根据权利要求24所述的融合蛋白，其中所述人ACE2的片段的变体由具有根据SEQID No.28或29的氨基酸序列的蛋白质组成。

26.根据权利要求24或25所述的融合蛋白，其中所述人ACE2的片段的变体还包含H374N和H378N突变，编号参考SEQ ID No.1。

27.根据权利要求26所述的融合蛋白，其中所述人ACE2的片段的变体由具有根据SEQID No.32或33的氨基酸序列的蛋白质组成。

28.根据权利要求24或25所述的融合蛋白，其中所述人ACE2的片段的变体还包含位置273处的突变，编号参考SEQ ID No.1。

29.根据权利要求28所述的融合蛋白，其中所述位置273处的突变是R273A突变。

30.根据权利要求28或29所述的融合蛋白，其中所述人ACE2的片段的变体由具有根据SEQ ID No.36或37的氨基酸序列的蛋白质组成。

31.根据权利要求24至30中任一项所述的融合蛋白，其中所述第二部分包含人IgG1或IgG4的Fc部分或者人IgG1或IgG4的Fc部分的变体。

32.根据权利要求31所述的融合蛋白，其中所述第二部分包含根据SEQ ID No.16的人IgG1的Fc部分。

33.根据权利要求32所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.15的氨基酸序列连接。

34.根据权利要求32或33所述的融合蛋白，其具有根据SEQ ID No.40或41的氨基酸序列。

35.根据权利要求31所述的融合蛋白，其中所述第二部分包含根据SEQ ID No.5的人IgG4的Fc部分。

36.根据权利要求35所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.4的氨基酸序列连接。

37.根据权利要求35或36所述的融合蛋白，其具有根据SEQ ID No.42或43的氨基酸序列。

38.根据权利要求31所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.44的序列的人IgG4的Fc部分的变体。

39.根据权利要求38所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.4的氨基酸序列连接。

40.根据权利要求38或39所述的融合蛋白，其具有根据SEQ ID No.45或46的氨基酸序列。

41.根据权利要求26和31至33中任一项所述的融合蛋白，其具有根据SEQ ID No.47或48的氨基酸序列。

42.根据权利要求28、29和31至33中任一项所述的融合蛋白，其具有根据SEQ ID No.49或50的氨基酸序列。

43.根据权利要求26、31、35和36中任一项所述的融合蛋白，其具有根据SEQ ID No.51或52的氨基酸序列。

44.根据权利要求28、29、35和36中任一项所述的融合蛋白，其具有根据SEQ ID No.53或54的氨基酸序列。

45.根据权利要求26、31、38和39中任一项所述的融合蛋白，其具有根据SEQ ID No.55或56的氨基酸序列。

46.根据权利要求28、29、38和39中任一项所述的融合蛋白，其具有根据SEQ ID No.57或58的氨基酸序列。

47.根据权利要求31所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.59的序列的人IgG1的Fc部分的变体或者具有根据SEQ IDNo.60的序列的人IgG4的Fc部分的变体。

48.根据权利要求47所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.59的序列的人IgG1的Fc部分的变体，并且所述第一部分和所述第二部分通过根据SEQ IDNo.15的氨基酸序列连接。

49.根据权利要求24、25、47和48中任一项所述的融合蛋白，其具有根据SEQ ID No.61或62的氨基酸序列。

50.根据权利要求26、47和48中任一项所述的融合蛋白，其具有根据SEQ ID No.63或64的氨基酸序列。

51.根据权利要求28、29、47和48中任一项所述的融合蛋白，其具有根据SEQ ID No.65或66的氨基酸序列。

52.根据权利要求47所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.60的序列的人IgG4的Fc部分的变体，并且所述第一部分和所述第二部分通过根据SEQ IDNo.4的氨基酸序列连接。

53.根据权利要求24、25、47和50中任一项所述的融合蛋白，其具有根据SEQ ID No.67或68的氨基酸序列。

54.根据权利要求26、47和50中任一项所述的融合蛋白，其具有根据SEQ ID No.69或70的氨基酸序列。

55.根据权利要求28、29、47和50中任一项所述的融合蛋白，其具有根据SEQ ID No.71或72的氨基酸序列。

56.融合蛋白，其包含：第一部分，所述第一部分包含人ACE2的片段或所述片段的变体，所述人ACE2具有根据SEQ ID No.1的氨基酸序列；以及第二部分，所述第二部分包含人IgG1的Fc部分的变体，所述变体具有根据SEQ ID No.59的序列，或人IgG4的Fc部分的变体，所述变体具有根据SEQ ID No.60的序列。

57.根据权利要求56所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.59的序列的人IgG1的Fc部分的变体，并且所述第一部分和所述第二部分通过根据SEQ IDNo.15的氨基酸序列连接。

58.根据权利要求56所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.60的序列的人IgG4的Fc部分的变体，并且所述第一部分和所述第二部分通过根据SEQ IDNo.4的氨基酸序列连接。

59.根据权利要求56至58中任一项所述的融合蛋白，其中所述人ACE2的片段由具有根据SEQ ID No.2的氨基酸序列的蛋白质组成。

60.根据权利要求56至58所述的融合蛋白，其中所述人ACE2的片段是由具有根据SEQID No.3的氨基酸序列的蛋白质组成的ACE2的胞外域。

61.根据权利要求56、57、59或60中任一项所述的融合蛋白，其具有根据SEQ ID No.73或74的氨基酸序列。

62.根据权利要求56或58至60中任一项所述的融合蛋白，其具有根据SEQ ID No.75或76的氨基酸序列。

63.根据权利要求56至60中任一项所述的融合蛋白，其中所述人ACE2片段的变体是人ACE2的酶促失活变体。

64.根据权利要求63所述的融合蛋白，其中所述人ACE2的酶促失活变体包含H374N和H378N突变，编号参考SEQ ID No.1。

65.根据权利要求63或64所述的融合蛋白，其中所述人ACE2的酶促失活变体由具有根据SEQ ID No.91或92的氨基酸序列的蛋白质组成。

66.根据权利要求63至65中任一项所述的融合蛋白，其具有根据SEQ ID No.77至80中任一者的氨基酸序列。

67.根据权利要求63所述的融合蛋白，其中所述人ACE2的酶促失活变体包含位置273处的突变，编号参考SEQ ID No.1。

68.根据权利要求67所述的融合蛋白，其中所述位置273处的突变是R273A突变。

69.根据权利要求67或68所述的融合蛋白，其具有根据SEQ ID No.81至84中任一者的氨基酸序列。

70.融合蛋白，其包含：

(a)第一部分，所述第一部分包含人ACE2的片段的变体，所述人ACE2具有根据SEQ IDNo.1的氨基酸序列，其中所述人ACE2片段的变体包含R273A突变，编号参考SEQ ID No.1，以及

(b)第二部分，所述第二部分包含人IgG的Fc部分或人IgG的Fc部分的变体。

71.根据权利要求70所述的融合蛋白，其中所述人ACE2的片段的变体由具有根据SEQID No.24或25的氨基酸序列的蛋白质组成。

72.根据权利要求70或71所述的融合蛋白，其中所述第二部分包含人IgG1或IgG4的Fc部分。

73.根据权利要求72所述的融合蛋白，其中所述第二部分包含根据SEQ ID No.16的人IgG1的Fc部分。

74.根据权利要求73所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.15的氨基酸序列连接。

75.根据权利要求70至74中任一项所述的融合蛋白，其具有根据SEQ ID No.85或86的氨基酸序列。

76.根据权利要求72所述的融合蛋白，其中所述第二部分包含根据SEQ ID No.5的人IgG4的Fc部分。

77.根据权利要求76所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.4的氨基酸序列连接。

78.根据权利要求76或77所述的融合蛋白，其具有根据SEQ ID No.87或88的氨基酸序列。

79.根据权利要求72所述的融合蛋白，其中所述第二部分包含具有根据SEQ ID No.44的序列的人IgG4的Fc部分的变体。

80.根据权利要求79所述的融合蛋白，其中所述第一部分和所述第二部分通过根据SEQID No.4的氨基酸序列连接。

81.根据权利要求79或80所述的融合蛋白，其具有根据SEQ ID No.89或90的氨基酸序列。

82.融合蛋白，其具有根据SEQ ID No.93或94的氨基酸序列。

83.核酸分子，其包含编码根据权利要求1至82中任一项所述的融合蛋白的核酸序列。

84.表达载体，其包含根据权利要求83所述的核酸分子。

85.宿主细胞，其包含根据权利要求83所述的核酸分子或根据权利要求84所述的表达载体。

86.用于产生根据权利要求1至82中任一项所述的融合蛋白的方法，其包括在合适的培养基中培养根据权利要求85所述的宿主细胞。

87.根据权利要求1至82中任一项所述的融合蛋白，其用于医学用途。

88.根据权利要求1至82中任一项所述的融合蛋白，其用于预防和/或治疗结合ACE2的冠状病毒的感染。

89.根据权利要求88所述使用的融合蛋白，其中所述结合ACE2的冠状病毒选自SARS、SARS-CoV-2以及NL63，优选地其为SARS-CoV-2。

90.根据权利要求88或89所述使用的融合蛋白，其中所述融合蛋白与抗病毒剂组合施用。

91.根据权利要求90所述使用的融合蛋白，其中所述抗病毒剂选自瑞德西韦、盐酸阿比朵尔、利托那韦、洛匹那韦、地瑞那韦、利巴韦林、氯喹及其衍生物、硝唑尼特、甲磺酸卡莫司他、托珠单抗、司妥昔单抗、沙利鲁单抗以及巴瑞克替尼磷酸盐。

92.根据权利要求88或89所述使用的融合蛋白，其中所述融合蛋白与抗体组合施用。

93.根据权利要求92所述使用的融合蛋白，其中所述抗体选自巴尼韦单抗、埃特司韦单抗、卡斯瑞韦单抗、依米得韦单抗、索托韦单抗以及它们的混合物。

94.根据权利要求1至82中任一项所述的融合蛋白，其用于治疗高血压病(包括高血压)、充血性心力衰竭、慢性心力衰竭、急性心力衰竭、收缩性心力衰竭、心肌梗死、动脉硬化、肾脏衰竭、肾衰竭、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、慢性阻塞性肺病(COPD)、肺动脉高压、肾纤维化、慢性肾衰竭、急性肾衰竭、急性肾损伤、炎性肠病以及多器官功能障碍综合征。

95.药物组合物，其包含有效量的根据权利要求1至82中任一项所述的融合蛋白以及药学上可接受的载剂或赋形剂。

96.根据权利要求95所述的药物组合物，其还包含抗病毒剂。