CN116710120A - 重组ace2-fc融合分子及其制备和使用方法 - Google Patents

重组ace2-fc融合分子及其制备和使用方法 Download PDF

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CN116710120A
CN116710120A CN202180069760.6A CN202180069760A CN116710120A CN 116710120 A CN116710120 A CN 116710120A CN 202180069760 A CN202180069760 A CN 202180069760A CN 116710120 A CN116710120 A CN 116710120A
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蔡宗義
丹尼斯·R·古利特
麦雅丝
安德鲁·韦特
史蒂文·K·伦迪
马克·吉尔克里斯特
贾汉·哈利利
肖洒
丁沐然
张勇
卓识
朱海
朱义
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Abstract

一种用于预防、降低病毒感染的风险或治疗病毒感染，或预防或治疗由病毒引起的受试者症状的方法，方法包括向受试者施用有效量的融合蛋白，其中，融合蛋白包含与Fc结构域共价融合的变体血管紧张素转换酶2(ACE2)结构域。相对于具有SEQ ID NO.1的全长野生型ACE2，变体ACE2结构域包括N‑端缺失、C‑端缺失或两者，以及变体ACE2结构域具有ACE2活性。病毒可以是SARS‑CoV、SARS‑CoV‑2或MERS‑CoV。症状包括严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)、急性呼吸窘迫综合征(ARDS)、肺动脉高血压(PAH)或2019年冠状病毒病(COVID‑19)。

Description

重组ACE2-FC融合分子及其制备和使用方法
相关申请的交叉引用
根据35 U.S.C.119(e)，本申请要求于2020年10月1日提交的美国临时申请序列号63/086,593的申请日的优先权，其全部公开内容通过引用并入本文。
技术领域
本申请涉及预防或治疗涉及血管紧张素转换酶2(ACE2)的疾病、症状或病症，例如冠状病毒病2019(COVID-19)和相关病症。
背景技术
除非本文另有说明，否则本部分中描述的材料不是本申请中权利要求的现有技术，并且不因为包含在本部分中而承认是现有技术。
COVID-19是由严重急性呼吸综合征(severe acute respiratory syndrome，SARS)冠状病毒2(SARS-CoV-2)引起的传染病。COVID-19的并发症可包括长期肺损伤、肺炎、急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)、外周和嗅觉神经损伤、多器官衰竭、败血性休克和死亡。2020年1月在《柳叶刀》上发表的对前41例确诊COVID-19病例的研究报告称，最早出现症状的日期为2019年12月1日。到2020年3月11日，世界卫生组织(WHO)宣布COVID-19爆发大流行病。截至2020年9月26日，188个国家和地区报告了超过3260万例病例，死亡人数超过99万，其中美国报告了超过750万例病例和20.5万例死亡病例。
2020年12月2日，英国药品和保健品监管局(MHRA)对辉瑞-BioNTech mRNA疫苗给予临时监管批准，成为第一个批准该疫苗的国家，也是西方世界第一个批准使用任何COVID-19疫苗的国家。从那时起，至少一个国家监管机构批准了更多类型的疫苗：来自Pfizer-BioNTech和Moderna的两种RNA疫苗；来自Sinopharm、Bharat Biotech和Sinovac的三种常规灭活疫苗；来自Sputnik V、Oxford-AstraZeneca和Janssen的三种病毒载体疫苗；以及一种肽疫苗(EpiVacCorona)。
截至2021年8月16日，CDC的疫苗有效性研究提供了越来越多的证据，表明可用的RNA COVID-19疫苗在现实条件下的保护效果与在临床试验环境中一样好。这些疫苗可降低已完全接种疫苗的人群感染COVID-19的风险，尤其是患重病的风险。华盛顿州的一项研究发现，与接种过疫苗的人相比，未接种疫苗的人检测出COVID-19阳性的可能性高出6倍，住院的可能性高37倍，死亡的可能性高67倍。CDC的数据显示，未接种疫苗的人感染的可能性高出5倍，住院的可能性高10倍，死亡的可能性高11倍。
血管紧张素转化酶2(ACE2)是一种含锌的金属酶，主要位于肺的肺泡细胞、小肠的肠细胞、动脉和静脉的内皮细胞、动脉的平滑肌细胞以及肺、动脉、心脏、肾、肠和其他组织中的其他细胞谱系的细胞膜上。ACE2通过平衡心血管、肾和呼吸系统中的血管紧张素转化酶活性来调节肾素-血管紧张素系统(renin angiotensin system，RAS)，表明了其在控制血压中的重要作用。ACE2在高血压、心脏功能、心功能和糖尿病的生理学中起保护作用。在急性呼吸窘迫综合征(ARDS)中，ACE、AngII和AT1R促进疾病发病机制，而ACE2和AT2R保护免于ARDS。此外，ACE2已被鉴定为严重急性呼吸综合征(SARS)冠状病毒的受体，并在严重急性呼吸综合征(SARS)发病机理中起关键作用。在冠状病毒家族中，至少有三种病毒SARS-CoV、MERS CoV和SARS-CoV-2使用它们的病毒蛋白之一(也称为Spike)结合人宿主细胞表面上的ACE2蛋白以用于病毒进入人细胞。
SARS-CoV-2是七种已知的感染人类的冠状病毒之一，包括SARS-CoV-1和MERS CoV病毒，其于2003年在亚洲和2012年在中东引起SARS爆发。对SARS-CoV-2病毒的免疫应答包括细胞介导的免疫和抗体产生的组合。尽管有超过1亿人从COVID-19中痊愈，(截至2021年1月)，但仍然不清楚在个体中对SARS-CoV-2病毒的自然免疫是否会持久。其中一个问题涉及病毒突变的持续累积，其可改变病毒抗原性谱并引起病毒突变株的再感染。截至2021年1月，在欧洲和南非鉴定的SARS-CoV-2病毒的变异株似乎传播如此迅速。这些变体菌株可能含有突变，这些突变最终增强病毒识别并感染到宿主细胞中，从而增加传染性和/或致病性。
另一个关注点涉及抗体依赖性增强(ADE)的现象。当次优抗体(suboptimalantibody)的结合增强病毒进入宿主细胞时，就会产生ADE。在冠状病毒中，靶向病毒刺突(S)糖蛋白的抗体促进ADE(Wan et al.,J.Virol.2020)。在SARS-CoV-1病毒的情况下，发现中和大多数变体的抗体能够增强突变病毒的免疫细胞进入，这反过来恶化了设计疫苗来抵抗的疾病。因此，ADE会妨碍疫苗开发，因为疫苗可能导致产生次优抗体。在这种情况下，在暴露于SARS-CoV-2病毒之前或之后，除了疫苗之外的任何预防策略都应被认为是规避ADE的可行替代方案。
在疫情早期，由于感染人数较少，“突变”变异病毒很少，因此逃逸突变株出现的机会较少。随着时间的推移，SARS-CoV-2开始进化为许多变体，并变得更具传播性。几种SARS-CoV-2变体因其潜在的传播性增加、毒力增加或对抗它们的疫苗效力降低而特别重要(Planas et al.,Nature,2020；Kim et al.,bioRxiv,2021)。为了对SARS-CoV-2变体进行分类，祖先类型为“A”型，衍生类型为“B”型。B型突变为包括B.1在内的其他类型，B.1是主要全球变异毒株的祖先。世界卫生组织已将α(B.1.1.7，2020年12月)、β(B.1.351，2021年1月)、γ(P.1，2021年1月)、κ(B.1.617.1)、δ(B.1.617.2，2021年5月)、λ(C.37)和其他变体命名。α变体和δ变体的传播性明显高于2020年初发现的原始病毒。
δ变体的传染性比α变体高约40％，并于2021春季成为优势菌株。到2021年8月下旬，δ变体占美国病例的99％，发现未接种疫苗的人患重病和住院的风险增加了一倍，甚至RNA疫苗的疫苗保护率也从91％降至66％。CDC的研究表明，COVID-19疫苗提供了55％的抗感染保护，80％的抗症状感染保护，至少90％的抗住院治疗保护。最近的研究表明，疫苗效力降低了53.1％、42-76％或64.6％，这可能是由于免疫力下降结合对高度感染的δ毒株的保护较差所致(Nanduri,et al.,MMWR.2021；Puranik et al.,medRxiv,2021；Seppala etal.,Eurosurveillance,2021)。CDC还报告，在美国7500多万完全接种疫苗的人中，有5814例突破性感染(即接种疫苗的个人因与疫苗旨在预防的疾病相同的疾病而患病)和74例死亡。突破性感染和相关死亡的发生率可能非常低，这表明了疫苗的有效性。另一方面，新病毒株如δ可能会更频繁地发生突破性感染，正如以色列所证明的那样，2021年8月超过一半的病例和住院病例发生在完全接种疫苗的个人中(Wadman，M.Science，2021)。对于那些有突破性感染的个体患者，特别是那些体弱的老年人，患重病、精神错乱、住院和死亡的风险明显较高(Antonelli,et al.,Lancet,2021)。
缓解SARS-CoV-2致病性的两种主要医疗干预措施包括主动和被动免疫；即，接种疫苗、单克隆抗体治疗和使用先前感染患者的恢复期血浆进行治疗(Taylor et al.,NatRev Immunol.,2021；Yan et al.,Pharmaceuticals.2021)。这些策略中的每一种都依赖于抗体结合和病毒抗原的中和，特别是刺突蛋白的受体结合结构域，它介导病毒进入携带ACE2受体的宿主细胞。任何影响刺突蛋白结构的病毒突变都可能影响抗体结合和中和刺突的能力，从而降低大多数现有疫苗和疗法的疗效。
因此，仍然非常需要有效治疗或预防涉及血管紧张素转化酶2(ACE2)的疾病或病症，诸如SARS-CoV2，尤其是其毒性更强的突变株。
发明内容
以下概述仅是说明性的，并不旨在以任何方式进行限制。除了上述说明性方面、实施例和特征之外，通过参考附图和以下详细描述，其他方面、实施例和特征将变得显而易见。
本申请提供了用于预防、降低病毒感染的风险或治疗病毒感染的方法，或预防或治疗受试者中由病毒引起的症状的方法等。
在一个实施例中，病毒可以是冠状病毒。在一个实施例中，病毒可以是SARS-CoV、SARS-CoV-2、MERS-CoV或其组合。
在一个实施例中，症状可以是由冠状病毒引起的任何症状。在一个实施例中，症状可以是严重急性呼吸综合征(SARS)、中东呼吸综合征、急性呼吸窘迫综合征(ARDS)、2019年冠状病毒病(COVID-19)或其组合。在一个实施例中，症状(疾病或病症)涉及血管紧张素转换酶2(ACE2)。在一个实施例中，症状可以是病毒感染，例如SARS-CoV-2、SARS-CoV、SARS刺突蛋白、冠状病毒、SARS病毒或其片段或组合的感染。
在一个实施例中，SARS-CoV-2病毒基本上包括δ毒株。在一个实施例中，SARS-CoV-2病毒包含刺突蛋白突变。在一个实施例中，突变被配置为增加病毒对ACE2结构域的结合亲和力。
在一个实施例中，该方法包括向受试者施用有效量的融合蛋白或融合蛋白复合物的步骤。在一个实施例中，融合蛋白包含与Fc结构域共价融合的变体血管紧张素转换酶2(ACE2)结构域。相对于具有SEQ ID NO.1的全长野生型ACE2，变体ACE2结构域可以包括N-端缺失、C-端缺失或两者，并且变体ACE2结构域具有ACE2活性。
在一个实施例中，融合蛋白包括与Fc结构域共价融合的变体血管紧张素转化酶2(ACE2)结构域。在一个实施例中，变体ACE2结构域相对于全长野生型ACE2包含N-端缺失、C-端缺失或两者。在一个实施例中，全长野生型ACE2结构域具有与SEQ ID NO.1具有至少70％、80％、90％、95％、97％或98％的序列同一性的氨基酸序列。在一个实施例中，变体ACE2结构域具有ACE2活性。
在一个实施例中，变体ACE2结构域包含与来自全长野生型ACE2的氨基酸序列片段具有至少75％、80％、85％、90％、95％、97％、98％或99％的序列同一性的氨基酸序列。在一个实施例中，该片段可以从选自全长野生型ACE2的残基1-17的氨基酸残基开始。在一个实施例中，该片段可以以选自全长野生型ACE2的残基615-740的氨基酸残基结束。例如，变体ACE2结构域可以具有这样的氨基酸序列，其与来自全长野生型ACE2的残基1-615、残基2-618、残基2-740、残基4-615、残基17-615、残基18-615、残基17-740、或起始残基和终止残基的任何其他组合的氨基酸序列片段具有至少98％或99％的序列同一性。
在一个实施例中，变体ACE2结构域包括与SEQ ID NO.3具有至少75％、80％、85％、90％、95％、97％、98％或99％的序列同一性的氨基酸序列。
在一个实施例中，变体ACE2结构域可具有比全长野生型ACE2更高的对SARS-CoV或SARS Spike蛋白的结合亲和力。例如，变体ACE2结构域对SARS-CoV或SARS刺突蛋白(spikeprotein)可具有KD为0.1-100nM的结合亲和力(binding affinity)。
在一个实施例中，变体ACE2结构域可具有比全长野生型ACE2更高的对SARS-CoV或SARS Spike蛋白的结合亲合力。例如，变体ACE2结构域对SARS-CoV或SARS Spike蛋白可具有KD小于10nM的结合亲合力。
在一个实施例中，融合蛋白对κ变体的亲和力小于1.0E-12。在一个实施例中，融合蛋白对δSARS-CoV-2株的结合亲和力高于Wuhan-Hu-1株。在一个实施例中，对δSARS-CoV-2株的结合亲和力是Wuhan-Hu-1株的至少3倍。
在一个实施例中，Fc结构域来源于自免疫球蛋白的Fc结构域。免疫球蛋白可以为IgG1、IgG2、IgG3、IgG4、IgA1(d-IgA1、S-IgA1)、IgA2、IgD、IgE或IgM。在一个实施例中，Fc结构域可包含Fc铰链区。在一个实施例中，Fc铰链区可被工程改造为C220S。在一个实施例中，与野生型Fc结构域相比，Fc结构域可包含选自K322A、L234A和L235A的无效突变。在一个实施例中，野生型Fc结构域具有具有SEQ ID NO.5具有至少98％或99％的序列同一性的氨基酸序列。
在一个实施例中，Fc域可能缺乏效应子功能。在一个实施例中，Fc结构域可能缺乏抗体依赖性细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)和补体依赖性细胞毒性(CDC)。在一个实施例中，Fc结构域包含IgG1 Fc结构域。
在一个实施例中，Fc结构域包含与SEQ ID NO.6具有至少75％、80％、85％、90％、95％、97％、98％或99％的序列同一性的氨基酸序列。
在一个实施例中，融合蛋白可具有与SEQ ID NO.7、9、11、13、15、16、17、18、19或21具有至少75％、80％、85％、90％、95％、97％、98％或99％的序列同一性的氨基酸序列。
在一个实施例中，融合蛋白的分子量可为约50-250kDa。在一个实施例中，融合蛋白的分子量可为50kDa、60kDa、70kDa、80kDa、90kDa、100kDa、120kDa、150kDa、180kDa、200kDa、250kDa或其间的任何数值。
在一个实施例中，融合蛋白复合物可以是本文公开的融合蛋白的同型二聚体。在一个实施例中，融合蛋白复合物包含两个变体ACE2结构域。在一个实施例中，融合蛋白复合物包含至少两种融合蛋白。在一个实施例中，两个融合蛋白通过一个或两个二硫键配对。在一个实施例中，二硫键位于Fc结构域的铰链区。
在一个实施例中，融合蛋白或融合蛋白复合物对SARS-CoV-2、SARS-CoV或SARS刺突蛋白或其片段具有结合亲和力。在一个实施例中，结合亲和力的平衡解离常数(KD)不大于0.1nM、0.5nM、1nM、2nM、3nM、5nM、10nM、20nM、25nM、30nM、40nM、50nM、60nM、80nM或其间的任何数值。
在一个实施例中，融合蛋白或融合蛋白复合物对SARS-CoV-2、SARS-CoV或SARS刺突蛋白或其片段具有结合亲合力。在一个实施例中，结合亲合力的平衡解离常数(KD)不大于1.0E-12、0.001nM、0.01nM、0.05nM、1nM、2nM、3nM、5nM、10nM或其间的任何数值。
在一个实施例中，融合蛋白或融合蛋白复合物的比酶活性为约50pmol/min/μg至约5000pmol/min/μg。在一个实施例中，融合蛋白的比酶活性为约568pmol/min/μg。
融合蛋白以有效剂量施用，用于治疗和预防本文公开的感染或疾病。在一个实施例中，每次治疗施用的融合蛋白的剂量为约1mg/Kg至约200mg/Kg，约5mg/Kg至大约100mg/Kg，约3mg/Kg至约70mg/Kg体重，或约10mg/Kg至150mg/Kg。
在一个实施例中，每天施用的融合蛋白的剂量小于或等于约100、120、140、150、180、200mg/Kg体重。在一个实施例中，融合蛋白以小于或等于约25、50、70、90、100、150、200mg/Kg体重的剂量每天施用两次。
在一个实施例中，融合蛋白作为液体制剂施用。在一个实施例中，融合蛋白以溶液中的液体悬浮液的形式施用。在一个实施例中，溶液可包括包含盐、碳水化合物、表面活性剂或其组合。在一个实施例中，盐可以是氯化钠、组氨酸盐酸盐或其组合。在一个实施例中，碳水化合物可以是蔗糖、葡萄糖或其组合。在一个实施例中，表面活性剂可以是聚山梨醇酯80。
在一个实施例中，液体制剂可以包括浓度为约2mg/ml至约20mg/ml、约5mg/ml至约10mg/ml或约5mg/ml～约20mg/ml的融合蛋白。
本申请中公开的方法可用于治疗或预防受试者的病毒感染、急性呼吸窘迫综合征、肺动脉高血压或急性肺损伤。在一个实施例中，融合蛋白的施用可以防止受试者感染SARS-CoV-2病毒。在一个实施例中，融合蛋白的施用可以降低受试者感染SARS-CoV-2病毒的风险。在一个实施例中，融合蛋白的施用可以防止患有SARS-CoV-2病毒感染的受试者住院。在一个实施例中，融合蛋白的施用可以降低患有SARS-CoV-2病毒感染的受试者住院的风险。在一个实施例中，融合蛋白的施用可以缩短患有SARS-CoV-2病毒感染的受试者的住院时间。在一个实施例中，融合蛋白的施用可以防止患有SARS-CoV-2病毒感染的受试者的氧合和通气。在一个实施例中，融合蛋白的施用可以减少患有SARS-CoV-2病毒感染的受试者对氧合和通气的需求。在一个实施例中，融合蛋白的施用可以防止患有SARS-CoV-2病毒感染的受试者死亡。在一个实施例中，融合蛋白的施用可以降低患有SARS-CoV-2病毒感染的受试者的死亡风险。在一个实施例中，融合蛋白的施用可以降低患有SARS-CoV-2病毒感染的受试者的COVID症状的严重程度。
在一个实施例中，该方法可以包括静脉内、皮下、通过鼻腔通道(诸如鼻喷雾剂)或通过肺通道给予融合蛋白或融合蛋白复合物。在一个实施例中，融合蛋白可以通过每日输注来施用。在一个实施例中，融合蛋白可以通过每日肌肉内注射施用。
在一个实施例中，融合蛋白可以与抗病毒试剂、免疫调节试剂或其组合共同施用。在一个实施例中，抗病毒药物可以是法匹拉韦、利巴韦林、加利地韦(galidesivir)、瑞德西韦(remdesvir)或其组合。
在一个实施例中，受试者是人。本申请中公开的方法可用于受试者，该受试者具有选自由以下组成的组的至少一种风险因素：年龄大于或等于65岁、中度或重度免疫系统受损、代谢综合征、对COVID疫苗过敏以及在接种COVID疫苗后具有低免疫应答或无免疫应答。在一个实施例中，受试者可能患有癌症、慢性肾脏疾病、慢性肺病、糖尿病或心脏病。
在另一方面，本申请提供了用于治疗涉及血管紧张素转化酶2(ACE2)的疾病或病症的药物组合物。在一个实施例中，药物组合物物包括融合蛋白或如其所公开的融合复合物和药学上可接受的载体。在一个实施例中，药物组合物还包括抗病毒剂。在一个实施例中，药物组合物包含如其所公开的蛋白质缀合物和药学上可接受的载体。
在一个实施例中，本申请提供了一种液体组合物，其包含本文公开的融合蛋白。在一个实施例中，液体组合物包含每剂量约100mg至约20000mg、约200mg至约10000mg、约100mg至约10000mg或约500mg至约10000mg的融合蛋白含量。
在一个实施例中，以重量计，液体组合物包含浓度为约0.1％至约10％、约0.5％至约5％、约0.5％至约1％或约0.5％至约2％的融合蛋白。
附图说明
结合附图，根据以下描述和所附权利要求，本公开的前述和其他特征将变得更加显而易见。应当理解的是，这些附图仅描绘了根据本公开布置的若干实施例并且因此不应被认为是对其范围的限制，将通过使用附图以附加的特征和细节来描述本公开，其中：
图1显示了(1A)ACE2功能域和工程改造的Fc(无效)片段(SI-69R2和SI-69R4)之间的重组融合蛋白图，(1B)SI-F019融合蛋白的序列，缺乏N-端17-氨基酸信号肽的翻译后修饰的SI-69R2，(1C)指示SI-F019融合蛋白复合物是同型二聚体的尺寸排阻色谱，和(1D)SI-F019-Spike蛋白复合物图；
图2显示了SI-F019而非SI-69R4对TMPRSS2依赖性水解具有抗性(2A)，并且SI-F019的酶活性可在体外荧光测定中定量(2B)；
图3表明SI-F019对VeroE6细胞的活SARS-CoV-2感染的剂量依赖性阻断在测试的所有三种MOI的病毒中达到100％；
图4显示在0.01的MOI下，在SARS-CoV-2或SARS-CoV-1病毒感染1h后，以10fM或更高的浓度加入SI-F019保护了一部分Vero E6细胞免于经受细胞裂解；
图5显示了在与假病毒预孵育后，SI-F019以剂量依赖性方式抑制病毒感染并在较高浓度下实现完全抑制(IC50＝32.56nM)；
图6显示了内化/感染介导测定的结果，其中在THP1(pH7.2)(6A)、THP1(pH6.0)(6B)和Daudi(6C)中48h，当用测试浓度的SI-FO19预处理时，不存在指示假病毒(PsV)的GFP信号摄取，而低GFP信号与SI-69C1(抗S1抗体)和SI-69R3(SARS-CoV-2ACE-2Fc WT)以及培养基、缓冲液和ACE2-his(SI-69C1)相关；
图7显示了如通过指示PsV感染的GFP信号测量的，SI-F019可以与天然抗SARS-CoV-2抗体或ACE2-Fc(野生型)融合蛋白竞争以阻断Fc介导的抗体依赖性增强(ADE)；
图8显示了如通过使用抗Spike抗体和抗人Fc抗体检测的，表达SARS-CoV-2Spike蛋白的HEK293-T细胞的流式细胞仪分析；
图9显示了通过几何平均荧光强度(gMFI)测量的SI-F019与表达SARS-CoV-2Spike蛋白的HEK293-T细胞的剂量依赖性结合；
图10展示了抗体依赖性细胞毒性(ADCC)测定的FACS分析，显示如通过钙黄绿素-AM和碘化丙啶染色测量的，人抗S1抗体(SI-69C3)指导人NK细胞靶向表达SARS-CoV-2Spike蛋白的HEK293-T细胞；
图11显示当与人抗S1抗体(SI-69C3)相比时，在ADCC测定中SI-F019和对照分子对HEK293-T细胞的剂量结合反应(11A)，以及SI-F019在100μM和100nM之间的治疗剂量下不介导ADCC，而其具有野生型Fc的变体(SI-69R3)以剂量依赖性方式介导ADCC，即使活性水平较低(11B)；
图12显示了如通过表达SARS-CoV-2S蛋白的HEK293-T细胞的活力所测量的，Fc无效突变使得SI-F019能够在体外降低血清介导的补体依赖性细胞毒性(CDC)；
图13显示了通过测量在各种处理后表达SARS-CoV-2S蛋白的HEK293-T细胞的活力，SI-F019在体外不诱导血清补体依赖性细胞毒性(CDC)(13A)；并且SI-F019的Fc无效突变在体外处理96h后对后续的细胞生长没有影响(13B)；
图14显示了SI-F019在PBMC培养物中不引起细胞因子以可溶性或平板结合形式的释放：(14A)IFNγ；(14B)TNFα；(14C)GM-CSF；(14D)IL-2；(14E)IL-10；(14F)IL-6；(14G)IL-1β；(14H)IL-12p70；以及(14I)MCP-1。
图15显示了SI-F019(15a)和中和抗体对新冠肺炎RBD变体的结合动力学(亲和力)的生物膜层干涉技术测量，中和抗体包括Bamlanivimab(SI-69C4)(15b),Casirivimab(SI-69C5)(15c)、Etesevimab(SI-69C6)(15d)、Imdevimab(SI-69C7)(15e)、Cilgavimab(SI-69C8)(15f))和Tixagevimab(SI-69C9)(15g)；
图16显示了SI-F019(16a)和中和抗体对RBD变体的结合动力学(亲和力)的生物膜层干涉测量法，中和抗体包括Bamlanivimab(SI-69C4)(16b)、Casirivimab(SI-69C5)(16c)、Etesevimab(SI-69C6)(16d)、Imdevimab(SI-69C7)(16e)、Cilgavimab(SI-69C8)(16f)和Tixagevimab(SI-69C9)(16g)；以及
图17显示了SI-F019保护表达ACE2的293T细胞免受病毒抑制的效力，在荧光素酶报告基因测定中使用S蛋白包装的假病毒(NICPBP)变体(17a)，以及IC50与结合亲和力(17b)或亲合力(17c)之间的线性相关性表明SI-F019的竞争性抑制。
具体实施方式
在下面的详细描述中，参考了构成其一部分的附图。在附图中，除非上下文另有规定，否则相似的符号通常标识相似的组件。在详细描述、附图和权利要求中描述的说明性实施例并不意味着是限制性的。在不脱离本文所呈现的主题的精神或范围的情况下，可利用其他实施例，且可作出其他改变。将容易理解的是，如本文中一般性描述的以及在附图中示出的本公开的方面可以以各种各样的不同配置来布置、替换、组合、分离和设计，所有这些在本文都是明确地预期的。
本申请尤其涉及融合蛋白如重组人ACE2-Fc融合蛋白的产生和表征。在一些实施例中，这些融合蛋白能够保护人宿主细胞的膜ACE2免受病毒颗粒或病毒的侵害。在一个实施例中，病毒颗粒或病毒可以利用病毒刺突蛋白在感染后使病毒进入宿主细胞。在一个实施例中，病毒颗粒包括但不限于SARS-CoV-2病毒、COVID-19病毒、SARS-CoV-2的变体和其他冠状病毒。在一个实施例中，病毒可引起严重急性呼吸综合征(SARS)。在一个实施例中，SARS可以包括冠状病毒病2019或COVID-19。
在一个实施例中，重组人ACE2-Fc融合蛋白可以是ACE2锌金属肽酶结构域(也称为ACE2胞外结构域，ACE2-ECD)和IgG1Fc片段的融合蛋白。在一个实施例中，融合蛋白是SI-F019、ACE2-ECD和IgG1 Fc片段的融合蛋白，具有根据EU编号系统的C220S、L234A、L235A和K322A的突变(表1和图1)。活性ACE2-ECD保持宿主受体-病毒相互作用的结构构象。IgG1 Fc片段中的每个突变可削减某些免疫应答。突变C220S可去除未配对的半胱氨酸以配对重链和轻链，从而提供避免蛋白质形成聚集、提高蛋白质稳定性和提高生产效率和可扩展性等技术优势。L234A和L235A的引入可以降低Fc的效应子功能，例如抗体依赖性细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)。K322A突变可以降低C1q结合触发的补体依赖性细胞毒性(CDC)。SI-F019被设计用于中和SARS-CoV-2病毒，同时触发较少的效应子应答。
除非上下文不合适，否则本文所用的术语“一”、“一个”和“该”被定义为意指“一个或多个”并且包括复数。
术语“重组融合蛋白”是指通过对编码两个或多个最初编码不同蛋白质的基因的融合基因进行基因工程而产生的蛋白质。
术语“ACE2-Fc”指人ACE2蛋白片段和人免疫球蛋白的片段可结晶区(Fc区)的工程片段的重组融合蛋白，其中人免疫球蛋白包括但不限于IgG1、IgG2、IgG3、IgG4、IgA1(d-IgA1、S-IgA1)、IgA2、IgD、IgE和IgM。
术语“刺突蛋白(spike)”、“Spikes”、“S蛋白”或变体是指负责允许病毒附着(“S1亚基”或“S1蛋白”)并与宿主细胞膜融合(“S2亚基”或“S2蛋白”)的蛋白。在COVID-19的情况下，SARS-CoV-2对人细胞上的ACE2受体具有足够的亲和力以将它们用作细胞进入的机制，并且SARS-CoV-2对人ACE2的亲和力高于原始SARS病毒。
术语“Fc结构域”、“Fc片段”和“Fc区”是指来源于铰链的IgG、IgA和IgD抗体同种型中的Fc区的相同结构域或片段(分别为“Fc结构域”和“Fc片段”)，以及抗体的两条重链的第二和第三恒定结构域(CH2-CH3)。
术语“亲和力(affinity)”是指两种多肽之例如受体/配体、ACE2/刺突蛋白或其变体间吸引力的量度。两个多肽之间的内在吸引力可以表示为特定相互作用的结合亲和力平衡常数(KD)。KD结合亲和力常数可以例如通过生物膜层干涉技术来测量。
术语“亲合力(avidity)”是指单个非共价结合相互作用的多重亲和力的累积强度，例如在蛋白质受体与其配体之间，并且通常称为功能亲和力。因此，亲合力不同于描述单一相互作用的强度的亲和力。
术语“抗原性漂移(antigenic drift)”是指感染性病毒的随机遗传突变，其产生抗原性具有微小变化的新病毒株，防止由先前病毒株感染的抗体可能对该抗原性无效。
术语“细胞因子释放综合征”(CRS)是指在严重的COVID-19病例中与炎性介质水平升高相关的CRS，该炎性介质包括细胞因子和趋化因子，例如白介素(IL)-2、IL-6、IL-7、IL-10、肿瘤坏死因子(TNF)、粒细胞集落刺激因子(G-CSF)、单核细胞趋化蛋白-1(MCP1；也称为CCL2)、巨噬细胞炎性蛋白1α(MIP1α；也称为CCL3)、CXC-趋化因子配体10(CXCL10)、C-反应蛋白、铁蛋白和DSARS-CoV-2感染后的血液中-二聚体。
术语“中和抗体”是指通过中和其具有的任何生物学效应来保护细胞免受病原体或传染性颗粒侵害的抗体。中和作用使颗粒不再具有传染性或致病性。中和抗体是过继性免疫系统针对病毒、细胞内细菌和微生物毒素的体液反应的一部分。通过特异性结合感染性颗粒的表面结构(抗原)，中和抗体可防止颗粒与其可能感染和破坏的宿主细胞相互作用。由于中和抗体而产生的免疫力也称为杀菌免疫力，因为免疫系统会在任何感染发生之前消除感染性颗粒。
术语“疫苗”是指对特定传染病提供主动获得性免疫的生物制品。疫苗可以是预防性的(预防或11改善未来自然或“野生”病原体感染的影响)或治疗(对抗已经发生的疾病)。
术语“突破性感染”是指接种疫苗的个体患上疫苗旨在预防的相同疾病的情况。突破性感染的特征取决于病毒本身。与自然感染相比，接种疫苗的个体感染通常会导致较轻的症状并且持续时间较短。突破性感染的原因包括年龄、病毒和中和抗体的突变、疫苗的使用或储存不当。
术语“消除性免疫”是指由于中和抗体能够通过与病原体(例如所有SARS-CoV-2变体)结合并阻断细胞进入所需的分子(即由变体编码的刺突)来抑制传染性，可以完全防止感染。由于突破性感染，COVID-19疫苗和中和抗体都不能提供完全的消除性免疫。根据这些定义，SI-F019可用作治疗性疫苗，以实现对SARS-CoV-2病毒变体以及任何其他使用ACE2作为病毒进入人体细胞的SARS病毒的治疗性消除性免疫。
实施例
实施例1.重组ACE2-Fc融合蛋白的克隆、表达和纯化
人膜ACE-2是介导SARS-CoV病毒进入人宿主细胞的关键受体。人ACE2蛋白具有至少三个功能域：信号肽(残基1-17)、锌金属肽酶结构域(残基18-615)和TMPRSS2蛋白酶切割位点(残基697-716)(SEQ ID NO.1为来自Genbank号NP_001358344.1的全长人ACE2蛋白质序列)，其中SARS-CoV病毒蛋白、Spike与锌金属肽酶结构域相互作用(SEQ ID NO.3为残基1-615截短的ACE2的蛋白质序列。另一方面，人抗体的Fc区(SEQ ID NO.5)能够与许多免疫细胞上的Fc受体(FcR)和补体系统的一些蛋白质相互作用。IgG1 Fc区的每个Fc片段(根据EU编号系统)在C220含有半胱氨酸，其可以固有地与κ或λ轻链形成二硫键。为了降低具有可能使蛋白质去稳定和/或失活的游离半胱氨酸的风险，C220可由丝氨酸(C220S)或其他氨基酸取代。为了减少Fc与FcγR和C1q的结合，可以将其他点突变如K322A、L234A和L235A工程改造成野生型IgG1 Fc片段。携带四个突变的IgG1 Fc片段统称为IgG1 Fc无效(SEQ IDNO.6)。
重组人ACE2-Fc融合蛋白(如表1所列)经工程改造以产生可溶性融合蛋白，其中SI-69R2(SEQ ID NO.7)为不具有TMPRSS2蛋白酶切割位点的截短的ACE2片段与IgG1Fc无效片段的重组融合蛋白。产生其他重组融合蛋白以提供Ig同种型的Fc片段，如SI-69R2-G4(IgG4 Fc，SEQ ID NO.9)、SI-69R2-A1(IgA1 Fc,SEQ ID NO.11)、SI-69R2-A2(IgA2 Fc，SEQID NO.13)、或野生型IgG1 Fc片段(IgG1 Fc，SEQ ID NO.19)。还产生了具有所有三个结构域和野生型IgG1 Fc片段的截短的ACE2的重组融合蛋白(SI-69R4，1-740，SEQ ID NO.21)。在所有重组ACE2-Fc融合蛋白中，信号肽(ACE2残基1-17)可以用不同长度的其他信号肽替换，而不影响人ACE蛋白或ACE2-Fc融合蛋白中其他结构域的功能。
将表1中编码融合蛋白的重组融合基因克隆到pCGS3.0(如SI-69R2)或pTT5表达载体(如SI-69R4和SI-69R10)中并在ExpiCHO细胞中表达。按照标准蛋白表达方案纯化所有融合蛋白，使用0.22μm滤器灭菌，并保存在4℃的冷冻保存缓冲液中。在表达和纯化过程中，每个重组融合蛋白可以进行翻译后修饰，包括N-糖基化和N-端信号肽(17个氨基酸)的裂解。在SI-69R2的情况下，纯化的融合蛋白被赋予新的名称SI-F019。
如图1A和1B所示，SI-F019保留了截短的ACE2片段(残基18-615)，其包含人ACE2的锌金属肽酶结构域(残基19-611)，但不包含TMPRSS2蛋白酶切割位点。此外，SI-F019保留了没有与Fcγ受体结合的IgG1 Fc无效片段。这样，预期可溶性形式的SI-F019不会结合外周血中的任何靶细胞。
SI-F019融合蛋白可能进行翻译后修饰，例如N-糖基化和通过Fc区的两个二硫键连接的同源二聚化。为了评估SI-F019二聚体的实际分子量，在多角度光散射(MALS)、吸光度(UV)和/或折射率(RI)浓度检测器技术的组合中使用分析型尺寸排阻色谱法(SEC)，如图1C中所示。该方法结合了通过分子大小的色谱分离和通过光散射(LS)的绝对摩尔质量的测定，而不受分子量标准校准的限制。SI-F019表现出209.6kDa的平均总分子量(主峰)，其中SI-F019二聚体及其修饰物(即聚糖)的分子量分别测量为189.3kDa和20.3kDa。在其氨基酸的理论计算中，SI-F019单体的分子量为95.1kDa。因此，纯化的SI-F019融合蛋白复合物是同型二聚体，而SI-F019蛋白复合物是指作为单体或二聚体的SI-F019与其他蛋白如刺突蛋白和效应蛋白之间的蛋白-蛋白相互作用。SI-F019-Spike蛋白复合物的形成(如图1D所示)是该机制的基础，通过该机制，SI-F019作为一种候选抑制剂可防止SARS-CoV-2病毒与膜ACE2对接以使病毒进入宿主人体细胞。
实施例2：SI-F019对刺突、Fc受体和C1q的结合
SI-F019被设计成通过阻止刺突蛋白与人宿主细胞上的膜ACE2蛋白结合来阻断SARS-CoV病毒进入人体。刺突是冠状病毒最显著的特征，其是负责冠状或环状表面的球状结构。刺突蛋白通常由糖蛋白组成，每个刺突由Spike蛋白的三聚体组成，而S蛋白又由S1和S2亚基组成。同源三聚体Spike蛋白介导病毒和宿主细胞之间的受体结合和膜融合。S1亚基形成刺突的头部并具有受体结合结构域(RBD)。S2亚基形成茎，其将刺突锚定在病毒包膜中，并且在蛋白酶激活时能够融合。在功能活性状态下，当病毒在宿主细胞的蛋白酶如组织蛋白酶家族和跨膜蛋白酶丝氨酸2(TMPRSS2)的作用下与宿主细胞结合并融合时，S1和S2的亚基复合物分裂成单个亚基。刺突在冠状病毒感染过程的病毒进入中起重要作用。在COVID-19的情况下，SARS-CoV-2病毒与宿主细胞表面上的膜结合的ACE2受体对接，刺突和ACE2的功能域之间的相互作用通过触发病毒包膜和宿主细胞膜之间的融合而引起病毒核衣壳释放到宿主细胞细胞质中。
评估了SI-F019的ACE-Fc融合蛋白与病毒刺突蛋白的结合亲和力和亲合力。在生物膜层干涉技术分析中，刺突蛋白的样品包括SARS-CoV-2刺突三聚体、SARS-CoV-2S1蛋白、SARS-CoV-2S1蛋白RBD结构域和SARS-CoV-1RBD结构域(表2)。这些试剂购自ACROBiosystems。结合亲和力测定测量了固定在抗人IgG Fc捕获生物传感器尖端表面(AHC)上的SI-F019与溶液中的刺突蛋白或其亚基的结合。亲合力测定测量了固定在链霉抗生物素生物传感器尖端(SA)表面上的生物素化刺突蛋白与溶液中的SI-FO19的结合。这些试剂通过NHS酯活化反应进行化学生物素化，生物素/蛋白质的化学计量比为2:1。数据分析使用1:1拟合模型计算结合亲和力和亲合力。结果表明SI-F019对这些刺突蛋白、片段或结构域的结合亲和力和亲合力似乎在它们各自的以纳摩尔(nM)计的KD范围内(表2)。该特征和信息数据可以是用于测量具有指示SARS-CoV-2变体中潜在抗原漂移的病毒刺突蛋白变体的SI-F019蛋白复合物的有用参考。事实上，在SARS-CoV-2病毒的某些毒株中已经发现了这种类型的病毒突变，例如刺突蛋白中的D614G(Zhang等人，2020)，其改变了病毒对膜ACE2的亲和力和病毒进入宿主细胞。
与其结合至刺突并行，通过使用生物膜层干涉技术评估SI-F019与人FcγR、C1q和FcRn的结合。如表3所示，未检测到与FcγR(包括FcγRI、FcγRIIa、FcγRIIb和FcγRIIIa)的结合，也未检测到与C1q的结合。然而，SI-F019确实与FcRn结合，在KD为37.6nM时测定结合亲和力，其与人IgG1 Fc区相当。
实施例3.SI-F019对TMPRSS2蛋白酶活性具有抗性
人ACE2通过TMPRSS2进行膜蛋白酶水解，单体细胞外ACE2从细胞中脱落，这可以在血清中容易检测到。在重组ACE2-Fc融合蛋白中，截短的ACE2结构域与Fc片段融合，但仍保持与病毒刺突蛋白的结合亲和力。
SI-F019被工程改造为在截短的ACE2结构域中不含TMPRSS2切割位点。如图1所示，SI-F019含有残基18-615，而SI-69R4编码包括TMPRSS2切割位点的所有三个ACE2结构域(残基：1-740，SEQ ID NO.21)。为了证明SI-F019没有TMPRSS2特异性蛋白水解，将SI-69R4用作对照。为了进行TMPRSS2特异性水解的测定，根据Genbank：NP_001358344.1克隆、表达并纯化TMPRSS2(106-492)催化结构域。如图2A所示，在不存在TMPRSS2的情况下，SI-F019和SI-69R4均稳定地迁移至它们各自的分子量(作为还原(reducing)、变性条件下的单体)。当添加TMPRSS2时，SI-F019显示出其对TMPRSS2的抗性，而SI-69R4进行了蛋白水解，表明其对TMPRSS2的敏感性与预期的一致。因此，SI-F019是稳定的并且对TMPRSS2介导的蛋白酶活性具有抗性。
实施例4.SI-F019发挥ACE2的酶活性
SI-F019是截短的ACE2(残基18-615)和IgG1 Fc无效片段的融合蛋白。截短的ACE2编码一种锌金属肽酶，其酶活性可以通过使用已建立的测定法重新评估。具有MCA(7-甲氧基香豆素-4-乙酸)荧光标签的ACE2的肽底物[MCA-YVADAPK(Dnp)-OH荧光肽底物]用于测量SI-F019的ACE2酶活性。制备MCA分子作为游离荧光团定量的标准曲线校准，并将底物在DMSO中稀释至0.97mg/ml。将SI-F019稀释至100、200和300ng/ml并用于体外裂解荧光肽以释放游离MCA。在室温下将该测定孵育20分钟，并在2分钟间隔的时间点收集荧光信号的数据。
使用MCA标准曲线以摩尔计对裂解的MCA进行定量。根据如图2B所示的线性曲线的斜率(MCA量对时间)测定酶活性。SI-F019在所有三种浓度下显示良好的线性(R2>0.99)，表明肽的稳定裂解是浓度依赖性的。为了计算酶活性，将斜率除以SI-F019的质量数(μg)。最终的比酶活性为568pmol/min/g。SI-F019保留了膜ACE2的酶活性的事实表明ACE2的独立结构域也保留了宿主受体-病毒相互作用的结构构象。
实施例5.SI-F019抑制活SARS-CoV-2感染VeroE6细胞
测试SI-F019体外抑制活SARS-CoV-2感染和VeroE6(ATCC：CRL-1586)细胞裂解的能力。将1.5-1200nM的SI-F019测试浓度与3种浓度的活SARS-CoV-2病毒(USA-WA1/2020株，代表100倍范围的感染复数，MOI)预孵育1h，然后加入到90％汇合的VeroE6细胞单层中。1h后，去除含有病毒的培养基，并替换为含有匹配测试浓度的SI-F019的培养基，测试一式三份进行。72h后通过中性红染料的摄取来测量细胞活力，并通过与其中在没有SI-F019的情况下以各MOI加入病毒的孔比较确定裂解性病毒感染的抑制百分比。使用GraphPad Prism软件计算各病毒浓度(1MOI＝40,000个病毒颗粒)的50％抑制浓度(IC50)，并显示在每张图上。SI-F019与活SARS-CoV-2的预孵育导致感染的剂量依赖性阻断，在测试的所有三种MOI的病毒中达到100％。如图3所示，SI-F019在1.0的MOI下中和多达40,000个病毒颗粒，IC50为97.62nM。在0.1和0.01的MOI下，SI-F019能够分别在79.95nM和36.5nM的IC50下阻断感染。
实施例6.SI-F019减少病毒复制和再感染
测试了SI-F019抑制复制和再感染的能力，即从以前感染了低MOI的SARS-CoV-2或SARS-CoV-1病毒的细胞向VeroE6细胞进一步转移感染的能力。将90％汇合单层中的VeroE6细胞(约20,000个细胞)暴露于SARS-CoV-2(USA-WA1/2020株)或SARS-CoV-1(Urbani2003000592株)1h，MOI为0.01(计算为400个病毒感染性颗粒)。洗去游离病毒颗粒后，将SI-F019以10fM-100nM的范围一式三份加入细胞中，并将细胞培养物保持72h。通过中性红染料摄取来测定细胞活力，并计算病毒细胞毒性的抑制％。使用无病毒或无药物条件(NVND)下的最大吸光度表示100％细胞活力，在每个平板上归一化吸光度值，并使用下式确定病毒/无药物条件(VND)下的平均吸光度值：
细胞存活％＝[(孔OD540-VND OD540)/(NVND OD540-VND OD540)]*100
如图4所示，以10fM的浓度加入SI-F019保护Vero E6细胞免受二次感染。以0.01的MOI感染SARS-CoV-2或SARS-CoV-1病毒1h的培养物使细胞裂解减少至少20％。然而，当SI-F019的浓度以10倍增量增加至100nM时，在该测定中未观察到保护的显著增加。该发现表明，向感染低滴度病毒的细胞中加入SI-F019可以降低病毒的传播以及细胞毒性的程度，即使在低浓度下也是如此。
实施例7.SI-F019抑制HEK293T-ACE2细胞的假病毒感染
HEK293T(ATCC:CRL-3216)-3D4通过慢病毒转导人ACE2蛋白产生克隆细胞系。表达的人ACE2的功能通过酶底物转化测定并通过FACS的特异性抗体的结合来证实。含有荧光素酶报道基因的SARS-CoV-2S蛋白包装的假病毒获自国家药品生物制品检定所(NationalInstitute for the Control of Pharmaceutical&Biological Products)。根据制造商的说明书进行测试。将S-假病毒原液在MRD为20的培养基中稀释，以产生300TCID50/孔的病毒载量。将浓度为0.07-1500nM的SI-F019与稀释的病毒溶液预孵育1h。将HEK293T-3D4细胞分散在96孔板中。1h后，将混合物加入到细胞板中。孵育24h后，通过测试荧光素酶活性来测量感染的细胞。使用GraphPad Prism软件计算确定病毒载量的50％抑制浓度(IC50)。图5显示了在与假病毒预孵育后，SI-F019以剂量依赖性方式抑制病毒感染并在较高浓度下实现完全抑制(IC50＝32.56nM)。
实施例8.SI-F019降低ADE的发生率
抗体依赖性增强(ADE)是病毒与次优抗体的结合增强其进入宿主细胞的现象。在COVID-19的情况下，SARS-CoV-2病毒对具有由初次感染产生的抗SARS-CoV-2抗体的患者或对已接种疫苗的个体的继发感染可导致单核细胞和B细胞对病毒的摄取增加。与病毒接触的抗病毒抗体可以结合在某些免疫细胞或某些补体蛋白上表达的Fc受体。后者的结合依赖于抗体的Fc区。通常，病毒在称为吞噬作用的过程中降解，由此病毒颗粒被宿主细胞通过质膜吞噬。然而，如果病毒没有被抗体中和，由于低亲和力结合或靶向非中和表位，抗体结合可能导致病毒逃逸。结果是抗体增强的感染。
通过天然免疫或接种产生的抗体具有野生型Fc区。虽然SI-F019能够与抗刺突抗体竞争结合SARS-CoV2病毒，但是IgG1 Fc无效片段不能结合Fc受体或C1q(参见表3)。为了证明SI-F019在降低ADE作用方面的比较优势，评估了SI-F019在内化、复制和再感染中的作用。
在测量Fc介导的内化的试验中，将SARS-CoV-2S蛋白包装到表达GFP的假病毒(PsV)中，表达Fc受体和补体受体2(CR2)的两种细胞系THP1(单核细胞)和Daudi(B细胞)用于测试FcRg和CR2介导的ADE机制。SI-69R3用作SI-F019的对照，其具有野生型Fc，与具有IgG1 Fc无效修饰的SI-F019相反(参见表1)。在暴露于PsV 48h后，将来自细胞的绿色荧光信号定量为PsV感染的指示。在用PsV和SI-69C1处理的条件下，在THP1(pH7.2)(6A)、THP1(pH6.0)(6B)和Daudi(6C)细胞中测量48h的抗S1抗体或SI-69R3低水平的绿色荧光。该结果表明PsV的一些转移可通过Fc受体发生。相反，SI-F019在所示浓度的条件下导致THP1或Daudi细胞没有摄取PsV，与在阴性对照条件(包括测定培养基、制剂缓冲液和SI-69C1)中测量的绿色荧光信号相当(图6)。Fc介导的ADE的作用是剂量依赖性的，因为对细胞的处理使用1pM-100nM的剂量进行。这表明通过FcγR或CR2机制可能摄取一些PsV。
实施例9.SI-F019降低PsV的病毒载量
由于缺乏功能性Fc片段，SI-F019可能不介导S蛋白包装的表达GFP的假病毒(PsV)的内化。为了确定SI-F019是否可以抑制假病毒的摄取，SI-F019以竞争模式与SI-69R3或天然抗SARS-CoV-2抗体共同处理。在感染相同组的靶细胞之前，将PsV与SI-F019以1pM-100nM的剂量范围与10pM的抗SARS-CoV-2(S1)抗体或10pM的SI-69R3一起孵育1h。检测PsV来源的GFP信号作为感染的病毒载量。SI-F019能够从10fM开始抑制靶细胞中PsV的病毒载量(图7)。
虽然诸如抗SARS-CoV-2(S1)抗体的抗体和SI-69R3中的截短的ACE2-野生型Fc片段的融合蛋白都显示能够介导SARS-CoV-2刺突假型慢病毒的内化，但是SI-F019由于缺乏功能性Fc片段而无法介导内化。本文中，SI-F019在10pM抗SARS-CoV-2(S1)抗体或10pM SI-69R3的存在下，甚至在10fM的低浓度下也有助于降低PsV的病毒载量。总之，这些结果表明SI-F019可以分别降低THP1单核细胞和DaudiB细胞中由FcRg和CR2依赖性机制诱导的ADE的发生率。
实施例10.表达SARS-CoV-2刺突蛋白的HEK293-T细胞
通过转导用编码SARS-CoV-2刺突蛋白的cDNA(登录号：YP_009724390.1)包装的慢病毒并表达IRES，并基于由相同表达构建体(LPP-CoV219-Lv105-050,GeneCopoeia)驱动的嘌呤霉素抗性进行选择，建立稳定表达SARS-CoV-2刺突蛋白的HEK293-T细胞(ATCC：CRL-3216)。SARS-CoV-2刺突蛋白的表达通过结合人IgG克隆AM001414来证实，其对SARS-CoV-2Spike蛋白“抗Spike”(SKU938701，Biolegend)具有特异性，并且人IgG同种型匹配的克隆QA16A12用作对照“同种型”(SKU403502，Biolegend)。如图8所示，通过与多克隆抗人FcAF647 Fab(SKU109-607-008，Jackson ImmunoResearch)二次孵育和FACS评估来定量结合的蛋白质。
将表达SARS-CoV-2刺突蛋白的HEK293-T细胞和亲本HEK293细胞于37℃在内化抑制剂叠氮化钠存在下用指定材料染色30分钟。去除游离的SI-F019后，使用抗人Fc AF647fab(SKU109-607-008，Jackson ImmunoResearch)和流式细胞仪分析来检测和定量SI-F109。几何平均信号强度用于定量SI-F019与靶细胞系的结合，如图9所示。表达SARS-CoV-2刺突蛋白的HEK293-T细胞可用作COVID-19感染细胞的模型。
实施例11.SI-F019对抗体依赖性细胞毒性(ADCC)的影响
抗体依赖性细胞毒性(ADCC)是对病毒感染的重要免疫应答之一，例如在COVID-19的情况下感染SARS-CoV-2病毒。在最初的病毒感染后，抗病毒抗体直接结合病毒颗粒以用于中和和凝集。病毒-抗体复合物与吞噬细胞上的Fc受体的结合可触发吞噬作用，导致病毒的破坏；与免疫效应细胞(例如单核细胞、嗜中性粒细胞、嗜酸性粒细胞和NK细胞)上的Fc受体结合可触发细胞毒性因子(例如抗病毒干扰素)的释放，产生对病毒复制有害的微环境。
为了区分SI-F019与抗刺突抗体的作用，用钙黄绿素-AM装载表达SARS-CoV-2刺突蛋白的HEK293-T细胞，并与纯化的人NK细胞以5:1的效应子与靶标比率共培养。测试的处理包括SI-F019和S1特异性人IgG克隆SI-69C3。SI-69C3是人抗体克隆CC12.3，分离自住院的COVID-19患者(10.1126/science.abc7520)。共培养12h后，将细胞用碘化丙啶染色并评估活力。如图10所示，基于钙黄绿素-AM和碘化丙啶染色的表达的活靶细胞频率(群体3)的降低被评估为细胞溶解的量度。
当暴露于S1特异性人IgG克隆SI-69C3(克隆CC12.3)时，NK细胞介导的ADCC可针对表达SARS-CoV-2蛋白的HEK293-T细胞。在100nM-100fM的处理范围内，与SI-69C3相比，SI-F019不介导ADCC。在这些测定条件下，具有野生型Fc的SI-F019药物变体(SI-69R3)能够以剂量依赖性方式介导ADCC，但活性水平与S1特异性人IgG克隆CC12.3相比更低，如图11和图12所示。这些数据表明，与SARS-CoV-2S1特异性人IgG抗体不同，SI-F019不介导NK细胞介导的ADCC。
实施例12.SI-F019对补体依赖性细胞毒性(CDC)的影响
补体级联在介导COVID-19患者中基于抗体的细胞和组织损伤中的作用在天然免疫应答和基于中和抗体的治疗中都是明显的(Perico等人，2021)。由病毒和特异性IgG形成的免疫复合物介导补体诱导的血液凝固、血栓栓塞和全身性微血管病。COVID-19患者中的这些广泛并发症可能危及生命，并且依赖于与IgG结合的补体蛋白。通过C1q桥接红细胞的病毒免疫复合物和具有FcγRIIA的血小板是COVID-19患者中血栓栓塞的介质(Nazy等人，2020)。免疫复合物对内皮血管壁的固定和补体介导的凝血是COVID-19患者的主要关注点，其中内皮细胞的活化是血栓栓塞级联的一部分。
与天然IgG抗体不同，SI-F019不能结合C1q，如表3所示。该特征消除了感染的上皮和内皮诱导细胞死亡的风险，这些上皮和内皮可能在其表面瞬时表达SARS-CoV-2刺突蛋白。SI-F019的这种保护作用与抗刺突人IgG抗体相比得到证实。
为了证明SI-F019的保护作用，将表达SARS-CoV-2刺突蛋白的HEK293-T细胞在无血清培养基(Optimem)中培养处理30分钟，然后以1:10的血清与培养基比率加入人血清补体。测试的处理包括SI-F019和S1特异性人IgG克隆AM001414(BioLegend)。将细胞在37℃下培养3h，然后加入碘化丙啶染色并在每个孔中计数阳性染色细胞。如图12和图13所示，用Incucyte Zoom软件在3h计数的红细胞作为CDC的量度进行评估。如图13所示，96h后评估总细胞汇合，作为CDC影响的量度。
通过这些细胞在人血清补体攻击后进一步增殖的能力进一步证实了组织细胞免受补体损伤的保护。当暴露于S1特异性人IgG克隆(克隆AM4141)时，由与无血清培养基的1:10体积比的人血清补体介导的CDC可针对表达SARS-cov-2S蛋白的HEK293T细胞来评估。结果表明人可溶性单体ACE2和SI-F019都不介导CDC，而SI-69R3与人IgG抗体相比具有有限的剂量依赖性的CDC活性增加。基于处理后96h的孔汇合，CDC细胞溶解反映为细胞生长减少。
实施例13.由PBMC培养物中的可溶性或板结合的SI-F019引起的细胞因子释放。
SARS-CoV-2具有针对呼吸道和小肠的ACE2表达上皮的趋向性。升高的IL-2、IL-6、IL-7、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、干扰素γ诱导蛋白10(IP-10)、单核细胞趋化蛋白1(MCP-1)、巨噬细胞炎性蛋白1-α(MIP-1α)和指示细胞因子释放综合征(CRS)的肿瘤坏死因子-α(TNF-α)的临床实验室发现表明了潜在的免疫病理学。CRS是主要的不良副作用，其可以限制使用生物制剂的处理的效用，并且使用体外细胞因子释放测定进行测试。
SI-F019是由人ACE2和不能结合Fcγ受体的人IgG1 Fc的突变形式组成的融合蛋白。因此，预期SI-F019不会结合外周血中的任何靶细胞或引起细胞因子释放。将从5个健康供体分离的包括嗜中性粒细胞的白细胞(WBC)置于含有2000nM和200nM浓度的板结合或可溶性SI-F019的培养孔中。
作为阳性对照，TGN1412抗体以相同的浓度和相同的形式使用，这是由于其在该测定的板结合形式中诱导细胞因子释放的充分证明的能力。通过与具有能够结合由外周血中几种细胞类型表达的Fcγ受体的野生型Fc片段的SI-69R3比较，评估IgG1 Fc无效片段减少细胞因子释放的潜在贡献。仅含有相似稀释度的SI-F019制剂缓冲液的WBC培养物用作阴性对照。在24h和48h时间点收集培养物上清液，并使用Meso Scale Discovery(MSD)平台检测9种细胞因子的存在。
如图14A-14E所示，细胞因子组中包括T细胞相关细胞因子IFNγ、TNFα、GM-CSF、IL-2和IL-10。如图14F-14I所示，还测试了促炎性非T细胞相关细胞因子IL-1□、IL-12p70和IL-6以及单核细胞趋化蛋白MCP-1的水平。取每个血液供体的重复孔的结果的平均值，并使用JMP14软件绘制成框图，显示95％置信区间和离群值。
结果表明，在200nM和2000nM浓度下，SI-F019不诱导任何测试的细胞因子暴露于板结合或可溶性形式的WBC。在所有条件下，SI-F019处理的样品中的细胞因子水平显示与缓冲液对照相似的浓度。阳性对照TGN1412强烈诱导板结合形式中的大多数细胞因子，但不诱导可溶性形式，这与先前公布的结果一致。当使用板结合的ACE2-Fc野生型刺激WBC时，可检测到IFNγ、GM-CSF和TNFα的一些中间产物，表明SI-F019的Fc无效片段的安全性增加。
最近在接受介入性IgG治疗的患者中提出了针对SARS-CoV-2病毒的体液反应的致病作用(Weinreich等人，2021；Chen等人，2021)。小血管高炎症反应是不良事件的基础，包括血小板增多症、瘙痒、发热和高血压。本申请表明，SI-F019可提供与IgG治疗相当的病毒中和的益处，同时保护组织和器官免于多种途径的功能障碍。因此，SI-F019可用于治疗、预防或缓和病毒感染，具体地用于预防和控制COVID-19的进展，同时减少临床并发症，并且另外用于急性呼吸窘迫综合征、肺动脉高血压或急性肺损伤。
实施例14.SI-F019与SARS-CoV-2RBD变体的结合动力学(亲和力)
随着疫情的持续，突变和选择推动了SARS-CoV-2病毒的进化，以获得与ACE2更高的结合亲和力，从而提高病毒传播率，以产生包括新出现的高度传染性δ变体在内的变体。事实上，α变体和δ变体都比原始的SARS-CoV-2病毒更具传播性。SARS-CoV-2变体的流行是开发治疗和预防的尚未解决的挑战。虽然SI-F019是一种候选中和剂，但美国食品药品监督管理局已经批准了几种用于治疗患者的中和抗体，包括b)Bamlanivimab(Eli Lilly’s LY-CoV555；SI-69C4,SEQ ID No.29和30)；c)Casirivimab(Regeneron’sREGN10933；SI-69C5,SEQ ID NO.31和32)；d)Etesevimab(Eli Lilly’s CB-6；SI-69C6,SEQ ID NO.33和34)；e)Imdevimab(Regeneron’s REGN10987；SI-69C7,SEQ ID NO.35和36)；f)Cilgavimab(AstraZeneca’s AZD1061；SI-69C8,SEQ ID NO.37和38)；以及g)Tixagevimab(AstraZeneca’s AZD8895；SI-69C9,SEQ ID NO.39和40)。
为了确定重组ACE2-Fc融合蛋白SI-F019与这些中和抗体的比较优势，使用OctetRed384，使用生物膜层干涉法量化其与模拟COVID-19变异的SARS-CoV-2RBD变异的结合相互作用强度。这些变体蛋白购自Sino Biological。首先，将测定缓冲液(含有1％BSA和0.05％吐温20的PBS)中的10μg/ml SI-F019蛋白加载到AHC传感器上180秒。在180秒的基线步骤后，使加载的蛋白质与测定缓冲液中的RBD变体蛋白的1:2系列稀释液(最高浓度为50nM)缔合(to associate with)180秒，然后在测定缓冲液中进行300秒的解离步骤。使用pH为1.5的10mM甘氨酸进行再生。使用完全缔合阶段和前60秒的解离阶段，将数据全局拟合到1:1结合模型，以提取动力学参数KD、kon和kdis。表2和表4所示的相同变体和野生型RBD蛋白的结合亲和力具有可比性，因为不同的读数可能来自不同的供应商(ACROBiosystem和Sino Biological)。
图15(a-g)显示了SI-F019和中和抗体在与RBD变体结合时的传感图，表4(a-g)列出了提取的结合动力学(亲和力)参数。结果表明，与SI-F019(15a)相比，Bamlanivimab(SI-69C4)不能与κ、γ、β和λ变体结合(15b)；Casirivimab(SI-69C5)对γ和β变体的结合亲和力显著降低(15c)；Etesevimab(SI-69C6)对γ和β变体的结合亲和力也显著降低(15d)。虽然其他单克隆抗体，如Imdevimab(SI-69C7)(4e)、Cilgavimab(SI-69C8)(4f)和Tixagevimab(SI-69C9)(4g)，其结合亲和力可能没有任何显著变化，但传感图显示，一些变体的结合反应降低(图15e、15f和15g)。与中和抗体相比，SI-F019对祖先野生型RBD的新出现的变体(包括高度传染性的δ变体)表现出更好的结合亲和力(图15a，表4a)。该观察结果支持的观点为SI-F019的ACE2部分保留了野生型全长ACE2的构象，用于病毒进入人体细胞，这是选择高亲和力变体的靶点。因此，SI-F019与美国食品药品监督管理局批准的中和抗体相比具有相对优势，因此可以用作结合剂和阻断剂。
实施例15.SI-F019和中和抗体与变体的结合动力学(亲和力)
虽然上述结合亲和性测定测量固定在抗人IgG Fc捕获生物传感器尖端(AHC)表面上的SI-F019与溶液中的SARS-CoV-2RBD蛋白变体的结合，但亲合力测定则测量固定在链霉亲和素生物传感器尖端表面上的生物素化SARS-CoV-2RBD蛋白变体与溶液中SI-F19的结合。
使用Octet Red 384，使用生物膜层干涉法来量化SI-F019和SARS-CoV-2S蛋白变体RBD结构域之间的结合相互作用强度。试剂购自Sino Biological，以及通过NHS酯活化反应进行化学生物素化，生物素/蛋白质的化学计量比为2:1。首先，将测定缓冲液(含有1％BSA和0.05％吐温20的PBS)中的2μg/ml生物素化RBD或其变体蛋白加载到SA传感器上180秒。在180秒的基线步骤后，使加载的蛋白质在测定缓冲液中与1:2系列稀释液(最高浓度为50nM)的SI-F019蛋白质(GMP批次)缔合300秒，然后在测定缓冲溶液中进行600秒的解离步骤。使用pH为1.5的10mM甘氨酸进行再生。使用完全缔合阶段和完全解离阶段，将数据全局拟合到1:1结合模型，以计算动力学参数KD、kon和kdis。表2和表5所示的相同变体和野生型RBD蛋白的结合亲和力具有可比性，因为不同的读数可能来自不同的供应商(ACROBiosystem和Sino Biological)。
图16(a-g)显示了与SI-F019结合的SARS-CoV-2RBD蛋白变体的传感图，表5(a-g。列出了提取的结合动力学(亲合力)参数。值得注意的是，与野生型RBD相比，SI-F019对变体形式的RBD具有更高的亲合力，亲合力的增加主要是由较慢的解离速率驱动的。结果显示，相对于野生型RBD，SI-F019对RBD变体的结合亲和力增加，解离速率降低；以及某些中和抗体的效力降低或减弱。
实施例16.SI-F019与中和抗体的相对优势
为了证明SI-F019与中和抗体的相对优势，使用了结合应答或应答的值。如图15、16所示，应答是以干涉图案中的nm偏移来测量的，并且与结合到生物传感器表面的分子数量成比例。应答是与最高浓度的分析物结合时获得的最大结合信号，是一种复杂的功能，取决于动力学结合参数、蛋白质大小和测定条件，并且只要相互作用的蛋白质具有相似的大小和形式，就应该在给定的测定中具有可比性。应答的差异可以表明蛋白质-蛋白质相互作用的有效强度的差异，其中高应答表明强烈的相互作用，低应答表明较弱的相互作用。
表6列出了从图15和16中SI-F019和中和抗体的结合亲和力和亲合力中提取的应答值(分析物的最高浓度)。为了评估每种中和剂和变体的结合动力学变化，应用了以下定义：1)当应答<WT的10％时，无结合；2)当应答<WT的30％时，极小的结合；3)当应答<WT的75％时，低结合；和4)用于复杂的动力学，包括向上解离、非特异性结合。当将这些标准应用于每个应答时，每个中和抗体显示出与至少一种变体的低结合或无结合。特别是对于亲合力测定，Bamlanivimab(SI-69C4)对δ、κ、γ、β和λ的结合应答降低；Etesevimab(SI-69C6)对γ和β的结合应答降低；Casirivimab(SI-69C5)、Imdevimab(SI-69C7)、Cilgavimab(SI-69C8)和Tixagevimab(SI-69C9)均对β的结合应答降低。相反，SI-F019保留了其对所有变体的结合亲和力和亲合力。
实施例17.SI-F019作为阻断剂能够抑制COVID-19RBD变体的病毒感染性
为了测试SI-F019预防病毒感染的能力，使用荧光素酶报告基因测定来表征病毒感染性。将含有荧光素酶报告基因(NICPBP)的SARS-CoV-2S蛋白包装的假病毒(野生型或变异株，Sino Biological)与过表达ACE2的293T细胞(克隆3D4)和1:3系列稀释液(30μg/ml)的SI-F019共同孵育。通过酶促和FACS测定证实了ACE2在转染细胞上的表达。假病毒可能通过与ACE2结合的S蛋白进入ACE2阳性细胞，从而导致荧光素酶的表达。因此，发光被用作病毒传染性的读数。
特别地，在培养基中制备S蛋白假病毒的10倍储备溶液，最终病毒载量为227-394TCID50/孔。将培养基中的SI-F019连续稀释3倍，最大浓度为150μg/ml(最终浓度为30μg/ml)。使用缺乏胰蛋白酶的解离缓冲液收获3D4细胞。将假病毒(20μl)和SI-F019(30μl)在96孔板的孔中合并，混合，并在室温下孵育1小时。然后，将100μl收获的3D4细胞添加到每个孔(20000/孔)中，并在37℃、5％CO2下孵育18小时。孵育后，去除上清液，加入50μl荧光素酶底物溶液，混合，并在室温下孵育1分钟。使用I3X平板阅读器读取发光，其中RLU中的发光信号(相对发光单位)代表S蛋白假病毒感染性。
可以计算与没有SI-F019的条件相比发光的降低，以确定感染性的抑制百分比。然后将该数据拟合到GraphPad Prism 6.0中的S形函数，以提取SI-F019抑制假病毒传染性的IC50值，其中假病毒包含S蛋白的不同变体。病毒抑制数据如图17a所示，IC50值如表7所示。结果表明：与对野生型菌株的效力相比，SI-F019能够抑制所有变体的传染性，其效力增加了2至15倍；以及IC50和亲和力或亲合力的KD值之间的线性关联(图17b，17c)表明SI-F019具有竞争性抑制作用。体外实验数据表明，ACE2蛋白，如与膜结合的ACE2蛋白有关的SI-F019融合蛋白，不仅能够紧密结合，而且能够抑制SARS-CoV-2病毒变体，RBD-ACE2相互作用的亲和力增加，这种相互作用随着传染性和传播性的增加而进化。
实施例18.SI-F019在中国健康参与者的I期临床试验(NCT04851444)
三种抗SARS-CoV-2单克隆抗体产品目前已获得美国食品和药物管理局(FDA)的紧急使用授权(EUA)，用于治疗实验室确认的SARS-CoV 2感染的非住院患者中的轻度至中度COVID-19，这些患者进展为重症和/或住院的高危人群。第一.Bamlanivimab加Etesevimab：这些是中和单克隆抗体，其结合至与SARS-CoV-2的刺突蛋白RBD中不同但重叠的表位；第二.Casirivimab加Imdevimab：这些是重组人单克隆抗体，其结合至SARS-CoV-2的刺突蛋白RBD的非重叠表位；第三.Sotrovimab：这种单克隆抗体最初于2003年从一名SARS-CoV幸存者身上鉴定出来。它靶向刺突蛋白RBD中的一个表位，该表位保守在SARS-CoV和SARS-CoV-2之间。
与那些与单个表位结合的单克隆抗体不同，SI-F019具有与人类细胞上的ACE2蛋白竞争与SARS-CoV-2的刺突蛋白RBD的所有对接位点结合的技术优势，其中一些可能与这些表位重叠。减少了将两种或多种单克隆抗体组合作为治疗方案的负担和技术困难，目前正在进行临床试验的SI-F019，具有作为单一有效治疗剂的优势，用于治疗轻度至中度COVID-19以及用于有发展为重度新冠肺炎的高风险的人群SARS-CoV-2感染的暴露后预防(PEP)。SI-F019能够与其他冠状病毒竞争，这些冠状病毒也靶向人类细胞上的膜结合ACE2蛋白，诸如SARS-CoV-1(图4)。除COVID-19外，SI-F019还可用于治疗SARS-CoV-1病毒引起的严重急性呼吸综合征(SARS)、MERS-CoV病毒引起的中东呼吸综合征(MERS)，以及急性呼吸窘迫综合征(ARDS)和其他肺部损伤。在这些情况下，SI-F019也可以根据需要与其他治疗剂联合使用。
I期试验的目的是测试单次静脉注射SI-F019的安全性、耐受性和药代动力学特性。该试验以双盲、安慰剂对照和随机方式设计，剂量从3mg/kg递增到70mg/kg SI-F019(表8a、8b)。融合蛋白以组氨酸/组氨酸盐酸盐、氯化钠、蔗糖和聚山梨醇酯80的液体悬浮液的形式施用。共有36名参与者在第1天接受了单次施用，并随继续进行至第29天。治疗突发不良事件(TEAE)、治疗相关不良事件(TRAE)、严重程度和实验室异常通过NCI-TCAE v5.0进行记录和分级。截至2021年9月16日，电子数据捕获(EDC)数据库尚未锁定。根据盲法数据回顾，36名参与者中有21人经历了44次不良事件(AE)，其中16名参与者发生了31次TRAE。所有AE均为1级，未发现与SI-F019剂量有显著关联(表9a、9b)。SI-F019良好的总体耐受性和安全性支持其作为预防和治疗COVID-19及其他相关疾病的药物的进一步探索。
表格
表1重组ACE2-Fc融合蛋白的克隆、表达和纯化
表2 SI-F019结合病毒蛋白的亲和力和亲合力
表3 Fc无效突变对其与Fc受体结合的影响
表4.SI-F019(4a)和中和抗体与S蛋白RBD的不同变体的结合动力学(亲和力)，包括Bamlanivimab(SI-69C4)(4b)；Casirivimab(SI-69C5)(4c)；Etesevimab(SI-69C6)(4d)；Imdevimab(SI-69C7)(4e)；Cilgavimab(SI-69C8)(4f)；和Tixagevimab(SI-69C9)(4g)，表明相对于野生型RBD，SI-F019与变体形式的RBD结合的亲和力增加，这主要是由较慢的解离速率驱动的，而至少三种中和抗体失去了与至少一种变体的结合(N.D.)。
表4(续表-1)
表4(续表-2)
表4(续表-3)
表5.生物膜层干涉测量法用于量化SI-F019(5a)和中和抗体对S蛋白RBD不同变体的结合动力学(亲合力)，包括Bamlanivimab(SI-69C4)(5b)；Casirivimab(SI-69C5)(5c)；Etesevimab(SI-69C6)(5d)；Imdevimab(SI-69C7)(5e)；Cilgavimab(SI-69C8)(5f)；以及Tixagevimab(SI-69C9)(5g)。
表5(续表-1)
表5(续表-2)
表5(续表-3)
表6a.对SI-F019和中和抗体对SARS-CoV-2病毒RBD的最大结合反应(亲和力)的比较分析表明，这些抗体中的四种对至少一种变体的应答在低到无的范围内，而SI-F019对所有变体的应答都有所增加。
WHO命名 SI-F019 SI-69C4 SI-68C5 SI-69C6 SI-69C7 SI-69C8 SI-69C9
原始 0.255 0.6224 0.5842 0.3512 0.561 0.3973 0.4767
α 0.3801 0.6714 0.6233 0.3763 0.6723 0.4521 0.5523
δ 0.3115 0.326 0.5787 0.4078 0.6585 0.3566 0.5133
低
κ 0.2905 0.0516 0.509 0.3368 0.6459 0.3223 0.4717
无
γ 0.3336 0.0624 0.4199 0.0923 0.6419 0.4283 0.4742
极小的 低 极小的
β 0.3046 0.031 0.139 0.0246 0.658 0.4384 0.4602
无 非特异性 无
λ 0.278 0.1124 0.4976 0.3516 0.429 0.236 0.4113
极小的 低
表6b.通过SI-F019或中和抗体对SARS-CoV-2病毒RBD的结合反应(亲合力)的比较分析，表明抗体的的应答在低到无的范围内，而SI-F019没有显著变化。
WHO命名 SI-F019 SI-69C4 SI-68C5 SI-69C6 SI-69C7 SI-69C8 SI-69C9
WT 0.7116 1.089 1.5033 0.7459 1.4517 0.6397 1.6959
α 0.7596 1.237 1.2967 0.7718 1.1912 0.6967 1.3498
δ 0.6226 0.6171 1.1999 0.7103 1.145 0.5252 1.2973
低
κ 0.8529 0.0072 1.4715 0.9705 1.3218 0.6285 1.5444
无
γ 0.7085 0.0261 1.1662 0.1694 1.3319 0.6571 1.5804
无 低
β 0.5671 0.0212 0.9041 0.0398 1.068 0.4734 1.1393
无 低 无 低 低 低
λ 0.9729 0.4863 1.6376 1.1007 1.4551 0.727 1.7596
低
表7.在使用S蛋白包装的假病毒(NICPBP)感染表达ACE2的293T细胞的荧光素酶报告基因测定中抑制病毒感染性的IC50值。值得注意的是，基于较低的IC50值，SI-F019对含有变体形式的S蛋白的假病毒的抑制比对含有野生型S蛋白的假病毒的抑制更有效。
表8a.SI-F019I的I期临床试验(NCT04851444)的人口学总结(年龄、体重)。
表8b.SI-F019的I期临床试验(NCT04851444)的剂量递增和分配设计
组 1 2 3 4 5
计量(mg/kg) 3 10 30 52 70
剂量增量 / 233％ 200％ 73％ 34％
参与者人数(治疗+对照) 2+2 6+2 6+2 6+2 6+2
表9a.SI-F019的I期临床试验(NCT04851444)基于系统器官类别/首选术语(SOC/PT)的所有不良事件(AE)汇总
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*N:经历AE的患者人数.
表9b.SI-F019的I期临床试验(NCT04851444)基于系统器官类别/首选术语(SOC/PT)的所有治疗相关不良事件(TRAE)汇总
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*N:经历TRAE的患者人数。
序列表
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>序列ID 1：huACE2全长蛋白质序列(Genbank_number：NP_001358344.1，TMPRSS2蛋白酶切割位点)
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKNQMILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLNDNSLEFLGIQPTLGPPNQPPVSIWLIVFGVVMGVIVVGIVILIFTGIRDRKKKNKARSGENPYASIDISKGENNPGFQNTDDVQTSF
>序列ID 2：huACE2全长DNA序列
(Genbank_number：NM_021804.3)
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACCAAAGCATCAAAGTGAGGATAAGCCTAAAATCAGCTCTTGGAGATAAAGCATATGAATGGAACGACAATGAAATGTACCTGTTCCGATCATCTGTTGCATATGCTATGAGGCAGTACTTTTTAAAAGTAAAAAATCAGATGATTCTTTTTGGGGAGGAGGATGTGCGAGTGGCTAATTTGAAACCAAGAATCTCCTTTAATTTCTTTGTCACTGCACCTAAAAATGTGTCTGATATCATTCCTAGAACTGAAGTTGAAAAGGCCATCAGGATGTCCCGGAGCCGTATCAATGATGCTTTCCGTCTGAATGACAACAGCCTAGAGTTTCTGGGGATACAGCCAACACTTGGACCTCCTAACCAGCCCCCTGTTTCCATATGGCTGATTGTTTTTGGAGTTGTGATGGGAGTGATAGTGGTTGGCATTGTCATCCTGATCTTCACTGGGATCAGAGATCGGAAGAAGAAAAATAAAGCAAGAAGTGGAGAAAATCCTTATGCCTCCATCGATATTAGCAAAGGAGAAAATAATCCAGGATTCCAAAACACTGATGATGTTCAGACCTCCTTTTAG
>序列ID 3：huACE2功能域(残基：1-615)蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYAD
>序列ID 4：huACE2功能域(残基：1-615)DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGAC
>序列ID 5：Fc野生型IgG1 Fc(EU编号216-447)
EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 6：FC无效版本(EU编号216-447，具有突变C220S、L234A、L235A和K322A)
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 7：SI-69R2_huACE2功能域(残基：1-615)-IgG1 Fc(无效)蛋白质序列(EU编号216-447，具有突变C220S、L234A、L235A和K322A)
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 8：Si-69R2：huACE2功能域(残基：1-615)-IgG1Fc(无效)DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACGAGCCCAAATCTTCCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAG
>序列ID 9：huACE2功能域(残基：1-615)-IgG4 Fc蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
>序列ID 10：huACE2功能域(残基：1-615)-IgG4 Fc DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACGAGTCCAAATATGGTCCCCCGTGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTCCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCTGGGTAAATGA
>序列ID 11：huACE2功能域(残基：1-615)-IgA1 Fc蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY
>序列ID 12：huACE2功能域(残基：1-615)-IgA1 Fc DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACAGCCAGGATGTGACTGTGCCCTGCCCAGTTCCCTCAACTCCACCTACCCCATCTCCCTCAACTCCACCTACCCCATCTCCCTCATGCTGCCACCCCCGACTGTCACTGCACCGACCGGCCCTCGAGGACCTGCTCTTAGGTTCAGAAGCGAACCTCACGTGCACACTGACCGGCCTGAGAGATGCCTCAGGTGTCACCTTCACCTGGACGCCCTCAAGTGGGAAGAGCGCTGTTCAAGGACCACCTGAGCGTGACCTCTGTGGCTGCTACAGCGTGTCCAGTGTCCTGCCGGGCTGTGCCGAGCCATGGAACCATGGGAAGACCTTCACTTGCACTGCTGCCTACCCCGAGTCCAAGACCCCGCTAACCGCCACCCTCTCAAAATCCGGAAACACATTCCGGCCCGAGGTCCACCTGCTGCCGCCGCCGTCGGAGGAGCTGGCCCTGAACGAGCTGGTGACGCTGACGTGCCTGGCACGCGGCTTCAGCCCCAAGGACGTGCTGGTTCGCTGGCTGCAGGGGTCACAGGAGCTGCCCCGCGAGAAGTACCTGACTTGGGCATCCCGGCAGGAGCCCAGCCAGGGCACCACCACCTTCGCTGTGACCAGCATACTGCGCGTGGCAGCCGAGGACTGGAAGAAGGGGGACACCTTCTCCTGCATGGTGGGCCACGAGGCCCTGCCGCTGGCCTTCACACAGAAGACCATCGACCGCTTGGCGGGTAAACCCACCCATGTCAATGTGTCTGTTGTCATGGCGGAGGTGGACGGCACCTGCTACTGA
>序列ID 13：huACE2功能域(残基：1-615)-IgA2 Fc蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADSQDVTVPCRVPPPPPCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHGETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTYAVTSILRVAAEDWKKGETFSCMVGHEA
LPLAFTQKTIDRMAGKPTHINVSVVMAEADGTCY
>序列ID 14：huACE2功能域(残基：1-615)-IgA2 Fc DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACAGCCAGGATGTGACTGTGCCCTGCCGAGTTCCCCCACCTCCCCCATGCTGCCACCCCCGACTGTCGCTGCACCGACCGGCCCTCGAGGACCTGCTCTTAGGTTCAGAAGCGAACCTCACGTGCACACTGACCGGCCTGAGAGATGCCTCTGGTGCCACCTTCACCTGGACGCCCTCAAGTGGGAAGAGCGCTGTTCAAGGACCACCTGAGCGTGACCTCTGTGGCTGCTACAGCGTGTCCAGTGTCCTGCCTGGCTGTGCCCAGCCATGGAACCATGGGGAGACCTTCACCTGCACTGCTGCCCACCCCGAGTTGAAGACCCCACTAACCGCCAACATCACAAAATCCGGAAACACATTCCGGCCCGAGGTCCACCTGCTGCCGCCGCCGTCGGAGGAGCTGGCCCTGAACGAGCTGGTGACGCTGACGTGCCTGGCACGTGGCTTCAGCCCCAAGGATGTGCTGGTTCGCTGGCTGCAGGGGTCACAGGAGCTGCCCCGCGAGAAGTACCTGACTTGGGCATCCCGGCAGGAGCCCAGCCAGGGCACCACCACCTATGCTGTGACCAGCATACTGCGCGTGGCAGCCGAGGACTGGAAGAAGGGGGAAACCTTCTCCTGCATGGTGGGCCACGAGGCCCTGCCGCTGGCCTTCACACAGAAGACCATCGACCGCATGGCGGGTAAACCCACCCATATCAATGTGTCTGTTGTCATGGCGGAGGCGGACGGCACCTGCTACTGA
>序列ID 15：SI-F019_huACE2功能域(残基：18-615)-IgG1Fc(无效)蛋白质序列(具有C220S、L234A、L235A和K322A处的突变，EU编号)
QSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 16：huACE2功能域(残基：18-615)-IgG4 Fc蛋白质序列
QSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
>序列ID 17：huACE2功能域(残基：18-615)-IgA1 Fc蛋白质序列
QSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY
>序列ID 18：huACE2功能域(残基：18-615)-IgA2 Fc蛋白质序列
QSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADSQDVTVPCRVPPPPPCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHGETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTYAVTSILRVAAEDWKKGETFSCMVGHEALPLAFTQKTIDRMAGKPTHINVSVVMAEADGTCY
>序列ID 19：SI-69R3_human ACE2-ECD-1-615-Fc-w2(EU编号216-447)-蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 20：SI-69R3_human ACE2-ECD-1-615-Fc-w2-DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTCCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACGAGCCCAAATCTTCCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAG
>序列ID21：SI-69R4-human ACE2-ECD-1-740(TMPRSS2蛋白酶切割位点)-Fc-w2(EU编号216-447)-蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKNQMILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLNDNSLEFLGIQPTLGPPNQPPVSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 22：SI-69R4_human ACE2-ECD-1-740-Fc-w2-DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTCCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACCAAAGCATCAAAGTGAGGATAAGCCTAAAATCAGCTCTTGGAGATAAAGCATATGAATGGAACGACAATGAAATGTACCTGTTCCGATCATCTGTTGCATATGCTATGAGGCAGTACTTTTTAAAAGTAAAAAATCAGATGATTCTTTTTGGGGAGGAGGATGTGCGAGTGGCTAATTTGAAACCAAGAATCTCCTTTAATTTCTTTGTCACTGCACCTAAAAATGTGTCTGATATCATTCCTAGAACTGAAGTTGAAAAGGCCATCAGGATGTCCCGGAGCCGTATCAATGATGCTTTCCGTCTGAATGACAACAGCCTAGAGTTTCTGGGGATACAGCCAACACTTGGACCTCCTAACCAGCCCCCTGTTTCCGAGCCCAAATCTTCCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAG
>序列ID 23：SI-69R1_huACE2功能域(残基：1-615)-6XHis蛋白质序列
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADHHHHHH
>序列ID 24：SI-69R1_huACE2功能域(残基：1-615)-6XHis DNA序列
ATGTCAAGCTCTTCCTGGCTCCTTCTCAGCCTTGTTGCTGTAACTGCTGCTCAGTCCACCATTGAGGAACAGGCCAAGACATTTTTGGACAAGTTTAACCACGAAGCCGAAGACCTGTTCTATCAAAGTTCACTTGCTTCTTGGAATTATAACACCAATATTACTGAAGAGAATGTCCAAAACATGAATAATGCTGGGGACAAATGGTCTGCCTTTTTAAAGGAACAGTCCACACTTGCCCAAATGTATCCACTACAAGAAATTCAGAATCTCACAGTCAAGCTTCAGCTGCAGGCTCTTCAGCAAAATGGGTCTTCAGTGCTCTCAGAAGACAAGAGCAAACGGTTGAACACAATTCTAAATACAATGAGCACCATCTACAGTACTGGAAAAGTTTGTAACCCAGATAATCCACAAGAATGCTTATTACTTGAACCAGGTTTGAATGAAATAATGGCAAACAGTTTAGACTACAATGAGAGGCTCTGGGCTTGGGAAAGCTGGAGATCTGAGGTCGGCAAGCAGCTGAGGCCATTATATGAAGAGTATGTGGTCTTGAAAAATGAGATGGCAAGAGCAAATCATTATGAGGACTATGGGGATTATTGGAGAGGAGACTATGAAGTAAATGGGGTAGATGGCTATGACTACAGCCGCGGCCAGTTGATTGAAGATGTGGAACATACCTTTGAAGAGATTAAACCATTATATGAACATCTTCATGCCTATGTGAGGGCAAAGTTGATGAATGCCTATCCTTCCTATATCAGTCCAATTGGATGCCTCCCTGCTCATTTGCTTGGTGATATGTGGGGTAGATTTTGGACAAATCTGTACTCTTTGACAGTTCCCTTTGGACAGAAACCAAACATAGATGTTACTGATGCAATGGTGGACCAGGCCTGGGATGCACAGAGAATATTCAAGGAGGCCGAGAAGTTCTTTGTATCTGTTGGTCTTCCTAATATGACTCAAGGATTCTGGGAAAATTCCATGCTAACGGACCCAGGAAATGTTCAGAAAGCAGTCTGCCATCCCACAGCTTGGGACCTGGGGAAGGGCGACTTCAGGATCCTTATGTGCACAAAGGTGACAATGGACGACTTCCTGACAGCTCATCATGAGATGGGGCATATCCAGTATGATATGGCATATGCTGCACAACCTTTTCTGCTAAGAAATGGAGCTAATGAAGGATTCCATGAAGCTGTTGGGGAAATCATGTCACTTTCTGCAGCCACACCTAAGCATTTAAAATCCATTGGTCTTCTGTCACCCGATTTTCAAGAAGACAATGAAACAGAAATAAACTTCCTGCTCAAACAAGCACTCACGATTGTTGGGACTCTGCCATTTACTTACATGTTAGAGAAGTGGAGGTGGATGGTCTTTAAAGGGGAAATTCCCAAAGACCAGTGGATGAAAAAGTGGTGGGAGATGAAGCGAGAGATAGTTGGGGTGGTGGAACCTGTGCCCCATGATGAAACATACTGTGACCCCGCATCTCTGTTCCATGTTTCTAATGATTACTCATTCATTCGATATTACACAAGGACCCTTTACCAATTCCAGTTTCAAGAAGCACTTTGTCAAGCAGCTAAACATGAAGGCCCTCTGCACAAATGTGACATCTCAAACTCTACAGAAGCTGGACAGAAACTGTTCAATATGCTGAGGCTTGGAAAATCAGAACCCTGGACCCTAGCATTGGAAAATGTTGTAGGAGCAAAGAACATGAATGTAAGGCCACTGCTCAACTACTTTGAGCCCTTATTTACCTGGCTGAAAGACCAGAACAAGAATTCTTTTGTGGGATGGAGTACCGACTGGAGTCCATATGCAGACCATCATCACCATCACCAC
>序列ID 25：SI-69R10_Human TMPRSS2蛋白，His-标签(106-492)-蛋白质序列
MYRMQLLSCIALSLALVTNSWKFMGSKCSNSGIECDSSGTCINPSNWCDGVSHCPGGEDENRCVRLYGPNFILQVYSSQRKSWHPVCQDDWNENYGRAACRDMGYKNNFYSSQGIVDDSGSTSFMKLNTSAGNVDIYKKLYHSDACSSKAVVSLRCIACGVNLNSSRQSRIVGGESALPGAWPWQVSLHVQNVHVCGGSIITPEWIVTAAHCVEKPLNNPWHWTAFAGILRQSFMFYGAGYQVEKVISHPNYDSKTKNNDIALMKLQKPLTFNDLVKPVCLPNPGMMLQPEQLCWISGWGATEEKGKTSEVLNAAKVLLIETQRCNSRYVYDNLITPAMICAGFLQGNVDSCQGDSGGPLVTSKNNIWWLIGDTSWGSGCAKAYRPGVYGNVMVFTDWIYRQMRADGHHHHHH
>序列ID 26：SI-69R10_Human TMPRSS2蛋白，His-标签(106-492)-DNA序列
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACCAATTCGTGGAAGTTTATGGGTTCTAAATGCTCTAATAGCGGGATAGAATGTGACAGTAGTGGCACTTGCATTAACCCTTCAAACTGGTGTGATGGGGTAAGCCATTGCCCCGGGGGGGAAGATGAAAATAGATGTGTTAGGCTCTACGGTCCCAACTTTATACTCCAGGTATATTCAAGTCAACGCAAATCATGGCATCCAGTGTGTCAAGACGACTGGAACGAAAACTATGGACGCGCTGCATGTCGAGATATGGGATATAAGAATAACTTCTATAGTTCACAGGGAATCGTAGATGACTCTGGATCTACTAGTTTCATGAAACTGAACACCTCTGCCGGAAACGTAGATATATATAAAAAGCTTTACCACTCCGACGCTTGTAGCTCTAAGGCCGTAGTTAGCCTCAGATGCATCGCCTGCGGAGTAAACCTCAATTCATCTCGCCAGAGTAGGATCGTTGGCGGGGAAAGCGCCCTCCCAGGCGCTTGGCCTTGGCAAGTTTCCCTTCATGTCCAGAATGTTCATGTATGTGGCGGGTCTATAATCACCCCAGAATGGATCGTCACAGCTGCCCACTGCGTGGAGAAACCCCTCAACAATCCTTGGCATTGGACCGCATTTGCCGGAATACTGAGACAATCATTTATGTTCTATGGAGCCGGGTACCAAGTCGAAAAGGTCATTTCCCATCCCAATTATGATTCCAAAACCAAAAACAATGACATAGCCTTGATGAAACTCCAGAAGCCTTTGACATTTAATGACCTGGTCAAACCAGTGTGCCTCCCAAATCCTGGAATGATGTTGCAGCCTGAACAGTTGTGCTGGATCAGCGGTTGGGGTGCTACCGAGGAGAAGGGTAAGACAAGCGAGGTCCTTAACGCTGCAAAGGTTTTGCTGATAGAAACACAGAGATGTAACAGCCGCTATGTGTACGATAACCTGATCACCCCAGCTATGATTTGCGCCGGGTTTTTGCAAGGTAACGTCGATTCTTGCCAAGGTGACTCAGGCGGCCCTCTTGTTACATCAAAGAACAATATATGGTGGCTTATCGGCGATACATCATGGGGTTCTGGATGTGCTAAAGCCTATCGCCCAGGGGTGTATGGCAATGTAATGGTGTTTACAGACTGGATCTATAGGCAGATGCGGGCTGACGGTCACCATCATCACCATCACTGA
>序列ID 27：IgJ链
MKNHLLFWGVLAVFIKAVHVKAQEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDLCKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPDACYPD
>序列ID 28：分泌成分
KSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSSKYAGRANLTNFPE
NGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVSQGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQLRLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTNGDTLWRTTVEIKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALPSQDEGPSKAFVNCDENSRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAAGSRDVSLAKADAAPDEKVLDSGFREIENKAIQDPR
>序列ID 29:Bamlanivimab_重链
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGYYEARHYYYYYAMDVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 30:Bamlanivimab_轻链
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLSWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTITSLQPEDFATYYCQQSYSTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>序列ID 31:Casirivimab_重链
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYITYSGSTIYYADSVKGRFTISRDNAKSSLYLQMNSLRAEDTAVYYCARDRGTTMVPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 32:Casirivimab_轻链
DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNWYQQKPGKAPKLLIYAASNLETGVPSRFSGSGSGTDFTFTISGLQPEDIATYYCQQYDNLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>序列ID 33:Etesevimab_重链
EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYSGGSTFYADSVKGRFTISRDNSMNTLFLQMNSLRAEDTAVYYCARVLPMYGDYLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 34:Etesevimab_轻链
DIVMTQSPSSLSASVGDRVTITCRASQSISRYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPEYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>序列ID 35:Imdevimab_重链
QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYAMYWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCASGSDYGDYLLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 36:Imdevimab_轻链
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFSGSKSGNTASLTISGLQSEDEADYYCNSLTSISTWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
>序列ID 37:Cilgavimab_重链
EVQLVESGGGLVKPGGSLRLSCAASGFTFRDVWMSWVRQAPGKGLEWVGRIKSKIDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTAGSYYYDTVGPGLPEGKFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 38:Cilgavimab_轻链
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLMYWASTRESGVPDRFSGSGSGAEFTLTISSLQAEDVAIYYCQQYYSTLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>序列ID 39:Tixagevimab_重链
QMQLVQSGPEVKKPGTSVKVSCKASGFTFMSSAVQWVRQARGQRLEWIGWIVIGSGNTNYAQKFQERVTITRDMSTSTAYMELSSLRSEDTAVYYCAAPYCSSISCNDGFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>序列ID 40:Tixagevimab_轻链
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSRGWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
序列表
<110> 西雅图免疫公司
成都百利多特生物药业有限责任公司
<120> 重组ACE2-FC融合分子及其制备和使用方法
<130> SIBA202PCT2
<150> 63/086,593
<151> 2020-10-01
<160> 40
<170> PatentIn version 3.5
<210> 1
<211> 805
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 1
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Gln Ser Ile Lys Val Arg Ile Ser Leu
610 615 620
Lys Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met
625 630 635 640
Tyr Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu
645 650 655
Lys Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val
660 665 670
Ala Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro
675 680 685
Lys Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile
690 695 700
Arg Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn
705 710 715 720
Ser Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln
725 730 735
Pro Pro Val Ser Ile Trp Leu Ile Val Phe Gly Val Val Met Gly Val
740 745 750
Ile Val Val Gly Ile Val Ile Leu Ile Phe Thr Gly Ile Arg Asp Arg
755 760 765
Lys Lys Lys Asn Lys Ala Arg Ser Gly Glu Asn Pro Tyr Ala Ser Ile
770 775 780
Asp Ile Ser Lys Gly Glu Asn Asn Pro Gly Phe Gln Asn Thr Asp Asp
785 790 795 800
Val Gln Thr Ser Phe
805
<210> 2
<211> 2418
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 2
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagaccaaag catcaaagtg 1860
aggataagcc taaaatcagc tcttggagat aaagcatatg aatggaacga caatgaaatg 1920
tacctgttcc gatcatctgt tgcatatgct atgaggcagt actttttaaa agtaaaaaat 1980
cagatgattc tttttgggga ggaggatgtg cgagtggcta atttgaaacc aagaatctcc 2040
tttaatttct ttgtcactgc acctaaaaat gtgtctgata tcattcctag aactgaagtt 2100
gaaaaggcca tcaggatgtc ccggagccgt atcaatgatg ctttccgtct gaatgacaac 2160
agcctagagt ttctggggat acagccaaca cttggacctc ctaaccagcc ccctgtttcc 2220
atatggctga ttgtttttgg agttgtgatg ggagtgatag tggttggcat tgtcatcctg 2280
atcttcactg ggatcagaga tcggaagaag aaaaataaag caagaagtgg agaaaatcct 2340
tatgcctcca tcgatattag caaaggagaa aataatccag gattccaaaa cactgatgat 2400
gttcagacct ccttttag 2418
<210> 3
<211> 615
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 3
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp
610 615
<210> 4
<211> 1845
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 4
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagac 1845
<210> 5
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 5
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 6
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 6
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 7
<211> 847
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 7
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Glu Pro Lys Ser Ser Asp Lys Thr His
610 615 620
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
625 630 635 640
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
645 650 655
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
660 665 670
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
675 680 685
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
690 695 700
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
705 710 715 720
Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
725 730 735
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
740 745 750
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
755 760 765
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
770 775 780
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
785 790 795 800
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
805 810 815
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
820 825 830
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
835 840 845
<210> 8
<211> 2544
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 8
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagacgagcc caaatcttcc 1860
gacaaaactc acacatgccc accgtgccca gcacctgaag ccgcgggggg accgtcagtc 1920
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1980
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 2040
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 2100
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 2160
tgcgcggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 2220
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 2280
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 2340
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 2400
gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg 2460
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 2520
ctctccctgt ctccgggtaa atag 2544
<210> 9
<211> 844
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 9
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Glu Ser Lys Tyr Gly Pro Pro Cys Pro
610 615 620
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
625 630 635 640
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
645 650 655
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
660 665 670
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
675 680 685
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
690 695 700
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
705 710 715 720
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
725 730 735
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
740 745 750
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
755 760 765
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
770 775 780
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
785 790 795 800
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
805 810 815
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
820 825 830
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
835 840
<210> 10
<211> 2535
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 10
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagacgagtc caaatatggt 1860
cccccgtgcc caccatgccc agcacctgag ttcctggggg gaccatcagt cttcctgttc 1920
cccccaaaac ccaaggacac tctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 1980
gtggacgtga gccaggaaga ccccgaggtc cagttcaact ggtacgtgga tggcgtggag 2040
gtgcataatg ccaagacaaa gccgcgggag gagcagttca acagcacgta ccgtgtggtc 2100
agcgtcctca ccgtcctcca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 2160
tccaacaaag gcctcccgtc ctccatcgag aaaaccatct ccaaagccaa agggcagccc 2220
cgagagccac aggtgtacac cctgccccca tcccaggagg agatgaccaa gaaccaggtc 2280
agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 2340
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 2400
ttcttcctct acagcaggct aaccgtggac aagagcaggt ggcaggaggg gaatgtcttc 2460
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2520
tctctgggta aatga 2535
<210> 11
<211> 875
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 11
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Ser Gln Asp Val Thr Val Pro Cys Pro
610 615 620
Val Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro
625 630 635 640
Ser Pro Ser Cys Cys His Pro Arg Leu Ser Leu His Arg Pro Ala Leu
645 650 655
Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn Leu Thr Cys Thr Leu Thr
660 665 670
Gly Leu Arg Asp Ala Ser Gly Val Thr Phe Thr Trp Thr Pro Ser Ser
675 680 685
Gly Lys Ser Ala Val Gln Gly Pro Pro Glu Arg Asp Leu Cys Gly Cys
690 695 700
Tyr Ser Val Ser Ser Val Leu Pro Gly Cys Ala Glu Pro Trp Asn His
705 710 715 720
Gly Lys Thr Phe Thr Cys Thr Ala Ala Tyr Pro Glu Ser Lys Thr Pro
725 730 735
Leu Thr Ala Thr Leu Ser Lys Ser Gly Asn Thr Phe Arg Pro Glu Val
740 745 750
His Leu Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val
755 760 765
Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser Pro Lys Asp Val Leu Val
770 775 780
Arg Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr
785 790 795 800
Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val
805 810 815
Thr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr
820 825 830
Phe Ser Cys Met Val Gly His Glu Ala Leu Pro Leu Ala Phe Thr Gln
835 840 845
Lys Thr Ile Asp Arg Leu Ala Gly Lys Pro Thr His Val Asn Val Ser
850 855 860
Val Val Met Ala Glu Val Asp Gly Thr Cys Tyr
865 870 875
<210> 12
<211> 2628
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 12
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagacagcca ggatgtgact 1860
gtgccctgcc cagttccctc aactccacct accccatctc cctcaactcc acctacccca 1920
tctccctcat gctgccaccc ccgactgtca ctgcaccgac cggccctcga ggacctgctc 1980
ttaggttcag aagcgaacct cacgtgcaca ctgaccggcc tgagagatgc ctcaggtgtc 2040
accttcacct ggacgccctc aagtgggaag agcgctgttc aaggaccacc tgagcgtgac 2100
ctctgtggct gctacagcgt gtccagtgtc ctgccgggct gtgccgagcc atggaaccat 2160
gggaagacct tcacttgcac tgctgcctac cccgagtcca agaccccgct aaccgccacc 2220
ctctcaaaat ccggaaacac attccggccc gaggtccacc tgctgccgcc gccgtcggag 2280
gagctggccc tgaacgagct ggtgacgctg acgtgcctgg cacgcggctt cagccccaag 2340
gacgtgctgg ttcgctggct gcaggggtca caggagctgc cccgcgagaa gtacctgact 2400
tgggcatccc ggcaggagcc cagccagggc accaccacct tcgctgtgac cagcatactg 2460
cgcgtggcag ccgaggactg gaagaagggg gacaccttct cctgcatggt gggccacgag 2520
gccctgccgc tggccttcac acagaagacc atcgaccgct tggcgggtaa acccacccat 2580
gtcaatgtgt ctgttgtcat ggcggaggtg gacggcacct gctactga 2628
<210> 13
<211> 862
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 13
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Ser Gln Asp Val Thr Val Pro Cys Arg
610 615 620
Val Pro Pro Pro Pro Pro Cys Cys His Pro Arg Leu Ser Leu His Arg
625 630 635 640
Pro Ala Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn Leu Thr Cys
645 650 655
Thr Leu Thr Gly Leu Arg Asp Ala Ser Gly Ala Thr Phe Thr Trp Thr
660 665 670
Pro Ser Ser Gly Lys Ser Ala Val Gln Gly Pro Pro Glu Arg Asp Leu
675 680 685
Cys Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly Cys Ala Gln Pro
690 695 700
Trp Asn His Gly Glu Thr Phe Thr Cys Thr Ala Ala His Pro Glu Leu
705 710 715 720
Lys Thr Pro Leu Thr Ala Asn Ile Thr Lys Ser Gly Asn Thr Phe Arg
725 730 735
Pro Glu Val His Leu Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn
740 745 750
Glu Leu Val Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser Pro Lys Asp
755 760 765
Val Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys
770 775 780
Tyr Leu Thr Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr
785 790 795 800
Tyr Ala Val Thr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys
805 810 815
Gly Glu Thr Phe Ser Cys Met Val Gly His Glu Ala Leu Pro Leu Ala
820 825 830
Phe Thr Gln Lys Thr Ile Asp Arg Met Ala Gly Lys Pro Thr His Ile
835 840 845
Asn Val Ser Val Val Met Ala Glu Ala Asp Gly Thr Cys Tyr
850 855 860
<210> 14
<211> 2589
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 14
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagacagcca ggatgtgact 1860
gtgccctgcc gagttccccc acctccccca tgctgccacc cccgactgtc gctgcaccga 1920
ccggccctcg aggacctgct cttaggttca gaagcgaacc tcacgtgcac actgaccggc 1980
ctgagagatg cctctggtgc caccttcacc tggacgccct caagtgggaa gagcgctgtt 2040
caaggaccac ctgagcgtga cctctgtggc tgctacagcg tgtccagtgt cctgcctggc 2100
tgtgcccagc catggaacca tggggagacc ttcacctgca ctgctgccca ccccgagttg 2160
aagaccccac taaccgccaa catcacaaaa tccggaaaca cattccggcc cgaggtccac 2220
ctgctgccgc cgccgtcgga ggagctggcc ctgaacgagc tggtgacgct gacgtgcctg 2280
gcacgtggct tcagccccaa ggatgtgctg gttcgctggc tgcaggggtc acaggagctg 2340
ccccgcgaga agtacctgac ttgggcatcc cggcaggagc ccagccaggg caccaccacc 2400
tatgctgtga ccagcatact gcgcgtggca gccgaggact ggaagaaggg ggaaaccttc 2460
tcctgcatgg tgggccacga ggccctgccg ctggccttca cacagaagac catcgaccgc 2520
atggcgggta aacccaccca tatcaatgtg tctgttgtca tggcggaggc ggacggcacc 2580
tgctactga 2589
<210> 15
<211> 830
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 15
Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp 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 Glu Pro Lys Ser Ser Asp Lys Thr His Thr
595 600 605
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
610 615 620
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
625 630 635 640
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
645 650 655
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
660 665 670
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
675 680 685
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
690 695 700
Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
705 710 715 720
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
725 730 735
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
740 745 750
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
755 760 765
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
770 775 780
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
785 790 795 800
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
805 810 815
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
820 825 830
<210> 16
<211> 827
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 16
Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp 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 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
595 600 605
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
610 615 620
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
625 630 635 640
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
645 650 655
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
660 665 670
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
675 680 685
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
690 695 700
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
705 710 715 720
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
725 730 735
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
740 745 750
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
755 760 765
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
770 775 780
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
785 790 795 800
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
805 810 815
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
820 825
<210> 17
<211> 858
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 17
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 Ser Gln Asp Val Thr Val Pro Cys Pro Val
595 600 605
Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser
610 615 620
Pro Ser Cys Cys His Pro Arg Leu Ser Leu His Arg Pro Ala Leu Glu
625 630 635 640
Asp Leu Leu Leu Gly Ser Glu Ala Asn Leu Thr Cys Thr Leu Thr Gly
645 650 655
Leu Arg Asp Ala Ser Gly Val Thr Phe Thr Trp Thr Pro Ser Ser Gly
660 665 670
Lys Ser Ala Val Gln Gly Pro Pro Glu Arg Asp Leu Cys Gly Cys Tyr
675 680 685
Ser Val Ser Ser Val Leu Pro Gly Cys Ala Glu Pro Trp Asn His Gly
690 695 700
Lys Thr Phe Thr Cys Thr Ala Ala Tyr Pro Glu Ser Lys Thr Pro Leu
705 710 715 720
Thr Ala Thr Leu Ser Lys Ser Gly Asn Thr Phe Arg Pro Glu Val His
725 730 735
Leu Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr
740 745 750
Leu Thr Cys Leu Ala Arg Gly Phe Ser Pro Lys Asp Val Leu Val Arg
755 760 765
Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp
770 775 780
Ala Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr
785 790 795 800
Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe
805 810 815
Ser Cys Met Val Gly His Glu Ala Leu Pro Leu Ala Phe Thr Gln Lys
820 825 830
Thr Ile Asp Arg Leu Ala Gly Lys Pro Thr His Val Asn Val Ser Val
835 840 845
Val Met Ala Glu Val Asp Gly Thr Cys Tyr
850 855
<210> 18
<211> 845
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 18
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 Ser Gln Asp Val Thr Val Pro Cys Arg Val
595 600 605
Pro Pro Pro Pro Pro Cys Cys His Pro Arg Leu Ser Leu His Arg Pro
610 615 620
Ala Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn Leu Thr Cys Thr
625 630 635 640
Leu Thr Gly Leu Arg Asp Ala Ser Gly Ala Thr Phe Thr Trp Thr Pro
645 650 655
Ser Ser Gly Lys Ser Ala Val Gln Gly Pro Pro Glu Arg Asp Leu Cys
660 665 670
Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly Cys Ala Gln Pro Trp
675 680 685
Asn His Gly Glu Thr Phe Thr Cys Thr Ala Ala His Pro Glu Leu Lys
690 695 700
Thr Pro Leu Thr Ala Asn Ile Thr Lys Ser Gly Asn Thr Phe Arg Pro
705 710 715 720
Glu Val His Leu Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu
725 730 735
Leu Val Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser Pro Lys Asp Val
740 745 750
Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr
755 760 765
Leu Thr Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Tyr
770 775 780
Ala Val Thr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly
785 790 795 800
Glu Thr Phe Ser Cys Met Val Gly His Glu Ala Leu Pro Leu Ala Phe
805 810 815
Thr Gln Lys Thr Ile Asp Arg Met Ala Gly Lys Pro Thr His Ile Asn
820 825 830
Val Ser Val Val Met Ala Glu Ala Asp Gly Thr Cys Tyr
835 840 845
<210> 19
<211> 847
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 19
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Glu Pro Lys Ser Ser Asp Lys Thr His
610 615 620
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
625 630 635 640
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
645 650 655
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
660 665 670
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
675 680 685
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
690 695 700
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
705 710 715 720
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
725 730 735
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
740 745 750
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
755 760 765
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
770 775 780
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
785 790 795 800
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
805 810 815
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
820 825 830
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
835 840 845
<210> 20
<211> 2544
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 20
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agctccagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagacgagcc caaatcttcc 1860
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 1920
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1980
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 2040
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 2100
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 2160
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 2220
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 2280
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 2340
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 2400
gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg 2460
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 2520
ctctccctgt ctccgggtaa atag 2544
<210> 21
<211> 972
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 21
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Gln Ser Ile Lys Val Arg Ile Ser Leu
610 615 620
Lys Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met
625 630 635 640
Tyr Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu
645 650 655
Lys Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val
660 665 670
Ala Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro
675 680 685
Lys Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile
690 695 700
Arg Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn
705 710 715 720
Ser Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln
725 730 735
Pro Pro Val Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
740 745 750
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
755 760 765
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
770 775 780
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
785 790 795 800
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
805 810 815
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
820 825 830
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
835 840 845
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
850 855 860
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
865 870 875 880
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
885 890 895
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
900 905 910
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
915 920 925
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
930 935 940
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
945 950 955 960
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
965 970
<210> 22
<211> 2919
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 22
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agctccagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagaccaaag catcaaagtg 1860
aggataagcc taaaatcagc tcttggagat aaagcatatg aatggaacga caatgaaatg 1920
tacctgttcc gatcatctgt tgcatatgct atgaggcagt actttttaaa agtaaaaaat 1980
cagatgattc tttttgggga ggaggatgtg cgagtggcta atttgaaacc aagaatctcc 2040
tttaatttct ttgtcactgc acctaaaaat gtgtctgata tcattcctag aactgaagtt 2100
gaaaaggcca tcaggatgtc ccggagccgt atcaatgatg ctttccgtct gaatgacaac 2160
agcctagagt ttctggggat acagccaaca cttggacctc ctaaccagcc ccctgtttcc 2220
gagcccaaat cttccgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 2280
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 2340
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 2400
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 2460
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 2520
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 2580
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 2640
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 2700
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 2760
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 2820
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 2880
tacacgcaga agagcctctc cctgtctccg ggtaaatag 2919
<210> 23
<211> 621
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 23
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp His His His His His His
610 615 620
<210> 24
<211> 1863
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 24
atgtcaagct cttcctggct ccttctcagc cttgttgctg taactgctgc tcagtccacc 60
attgaggaac aggccaagac atttttggac aagtttaacc acgaagccga agacctgttc 120
tatcaaagtt cacttgcttc ttggaattat aacaccaata ttactgaaga gaatgtccaa 180
aacatgaata atgctgggga caaatggtct gcctttttaa aggaacagtc cacacttgcc 240
caaatgtatc cactacaaga aattcagaat ctcacagtca agcttcagct gcaggctctt 300
cagcaaaatg ggtcttcagt gctctcagaa gacaagagca aacggttgaa cacaattcta 360
aatacaatga gcaccatcta cagtactgga aaagtttgta acccagataa tccacaagaa 420
tgcttattac ttgaaccagg tttgaatgaa ataatggcaa acagtttaga ctacaatgag 480
aggctctggg cttgggaaag ctggagatct gaggtcggca agcagctgag gccattatat 540
gaagagtatg tggtcttgaa aaatgagatg gcaagagcaa atcattatga ggactatggg 600
gattattgga gaggagacta tgaagtaaat ggggtagatg gctatgacta cagccgcggc 660
cagttgattg aagatgtgga acataccttt gaagagatta aaccattata tgaacatctt 720
catgcctatg tgagggcaaa gttgatgaat gcctatcctt cctatatcag tccaattgga 780
tgcctccctg ctcatttgct tggtgatatg tggggtagat tttggacaaa tctgtactct 840
ttgacagttc cctttggaca gaaaccaaac atagatgtta ctgatgcaat ggtggaccag 900
gcctgggatg cacagagaat attcaaggag gccgagaagt tctttgtatc tgttggtctt 960
cctaatatga ctcaaggatt ctgggaaaat tccatgctaa cggacccagg aaatgttcag 1020
aaagcagtct gccatcccac agcttgggac ctggggaagg gcgacttcag gatccttatg 1080
tgcacaaagg tgacaatgga cgacttcctg acagctcatc atgagatggg gcatatccag 1140
tatgatatgg catatgctgc acaacctttt ctgctaagaa atggagctaa tgaaggattc 1200
catgaagctg ttggggaaat catgtcactt tctgcagcca cacctaagca tttaaaatcc 1260
attggtcttc tgtcacccga ttttcaagaa gacaatgaaa cagaaataaa cttcctgctc 1320
aaacaagcac tcacgattgt tgggactctg ccatttactt acatgttaga gaagtggagg 1380
tggatggtct ttaaagggga aattcccaaa gaccagtgga tgaaaaagtg gtgggagatg 1440
aagcgagaga tagttggggt ggtggaacct gtgccccatg atgaaacata ctgtgacccc 1500
gcatctctgt tccatgtttc taatgattac tcattcattc gatattacac aaggaccctt 1560
taccaattcc agtttcaaga agcactttgt caagcagcta aacatgaagg ccctctgcac 1620
aaatgtgaca tctcaaactc tacagaagct ggacagaaac tgttcaatat gctgaggctt 1680
ggaaaatcag aaccctggac cctagcattg gaaaatgttg taggagcaaa gaacatgaat 1740
gtaaggccac tgctcaacta ctttgagccc ttatttacct ggctgaaaga ccagaacaag 1800
aattcttttg tgggatggag taccgactgg agtccatatg cagaccatca tcaccatcac 1860
cac 1863
<210> 25
<211> 413
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 25
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Trp Lys Phe Met Gly Ser Lys Cys Ser Asn Ser Gly
20 25 30
Ile Glu Cys Asp Ser Ser Gly Thr Cys Ile Asn Pro Ser Asn Trp Cys
35 40 45
Asp Gly Val Ser His Cys Pro Gly Gly Glu Asp Glu Asn Arg Cys Val
50 55 60
Arg Leu Tyr Gly Pro Asn Phe Ile Leu Gln Val Tyr Ser Ser Gln Arg
65 70 75 80
Lys Ser Trp His Pro Val Cys Gln Asp Asp Trp Asn Glu Asn Tyr Gly
85 90 95
Arg Ala Ala Cys Arg Asp Met Gly Tyr Lys Asn Asn Phe Tyr Ser Ser
100 105 110
Gln Gly Ile Val Asp Asp Ser Gly Ser Thr Ser Phe Met Lys Leu Asn
115 120 125
Thr Ser Ala Gly Asn Val Asp Ile Tyr Lys Lys Leu Tyr His Ser Asp
130 135 140
Ala Cys Ser Ser Lys Ala Val Val Ser Leu Arg Cys Ile Ala Cys Gly
145 150 155 160
Val Asn Leu Asn Ser Ser Arg Gln Ser Arg Ile Val Gly Gly Glu Ser
165 170 175
Ala Leu Pro Gly Ala Trp Pro Trp Gln Val Ser Leu His Val Gln Asn
180 185 190
Val His Val Cys Gly Gly Ser Ile Ile Thr Pro Glu Trp Ile Val Thr
195 200 205
Ala Ala His Cys Val Glu Lys Pro Leu Asn Asn Pro Trp His Trp Thr
210 215 220
Ala Phe Ala Gly Ile Leu Arg Gln Ser Phe Met Phe Tyr Gly Ala Gly
225 230 235 240
Tyr Gln Val Glu Lys Val Ile Ser His Pro Asn Tyr Asp Ser Lys Thr
245 250 255
Lys Asn Asn Asp Ile Ala Leu Met Lys Leu Gln Lys Pro Leu Thr Phe
260 265 270
Asn Asp Leu Val Lys Pro Val Cys Leu Pro Asn Pro Gly Met Met Leu
275 280 285
Gln Pro Glu Gln Leu Cys Trp Ile Ser Gly Trp Gly Ala Thr Glu Glu
290 295 300
Lys Gly Lys Thr Ser Glu Val Leu Asn Ala Ala Lys Val Leu Leu Ile
305 310 315 320
Glu Thr Gln Arg Cys Asn Ser Arg Tyr Val Tyr Asp Asn Leu Ile Thr
325 330 335
Pro Ala Met Ile Cys Ala Gly Phe Leu Gln Gly Asn Val Asp Ser Cys
340 345 350
Gln Gly Asp Ser Gly Gly Pro Leu Val Thr Ser Lys Asn Asn Ile Trp
355 360 365
Trp Leu Ile Gly Asp Thr Ser Trp Gly Ser Gly Cys Ala Lys Ala Tyr
370 375 380
Arg Pro Gly Val Tyr Gly Asn Val Met Val Phe Thr Asp Trp Ile Tyr
385 390 395 400
Arg Gln Met Arg Ala Asp Gly His His His His His His
405 410
<210> 26
<211> 1242
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 26
atgtacagga tgcaactcct gtcttgcatt gcactaagtc ttgcacttgt caccaattcg 60
tggaagttta tgggttctaa atgctctaat agcgggatag aatgtgacag tagtggcact 120
tgcattaacc cttcaaactg gtgtgatggg gtaagccatt gccccggggg ggaagatgaa 180
aatagatgtg ttaggctcta cggtcccaac tttatactcc aggtatattc aagtcaacgc 240
aaatcatggc atccagtgtg tcaagacgac tggaacgaaa actatggacg cgctgcatgt 300
cgagatatgg gatataagaa taacttctat agttcacagg gaatcgtaga tgactctgga 360
tctactagtt tcatgaaact gaacacctct gccggaaacg tagatatata taaaaagctt 420
taccactccg acgcttgtag ctctaaggcc gtagttagcc tcagatgcat cgcctgcgga 480
gtaaacctca attcatctcg ccagagtagg atcgttggcg gggaaagcgc cctcccaggc 540
gcttggcctt ggcaagtttc ccttcatgtc cagaatgttc atgtatgtgg cgggtctata 600
atcaccccag aatggatcgt cacagctgcc cactgcgtgg agaaacccct caacaatcct 660
tggcattgga ccgcatttgc cggaatactg agacaatcat ttatgttcta tggagccggg 720
taccaagtcg aaaaggtcat ttcccatccc aattatgatt ccaaaaccaa aaacaatgac 780
atagccttga tgaaactcca gaagcctttg acatttaatg acctggtcaa accagtgtgc 840
ctcccaaatc ctggaatgat gttgcagcct gaacagttgt gctggatcag cggttggggt 900
gctaccgagg agaagggtaa gacaagcgag gtccttaacg ctgcaaaggt tttgctgata 960
gaaacacaga gatgtaacag ccgctatgtg tacgataacc tgatcacccc agctatgatt 1020
tgcgccgggt ttttgcaagg taacgtcgat tcttgccaag gtgactcagg cggccctctt 1080
gttacatcaa agaacaatat atggtggctt atcggcgata catcatgggg ttctggatgt 1140
gctaaagcct atcgcccagg ggtgtatggc aatgtaatgg tgtttacaga ctggatctat 1200
aggcagatgc gggctgacgg tcaccatcat caccatcact ga 1242
<210> 27
<211> 159
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 27
Met Lys Asn His Leu Leu Phe Trp Gly Val Leu Ala Val Phe Ile Lys
1 5 10 15
Ala Val His Val Lys Ala Gln Glu Asp Glu Arg Ile Val Leu Val Asp
20 25 30
Asn Lys Cys Lys Cys Ala Arg Ile Thr Ser Arg Ile Ile Arg Ser Ser
35 40 45
Glu Asp Pro Asn Glu Asp Ile Val Glu Arg Asn Ile Arg Ile Ile Val
50 55 60
Pro Leu Asn Asn Arg Glu Asn Ile Ser Asp Pro Thr Ser Pro Leu Arg
65 70 75 80
Thr Arg Phe Val Tyr His Leu Ser Asp Leu Cys Lys Lys Cys Asp Pro
85 90 95
Thr Glu Val Glu Leu Asp Asn Gln Ile Val Thr Ala Thr Gln Ser Asn
100 105 110
Ile Cys Asp Glu Asp Ser Ala Thr Glu Thr Cys Tyr Thr Tyr Asp Arg
115 120 125
Asn Lys Cys Tyr Thr Ala Val Val Pro Leu Val Tyr Gly Gly Glu Thr
130 135 140
Lys Met Val Glu Thr Ala Leu Thr Pro Asp Ala Cys Tyr Pro Asp
145 150 155
<210> 28
<211> 585
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 28
Lys Ser Pro Ile Phe Gly Pro Glu Glu Val Asn Ser Val Glu Gly Asn
1 5 10 15
Ser Val Ser Ile Thr Cys Tyr Tyr Pro Pro Thr Ser Val Asn Arg His
20 25 30
Thr Arg Lys Tyr Trp Cys Arg Gln Gly Ala Arg Gly Gly Cys Ile Thr
35 40 45
Leu Ile Ser Ser Glu Gly Tyr Val Ser Ser Lys Tyr Ala Gly Arg Ala
50 55 60
Asn Leu Thr Asn Phe Pro Glu Asn Gly Thr Phe Val Val Asn Ile Ala
65 70 75 80
Gln Leu Ser Gln Asp Asp Ser Gly Arg Tyr Lys Cys Gly Leu Gly Ile
85 90 95
Asn Ser Arg Gly Leu Ser Phe Asp Val Ser Leu Glu Val Ser Gln Gly
100 105 110
Pro Gly Leu Leu Asn Asp Thr Lys Val Tyr Thr Val Asp Leu Gly Arg
115 120 125
Thr Val Thr Ile Asn Cys Pro Phe Lys Thr Glu Asn Ala Gln Lys Arg
130 135 140
Lys Ser Leu Tyr Lys Gln Ile Gly Leu Tyr Pro Val Leu Val Ile Asp
145 150 155 160
Ser Ser Gly Tyr Val Asn Pro Asn Tyr Thr Gly Arg Ile Arg Leu Asp
165 170 175
Ile Gln Gly Thr Gly Gln Leu Leu Phe Ser Val Val Ile Asn Gln Leu
180 185 190
Arg Leu Ser Asp Ala Gly Gln Tyr Leu Cys Gln Ala Gly Asp Asp Ser
195 200 205
Asn Ser Asn Lys Lys Asn Ala Asp Leu Gln Val Leu Lys Pro Glu Pro
210 215 220
Glu Leu Val Tyr Glu Asp Leu Arg Gly Ser Val Thr Phe His Cys Ala
225 230 235 240
Leu Gly Pro Glu Val Ala Asn Val Ala Lys Phe Leu Cys Arg Gln Ser
245 250 255
Ser Gly Glu Asn Cys Asp Val Val Val Asn Thr Leu Gly Lys Arg Ala
260 265 270
Pro Ala Phe Glu Gly Arg Ile Leu Leu Asn Pro Gln Asp Lys Asp Gly
275 280 285
Ser Phe Ser Val Val Ile Thr Gly Leu Arg Lys Glu Asp Ala Gly Arg
290 295 300
Tyr Leu Cys Gly Ala His Ser Asp Gly Gln Leu Gln Glu Gly Ser Pro
305 310 315 320
Ile Gln Ala Trp Gln Leu Phe Val Asn Glu Glu Ser Thr Ile Pro Arg
325 330 335
Ser Pro Thr Val Val Lys Gly Val Ala Gly Gly Ser Val Ala Val Leu
340 345 350
Cys Pro Tyr Asn Arg Lys Glu Ser Lys Ser Ile Lys Tyr Trp Cys Leu
355 360 365
Trp Glu Gly Ala Gln Asn Gly Arg Cys Pro Leu Leu Val Asp Ser Glu
370 375 380
Gly Trp Val Lys Ala Gln Tyr Glu Gly Arg Leu Ser Leu Leu Glu Glu
385 390 395 400
Pro Gly Asn Gly Thr Phe Thr Val Ile Leu Asn Gln Leu Thr Ser Arg
405 410 415
Asp Ala Gly Phe Tyr Trp Cys Leu Thr Asn Gly Asp Thr Leu Trp Arg
420 425 430
Thr Thr Val Glu Ile Lys Ile Ile Glu Gly Glu Pro Asn Leu Lys Val
435 440 445
Pro Gly Asn Val Thr Ala Val Leu Gly Glu Thr Leu Lys Val Pro Cys
450 455 460
His Phe Pro Cys Lys Phe Ser Ser Tyr Glu Lys Tyr Trp Cys Lys Trp
465 470 475 480
Asn Asn Thr Gly Cys Gln Ala Leu Pro Ser Gln Asp Glu Gly Pro Ser
485 490 495
Lys Ala Phe Val Asn Cys Asp Glu Asn Ser Arg Leu Val Ser Leu Thr
500 505 510
Leu Asn Leu Val Thr Arg Ala Asp Glu Gly Trp Tyr Trp Cys Gly Val
515 520 525
Lys Gln Gly His Phe Tyr Gly Glu Thr Ala Ala Val Tyr Val Ala Val
530 535 540
Glu Glu Arg Lys Ala Ala Gly Ser Arg Asp Val Ser Leu Ala Lys Ala
545 550 555 560
Asp Ala Ala Pro Asp Glu Lys Val Leu Asp Ser Gly Phe Arg Glu Ile
565 570 575
Glu Asn Lys Ala Ile Gln Asp Pro Arg
580 585
<210> 29
<211> 455
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Tyr Glu Ala Arg His Tyr Tyr Tyr Tyr Tyr Ala Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Ala Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 30
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 30
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 31
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 31
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Tyr Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Thr Thr Met Val Pro Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 32
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Gly Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 33
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Met Asn Thr Leu Phe Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Val Leu Pro Met Tyr Gly Asp Tyr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 34
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro
85 90 95
Glu Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 35
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 35
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Ser Asp Tyr Gly Asp Tyr Leu Leu Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 36
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 36
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Leu Thr Ser Ile
85 90 95
Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 37
<211> 461
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asp Val
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Ile Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Ala Gly Ser Tyr Tyr Tyr Asp Thr Val Gly Pro Gly
100 105 110
Leu Pro Glu Gly Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
115 120 125
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
130 135 140
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
145 150 155 160
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
165 170 175
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
180 185 190
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
195 200 205
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
210 215 220
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu
245 250 255
Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu
260 265 270
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
275 280 285
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
290 295 300
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
305 310 315 320
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
325 330 335
Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys
340 345 350
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
355 360 365
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
370 375 380
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
385 390 395 400
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
405 410 415
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
435 440 445
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 38
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 38
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 39
<211> 453
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 39
Gln Met Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Met Ser Ser
20 25 30
Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Trp Ile Val Ile Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Pro Tyr Cys Ser Ser Ile Ser Cys Asn Asp Gly Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe
225 230 235 240
Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 40
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 40
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Arg
85 90 95
Gly Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215

Claims (31)

1.一种用于预防、降低病毒感染的风险或治疗病毒感染，或预防或治疗由病毒引起的受试者症状的方法，所述方法包括向所述受试者施用有效量的融合蛋白，其中，所述融合蛋白包含与Fc结构域共价融合的变体血管紧张素转换酶2(ACE2)结构域，其中，相对于具有SEQ ID NO.1的全长野生型ACE2，所述变体ACE2结构域包括N-端缺失、C-端缺失或两者，其中，所述变体ACE2结构域具有ACE2活性，其中，所述病毒包括SARS-CoV、SARS-CoV-2或MERS-CoV，以及其中，所述症状包括严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)、急性呼吸窘迫综合征(ARDS)、肺动脉高血压(PAH)或2019年冠状病毒病(COVID-19)。
2.根据权利要求1所述的方法，其中，所述融合蛋白包含与SEQ ID NO.15、16、17或18具有至少98％的序列同一性的氨基酸。
3.根据权利要求1所述的方法，其中，每次治疗施用的所述融合蛋白的剂量为约3mg/Kg至约70mg/Kg体重。
4.根据权利要求1所述的方法，其中，每天施用的所述融合蛋白的剂量小于或等于约140mg/Kg体重。
5.根据权利要求1所述的方法，其中，所述融合蛋白以小于或等于约70mg/Kg体重的剂量每天施用两次。
6.根据权利要求1所述的方法，其中，所述融合蛋白通过每日输注施用。
7.根据权利要求1所述的方法，其中，所述融合蛋白通过每日肌肉注射施用。
8.根据权利要求1所述的方法，其中，所述融合蛋白作为液体制剂施用。
9.根据权利要求1所述的方法，其中，所述融合蛋白以包含盐和表面活性剂的溶液中的液体悬浮液的形式施用。
10.根据权利要求8所述的方法，其中，所述液体制剂包含浓度为约5mg/ml至约10mg/ml的所述融合蛋白。
11.根据权利要求1所述的方法，其中，所述融合蛋白的施用防止所述受试者感染SARS-CoV-2病毒。
12.根据权利要求1所述的方法，其中，所述融合蛋白的施用降低了所述受试者感染SARS-CoV-2病毒的风险。
13.根据权利要求1所述的方法，其中，所述融合蛋白的施用防止患有SARS-CoV-2病毒感染的所述受试者住院。
14.根据权利要求1所述的方法，其中，所述融合蛋白的施用降低了患有SARS-CoV-2病毒感染的所述受试者住院的风险。
15.根据权利要求1所述的方法，其中，所述融合蛋白的施用减少了患有SARS-CoV-2病毒感染的所述受试者的住院时间。
16.根据权利要求1所述的方法，其中，所述融合蛋白的施用防止患有SARS-CoV-2病毒感染的所述受试者的氧合和通气。
17.根据权利要求1所述的方法，其中，所述融合蛋白的施用减少了患有SARS-CoV-2病毒感染的所述受试者对氧合和通气的需求。
18.根据权利要求1所述的方法，其中，所述融合蛋白的施用防止患有SARS-CoV-2病毒感染的所述受试者死亡。
19.根据权利要求1所述的方法，其中，所述融合蛋白的施用降低了患有SARS-CoV-2病毒感染的是受试者的死亡风险。
20.根据权利要求18所述的方法，其中，所述SARS-CoV-2病毒基本上包括δ毒株。
21.根据权利要求18所述的方法，其中，所述SARS-CoV-2病毒包括刺突蛋白突变，其中，所述突变被配置为增加病毒对所述ACE2结构域的结合亲和力。
22.根据权利要求1所述的方法，其中，所述融合蛋白的施用降低了患有SARS-CoV-2病毒感染的所述受试者的COVID症状的严重程度。
23.根据权利要求1所述的方法，其中，所述受试者具有选自由以下组成的组的至少一种风险因素：
年龄大于或等于65岁；
中度或重度免疫系统受损；
代谢综合征；
对COVID疫苗过敏；和
在接种COVID疫苗后具有低免疫应答或无免疫应答。
24.根据权利要求23所述的方法，其中，所述受试者患有癌症、慢性肾脏疾病、慢性肺病、糖尿病或心脏病。
25.根据权利要求1所述的方法，其中，所述受试者是人。
26.一种液体组合物，包含融合蛋白，其中，所述融合蛋白包含与Fc结构域共价融合的变异体血管紧张素转换酶2(ACE2)结构域，其中，相对于具有SEQ ID NO.1的全长野生型ACE2，所述变异体ACE2结构域包含N端缺失、C端缺失或二者，其中，所述变异体ACE2结构域具有ACE2活性。
27.根据权利要求26所述的液体组合物，其具有每剂量约100mg至约10000mg的融合蛋白含量。
28.根据权利要求26所述的液体组合物，其具有按重量计约0.5％至约1％的浓度的融合蛋白。
29.根据权利要求26所述的液体组合物，其中，所述变体ACE2结构域包含与SEQ IDNO.3具有至少98％的序列同一性的氨基酸序列。
30.根据权利要求26所述的液体组合物，其中，所述Fc结构域包含与SEQ ID NO.6具有至少98％的序列同一性的氨基酸序列。
31.根据权利要求26所述的液体组合物，其中，所述融合蛋白包含与SEQ ID NO.7、9、11、13、15、16、17、18、19或21具有至少98％的序列同一性的氨基酸序列。
CN202180069760.6A 2020-10-01 2021-10-01 重组ace2-fc融合分子及其制备和使用方法 Pending CN116710120A (zh)

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