CN116724049A - 针对sars相关冠状病毒的中和抗体 - Google Patents
针对sars相关冠状病毒的中和抗体 Download PDFInfo
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- CN116724049A CN116724049A CN202180059341.4A CN202180059341A CN116724049A CN 116724049 A CN116724049 A CN 116724049A CN 202180059341 A CN202180059341 A CN 202180059341A CN 116724049 A CN116724049 A CN 116724049A
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Abstract
本发明涉及针对SARS相关冠状病毒的抗体或其结合片段、包含此类抗体或其结合片段的药物组合物、包含此类抗体或其结合片段的试剂盒、和所述单克隆抗体或其结合片段和所述药物组合物和所述试剂盒用作药物、以及用于治疗或预防由SARS相关冠状病毒引起的疾病的用途。
Description
技术领域
本发明涉及针对SARS相关冠状病毒的抗体或其结合片段、包含此类抗体或其结合片段的药物组合物、包含此类抗体或其结合片段的试剂盒，和抗体或其结合片段和药物组合物和试剂盒用作药物、以及用于治疗或预防由SARS相关冠状病毒引起的疾病的用途。
背景技术
一种新的高度致病性的冠状病毒(严重急性呼吸综合征冠状病毒2，SARS-CoV-2)的出现及其迅速的国际传播造成了严重的全球公共卫生紧急事件。类似于感染其它高致病性冠状病毒毒株如2003年出现的严重急性呼吸综合征冠状病毒(SARS-CoV)或2012年出现的中东呼吸综合征冠状病毒(MERS-CoV)的个体，SARS-CoV-2感染的患者可表现为一系列的症状，包括干咳、发烧、头痛、呼吸困难和肺炎，估计死亡率在3-5％的范围内。
截至2020年5月27日，全球已确认5,488,825例病毒感染，其中349,095例确认受感染的患者死亡(https://www.who.int/emergencies/diseases/novel-coronavirus- 2019)。
为了应对在2020年演变为全球大流行并且已被WHO宣布为全球大流行的病毒的传播，世界各地的各个城市和国家都在不同程度上处于封锁(lockdown)以将继续传播最小化。2020年的SARS-CoV-2大流行已对公共卫生、社会生活、和世界经济产生了前所未有的影响。
由于未获得经批准的药物和疫苗用于应对此次爆发，迫切需要用于COVID-19治疗和预防的新选项。因此，解码SARS-CoV-2免疫以开发疫苗和有效的抗病毒药物是一项迫切的健康需求。
单克隆抗体(mAb)已证实为有效靶向且中和病毒如埃博拉病毒、呼吸道合胞病毒(RSV)、或人类免疫缺陷病毒1(HIV-1)。SARS-CoV-2病毒粒子的表面上抗体介导的应答的最突出的靶标是同源三聚体刺突(S)蛋白。S蛋白通过受体结合结构域(RBD)与血管紧张素转化酶2(ACE2)的相互作用促进细胞进入。因此，靶向S蛋白的单克隆人类抗体对于预防和治疗COVID-19具有很高的价值。
虽然最近已公开在不同实验设置中显示针对SARS-CoV-2的中和活性的少数抗体的有前景的数据(大部分是未经正式同行评审的预印本(pre-print)的形式)，但是这些数据要么缺少所测试的抗体的氨基酸序列的公开可用性，缺少所述抗体的针对活病毒的中和活性、自身反应性(autoreactivity)或自反应性(self-reactivity)的实验证据，要么针对活SARS-CoV-2病毒的中和效力相对较低。
由于上述提及的缺点，仍然需要针对SARS相关冠状病毒的人类抗体，所述抗体与足够详细地公开的公开可用抗体相比，不显示自身反应性并且具有针对活病毒的更好的中和效力。
因此，本发明的一个目的是提供针对SARS相关冠状病毒的新的单克隆抗体，所述抗体不显示自身反应性，并具有针对活病毒的优异中和效力。本发明的进一步的目的是提供针对SARS相关冠状病毒的新的单克隆抗体，其可用于治疗或预防人类或动物受试者中由SARS相关冠状病毒引起的疾病，以及用于预防人类或动物受试者感染SARS相关冠状病毒。
发明内容
这些目的已经通过如下文中具体说明的本发明的方面得以解决。
根据本发明的第一方面，提供了针对SARS相关冠状病毒的抗体或其结合片段，其中所述抗体或其结合片段包含来自包括以下的组的一种抗体的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6(具有SEQ ID No.1的可变区重链氨基酸序列和SEQID No.2的可变区轻链氨基酸序列)，HbnC3t1p1_G4(具有SEQ ID No.3的可变区重链氨基酸序列和SEQ ID No.4的可变区轻链氨基酸序列)，HbnC3t1p2_B10具有SEQ ID No.5的可变区重链氨基酸序列和SEQ ID No.6的可变区轻链氨基酸序列)，MnC2t2p1_C11(具有SEQ IDNo.7的可变区重链氨基酸序列和SEQ ID No.8的可变区轻链氨基酸序列)，FnC1t2p1_D4(具有SEQ ID No.9的可变区重链氨基酸序列和SEQ IDNo.10的可变区轻链氨基酸序列)，FnC1t2p1_G5(具有SEQ ID No.11的可变区重链氨基酸序列和SEQ ID No.12的可变区轻链氨基酸序列)，HbnC3t1p2_C6(具有SEQ ID No.13的可变区重链氨基酸序列和SEQ ID No.14的可变区轻链氨基酸序列)，MnC4t2p1_B3(具有SEQ ID No.15的可变区重链氨基酸序列和SEQ ID No.16的可变区轻链氨基酸序列)，MnC2t1p1_A3(具有SEQ ID No.17的可变区重链氨基酸序列和SEQ ID No.18的可变区轻链氨基酸序列)，CnC2t1p1_B4(具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列)，HbnC3t1p1_F4(具有SEQ ID No.21的可变区重链氨基酸序列和SEQ ID No.22的可变区轻链氨基酸序列)，HbnC2t1p2_D9(具有SEQ ID No.23的可变区重链氨基酸序列和SEQ ID No.24的可变区轻链氨基酸序列)，MnC5t2p1_G1(具有SEQ ID No.25的可变区重链氨基酸序列和SEQ ID No.26的可变区轻链氨基酸序列)，CnC2t1p1_E12(具有SEQ ID No.27的可变区重链氨基酸序列和SEQ ID No.28的可变区轻链氨基酸序列)，CnC2t1p1_D6(具有SEQ ID No.29的可变区重链氨基酸序列和SEQ ID No.30的可变区轻链氨基酸序列)，MnC2t1p1_C5(具有SEQ ID No.31的可变区重链氨基酸序列和SEQ ID No.32的可变区轻链氨基酸序列)，CnC2t1p1_E8(具有SEQ ID No.33的可变区重链氨基酸序列和SEQ ID No.34的可变区轻链氨基酸序列)，MnC1t3p1_G9(具有SEQ ID No.35的可变区重链氨基酸序列和SEQ ID No.36的可变区轻链氨基酸序列)，HbnC4t1p1_D5(具有SEQ ID No.37的可变区重链氨基酸序列和SEQ ID No.38的可变区轻链氨基酸序列)，CnC2t1p1_B10(具有SEQ ID No.39的可变区重链氨基酸序列和SEQ ID No.40的可变区轻链氨基酸序列)，CnC2t1p1_G6(具有SEQ ID No.41的可变区重链氨基酸序列和SEQ ID No.42的可变区轻链氨基酸序列)，FnC1t1p2_A5(具有SEQ ID No.43的可变区重链氨基酸序列和SEQ ID No.44的可变区轻链氨基酸序列)，MnC4t2p1_D10(具有SEQ ID No.45的可变区重链氨基酸序列和SEQ ID No.46的可变区轻链氨基酸序列)，MnC4t2p2_A4(具有SEQ ID No.47的可变区重链氨基酸序列和SEQ ID No.48的可变区轻链氨基酸序列)，MnC4t1p1_A10(具有SEQ ID No.49的可变区重链氨基酸序列和SEQ ID No.50的可变区轻链氨基酸序列)，MnC4t2p1_E6(具有SEQ ID No.51的可变区重链氨基酸序列和SEQ ID No.52的可变区轻链氨基酸序列)，MnC4t1p1_A11(具有SEQ ID No.53的可变区重链氨基酸序列和SEQ ID No.54的可变区轻链氨基酸序列)，和MnC4t2p1_F5(具有SEQ IDNo.55的可变区重链氨基酸序列和SEQ ID No.56的可变区轻链氨基酸序列)，优选其中所述抗体或其结合片段包含选自包括以下的组的抗体之一的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，FnC1t2p1_D4，FnC1t2p1_G5，HbnC3t1p2_C6，MnC4t2p1_B3，MnC2t1p1_A3，CnC2t1p1_B4，HbnC3t1p1_F4，和HbnC2t1p2_D9，更优选来自包括以下的组的一种抗体的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，和FnC1t2p1_D4。
在本发明的第一方面的一个实施方案中，所述抗体或其结合片段包含选自包括以下的组的一种抗体的可变区重链序列和可变区轻链序列的组合：HbnC3t1p1_C6(具有SEQID No.1的可变区重链氨基酸序列和SEQ ID No.2的可变区轻链氨基酸序列)，HbnC3t1p1_G4(具有SEQ ID No.3的可变区重链氨基酸序列和SEQ ID No.4的可变区轻链氨基酸序列)，HbnC3t1p2_B10具有SEQ ID No.5的可变区重链氨基酸序列和SEQ ID No.6的可变区轻链氨基酸序列)，MnC2t2p1_C11(具有SEQ ID No.7的可变区重链氨基酸序列和SEQ IDNo.8的可变区轻链氨基酸序列)，FnC1t2p1_D4(具有SEQ ID No.9的可变区重链氨基酸序列和SEQ IDNo.10的可变区轻链氨基酸序列)，FnC1t2p1_G5(具有SEQ ID No.11的可变区重链氨基酸序列和SEQ ID No.12的可变区轻链氨基酸序列)，HbnC3t1p2_C6(具有SEQ ID No.13的可变区重链氨基酸序列和SEQ ID No.14的可变区轻链氨基酸序列)，MnC4t2p1_B3(具有SEQ IDNo.15的可变区重链氨基酸序列和SEQ ID No.16的可变区轻链氨基酸序列)，MnC2t1p1_A3(具有SEQ ID No.17的可变区重链氨基酸序列和SEQ ID No.18的可变区轻链氨基酸序列)，CnC2t1p1_B4(具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列)，HbnC3t1p1_F4(具有SEQ ID No.21的可变区重链氨基酸序列和SEQ ID No.22的可变区轻链氨基酸序列)，HbnC2t1p2_D9(具有SEQ ID No.23的可变区重链氨基酸序列和SEQ ID No.24的可变区轻链氨基酸序列)，MnC5t2p1_G1(具有SEQ ID No.25的可变区重链氨基酸序列和SEQ ID No.26的可变区轻链氨基酸序列)，CnC2t1p1_E12(具有SEQ ID No.27的可变区重链氨基酸序列和SEQ ID No.28的可变区轻链氨基酸序列)，CnC2t1p1_D6(具有SEQ ID No.29的可变区重链氨基酸序列和SEQ ID No.30的可变区轻链氨基酸序列)，MnC2t1p1_C5(具有SEQ ID No.31的可变区重链氨基酸序列和SEQ ID No.32的可变区轻链氨基酸序列)，CnC2t1p1_E8(具有SEQ ID No.33的可变区重链氨基酸序列和SEQ ID No.34的可变区轻链氨基酸序列)，MnC1t3p1_G9(具有SEQ ID No.35的可变区重链氨基酸序列和SEQ ID No.36的可变区轻链氨基酸序列)，HbnC4t1p1_D5(具有SEQ ID No.37的可变区重链氨基酸序列和SEQ ID No.38的可变区轻链氨基酸序列)，CnC2t1p1_B10(具有SEQ ID No.39的可变区重链氨基酸序列和SEQ ID No.40的可变区轻链氨基酸序列)，CnC2t1p1_G6(具有SEQ ID No.41的可变区重链氨基酸序列和SEQ ID No.42的可变区轻链氨基酸序列)，FnC1t1p2_A5(具有SEQ ID No.43的可变区重链氨基酸序列和SEQ ID No.44的可变区轻链氨基酸序列)，MnC4t2p1_D10(具有SEQ ID No.45的可变区重链氨基酸序列和SEQ ID No.46的可变区轻链氨基酸序列)，MnC4t2p2_A4(具有SEQ ID No.47的可变区重链氨基酸序列和SEQ ID No.48的可变区轻链氨基酸序列)，MnC4t1p1_A10(具有SEQ ID No.49的可变区重链氨基酸序列和SEQ ID No.50的可变区轻链氨基酸序列)，MnC4t2p1_E6(具有SEQ ID No.51的可变区重链氨基酸序列和SEQ ID No.52的可变区轻链氨基酸序列)，MnC4t1p1_A11(具有SEQ ID No.53的可变区重链氨基酸序列和SEQ ID No.54的可变区轻链氨基酸序列)，和MnC4t2p1_F5(具有SEQ IDNo.55的可变区重链氨基酸序列和SEQ ID No.56的可变区轻链氨基酸序列)，优选来自包括以下的组的一种抗体的可变区重链序列和可变区轻链序列的组合：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，FnC1t2p1_D4，FnC1t2p1_G5，HbnC3t1p2_C6，MnC4t2p1_B3，MnC2t1p1_A3，CnC2t1p1_B4，HbnC3t1p1_F4，和HbnC2t1p2_D9，更优选来自包括以下的组的一种抗体的可变区重链序列和可变区轻链序列的组合：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，和FnC1t2p1_D4。
根据本发明的第一方面的另一实施方案，SARS相关冠状病毒毒株是严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。
根据本发明的第一方面的又另一实施方案，所述抗体或结合片段针对SARS-CoV-2的刺突(S)蛋白的胞外域，优选针对如Wrapp等人,Science(2020)doi:10.1126/science.abb2507中所描述的病毒分离株Wuhan-Hu-1的融合前稳定化变体中SARS-CoV-2的刺突(S)同源三聚体的胞外域(SEQ ID NO.57)，更优选针对SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)，甚至更优选针对具有SEQ ID NO.58的序列的RBD。
根据本发明的第一方面的关于中和效力的实施方案，基于Koch等人,LancetInfect.Dis.(2020)doi:10.1016/s1473-3099(20)30248-6中描述的检测，当在37℃下共培养病毒和抗体1h后使用100TCID50的SARS-CoV-2施用至VeroE6细胞在病毒中和试验中进行测试时，所述抗体或其结合片段表现小于10μg/ml的针对VeroE6细胞上的真实SARS-CoV-2分离株BavPat1/2020的中和效力(IC100；导致完全不存在细胞病变效应的最低抗体剂量)。
根据本发明的第一方面的关于中和效力的其它实施方案，所述抗体或其结合片段表现小于1μg/ml的中和效力。
根据本发明的第一方面的关于中和效力的其它实施方案，所述抗体或其结合片段表现小于0.5μg/ml的中和效力。
根据本发明的第一方面的关于中和效力的其它实施方案，所述抗体或其结合片段表现0.25μg/ml以下的中和效力。
根据本发明的另一实施方案，当使用浓度为100μg/ml的抗体或其结合片段的抗核抗体(ANA)测试试剂盒(NOVA-Lite HEp-2 ANA试剂盒；Inova Diagnostics)针对透化HEp-2细胞进行测试时，所述抗体或其结合片段不表现定义为可检测的结合的自身反应性。
根据本发明的第二方面，提供了一种药物组合物，其包含根据本发明的第一方面的抗体或其结合片段和至少一种药学上可接受的赋形剂。
根据本发明的第二方面的一个实施方案，所述药物组合物是用于人类或动物受试者的疫苗接种组合物。
根据本发明的第三方面，提供了一种试剂盒，其包含根据本发明的第一方面的抗体或其结合片段和容器。
根据本发明的第四方面，提供了根据本发明的第一方面的抗体或其结合片段、根据本发明的第二方面的药物组合物、或根据本发明的第三方面的试剂盒用作药物，优选用作疫苗。
根据本发明的第五方面，提供了根据本发明的第一方面的抗体或其结合片段、根据本发明的第二方面的药物组合物、或根据本发明的第三方面的试剂盒用于治疗或预防人类或动物受试者中由SARS相关冠状病毒引起的疾病的用途，优选用于治疗或预防人类或动物受试者中由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)引起的疾病的用途。
根据本发明的第六方面，提供了根据本发明的第一方面的抗体或其结合片段、根据本发明的第二方面的药物组合物、或根据本发明的第三方面的试剂盒用于预防人类或动物受试者感染SARS相关冠状病毒的用途，优选用于预防人类或动物受试者感染严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的用途。
根据本发明的第四方面、第五方面或第六方面的一个实施方案，所述抗体通过静脉内输注来施用，其中所述抗体可以以1mg/kg患者体重至100mg/kg患者体重的剂量施用，其中所述抗体可以以2,5mg/kg、5mg/kg、10mg/kg、20mg/kg、25mg/kg、30mg/kg、40mg/kg、50mg/kg、或100mg/kg的剂量施用。
根据本发明的第四方面、第五方面或第六方面的另一实施方案，所述抗体通过吸入给药来施用，其中所述抗体在液体药物组合物中提供，所述液体药物组合物在施用前通过筛网雾化器或喷射雾化器来雾化，和/或所述抗体可以以50mg、100mg、200mg、250mg、300mg、400mg、500mg、750mg、或1000mg的剂量施用。
在另一实施方案中，本发明的抗体以初始计量通过吸入施用，接着进行全身施用，例如但不限于静脉内和/或腹膜内。
根据另一实施方案，提供了治疗人类或动物受试者中SARS相关冠状病毒的方法，所述方法包括向所述人类或动物受试者施用治疗有效量的至少一种抗体和/或其抗原结合片段或包含本发明的至少一种抗体和/或其抗原结合片段的药物组合物。
根据另一实施方案，提供了预防人类或动物受试者感染SARS相关冠状病毒的方法，所述方法包括向所述人类或动物受试者施用治疗有效量的至少一种抗体和/或其抗原结合片段或包含本发明的至少一种抗体和/或其抗原结合片段的药物组合物。
在又另一实施方案中，提供了降低患有SARS相关冠状病毒的人类或动物受试者中的疾病的严重程度的方法，所述方法包括向所述人类或动物受试者施用治疗有效量的至少一种抗体和/或其抗原结合片段或包含本发明的至少一种抗体和/或其抗原结合片段的药物组合物。
在一个实施方案中，SARS相关冠状病毒是SARS-CoV-2。在另一实施方案中，受试者是人类受试者。
附图说明
图1显示了(a)如通过ELISA识别的，255种分离的人单克隆抗体与SARS-CoV-2 S-胞外域的相互作用；通过限定EC50<30μg/ml和OD415-695>0.25(未示出)的截断值识别79种结合抗体(黑色至深灰色)；(b)每个分离出抗体的个体患者的SARS-CoV-2 S-胞外域相互作用抗体的EC50值(重复的平均值)；中和抗体根据其IC100值标记为不同的灰色阴影；(c)S胞外域特异性抗体的真实SARS-CoV-2中和活性(完全抑制VeroE6细胞感染，IC100，一式四份)，其中28种抗体具有等于或高于100μg/ml的IC100的截断值的中和活性。
图2显示针对真实SARS-CoV-2的中和效率，表示为IC100，以μg/ml计；条形描绘最低中和mAb浓度。
图3显示了如通过ELISA测定的SARS-CoV-2 S胞外域结合(EC50)与真实SARS-CoV-2的中和效力(IC100)之间的相关性；相关系数rS和近似p值通过斯皮尔曼秩顺序相关(Spearman's rank-order correlation)来计算。
图4显示了如通过用SARS-CoV-2S-胞外域抗体染色HEp-2细胞并通过荧光显微镜(Leica DMI microscope 6000)分析来测试的，所选SARS-CoV-2结合和中和抗体的自身反应性；显示了评分系统的代表性图片。
图5显示了汇总分离的SARS-CoV-2相互作用抗体的特性的扩展数据表。
图6显示了DZIF-10c在ACE2转导的SARS-CoV-2攻击的BALB/c小鼠中的治疗功效。(A)实验方案，数字表示实验天数。(B)在第4天肺组织中每纳克RNA的SARS-CoV-2基因组拷贝。(C)通过自Vero E6细胞上的25mg肺组织匀浆的病毒分离测定的TCID50滴度。i.n.，鼻内，i.p.，腹膜内。
图7显示DZIF-10c在SARS-CoV-2攻击的黄金叙利亚仓鼠中的治疗功效。(A)实验方案，数字表示实验天数。(B)鼻拭子中通过qRT-PCR测定的SARS-CoV-2滴度。(C)肺匀浆中通过qRT-PCR测定的SARS-CoV-2滴度。(D)通过自不同肺叶的病毒分离测定的传染性SARS-CoV-2滴度。
图8(A)在与DZIF-10c或同型对照抗体共孵育1小时后用SARS-CoV-2攻击的CD14+人巨噬细胞、或用MERS-CoV攻击后的CD14+人巨噬细胞的细胞培养物上清液中的传染性TCID50。(B)在与DZIF-10c或同型对照抗体共孵育1小时后用SARS-CoV-2攻击CD14+人巨噬细胞后的SARS-CoV-2基因组拷贝。在病毒攻击后，孵育细胞四天。LLOD，检测下限。
图9在气管内施用1mg/kg的剂量后，Wistar大鼠的ELF和血浆中的DZIF-10c浓度。
图10在气管内给药1mg/kg后2小时或24小时，或在第二次静脉内给药10mg/kg的剂量后24小时，Wistar大鼠的所有研究的组织中的DZIF-10c(在本图中称为EX14870)浓度。Bro&Tra，支气管和气管。
图11显示DZIF-10c在制剂F5-F8中在预期储存条件(5℃)下在(A)高分子量物质的百分比(HMW(％)和(B)单体的百分比方面的稳定性数据。
图12显示在感染前用DZIF-10c或溶媒预处理的动物的鼻咽拭子中的SARS-CoV-2载量；LOD＝检测极限。
图13显示在感染前用DZIF-10c或溶媒预处理的动物的支气管肺泡灌洗(BAL)中的SARS-CoV-2载量；LOD＝检测极限。
具体实施方式
为了更容易地理解本说明书，首先定义了某些术语。在详细描述通篇中记载了另外的定义。
应注意，术语“一”或“一个”实体指的是一个或更多个该实体；例如，“一核苷酸序列”被理解为代表一个或更多个核苷酸序列。因此，术语“一个”(或“一个”)、“一个或更多个”、和“至少一个”在本文中可交换地使用。
此外，“和/或”在本文中使用的地方将被认为特定公开两个特定特征或组分中的每一者，连同或不连同另一者。因此，如本文中例如“A和/或B”的短语中使用的术语“和/或”旨在包括“A和B”、“A或B”、“A”(单独)、和“B”(单独)。同样地，在例如“A、B、和/或C”的短语中使用的术语“和/或”旨在包括以下方面中的每一者：A、B、和C；A、B、或C；A或C；A或B；B或C；A和C；A和B；B和C；A(单独)；B(单独)；和C(单独)。
应理解，本文中在任何地方以语言“包含”描述的方面，也提供以“由…组成”和/或“基本上由…组成”描述的其它类似方面。
除非另有定义，否则本文所用的所有技术和科学术语具有与本公开相关领域的普通技术人员通常理解的相同的含义。例如，Concise Dictionary of Biomedicine andMolecular Biology,Juo,Pei-Show,2nd ed.,2002,CRC Press；The Dictionary of Celland Molecular Biology,3rd ed.,1999,Academic Press；和Oxford Dictionary OfBiochemistry And Molecular Biology,Revised,2000,Oxford University Press，向本领域技术人员提供本公开中所用的许多术语的通用词典。
单位、前缀和符号以其国际单位制(Système International d’Unités,SI)接受的形式表示。数值范围包括限定所述范围的数值。除非另有说明，否则核苷酸序列以5’至3’方向从左至右书写。氨基酸序列以氨基至羧基方向从左至右书写。本文所提供的标题不是对本公开的各个方面的限制，本公开的各个方面可以通过整体引用本说明书来获得。因此，通过引用本说明书以其整体更全面地定义在下文中所定义的术语。
术语“约”在本文中用于表示近似、大概、大约、或在...的范围内。当术语“约”与数值范围结合使用时，它通过扩展所述数值的上下界限来修饰该范围。一般而言，术语“约”可以修改数值高于和低于规定值如上下(较高或较低)10％的差异。
术语“抗体”在本文中最广义而言用于指代具有免疫球蛋白样结构域(例如IgG、IgM、IgA、IgD或IgE)的分子，并且包括单克隆、重组、多克隆、嵌合、人、人源化、多特异性抗体，包括双特异性抗体和异源偶联物抗体(heteroconjugate antibody)；单可变结构域(例如，VH、VHH、VL、结构域抗体)、抗原结合抗体片段、Fab、F(ab')2、Fv、二硫键连接的Fv、单链Fv、二硫键连接的scFv、双抗体(diabody)等、和前述中任一者的修饰版本。
如本文所用，术语“抗体”是指源自种系免疫球蛋白序列的能够与抗原特异性结合的蛋白质、或其抗原结合部分。所述术语包括任何类型或同型(即IgA、IgE、IgG、IgM和/或IgY)的全长抗体及其任何单链或片段。与抗原特异性结合的抗体或其抗原结合片段可以仅与该抗原或其部分结合，或者可以与有限数量的同源抗原或其部分结合。全长抗体通常包含至少四条多肽链：通过二硫键相互连接的两条重(H)链和两条轻(L)链。
药学上特别感兴趣的一个免疫球蛋白亚类是IgG家族。在人类中，IgG类别基于其重链恒定区的序列可细分为4个亚类：IgG1、IgG2、IgG3和IgG4。轻链基于其序列组成的差异可分为两型，κ和λ。IgG分子由通过两个或更多个二硫键相互连接的两条重链和各自通过二硫键与重链连接的两条轻链构成。重链可以包含重链可变区(VH)和至多三个重链恒定(CH)区：CH1、CH2、和CH3。轻链可以包含轻链可变区(VL)和轻链恒定区(CL)。
VH和VL区可进一步细分为称为互补决定区(CDR)的高变区，其中散布有称为框架区(FR)的更保守区域。VH和VL区通常由三个CDR和四个FR构成，自氨基末端至羧基末端按以下顺序配置：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链和轻链的高变区形成能够与抗原相互作用的结合结构域，而抗体的恒定区可介导免疫球蛋白与宿主组织或因子的结合，所述宿主组织或因子包括但不限于免疫系统的各种细胞(效应细胞)、Fc受体和经典补体系统的第一组分(C1q)。本发明的抗体可以是分离的。
术语“分离的抗体”是指从产生其的环境中的其它(另一)组分(一种或更多种)中分离和/或回收的抗体，和/或已从在产生其的环境中存在的组分的混合物中纯化的抗体。抗体的某些抗原结合片段在本发明的情况中可为合适的，因为已显示抗体的抗原结合功能可以通过全长抗体的片段来进行。
术语抗体的“抗原结合部分”、“结合片段”或“抗原结合片段”是指保留与抗原如SARS-CoV-2的刺突(S)蛋白特异性结合的能力的抗体的一个或更多个片段，如本文所述。
抗原结合片段的实例包括Fab、Fab'、F(ab)2、F(ab')2、F(ab)S、Fv(通常是抗体的单臂的VL和VH结构域)、单链Fv(scFv；参见，例如，Bird等人,Science 242:42S-426(1988)；Huston等人,PNAS 85:5879-5883(1988))、dsfv、Fd(通常是VH和CH1结构域)、和dAb(通常是VH结构域)片段；VH、VL、VHH和V-NAR结构域；包含单个VH链和单个VL链的单价分子；微型抗体(minibody)、双抗体、三抗体(triabodies)、四抗体(tetrabodies)、和κ体(参见，例如，Ill等人,Protein Eng 10:949-57(1997))；骆驼IgG；IgNAR；以及一个或更多个分离的CDR或功能性互补位(paratope)，其中分离的CDR或抗原结合残基或多肽可以结合或连接在一起以形成功能性抗体片段。
各种类型的抗体片段已经描述或综述于例如Holliger和Hudson,Nat Biotechnol2S:1126-1136(2005)；国际公开号WO 2005/040219、和美国公开号2005/0238646和2002/0161201。这些抗体片段可以使用本领域技术人员已知的常规技术获得，并且可以以与完整抗体相同的方式筛选这些片段的实用性(utility)。
“人类”抗体(HuMAb)是指具有其中框架区和CDR区二者均源自人类种系免疫球蛋白序列的可变区的抗体。此外，如果抗体包含恒定区，所述恒定区也源自人类种系免疫球蛋白序列。本文所描述的SARS-CoV-2抗体可包括不由人类种系免疫球蛋白序列编码的氨基酸残基(例如，通过体外随机或定点诱变或体内体细胞突变引入的突变)。然而，如本文所用，术语“人类抗体”并不旨在包括其中源自另一哺乳动物物种如小鼠的种系的CDR序列已移植到人类框架序列上的抗体。术语“人类”抗体和“完全人类”抗体同义地使用。
“人源化”抗体是指包含源自非人类免疫球蛋白的一条或更多条序列(CDR区或其部分)的人类/非人类嵌合抗体。因此，人源化抗体是这样的人类免疫球蛋白(接受者抗体(recipient antibody))，其中至少来自接受者的高变区的残基被具有所需的特异性、亲和力、序列组成和功能的来自非人类物种如来自小鼠、大鼠、兔或非人类灵长类动物的抗体(供体抗体)的高变区的残基替代。在一些情况中，人类免疫球蛋白的FR残基被相应的非人类残基替代。此类修饰的一个实例是引入一个或更多个所谓的回复突变，其通常是源自供体抗体的氨基酸残基。
抗体的人源化可以使用本领域技术人员已知的重组技术来进行(参见，例如，抗体Engineering,Methods in Molecular Biology,第248卷,Benny K.C.Lo编辑)。对轻链和重链可变结构域二者均适合的人类接受者框架可通过例如序列或结构同源性来识别。可选地，例如，可以基于结构、生物物理学和生物化学性质的知识，使用固定接受者框架。接受者框架可以是种系来源的或源自成熟抗体序列。来自供体抗体的CDR区可以通过CDR移植来进行转移。
可通过识别关键框架位置来进一步最优化CDR移植的人源化抗体的例如亲和力、功能性和生物物理学性质，在该关键框架位置处重新引入(回复突变)来自供体抗体的氨基酸残基对人源化抗体的性质具有有益影响。除了供体抗体来源的回复突变以外，还可通过在CDR或框架区中引入种系残基、消除免疫原性表位、定点诱变、亲和力成熟等对人源化抗体进行工程化。
此外，人源化抗体可包含未在接受者抗体或供体抗体中发现的残基。进行这些修饰以进一步改进抗体性能。一般而言，人源化抗体将包含至少一个--通常为两个--可变结构域，其中所有或基本上所有的CDR区对应于非人类免疫球蛋白的CDR区，并且其中所有或基本上所有的FR残基是人类免疫球蛋白序列的FR残基。任选地，人源化抗体也可以包含免疫球蛋白恒定区(Fc)、通常是人类免疫球蛋白的恒定区的至少一部分。术语“人源化抗体衍生物”是指人源化抗体的任何修饰形式，例如抗体和另一试剂或抗体的缀合物。
如本文所用，术语“重组人类抗体”包括通过重组方式制备、表达、产生或分离的所有人类抗体，例如(a)从对于人类免疫球蛋白基因而言转基因或转染色体的动物(例如小鼠)或由此制备的杂交瘤中分离的抗体，(b)从经转化以表达抗体的宿主细胞中分离的抗体，例如从转染瘤分离的抗体，(c)从重组、组合人类抗体文库中分离的抗体，和(d)通过涉及将人类免疫球蛋白基因序列剪接至其它DNA序列的任何其它方式制备、表达、产生或分离的抗体。
此类重组人类抗体包含可变区和恒定区，其使用由种系基因编码的特定人类种系免疫球蛋白序列，但包含例如在抗体成熟期间发生的后续重排和突变。如本领域已知的(参见，例如，Lonberg Nature Biotech.23(9):1117-1125(2005))，可变区包含抗原结合结构域，其由各种基因编码，所述各种基因发生重排以形成对外来抗原为特异性的抗体。除了重排以外，可变区还可以通过多次单氨基酸改变(称为体细胞突变或超突变)来进一步修饰以增加抗体对外来抗原的亲和力。恒定区将对抗原进一步反应而改变(即同型转换)。
因此，编码轻链和重链免疫球蛋白多肽的响应于抗原的重排和体细胞突变的核酸分子不能与原始核酸分子具有序列同一性，而是将基本上相同或相似的(即，具有至少80％同一性)。
“嵌合抗体”是指其中可变区源自一种物种而恒定区源自另一物种的抗体，例如其中可变区源自小鼠抗体而恒定区源自人类抗体的抗体。
替代抗体形式包括替代支架，其中抗原结合部分的一个或更多个CDR可以配置在合适的非免疫球蛋白支架或骨架上，例如亲和抗体(affibody)、SpA支架、LDL受体A类结构域、avimer或EGF结构域。
术语“结构域”是指折叠的蛋白质结构，该结构保留其独立于蛋白质的其余部分的三级结构。通常，结构域负责蛋白质的离散功能特性，并且在许多情况下可被添加、去除或转移至其它蛋白质，而不损失蛋白质的剩余部分和/或结构域的功能。
术语“单可变结构域”是指包含抗体可变结构域的序列特征的折叠多肽结构域。因此，它包括完整的抗体可变结构域，例如VH、VHH和VL，和修饰的抗体可变结构域，例如其中一个或更多个环已被不是抗体可变结构域的特征的序列替代，或已被截短或包含N-或C-末端延伸的抗体可变结构域，以及至少保留了全长结构域的结合活性和特异性的可变结构域的折叠的片段。
单可变结构域能够独立于不同可变区或结构域而与抗原或表位结合。“结构域抗体”或“dAbTM”可被认为与“单可变结构域”相同。单可变结构域可以是人类单可变结构域，但也包括来自其它物种如啮齿动物护士鲨(nurse shark)的单可变结构域和骆驼科动物VHHdAbsTM。骆驼科动物VHH是免疫球蛋白单可变结构域多肽，其源自包括骆驼、美洲驼、羊驼、单峰骆驼和原驼的物种，其产生天然缺少轻链的重链抗体。此类VHH结构域可以根据本领域可用的标准技术进行人源化，并且此类结构域被认为是“单可变结构域”。本文所用的VH包括骆驼科动物VHH结构域。
抗原结合片段可以借助于将一个或更多个CDR配置在非抗体蛋白质支架上来提供。如本文所用，“蛋白质支架”包括但不限于免疫球蛋白(Ig)支架，例如IgG支架，其可以是四链或双链抗体，或其可以仅包含抗体的Fc区，或其可以包含来自抗体的一个或更多个恒定区，所述恒定区可以是人类或灵长类动物来源的，或其可以是人类和灵长类动物恒定区的人工嵌合体。
如本文所用，“同型”是指由重链恒定区基因编码的抗体类型(例如，IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD、和IgE抗体)。
“同种异型”是指特定同型组内天然存在的变体，所述变体在几个氨基酸上不同(参见，例如，Jefferis等人,mAbs 1:1(2009))。
短语“识别抗原的抗体”和“对抗原为特异性的抗体”在本文中与术语“与抗原特异性结合的抗体”可交换地使用。
术语“治疗(treat/treating)”或“...的治疗”(或语法上等同的术语)是指受试者的病况的严重程度降低或至少部分地改善或减轻、和/或实现至少一种临床症状的某种程度的缓和、缓解或减少、和/或疾病的进展延迟。
如本文所用，术语“预防(prevent/prevents/prevention)”和“抑制(inhibit/inhibits/inhibition)”(及其语法上的等同物)并不意味着暗示疾病的完全消除，而是包括任何类型的预防性治疗，其减少病况的发生、延迟病况的发作、和/或减少发病后与病况相关的症状。
如本文所用，“有效”、“预防有效”或“治疗有效”量是足以向受试者提供某种改善或益处的量。可选地，“有效”、“预防有效”、或“治疗有效”量是提供受试者中的至少一种临床症状中的某种程度的缓和、缓解或减少的量。本领域技术人员将理解，效果不需要是完全的或治愈性的，只要向受试者提供某些益处即可。
如本文所用，“中和抗体”是与病原体结合并且干扰病原体在受试者中感染细胞和/或引起疾病的能力的任何抗体或其抗原结合片段。
如本文所用，“肽”包括作为本文具体例示的那些肽的保守变异的肽。如本文所用，“保守变异”和“保守氨基酸取代”表示一种氨基酸残基被另一生物学上相似的残基取代。保守变异的实例包括但不限于由一种疏水残基如异亮氨酸、缬氨酸、亮氨酸、丙氨酸、半胱氨酸、甘氨酸、苯丙氨酸、脯氨酸、色氨酸、酪氨酸、正亮氨酸或甲硫氨酸取代另一种，或由一种极性残基取代另一种，例如由精氨酸取代赖氨酸、由谷氨酸取代天冬氨酸、或由谷氨酰胺取代天冬酰胺等。可以相互取代的中性亲水氨基酸包括天冬酰胺、谷氨酰胺、丝氨酸和苏氨酸
“保守变异”也包括使用取代的氨基酸代替未取代的亲本氨基酸，条件是针对取代的多肽产生的抗体也与未取代的多肽免疫反应。此类保守取代在本发明的肽类别的定义内。肽的生物活性可以通过本领域技术人员已知和本文所描述的标准方法来确定。
对于核酸，术语“实质同源性”表示在最佳比对和比较时，两个核酸或其指定序列在至少约80％的核苷酸、至少约90％至95％、或至少约98％至99.5％的核苷酸中是相同的，具有适当的核苷酸插入或缺失。可选地，当片段在选择性杂交条件下与链的互补体杂交时，存在实质同源性。
对于多肽，术语“实质同源性”表示在最佳比对和比较时，两条多肽或其指定序列在至少约80％的氨基酸、至少约90％至95％、或至少约98％至99.5％的氨基酸中是相同的，具有适当的氨基酸插入或缺失。
两条序列之间的同一性百分比是序列共用的相同位置的数量的函数(即％同源性＝相同位置的#/位置的总#乘以100)，考虑到需要被引入用于两条序列的最佳比对的空位的数量和每个空位的长度。序列的比较和两条序列之间同一性百分比的测定可以使用数学算法来完成，如下文中非限制性实例中所描述的。
两条核苷酸序列之间的同一性百分比可以使用GCG软件包(可获得于worldwideweb.gcg.com)中的GAP程序、使用NWSgapdna.CMP矩阵和40、50、60、70、或80的空位权重以及1、2、3、4、5、或6的长度权重来测定。两条核苷酸或氨基酸序列之间的同一性百分比也可以使用已整合入ALIGN程序(版本2.0)的E.Meyers和W.Miller(CABIOS,4:11-17(1989))的算法、使用PAM120权重残基表(weight residue table)、12的空位长度罚分和4的空位罚分来测定。
此外，两条氨基酸序列之间的同一性百分比可以使用已整合入GCG软件包(可获得于worldwideweb.gcg.com)中的GAP程序的Needleman和Wunsch(J.Mol.Biol.(48):444-453(1970))算法、使用Blossum 62矩阵或PAM250矩阵、以及16、14、12、10、8、6、或4的空位权重和1、2、3、4、5、或6的长度权重来测定。
本文所描述的核酸和蛋白质序列可进一步用作“查询序列(query sequence)”以对公共数据库进行搜索来例如识别相关序列。此类搜索可以使用Altschul,等人(1990)J.Mol.Biol.215:403-10的NBLAST和XBLAST程序(版本2.0)。BLAST核苷酸搜索可利用NBLAST程序、得分＝100、字长＝12来进行以获得与本文所描述的核酸分子同源的核苷酸序列。
BLAST蛋白质搜索可利用XBLAST程序、得分＝50、字长＝3来进行以获得与本文所描述的蛋白质分子同源的氨基酸序列。为了获得用于比较目的的空位比对，可以如Altschul等人,(1997)Nucleic Acids Res.25(17):3389-3402中所述使用Gapped BLAST。当使用BLAST和Gapped BLAST程序时，可以使用各自程序(例如，XBLAST和NBLAST)的默认参数。参见worldwideweb.ncbi.nlm.nih.gov。
核酸可以存在于完整细胞、细胞裂解物中或以部分纯化或基本纯形式存在。当通过标准技术，包括碱/SDS处理、CsCl条带、柱层析、琼脂糖凝胶电泳和本领域众所周知的其它技术，从其它细胞组分或其它污染物，例如其它细胞核酸(例如，染色体的其它部分)或蛋白质中纯化时，核酸是“分离的”或“变得基本上纯”。参见，F.Ausubel,等人,编辑CurrentProtocols in Molecular Biology,Greene Publishing and Wiley Interscience,NewYork(1987)。
例如cDNA等核酸可以根据标准技术进行突变以提供基因序列。对于编码序列，根据需要，这些突变可以影响氨基酸序列。具体而言，与天然V、D、J、恒定、转换、和本文所描述的其它此类序列基本同源或源自其的DNA序列是预期的(其中“源自”表示序列与另一序列相同或从另一序列修饰)。
如本文所用，术语“载体”是指能够运输与其连接的另一核酸的核酸分子。一种类型的载体是“质粒”，它是指可以与其连接另外的DNA片段的环状双链DNA环。另一种类型的载体是病毒载体，其中可将另外的DNA片段连接至病毒基因组中。某些载体能够在引入其的宿主细胞中自主复制(例如，具有细菌复制起点的细菌载体和游离型哺乳动物载体)。
其它载体(例如，非游离型哺乳动物载体)可以在引入至宿主细胞中后整合至宿主细胞的基因组中，从而与宿主基因组一起复制。此外，某些载体能够指导其以可操作地连接的基因的表达。此类载体在本文中被称为“重组表达载体”(或简称为“表达载体”)。通常，用于重组DNA技术的表达载体通常是质粒的形式。在本说明书中，“质粒”和“载体”可交换地使用，因为质粒是最常用的载体形式。然而，也包括表达载体的其它形式，例如病毒载体(例如，复制缺陷型逆转录病毒、腺病毒和腺相关病毒)，它们起到相同的功能。
如本文所用，术语“重组宿主细胞”(或简称为“宿主细胞”)旨在指代包含非天然存在于细胞中的核酸的细胞，并且可以是其中已引入重组表达载体的细胞。应理解，此类术语不仅旨在指代特定的受试者细胞，还指代此类细胞的子代。因为某些修饰由于突变或环境影响而可能在随后的世代中发生，此类子代实际上不能与亲代细胞相同，但仍包含在本文所用的术语“宿主细胞”的范围内。
如本文所用，术语“连接”是指两个或更多个分子的结合。连接可以是共价的或非共价的。连接也可以是遗传的(即重组融合的)。此类连接可以使用多种本领域公认的技术来实现，例如化学共轭和重组蛋白生产。
“效应功能”是指抗体Fc区与Fc受体或配体的相互作用、或由此产生的生物化学事件。示例性“效应功能”包括C1q结合、补体依赖性细胞毒性(CDC)、Fc受体结合、FcγR介导的效应功能如ADCC和抗体依赖性细胞介导的吞噬作用(ADCP)、以及细胞表面受体(例如，B细胞受体；BCR)的下调。此类效应功能通常需要将Fc区与结合结构域(例如，抗体可变结构域)组合。
“Fc受体”或“FcR”是与免疫球蛋白的Fc区结合的受体。与IgG抗体结合的FCR包含Fc.γR家族的受体，包括这些受体的等位基因变体和替代性剪接形式(alternativelyspliced form)。FcγR家族由三种激活性(小鼠中的FcγRI、FcγRIII、和Fc.RIV；人类中的FcγRIA、FcγRIIA、和FcγRIIIA)和一种抑制性(FcγRIIB)受体组成。本领域已知人类FcγR的各种性质。大多数先天效应细胞类型共表达一种或更多种激活性FcγR和抑制性FcγRIIB，而自然杀伤(NK)细胞选择性表达一种激活性Fc受体(小鼠中的FcγRIII和人类中的FcγRIIIA)而不是小鼠和人类中的抑制性FcγRIIB。人类IgG1与大多数人类Fc受体结合，并被认为就其所结合的激活性Fc受体的类型方面等同于鼠IgG2a。
“Fc区”(片段可结晶区)或“Fc结构域”或“Fc”是指抗体的重链的C-末端区，其介导免疫球蛋白与宿主组织或因子的结合，包括与位于免疫系统的各种细胞(例如效应细胞)上的Fc受体的结合或与经典补体系统的第一组分(C1q)的结合。因此，Fc区包含抗体的除第一恒定区免疫球蛋白结构域(例如，CH1或CL)以外的恒定区。
在IgG中，Fc区包含免疫球蛋白结构域CH2和CH3以及CH1和CH2结构域之间的铰链。尽管免疫球蛋白重链的Fc区的边界的定义可能不同，如本文所定义的，人类IgG重链Fc区被限定为从对于IgG1为氨基酸残基D221、对于IgG2为氨基酸残基V222、对于IgG3为氨基酸残基L221和对于IgG4为氨基酸残基P224延伸至重链的羧基末端，其中编号是根据kabat中的EU索引。人类IgG Fc区的CH2结构域从氨基酸237延伸至氨基酸340，并且CH3结构域位于Fc区中CH2结构域的C-末端侧，即它从氨基酸341延伸至IgG的氨基酸447或446(如果不存在C-末端赖氨酸残基)或445(如果不存在C-末端甘氨酸和赖氨酸残基)。如本文所用，Fc区可以是天然序列Fc，包括任何同种异型变体，或变体Fc(例如非天然存在的Fc)。Fc也可以是指分离中的该区域或在包含Fc的蛋白质多肽如“包含Fc区域的结合蛋白”、也称为“Fc融合蛋白”(例如，抗体或免疫粘附(immunoadhesion))的情况中的该区域。
“天然序列Fc区”或“天然序列Fc”包含与在自然界中发现的Fc区的氨基酸序列相同的氨基酸序列。天然序列人类Fc区包括天然序列人类IgG1 Fc区；天然序列人类IgG2 Fc区；天然序列人类IgG3 Fc区；和天然序列人类IgG4 Fc区及其天然存在的变体。天然序列Fc包括Fc的各种同种异型(参见，例如，Jefferis等人,mAbs 1:1(2009))。
“变体序列Fc区”或“非天然存在的Fc”包含修饰，通常以改变或使其缺乏其一种或更多种功能性质，例如血清半衰期、补体结合、Fc受体结合、蛋白质稳定性和/或抗原依赖性细胞毒性，等等。在一些实施方案中，本公开的抗体可以被化学修饰(例如，可将一个或更多个化学部分附接至抗体)或被修饰以改变其糖基化，再次改变抗体的一种或更多种功能性质。
术语“铰链”、“铰链结构域”、“铰链区”、和“抗体铰链区”是指将CH1结构域连接至CH2结构域的重链恒定区的结构域并且包括铰链的上部、中部和下部(Roux等人,J Immunol161:4083(1998))。铰链在抗体的结合区和效应区之间提供不同水平的柔性，并且也为两个重链恒定区之间的分子间二硫键结合提供位点。如本文所用，铰链在所有IgG同型中起始于Glu216并且结束于Gly237(Roux等人,J Immunol 161:4083(1998))。本领域已知野生型IgG1、IgG2、IgG3和IgG4铰链的序列(例如，国际PCR公开号WO 2017/087678)。在一个实施方案中，对抗体的CH1的铰链区进行修饰，使得铰链区中半胱氨酸残基的数量发生改变，例如增加或减少。这种方法进一步描述于例如美国专利号5,677,425。
可对恒定区进行修饰以稳定抗体，例如，降低二价抗体分离成两个单价VH-VL片段的风险。例如，在IgG4恒定区中，残基S228(根据EU索引编号的残基)可以突变成脯氨酸(P)残基以稳定铰链处的重链间二硫键形成(参见，例如，Angal等人,Mol Immunol.30:105-8(1995))。抗体或其片段也可以根据它们的互补决定区(CDR)来定义。
术语“互补性决定区”或“高变区”在本文中使用时是指抗体的参与抗原结合的氨基酸残基所在的区域。高变区或CDR可被识别为在抗体可变结构域的氨基酸比对中具有最高可变性的区域。数据库可用于CDR识别，例如Kabat数据库，例如，CDR被定义为包含轻链可变结构域的氨基酸残基24-34(CDR1)、50-59(CDR2)和89-97(CDR3)和重链可变结构域中的31-35(CDR1)、50-65(CDR2)和95-102(CDR3)；(Kabat等人1991；Sequences of Proteins ofImmunological Interest,Fifth Edition,U.S.Department of Health and HumanServices,NIH Publication No.91-3242)。可选地，CDR可被定义为来自“高变环”的那些残基(轻链可变结构域中的残基26-33(L1)、50-52(L2)和91-96(L3)和重链可变结构域中的26-32(H1)、53-55(H2)和96-101(H3)(Chothia和Lesk,J.Mol.Biol 196:901-917(1987))。本文所描述的抗体序列的CDR区优选根据IMGT的编号方案定义，所述编号方案是Chothia的编号方案的改编(ImMunoGeneTics information Lefranc,M.-P.等人IMGT,theinternational ImMunoGeneTics database.Nucleic Acids Res 27,209–212(1999).；http://imgt.cines.fr)。
术语“表位”或“抗原决定簇”是指抗原上免疫球蛋白或抗体特异性结合的位点，例如通过用于识别其的特定方法所定义的。表位可以由连续氨基酸形成(通常是线性表位)或由通过蛋白质的三级折叠并置(juxtaposed)的非连续氨基酸形成(通常是构象表位)。由连续氨基酸形成的表位通常但不始终在暴露于变性溶剂时保留，然而通过三级折叠形成的表位通常在用变性溶剂处理时丢失。
表位通常在独特空间构象下包括至少3、4、5、6、7、8、9、10、11、12、13、14、或15个氨基酸。确定给定抗体结合哪些表位的方法(即表位作图(mapping))是本领域众所周知的，并且包括例如免疫印迹和免疫沉淀检测，其中测试来自(例如来自SARS-CoV-2的刺突(S)蛋白的)重叠或连续肽与给定抗体的反应性。确定表位的空间构象的方法包括本领域的技术和本文所描述的那些，例如，X射线晶体学、抗原突变分析、二维核磁共振和HDX-MS(参见，例如，Epitope Mapping Protocols in Methods in Molecular Biology,Vol.66,G.E.Morris,Ed.(1996))。
关于两种或更多种抗体的术语“与相同的表位结合”是指所述抗体与氨基酸残基的相同区段结合，如通过给定方法所确定的。用于确定抗体是否与本文所述抗体的结合“相同表位”的技术包括，例如表位作图方法，例如抗原:抗体复合物的晶体的X射线分析，其提供了表位的原子分辨率和氢/氘交换质谱法(HDX-MS)。
其它方法监测抗体与抗原片段或抗原的突变变体的结合，其中由于抗原序列内的氨基酸残基的修饰而丧失结合通常被认为是表位组分的指示。此外，也可以使用用于表位作图的计算组合方法。这些方法依赖于感兴趣的抗体从组合噬菌体展示肽文库中亲和分离特定短肽的能力。预期具有相同VH和VL或相同CDR1、2和3序列的抗体结合相同的表位。
“与另一抗体竞争结合至靶标”的抗体是指(部分或完全地)抑制其它抗体结合至靶标的抗体。两种抗体是否相互竞争结合至靶标，即一种抗体是否抑制其它抗体结合至靶标以及抑制到这样的程度，可以使用已知的竞争实验来确定，例如BIACORE.RTM.表面等离子共振(SPR)分析。在某些实施方案中，抗体与另一抗体竞争并抑制另一抗体结合至靶标至少50％、60％、70％、80％、90％或100％。抑制或竞争的水平可以不同，这取决于哪种抗体是“阻断抗体”(即，首先与靶标孵育的冷抗体)。
竞争试验可以按照例如Ed Harlow和David Lane,Cold Spring Harb Protoc；2006；doi:10.1101/pdb.prot4277或Ed Harlow和David Lane,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,USA 1999的“Using Antibodies”的第11章中所描述的来进行。如果抗体相互双向阻断至少50％，则两种抗体“交叉竞争”，即无论在竞争实验中是一种还是另一种抗体首先与抗原接触。
如本文所用，术语“特异性结合”、“选择性结合”、“选择性地结合”和“特异性地结合”是指抗体结合至预定抗原上的表位。通常，抗体(i)当通过例如使用预定抗原作为分析物和抗体作为配体在BIACORE.RTM.2000仪器中的表面等离子共振(SPR)技术、或抗体结合至抗原阳性细胞的Scatchard分析来测定时，以约小于10-7M如约小于10-8M、10-9M或10-10M或甚至更低的平衡解离常数(KD)结合，和(ii)以至少两倍大于其与除了预定抗原或密切相关抗原以外的非特异性抗原(例如BSA、酪蛋白)结合的亲和力的亲和力结合至预定抗原。
“结合亲和力”在本文中是指两种分子如抗体或其片段和抗原之间的非共价相互作用的强度的量度。术语“结合亲和力”用来描述单价相互作用(内在活性)。两种分子如抗体或其片段和抗原之间的通过单价相互作用的结合亲和力可通过测定平衡解离常数(KD)来定量。反过来，KD可以通过测定复合物形成和解离的动力学、例如通过SPR法来测定。对应于单价复合物的结合和解离的速率常数分别称为结合速率常数ka(或kon)和解离速率常数kd(或koff)。KD通过方程KD＝kd/ka与ka和kd相关联。根据上述定义，可以通过个别抗体/抗原复合物的KD值的比较来比较与不同分子相互作用相关的结合亲和力，例如不同抗体对给定抗原的结合亲和力的比较。
如本文所用，术语IgG抗体的“高亲和力”是指抗体对靶抗原具有KD 10-8M、10-9M或10-10M或甚至更低。然而，其它抗体同型的“高亲和力”结合可为不同的。例如，IgM同型的“高亲和力”结合是指抗体具有10-8M、10 -9M或10 -10M或甚至更低的KD。
术语“结合特异性”在本文中是指例如抗体或其片段的分子与单一排他性(singleexclusive)抗原或有限数量的高度同源抗原(或表位)的相互作用。相反地，能够与SARS-CoV-2的刺突(S)蛋白特异性结合的抗体不能结合不同的分子。
相互作用的特异性和平衡结合常数的值可以通过众所周知的方法直接测定。评价配体(例如抗体)与其靶标结合的能力的标准试验是本领域已知的，包括例如ELISA、免疫印迹法、RIA、和流式细胞术分析。抗体的结合动力学和结合亲和力也可以通过本领域已知的标准试验如SPR来评价。
如本文所用，术语“框组(bin)”使用参考抗体来定义。如果第二抗体不能与参考抗体同时结合至抗原，则称第二抗体与参考抗体属于相同“框组”。在这种情况下，参考抗体和第二抗体竞争性地结合抗原的相同部分，称为“竞争性抗体”。如果第二抗体能够与参考抗体同时结合至抗原，则称第二抗体属于不同的“框组”。在这种情况下，参考抗体和第二抗体不会竞争性地结合抗原的相同部分，称为“非竞争性抗体”。
抗体“框组法(binning)”不提供关于表位的直接信息。竞争性抗体，即属于相同“框组”的抗体可以具有相同的表位、重叠的表位、或者甚至不同的表位。如果与其在抗原上的表位结合的参考抗体占据了第二抗体与其在抗原上的表位接触所需的空间(“空间位阻”)，则是后一种情况。非竞争性抗体通常具有不同的表位。
术语“EC50”在使用抗体或其抗原结合片段的体外或体内试验的情况中指代诱导为最大反应的50％的反应的抗体或其抗原结合部分的浓度，即最大反应和基线之间的一半。
如本文所用，术语“天然存在的”在用于客体时是指客体可以发现于自然界中的事实。例如，可以从自然界的来源中分离并且没有在实验室中被人类有意修饰的存在于生物体(包括病毒)中的多肽或多核苷酸序列是天然存在的。
“多肽”是指包含至少两个连续连接的氨基酸残基的链，链的长度没有上限。蛋白质中的一个或更多个氨基酸残基可以包含修饰，例如但不限于糖基化、磷酸化或二硫键形成。“蛋白质”可以包含一个或更多个多肽。
如本文所用，术语“核酸分子”旨在包括DNA分子和RNA分子。核酸分子可以是单链或双链的，并且可以是cDNA。
术语“受试者”包括接受预防性或治疗性治疗的人类和其它哺乳动物受试者。如本文所用，术语“受试者”包括任何人类或非人类动物。术语“非人类动物”包括所有脊椎动物，例如哺乳动物和非哺乳动物，如非人类灵长类动物、羊、狗、牛、鸡、两栖动物、爬行动物等。
如本文所用，术语“ug”和“uM”分别与“.mu.g”和“.mu.M”可交换地使用。
“Fc受体”或“FcR”是与免疫球蛋白的Fc区结合的受体。与IgG抗体结合的FCR包含Fc.γR家族的受体，包括这些受体的等位基因变体和替代性剪接形式。FcγR家族由三种激活性(小鼠中的FcγRI、FcγRIII、和Fc.RIV；人类中的FcγRIA、FcγRIIA、和FcγRIIIA)和一种抑制性(FcγRIIB)受体组成。本领域已知人类FcγR的各种性质。大多数先天效应细胞类型共表达一种或更多种激活性FcγR和抑制性FcγRIIB，而自然杀伤(NK)细胞选择性表达一种激活性Fc受体(小鼠中的FcγRIII和人类中的FcγRIIIA)而不是小鼠和人类中的抑制性FcγRIIB。人类IgG1与大多数人类Fc受体结合，并被认为就其所结合的激活性Fc受体的类型方面等同于鼠IgG2a。
“Fc区”(片段可结晶区)或“Fc结构域”或“Fc”是指抗体的重链的C-末端区，其介导免疫球蛋白与宿主组织或因子的结合，包括与位于免疫系统的各种细胞(例如效应细胞)上的Fc受体的结合或与经典补体系统的第一组分(C1q)的结合。因此，Fc区包含抗体的除第一恒定区免疫球蛋白结构域(例如，CH1或CL)以外的恒定区。
在IgG中，Fc区包含免疫球蛋白结构域CH2和CH3以及CH1和CH2结构域之间的铰链。尽管免疫球蛋白重链的Fc区的边界的定义可能不同，如本文所定义的，人类IgG重链Fc区被限定为从对于IgG1为氨基酸残基D221、对于IgG2为氨基酸残基V222、对于IgG3为氨基酸残基L221和对于IgG4为氨基酸残基P224延伸至重链的羧基末端，其中编号是根据kabat中的EU索引。人类IgG Fc区的CH2结构域从氨基酸237延伸至氨基酸340，并且CH3结构域位于Fc区中CH2结构域的C-末端侧，即它从氨基酸341延伸至IgG的氨基酸447或446(如果不存在C-末端赖氨酸残基)或445(如果不存在C-末端甘氨酸和赖氨酸残基)。
如本文所用，Fc区可以是天然序列Fc，包括任何同种异型变体，或变体Fc(例如非天然存在的Fc)。Fc也可以是指分离中的该区域或在包含Fc的蛋白质多肽如“包含Fc区域的结合蛋白”、也称为“Fc融合蛋白”(例如，抗体或免疫粘附)的情况中的该区域。
如本文所用，“施用”是指使用任何本领域技术人员已知的各种方法和递送系统将包含治疗剂的组合物物理引入至受试者。用于本文所描述的抗体的不同施用途径包括静脉内、腹膜内、肌内、皮下、脊髓或其它肠胃外施用途径，例如通过注射或输注。
如本文所用，短语“肠胃外施用”是指除了肠内和局部施用以外的施用方式，通常通过注射，包括但不限于静脉内、腹膜内、肌内、动脉内、鞘内、淋巴内、病灶内、囊内、眶内、心脏内、皮内、经气管、皮下、表皮下、关节内、囊下(subcapsular)、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。
可选地，本文所描述的抗体可通过非肠胃外途径施用，例如局部、表皮或粘膜施用途径，例如鼻内、口服、阴道、直肠、舌下或局部地。施用也可以进行例如一次、多次和/或经过一个或更多个延长的时期。
术语“Cmax”是指在施用后在受试者中观察到的药物的最大或峰值血清或血浆浓度。
如本文所用，“疫苗接种组合物”是指包含至少一种本发明的抗体或其抗原结合部分的药物组合物，其能够提供主动和/或被动免疫。本文所用的“主动免疫”是指诱导或增强受试者对抗原的免疫应答。如本文所用，“被动免疫”是指通过提供中和抗原的抗体和/或其抗原结合部分来补充受试者对抗原或病原体的免疫应答。
在一个实施方案中，本发明的抗体或其抗原结合部分为静脉内施用的，并且表现出约5和约235μg/ml之间的最大血清浓度(Cmax)；约5和约8μg/ml之间的峰值浓度(Cmax)；约5和约10μg/ml之间的Cmax；约55和约90μg/ml之间的峰值浓度(Cmax)；约185和约250μg/ml之间的峰值浓度(Cmax)；约190和约235μg/ml之间的Cmax。在另一实施方案中，Cmax为约5和约50之间、约50和约75之间、约75和约100之间、约100和约125之间、约125和约150之间、约150和约175之间、约175和约200之间、或约200和约235μg/ml之间。
术语“Tmax”是指Cmax出现的时间。在一个实施方案中，本发明的抗体或其抗原结合部分为静脉内或皮下施用的，并且表现出约1和约5天之间的Tmax；约3和约5天之间的Tmax；小于或等于约5天的Tmax；约1天的Tmax、约2天的Tmax、约3天的Tmax、约4天的Tmax、约5天的Tmax、约6天的Tmax、约7天的Tmax、约8天的Tmax、约9天的Tmax、或约10天的Tmax。
术语“生物利用率”或“F％”是指在施用给定剂型后被吸收且进入体循环的剂量的分数或百分比。在另一实施方案中，抗体或其抗原结合部分表现出至少约35％、至少约40％、至少约45％、至少约50％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％、至少约95％、或至少约100％的生物利用率。
术语“AUC”或“曲线下面积”与清除(clearance)相关。较高的清除率与较小的AUC相关，较低的清除率与较大的AUC值相关。AUC值越高表示清除率越低。
本发明人自己致力于解决本发明的问题并成功地发现了针对SARS相关冠状病毒的新的且有用的人类单克隆抗体，其克服了已知抗体的缺点和不足。
在此，本发明人描述了针对SARS-CoV-2的刺突(S)蛋白的人类来源的新的单克隆抗体，其不表现自身反应性并且超过了现有技术的类似抗体的中和效力
因此，本发明的抗体包含用于有效治疗和预防SARS相关冠状病毒感染和由此类感染引起的疾病症状的抗体介导的策略的非常有前景的候选物。
因此，本发明提供针对SARS相关冠状病毒的抗体或其结合片段，其中所述抗体或其结合片段包含来自包括以下的组的一种抗体的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6(具有SEQ ID No.1的可变区重链氨基酸序列和SEQ ID No.2的可变区轻链氨基酸序列)，HbnC3t1p1_G4(具有SEQ ID No.3的可变区重链氨基酸序列和SEQ IDNo.4的可变区轻链氨基酸序列)，HbnC3t1p2_B10具有SEQ ID No.5的可变区重链氨基酸序列和SEQ ID No.6的可变区轻链氨基酸序列)，MnC2t2p1_C11(具有SEQ ID No.7的可变区重链氨基酸序列和SEQ ID No.8的可变区轻链氨基酸序列)，FnC1t2p1_D4(具有SEQ ID No.9的可变区重链氨基酸序列和SEQ IDNo.10的可变区轻链氨基酸序列)，FnC1t2p1_G5(具有SEQ ID No.11的可变区重链氨基酸序列和SEQ ID No.12的可变区轻链氨基酸序列)，HbnC3t1p2_C6(具有SEQ ID No.13的可变区重链氨基酸序列和SEQ ID No.14的可变区轻链氨基酸序列)，MnC4t2p1_B3(具有SEQ ID No.15的可变区重链氨基酸序列和SEQ ID No.16的可变区轻链氨基酸序列)，MnC2t1p1_A3(具有SEQ ID No.17的可变区重链氨基酸序列和SEQ ID No.18的可变区轻链氨基酸序列)，CnC2t1p1_B4(具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列)，HbnC3t1p1_F4(具有SEQ ID No.21的可变区重链氨基酸序列和SEQ ID No.22的可变区轻链氨基酸序列)，HbnC2t1p2_D9(具有SEQ ID No.23的可变区重链氨基酸序列和SEQ ID No.24的可变区轻链氨基酸序列)，MnC5t2p1_G1(具有SEQ ID No.25的可变区重链氨基酸序列和SEQ ID No.26的可变区轻链氨基酸序列)，CnC2t1p1_E12(具有SEQ ID No.27的可变区重链氨基酸序列和SEQ ID No.28的可变区轻链氨基酸序列)，CnC2t1p1_D6(具有SEQ ID No.29的可变区重链氨基酸序列和SEQ ID No.30的可变区轻链氨基酸序列)，MnC2t1p1_C5(具有SEQ ID No.31的可变区重链氨基酸序列和SEQ ID No.32的可变区轻链氨基酸序列)，CnC2t1p1_E8(具有SEQ ID No.33的可变区重链氨基酸序列和SEQ ID No.34的可变区轻链氨基酸序列)，MnC1t3p1_G9(具有SEQ ID No.35的可变区重链氨基酸序列和SEQ ID No.36的可变区轻链氨基酸序列)，HbnC4t1p1_D5(具有SEQ ID No.37的可变区重链氨基酸序列和SEQ ID No.38的可变区轻链氨基酸序列)，CnC2t1p1_B10(具有SEQ ID No.39的可变区重链氨基酸序列和SEQ ID No.40的可变区轻链氨基酸序列)，CnC2t1p1_G6(具有SEQ ID No.41的可变区重链氨基酸序列和SEQ ID No.42的可变区轻链氨基酸序列)，FnC1t1p2_A5(具有SEQ ID No.43的可变区重链氨基酸序列和SEQ ID No.44的可变区轻链氨基酸序列)，MnC4t2p1_D10(具有SEQ ID No.45的可变区重链氨基酸序列和SEQ ID No.46的可变区轻链氨基酸序列)，MnC4t2p2_A4(具有SEQ ID No.47的可变区重链氨基酸序列和SEQ ID No.48的可变区轻链氨基酸序列)，MnC4t1p1_A10(具有SEQ ID No.49的可变区重链氨基酸序列和SEQ ID No.50的可变区轻链氨基酸序列)，MnC4t2p1_E6(具有SEQ ID No.51的可变区重链氨基酸序列和SEQ ID No.52的可变区轻链氨基酸序列)，MnC4t1p1_A11(具有SEQ ID No.53的可变区重链氨基酸序列和SEQ ID No.54的可变区轻链氨基酸序列)，和MnC4t2p1_F5(具有SEQ ID No.55的可变区重链氨基酸序列和SEQ ID No.56的可变区轻链氨基酸序列)，优选其中所述抗体或其结合片段包含选自包括以下的组的抗体之一的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，FnC1t2p1_D4，FnC1t2p1_G5，HbnC3t1p2_C6，MnC4t2p1_B3，MnC2t1p1_A3，CnC2t1p1_B4，HbnC3t1p1_F4，和HbnC2t1p2_D9，更优选来自包括以下的组的一种抗体的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，和FnC1t2p1_D4。
在本发明的上下文中，本文产生和描述的抗体可以作为完整的单克隆人类抗体或作为其任何功能或结合片段使用并要求权利保护。优选地，抗体或其任何类型的功能或结合片段应至少包含抗体重链的互补决定区(CDR)1至3和轻链的CDR 1至3。
本文所描述的抗体序列的CDR区优选根据IMGT的编号方案定义，所述编号方案是Chothia的编号方案的改编(ImMunoGeneTics information Lefranc,M.-P.等人IMGT,the international ImMunoGeneTics database.Nucleic Acids Res 27,209–212(1999)；http://imgt.cines.fr)。
基于关于本发明的抗体的可变区重链氨基酸序列和可变区轻链氨基酸序列的一般常识和本文给出的信息，本领域技术人员可以容易且明确地确定CDR。
根据本发明的一个优选实施方案，本文所描述的抗体的轻链和重链序列的CDR序列如下：
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优选地，本发明进一步包含如本文所描述的具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列以及SEQ ID No.113至118的CDR氨基酸序列的抗体CnC2t1p1_B4的衍生物，其中所述衍生物具有SEQ ID No.227的重链的CDR2的序列和/或所述衍生物具有SEQ ID No.228的轻链的CDR3的序列。
在另一实施方案中，本发明涉及针对SARS相关冠状病毒2(SARS-CoV-2)、特别是针对SARS-CoV-2的刺突蛋白的抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：包含序列SEQ ID No:119的CDR1、序列SEQ ID No:120的CDR2、和序列SEQ ID No:121的CDR3的重链可变区，并且还包含：包含序列SEQ ID No:122的CDR1、序列SEQ ID No:123的CDR2、和序列SEQ ID No:124的CDR3的轻链可变区。
在另一实施方案中，本发明涉及针对SARS相关冠状病毒2(SARS-CoV-2)、特别是针对SARS-CoV-2的刺突蛋白的抗体或其抗原结合片段，其包含序列SEQ ID No:21的重链可变区和序列SEQ ID No:22的轻链可变区。
根据本发明的一个特别优选的实施方案，抗体具有SEQ ID No.229的重链氨基酸序列和SEQ ID No.230的轻链氨基酸序列。该抗体是HbnC3t1p1_F4的变体，其中重链恒定结构域的末端赖氨酸已被去除(本文称为DZIF-10c，可选地称为HbnC3t1p1_F4(-K))。在本发明的不同的实施方案中，抗体包含SEQ ID No.21的重链氨基酸序列和SEQ ID No.22的轻链氨基酸序列。在该实施方案中，抗体HbnC3t1p1_F4(-K)的重链恒定区的末端赖氨酸仍然存在。
在另一实施方案中，抗体由序列SEQ ID No:229的两条重链和序列SEQ ID No:230的两条轻链组成。
在另一实施方案中，本发明涉及编码如本文所描述的抗体的核酸。在另一实施方案中，核酸是包含与表达控制序列功能性缔合(association)的如本文所描述的核酸的表达载体。在另一实施方案中，本发明涉及包含如本文所描述的核酸的宿主细胞。在另一实施方案中，本发明涉及包含如本文所描述的表达载体的宿主细胞。
在另一实施方案中，本发明涉及一种生产如本文所描述的抗体的方法，其包括
(a)在允许抗体的表达的条件下培养宿主细胞，和
(b)回收抗体。
在另一实施方案中，本发明涉及如本文所描述的针对SARS相关冠状病毒2(SARS-CoV-2)的抗体，其与针对SARS相关冠状病毒2(SARS-CoV-2)的至少一种其它抗体组合用于药物中，其中所述其它抗体具有不同的结合特异性。
根据一个优选实施方案，本发明还提供抗体或其结合片段，其中所述抗体或其结合片段包含选自包括以下的组的一种抗体的可变区重链序列和可变区重链序列的组合：HbnC3t1p1_C6(具有SEQ ID No.1的可变区重链氨基酸序列和SEQ ID No.2的可变区轻链氨基酸序列)，HbnC3t1p1_G4(具有SEQ ID No.3的可变区重链氨基酸序列和SEQ ID No.4的可变区轻链氨基酸序列)，HbnC3t1p2_B10具有SEQ ID No.5的可变区重链氨基酸序列和SEQID No.6的可变区轻链氨基酸序列)，MnC2t2p1_C11(具有SEQ ID No.7的可变区重链氨基酸序列和SEQ ID No.8的可变区轻链氨基酸序列)，FnC1t2p1_D4(具有SEQ ID No.9的可变区重链氨基酸序列和SEQ ID No.10的可变区轻链氨基酸序列)，FnC1t2p1_G5(具有SEQ IDNo.11的可变区重链氨基酸序列和SEQ ID No.12的可变区轻链氨基酸序列)，HbnC3t1p2_C6(具有SEQ ID No.13的可变区重链氨基酸序列和SEQ ID No.14的可变区轻链氨基酸序列)，MnC4t2p1_B3(具有SEQ ID No.15的可变区重链氨基酸序列和SEQ ID No.16的可变区轻链氨基酸序列)，MnC2t1p1_A3(具有SEQ ID No.17的可变区重链氨基酸序列和SEQ ID No.18的可变区轻链氨基酸序列)，CnC2t1p1_B4(具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列)，HbnC3t1p1_F4(具有SEQ ID No.21的可变区重链氨基酸序列和SEQ ID No.22的可变区轻链氨基酸序列)，HbnC2t1p2_D9(具有SEQ ID No.23的可变区重链氨基酸序列和SEQ ID No.24的可变区轻链氨基酸序列)，MnC5t2p1_G1(具有SEQ ID No.25的可变区重链氨基酸序列和SEQ ID No.26的可变区轻链氨基酸序列)，CnC2t1p1_E12(具有SEQ ID No.27的可变区重链氨基酸序列和SEQ ID No.28的可变区轻链氨基酸序列)，CnC2t1p1_D6(具有SEQ ID No.29的可变区重链氨基酸序列和SEQ ID No.30的可变区轻链氨基酸序列)，MnC2t1p1_C5(具有SEQ ID No.31的可变区重链氨基酸序列和SEQ ID No.32的可变区轻链氨基酸序列)，CnC2t1p1_E8(具有SEQ ID No.33的可变区重链氨基酸序列和SEQ ID No.34的可变区轻链氨基酸序列)，MnC1t3p1_G9(具有SEQ ID No.35的可变区重链氨基酸序列和SEQ ID No.36的可变区轻链氨基酸序列)，HbnC4t1p1_D5(具有SEQ ID No.37的可变区重链氨基酸序列和SEQ ID No.38的可变区轻链氨基酸序列)，CnC2t1p1_B10(具有SEQ ID No.39的可变区重链氨基酸序列和SEQ ID No.40的可变区轻链氨基酸序列)，CnC2t1p1_G6(具有SEQ ID No.41的可变区重链氨基酸序列和SEQ ID No.42的可变区轻链氨基酸序列)，FnC1t1p2_A5(具有SEQ ID No.43的可变区重链氨基酸序列和SEQ ID No.44的可变区轻链氨基酸序列)，MnC4t2p1_D10(具有SEQ ID No.45的可变区重链氨基酸序列和SEQ ID No.46的可变区轻链氨基酸序列)，MnC4t2p2_A4(具有SEQ ID No.47的可变区重链氨基酸序列和SEQ ID No.48的可变区轻链氨基酸序列)，MnC4t1p1_A10(具有SEQ ID No.49的可变区重链氨基酸序列和SEQ ID No.50的可变区轻链氨基酸序列)，MnC4t2p1_E6(具有SEQ ID No.51的可变区重链氨基酸序列和SEQ ID No.52的可变区轻链氨基酸序列)，MnC4t1p1_A11(具有SEQ ID No.53的可变区重链氨基酸序列和SEQ ID No.54的可变区轻链氨基酸序列)，和MnC4t2p1_F5(具有SEQ ID No.55的可变区重链氨基酸序列和SEQ ID No.56的可变区轻链氨基酸序列)，优选来自包括以下的组的一种抗体的可变区重链序列和可变区重链序列的组合：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，FnC1t2p1_D4，FnC1t2p1_G5，HbnC3t1p2_C6，MnC4t2p1_B3，MnC2t1p1_A3，CnC2t1p1_B4，HbnC3t1p1_F4，和HbnC2t1p2_D9，更优选来自包括以下的组的一种抗体的可变区重链序列和可变区重链序列的组合：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，and FnC1t2p1_D4。
通常，如本文所描述的抗体或其结合片段还包含与如上定义的序列为至少80％同一性的抗体氨基酸序列，只要它们仍针对如SEQ ID No.57中的SARS-CoV-2的刺突(S)蛋白即可，优选地，只要它们仍针对如SEQ ID No.58中的SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)即可。
这意味着包括具有抗体氨基酸序列的微小突变、即保守突变的序列，所述突变不干扰结构折叠和抗体对刺突蛋白的亲和力。优选地，导致与本文明确公开的个体序列为至少80％、85％、90％或95％整体同一性的氨基酸序列中的偏差仅存在于根据本发明的抗体的CDR区域之外。特别地，本发明涵盖在抗体的恒定区内具有1、2、3、4或5个突变的抗体氨基酸序列。
根据本发明的抗体优选是人类来源的。因此，至少CDR之外的序列，例如抗体的框架区和恒定区，优选是人类来源的或可归因于人类来源的。此外，本发明的抗体优选是单克隆的。
在一个优选实施方案中，抗体是单克隆抗体或其片段，所述片段保留了结合特异性和中和传染性病原体的能力。在一个优选实施方案中，抗体是lgG1、lgG2、lgG3、或lgG4抗体。例如，抗体可以是包含任何人类IgG同型(例如，lgG1、lgG2、lgG3、或lgG4)的Fc结构域的抗体。
任选地，抗原结合化合物由Fab、Fab'、Fab'-SH、F(ab)2、Fv、双抗体、单链抗体片段、或包含多种不同抗体片段的多特异性抗体组成、或包含这些。
在本发明中，针对SARS-CoV-2的刺突(S)蛋白的抗体或结合片段是指与不相关的表位、蛋白质或蛋白质区域相比，以至少10倍、更优选至少50倍、特别优选至少100倍增加的亲和力与SARS-CoV-2的刺突(S)蛋白结合的抗体。
对于技术人员来说，基于上述或一般常识来确定表现出一定程度的同一性的抗体是否针对SARS-CoV-2的刺突(S)蛋白是一项简单的任务。
两条序列之间的百分比同一性的测定是根据本发明通过使用Karlin和Altschul(Proc.Natl.Acad.Sci.USA(1993)90:5873-5877)的数学算法来完成的。此类算法是Altschul等人(J.Mol.Biol.(1990)215:403-410)的BLASTN和BLASTP程序的基础。BLAST核苷酸搜索使用BLASTN程序来进行。为了获得用于比较目的的空位比对，如Altschul等人(Nucleic Acids Res.(1997)25:3389-3402)所述使用Gapped BLAST。在使用BLAST和Gapped BLAST程序时，使用各自程序的默认参数。
根据本发明的一个优选实施方案，抗体氨基酸序列构成本发明的一部分，其由与如上定义和本文公开的序列为至少85％同一性、更优选至少90％同一性、甚至更优选至少95％同一性的核酸序列组成、或包含这些。
根据本发明的一个优选实施方案，SARS相关冠状病毒毒株是严重急性呼吸综合征冠状病毒2(SARS-CoV-2)，其在本领域中可选地称为SARS相关冠状病毒2。根据本发明的另一优选实施方案，SARS相关冠状病毒毒株是严重急性呼吸综合征冠状病毒(SARS-CoV或SARS-CoV-1)。
根据本发明的另一优选实施方案，抗体或其结合片段针对SARS-CoV-2的刺突(S)蛋白的胞外域。
根据本发明的更优选的实施方案，抗体或其结合片段针对如Wrapp等人,Science(2020)doi:10.1126/science.abb2507中所述的病毒分离株Wuhan-Hu-1的融合前稳定化变体中SARS-CoV-2的刺突(S)同源三聚体的胞外域(SEQ IDNO.57)。该病毒分离株在提交申请时已进行深入研究并被最好的理解。
然而，优选地，抗体或其结合片段也应针对其它病毒变体的等效序列(equivalentsequence)。根据一个具体实施方案，抗体或其结合片段针对SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)(SEQ ID NO.58)。
根据本发明的一个优选实施方案，抗体或其结合片段针对SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)(SEQ ID NO.58)之外的、如Wrapp等人,Science(2020)doi:10.1126/science.abb2507中所述的病毒分离株Wuhan-Hu-1的融合前稳定化变体中SARS-CoV-2的刺突(S)同源三聚体的胞外域的序列(SEQ ID NO.57)。
根据本发明的一个优选实施方案，根据Koch等人,Lancet Infect.Dis.(2020)doi:10.1016/s1473-3099(20)30248-6，当在37℃下共培养病毒和抗体1h后使用100TCID50的SARS-CoV-2施用至VeroE6细胞在病毒中和试验中进行测试时，所述抗体或其结合片段表现小于10μg/ml的针对VeroE6细胞上的真实SARS-CoV-2分离株BavPat1/2020的中和效力(IC100；导致完全不存在细胞病变效应的最低抗体剂量)。
一方面，通过根据下文中实施例部分公开的“病毒中和试验”的方案来测试如上定义的中和效力。根据本发明的一个优选实施方案，抗体或其结合片段表现小于1μg/ml、更优选小于0.5μg/ml、甚至更优选0.25μg/ml以下、特别优选0.12μg/ml以下的中和效力。
根据本发明的一个优选实施方案，抗体或其结合片段表现如通过表面等离子共振测定的20nM以下、优选5nM以下、更优选1nM以下、甚至更优选0.2nM以下、特别优选0.1nM以下的与SEQ ID NO:58的RBD的结合常数(KD)。
根据本发明的一个优选实施方案，当使用浓度为100μg/ml的抗体或其结合片段的抗核抗体(ANA)测试试剂盒(NOVA-Lite HEp-2 ANA试剂盒；Inova Diagnostics)针对透化HEp-2细胞进行测试时，所述抗体或其结合片段不表现定义为可检测的结合的自身反应性。可选地，优选地，可以使用本领域已知的其它试验来确定或排除抗体或其结合片段的自身反应性。
在本申请的说明书中，可以使用抗体名称。指出了抗体由重链和轻链组成，其也构成了本说明书的一部分。如果抗体以其名称引用或引用SEQ ID No.时，应理解这些引用方式是可交换的。
本发明还涉及一种药物组合物，其包含如本文所定义和进一步描述的根据本发明的抗体或其结合片段以及至少一种药学上可接受的赋形剂。一方面，药物组合物是用于人类和/或动物受试者的疫苗接种组合物。本发明还涵盖包含如本文所定义和进一步描述的根据本发明的抗体或其结合片段以及容器的试剂盒。
一方面，本发明还涉及如本文所定义和进一步描述的根据本发明的抗体或其结合片段、如本文所描述的药物组合物和试剂盒用作药物、优选用作疫苗。
在另一方面，本发明还涉及如本文所定义和进一步描述的根据本发明的抗体或其结合片段、如本文所描述的药物组合物和试剂盒用于治疗或预防人类或动物受试者中由SARS相关冠状病毒引起的疾病的用途，优选用于治疗或预防人类或动物受试者中由SARS相关冠状病毒2(SARS-CoV-2)引起的疾病的用途。
一方面，本发明涉及如本文所定义和进一步描述的根据本发明的抗体或其结合片段、如本文所描述的药物组合物和试剂盒用于预防人类和/或动物受试者感染SARS相关冠状病毒的用途，优选用于预防人类和/或动物受试者感染SARS相关冠状病毒2(SARS-CoV-2)的用途。
在本发明的另一方面，根据本发明的抗体通过静脉内注射或输注施用至有需要的患者。在一个优选实施方案中，抗体以1mg/kg体重至100mg/kg患者体重的剂量通过静脉内输注施用。在一个优选实施方案中，抗体以2,5mg/kg、5mg/kg、10mg/kg、20mg/kg、25mg/kg、30mg/kg、40mg/kg、50mg/kg、或100mg/kg的剂量施用。要施用至受试者的本发明抗体的剂量可进一步根据例如所表现的症状的严重程度以及受试者的年龄、性别和健康等此类因素而变化。
在本发明的另一方面，根据本发明的抗体通过吸入给药施用至有需要的患者。在一个优选实施方案中，抗体通过吸入给药来施用，其中所述抗体以液体药物组合物提供，所述组合物在施用前通过筛网雾化器或喷射雾化器来雾化。在一个优选实施方案中，抗体以50mg、100mg、200mg、250mg、300mg、400mg、500mg、750mg、或1000mg的剂量通过吸入给药来施用。在另一实施方案中，抗体通过吸入给药来施用，然后是通过静脉内注射或输注来施用的第二剂。
本发明的药物组合物被配制成与其预期的施用途径相容。施用途径的实例包括但不限于肠胃外，例如静脉内、皮内、皮下、口服、鼻内(例如吸入和经口吸入)、经皮(例如局部)、经粘膜、和直肠施用。
在一个具体实施方案中，根据常规程序将组合物配制成适于静脉内、皮下、肌内、口服、鼻内、或局部施用至人的药物组合物。典型地，用于静脉内施用的组合物是无菌等渗水性缓冲液中的溶液。必要时，所述组合物还可以包含增溶剂和局部麻醉剂如利多卡因以减轻注射部位的疼痛。
本发明的方法可以包括用雾化剂配制的组合物的肺部施用，例如通过使用吸入器或喷雾器。参见，例如，美国专利号6,019,968、5,985,320、5,985,309、5,934,272、5,874,064、5,855,913、5,290,540、和4,880,078；和PCT公开号WO 92/19244、WO 97/32572、WO 97/44013、WO 98/31346、和WO 99/66903，这些的每一者通过引用以其整体并入本文。在一个具体实施方案中，本发明的抗体、组合疗法、和/或本发明的组合物使用Alkermes肺部药物递送技术(Alkermes,Inc.,Cambridge,Mass.,U.S.A.)来施用。在另一具体实施方案中，本发明的抗体、组合疗法、和/或本发明的组合物使用Aerogen />肺部药物递送技术(Aerogen GmbH,Ratingen,Germany)来施用。
本发明的方法还可以包括通过注射(例如，通过弹丸式注射(bolus injection)或连续输注)来施用配制用于胃肠外施用的组合物。
本发明的药物制剂可以以液体形式提供、或者可以以冻干形式提供。
根据本发明的药物制剂可以包含缓冲剂。缓冲剂包括但不限于柠檬酸、HEPES、组氨酸、乙酸钾、柠檬酸钾、磷酸钾(KH2PO4)、乙酸钠、碳酸氢钠、柠檬酸钠、磷酸钠(NAH2PO4)。Tris碱和Tris-HCl。
如本文所用，术语“提供约5.0至约7.0的pH的缓冲剂”是指其提供包含其的溶液通过其酸/碱缀合组分的作用抵抗pH的变化的试剂。根据本发明的制剂中使用的缓冲液可以具有约5.5至约7.5、或约5.8至约7.0的范围内的pH。在一个实施方案中，pH约为6.0。在一个实施方案中，pH约为7.0。将控制pH在该范围内的缓冲剂的实例包括乙酸盐、琥珀酸盐、葡萄糖酸盐、组氨酸、柠檬酸盐、甘氨酰甘氨酸和其它有机酸缓冲液。
根据本发明的药物制剂可以包含张度剂。张度剂包括但不限于葡萄糖、甘油、甘露醇、氯化钾、和氯化钠。在一个实施方案中，张度剂是氯化钠。在一个实施方案中，氯化钠浓度为约70至170mM；约90-150mM；或约115.+-.10mM。
“等渗”是指制剂具有与人血液基本相同的渗透压。等渗制剂通常将具有约250至350mOsm的渗透压。等渗性可以使用蒸汽压或冰点降低型渗透压计来测量。
在某些实施方案中，根据本发明的药物制剂包含稳定剂。稳定剂包括但不限于人血清白蛋白(hsa)、牛血清白蛋白(bsa)、α-酪蛋白、球蛋白、α-乳白蛋白、LDH、溶菌酶、肌红蛋白、卵白蛋白、和核糖核酸酶A。稳定剂还包括氨基酸及其代谢物，例如甘氨酸、丙氨酸(α-丙氨酸、β-丙氨酸)、精氨酸、甜菜碱、亮氨酸、赖氨酸、谷氨酸、天冬氨酸、脯氨酸、4-羟基脯氨酸、肌氨酸、γ-氨基丁酸(GABA)、冠瘿碱(opines)(阿兰碱(alanopine)、章鱼碱(octopine)、甘氨奥品(strombine))、和三甲胺N氧化物(TMAO)。在一个实施方案中，稳定剂是氨基酸。
在某些实施方案中，根据本发明的药物制剂包含非离子表面活性剂。非离子表面活性剂包括但不限于，聚氧乙烯失水山梨醇脂肪酸酯(例如聚山梨醇酯20和聚山梨醇酯80)、聚乙烯-聚丙烯共聚物、聚乙烯-聚丙二醇、聚氧乙烯硬脂酸酯、聚氧乙烯烷基醚，例如聚氧乙烯单月桂基醚、烷基苯基聚氧乙烯醚(alkylphenylpolyoxyethylene ether，Triton-X)、聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆(Poloxamer)、普兰尼克(Pluronic))、月桂基硫酸钠(SDS)。在一个实施方案中，非离子表面活性剂是聚山梨醇酯20或聚山梨醇酯80。在一个实施方案中，聚山梨醇酯浓度为约0.005至0.02％(w/v)。在一个实施方案中，聚山梨醇酯的浓度为约0.01％(w/v)。在一个实施方案中，聚山梨醇酯浓度为约0.02％(w/v)。
在某些实施方案中，根据本发明的药物制剂包含金属螯合剂。金属螯合剂包括但不限于EDTA和EGTA。在一个实施方案中，金属螯合剂是EDTA。在一个实施方案中，EDTA浓度为约0.01至约0.02mM。在一个实施方案中，EDTA浓度约为约0.05mM。
在一个其它方面，本发明还涉及治疗患有人类或动物受试者中由SARS相关冠状病毒引起的疾病的患者的方法，优选用于治疗或预防人类或动物受试者中的COVID-19的方法，其中向患者施用有效量的根据本发明的抗体或其结合片段或本发明的药物组合物。
另一方面，本发明还涉及根据本发明的抗体或其结合片段或本发明的药物组合物在制备用于治疗人类或动物受试者中由SARS相关冠状病毒引起的疾病的药物中的用途，优选用于治疗或预防人类或动物受试者中的COVID-19的药物。
如本文所描述的本发明的所有实施方案被认为可以以任何组合进行组合，除非技术人员认为这样的组合没有任何技术意义。
实施例
SARS-CoV-2感染的个体和样品收集
根据科隆大学的机构审查委员会(the Institutional Review Board of theUniversity of Cologne)批准的研究方案获取样品，所有参与者提供书面知情同意书并在医院或作为门诊患者招募。
从全血分离外周血单核细胞(PBMC)、血浆和总IgG
使用EDTA管和/或预填充有肝素的注射器进行血液抽取。根据制造商的说明书，使用预填充有密度梯度分离介质(Histopaque；Sigma-Aldrich)的Leucosep离心管(Histopaque；Sigma-Aldrich)在到达时立即进行PBMC分离。单独收集并储存血浆。
对于IgG分离，将1ml的收集的血浆热灭活(56℃，40分钟)并与蛋白G琼脂糖凝胶(GE Life Sciences)在4℃下孵育过夜。将悬浮液转移至层析柱并用PBS洗涤。使用0.1M甘氨酸(pH＝3.0)从蛋白G洗脱IgG，并在1M Tris(pH＝8.0)中缓冲。为了将缓冲液更换为PBS，使用30kDa Amicon旋转膜(Millipore)。利用Nanodrop(A280)测定纯化的IgG浓度，并将样品储存在4℃下。
SARS-CoV-2 S蛋白表达和纯化
编码融合前稳定的SARS-CoV-2 S胞外域(SARS-CoV-2 S的氨基酸1-1208；GenBank:MN908947)的构建体由Jason McLellan(Texas,USA)友情提供，并且先前进行了描述(Wrapp,D.等人Cryo-EM structure of the 2019-nCoV spike in the prefusionconformation.Science(80-.).(2020)doi:10.1126/science.aax0902.)。
具体而言，在残基986和987处引入两个脯氨酸取代以进行融合前状态稳定化，残基682-685处的“GSAS”取代以消除弗林蛋白酶(furin)切割位点和C末端T4纤维蛋白(fibritin)三聚化基序。为了纯化，蛋白质为C末端融合至TwinStrepTag和8XHisTag。在FreeStyle 293培养基(Thermo Fisher Scientific)中在0.8 106个细胞/mL的细胞密度下、用聚乙烯亚胺(PEI,Sigma-Aldrich)和每1mL细胞培养基1μg DNA通过瞬时转染以在HEK293-6E细胞中进行蛋白质生产。在37℃和5％ CO2下培养7天后，收获上清液并通过0.45μm聚醚砜(PES)过滤器(Thermo Fisher Scientific)过滤。
根据Strep-Tactin XT手册，通过Strep-Tactin亲和层析(IBA lifescience,Germany)纯化重组蛋白。简言之，通过添加100mL 10x缓冲液W(1M Tris/HCl，pH8.0，1.5M NaCl，10mM EDTA，IBA lifescience)将过滤的培养基调节至pH 8，并用低压泵以1mL/min加载在5mL床体积Strep-Tactin树脂上。用15柱体积(CV)1x缓冲液W(IBAlifescience)洗涤柱，并用6x 2.5mL 1x缓冲液BXT(IBA lifescience)洗脱。合并洗脱级分，并将缓冲液更换为PBS pH 7.4(Thermo Fisher Scientific)，通过在100kDa截断纤维素离心过滤器(Merck)上过滤4次。
不同SARS-CoV-2 S蛋白亚基和埃博拉病毒(Ebola)表面糖蛋白的克隆和表达
SARS-CoV-2刺突蛋白的RBD(MN908947；AA:319-541)在293T细胞中自由FlorianKrammer友情提供的质粒表达，并使用Ni-NTA琼脂糖(Macherey-Nagel)纯化，如先前公开的(Stadlbauer,D.等人.SARS-CoV-2Seroconversion in Humans:A Detailed Protocol fora Serological Assay,Antigen Production,and TestSetup.Curr.Protoc.Microbiol.57,(2020))。
通过PCR从合成基因质粒(弗林蛋白酶位点突变；；Wrapp,D.等人Cryo-EMstructure of the 2019-nCoV spike in the prefusion conformation.Science(80-.).(2020)doi:10.1126/science.aax0902)扩增不含刺突DNA的三聚化结构域(MN908947；AA:1-1207)和S1亚基(MN908947；AA:14-529)区的SARS-CoV-2 S胞外域“单体”。将PCR产物克隆至含有C-末端凝血酶切割和双Strep II纯化标签的修饰的睡美人转座子(sleepingbeauty)表达载体中。对于S1亚基，标签添加在5’端并且包含BM40信号肽。
对于重组蛋白生产，使用睡美人转座子系统(Kowarz,E.,D.&Marschalek,R.Optimized Sleeping Beauty transposons rapidly generate stabletransgenic cell lines.Biotechnol.J.10,647–653(2015).)产生稳定HEK293EBNA细胞系。
简言之，使用FuGENE HD转染试剂(Promega)将表达构建体转染至HEK293 EBNA细胞。用嘌呤霉素选择后，用强力霉素诱导细胞。过滤上清液，经由XT(IBALifescience)树脂纯化重组蛋白。然后通过含有生物素的TBS缓冲液(IBA Lifescience)洗脱蛋白质，并用TBS缓冲液透析蛋白质。如先前所述(Ehrhardt,S.A.等人.Polyclonal andconvergent antibody response to Ebola virus vaccine rVSV-ZEBOV.Nat.Med.25,1589–1600(2019).)生产和纯化均含有GCN4三聚化结构域的、埃博拉病毒表面糖蛋白(缺少跨膜结构域(Δ651–676)的EBOV Makona(GenBank KJ660347))和同样缺少跨膜结构域的HIV-gp140(YU2株)。
SARS-CoV-S胞外域特异性IgG+B细胞的分离
根据制造商的说明书，使用CD19-微珠(Miltenyi Biotec)从PBMC分离B细胞。使用MACS LS柱(Miltenyi Biotec)分离CD19标记的细胞。在冰上用含有4’,6-二脒基-2-苯基吲哚(DAPI；Thermo Fisher Scientific)、抗人CD20-Alexa Fluor 700(BD)、抗人IgG-APC(BD)、抗人CD27-PE(BD)和DyLight488标记的SARS-CoV-2刺突蛋白(10μg/mL)的荧光染色混合物染色分离的B细胞20分钟。
使用FACSAria Fusion(Becton Dickinson)以单细胞方式将Dapi-、CD20+、IgG+、SARC-CoV-2刺突蛋白阳性细胞分选至96孔板中。所有孔均含有4μl裂解缓冲液(0.5x PBS，0.5U/μl RNAsin(Promega)，0.5U/μl RNaseOUT(Thermo Fisher Scientific)和10mM DTT(Thermo Fisher Scientific)，分选后，将板立即储存在-80℃下直至进一步处理。
抗体重链/轻链扩增和序列分析
主要如先前所述(Schommers,P.等人.Restriction of HIV-1Escape by aHighlyBroad and Potent Neutralizing Antibody.Cell 180,471-489.e22(2020)进行抗体重链和轻链的单细胞扩增。
简言之，用无规六聚物(Random Hexamers)(Invitrogen)和在RNA酶抑制剂RNaseOUT(Thermo Fisher Sicentific)和RNasin(Promega)的存在下的Superscript IV(Thermo Fisher Scientific)进行逆转录。使用具有6％ KB扩展剂(extender)的PlatinumTaq HotStart聚合酶(Thermo Fisher Scientific)和最优化V基因特异性引物混合物(Schommers,P.等人Restriction of HIV-1Escape by aHighly Broad and PotentNeutralizing Antibody.Cell 180,471-489.e22(2020))以略微修改来增加产量(throughout)的顺序半巢式方法，使用cDNA扩增重链和轻链。通过凝胶电泳分析PCR产物的正确大小，并进行Sanger测序。
对于序列分析，层析图经过滤而得到28的平均Phred得分和240nt的最小长度。序列利用IgBLAST进行注释，并经修剪(trimmed)以仅提取自FWR1到J基因的末端的可变区。Phred得分低于16的可变区内的碱基识别(Base call)被隐藏，具有超过15个隐藏的核苷酸、终止密码子或移码的序列被排除在进一步的分析之外。
对每名患者分别进行纯系分析(Clonal analysis)。所有生产性重链序列通过相同VH/JH基因对分组，并确定其CDRH3的成对莱文斯坦距离(Levenshtein distance)。从随机序列开始，将纯系(clone)组分配为具有(相对于最短的CDRH3)至少75％的最小CDRH3氨基酸同一性的四条序列。进行100轮的输入序列随机化和纯系分配，并且选择具有最少数量的剩余未分配的(非纯系)序列的结果用于下游分析。
所有纯系均由研究人员交叉验证，也考虑了共有突变。对于不具有进一步崩溃(collapsing)的所有输入序列，确定了所有纯系序列的V基因使用、CDRH3长度和V基因种系同一性分布。基于Eisenberg-scale(Eisenberg,D.,Schwarz,E.,Komaromy,M.&Wall,R.Analysis of membrane and surface protein sequences with the hydrophobicmoment plot.J.Mol.Biol.179,125–142(1984).)计算CDRH3疏水性。从崩溃的纯系序列计算中和剂和非中和剂的V基因统计。
对于重复纯系(recurring clone)的突变频率进行纵向分析，用Clustal Omega(版本1.2.3；Sievers,F.等人Fast,scalable generation of high-quality proteinmultiple sequence alignments using Clustal Omega.Mol.Syst.Biol.7,(2011).)使用标准参数计算B细胞序列的多重序列比对。
单克隆抗体的克隆和生产
如先前所述(Schommers,P.等人.Restriction of HIV-1Escape by a HighlyBroad and Potent Neutralizing Antibody.Cell 180,471-489.e22(2020))通过略微修改的不依赖于序列和连接的克隆(SLIC；Von Boehmer,L.等人.Sequencing and cloningof antigen-specific antibodies from mouse memory B cells.Nat.Protoc.11,1908–1923(2016).)进行来自第一PCR产物的抗体克隆。
与已公开的方案相反，基于覆盖所有重链和轻链V基因的完整内源前导序列、利用延伸的引物(Kreer,C.等人.openPrimeR for multiplex amplification of highlydiverse templates.J.Immunol.Methods 480,(2020).)进行SLIC组装的PCR扩增。
如前所述(Schommers,P.等人.Restriction of HIV-1Escape by a HighlyBroad and Potent Neutralizing Antibody.Cell 180,471-489.e22(2020))，将具有内源前导序列的可变区组装至IgH、IgK、和IgL的哺乳动物表达载体中，并转染至HEK293-6E细胞用于单克隆抗体的表达和蛋白G纯化。
ELISA分析以测定对SARS-CoV-2 S和亚基结合的抗体结合活性
用PBS中(SARS-CoV-2刺突胞外域，RBD，或N末端截断S1)或2M尿素中(缺少三聚化结构域的SARS-CoV-2刺突胞外域“单体”)2μg ml-1的蛋白质包被ELISA板(Corning#3369)，在4℃下过夜。对于SARS-CoV-2刺突胞外域ELISA，在室温下用PBS中5％ BSA封闭板60分钟，用PBS中1％ BSA中一抗孵育90分钟，然后在室温下用PBS中1％ BSA中1:2500稀释的抗人IgG-HRP(Southern Biotech 2040-05)孵育60分钟。
按照已公开的方案(Stadlbauer,D.等人.SARS-CoV-2 Seroconversion inHumans:A Detailed Protocol for a Serological Assay,Antigen Production,andTest Setup.Curr.Protoc.Microbiol.57,(2020).)进行SARS-CoV-2刺突亚基ELISA。
用ABTS溶液(Thermo Fisher 002024)显影ELISA并在415nm-696nm下测定吸光度。阳性结合定义为OD>0.25和EC50<30μg/ml(参见图1)。用于免疫球蛋白G类的市售抗SARS-CoV-2ELISA试剂盒由Euroimmun(Euroimmun Diagnostik,Lübeck,Germany)提供。根据制造商的说明书进行抗体检测并使用浓度为50μg/ml的抗体。使用自动化平台Euroimmun分析仪1测试样品。
表面等离子共振(SPR)测量
对于SPR测量，用Superdex200 10/300柱(GE Healthcare)通过尺寸排阻色谱(SEC)纯化来额外地纯化如SEQ ID NO.58中的SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)。用Biacore T200仪器(GE Healthcare)使用单循环动力学实验来测定RBD与各种mAb的结合。
纯化的mAb首先以800-1200反应单位(response unit，RU)的偶联密度固定在PBS和0.02％叠氮化钠缓冲液中的系列S传感器芯片蛋白A(GE Healthcare)上。传感器芯片上的四个流动池之一是空的，用作空白。然后将可溶性RBD以在PBS中的一系列浓度(即0.8、4、20、100、和500nM)以60μL/min的流速注射。使用10mM甘氨酸-HCl pH 1.5缓冲液再生传感器芯片。
1:1结合模型用于描述实验数据并推导动力学参数。对于一些mAb，1:1结合模型没有提供对结合的充分描述。在这些情况下，我们拟合了双态结合模型，所述模型假设由于构象变化而产生两个结合常数。在这些情况下，我们报告了第一结合常数(KD 1)。
已经确定了本发明的以下抗体的KD值形式的结合常数：
FnC1t2p1_D4 0.20nM
FnC1t2p1_G5 0.10nM
MnC2t1p1_A3 0.70nM
MnC2t2p1_C11 0.02nM
MnC4t2p1_B3 0.09nM
MnC4t2p2_A4 14nM
MnC5t2p1_G1 17nM
病毒中和试验
基于用于MERS-CoV的先前公开的方案(Koch,T.等人Safety and immunogenicityof a modified vaccinia virus Ankara vector vaccine candidate for Middle Eastrespiratory syndrome:an open-label,phase 1trial.Lancet Infect.Dis.(2020)doi:10.1016/s1473-3099(20)30248-6.)，研究了poly-IgG样品或人单克隆抗体的SARS-CoV-2中和活性。
简言之，对于单克隆抗体，从100μg/ml的浓度开始，在96孔板中连续稀释样品。将样品与100 50％组织培养感染剂量(TCID50)的SARS-CoV-2(BavPat1/2020分离株，European Virus Archive Global#026V-03883)一起在37℃下孵育1小时。
感染后4天分析VeroE6细胞上的细胞病变效应(CPE)。中和被定义为与病毒对照相比不存在CPE。对于每项试验，一式两份地使用阳性对照(中和COVID-19患者血浆)作为试验间中和标准。结果示于图1至3和图5的表格中。
HEp-2细胞检验
根据制造商的说明书，使用NOVA Lite HEp-2 ANA试剂盒(Inova Diagnostics)以在PBS中100μg/ml的浓度测试单克隆抗体，包括每个基板载玻片上的阳性和阴性试剂盒对照。具有已知反应性概况的HIV-1反应性抗体作为附加对照被包括在内。使用DMI3000 B显微镜(Leica)和3.5s的曝光时间、100％的强度、以及10的增益获取图像。自身反应性检测的结果示于图4。
定量和统计
通过FlowJo10.GraphPad Prism(v7)、和Mac的Microsoft Excel(v14.7.3)进行流式细胞术分析和定量。在GraphPad Prism(v7)中计算Spearman相关系数rS和近似双尾p值。
利用本发明的抗体获得的结果的汇总示于图5的表中。
在经基因修饰以表达SARS-CoV-2受体人血管紧张素转化酶2(ACE2)的BALB/c小鼠中研究了DZIF-10c的体内治疗功效。DZIF-10c是HbnC3t1p1_F4的变体，其中重链恒定结构域的末端赖氨酸已被去除(HbnC3t1p1_F4(-K)；SEQ ID No.229的重链序列和SEQ IDNo.230的轻链序列)。对于本实验，气管内滴注编码hACE2的重组复制缺陷型腺病毒。在该模型中，hACE2的腺病毒介导的转导、接着在3天后进行SARS-CoV-2攻击(1.5x104 TCID50SARS-CoV-2 BavPat1/2020)导致肺部病毒复制和间质性肺炎的发展，在SARS-CoV-2攻击后4天达到峰值。
为了研究DZIF-10c治疗在用SARS-CoV-2攻击的ACE2转导的小鼠中的体内效果，在SARS-CoV-2攻击后的第1天和第3天，以40mg/kg的剂量腹膜内或鼻内施用DZIF-10c(参见图6A)。
当与IgG1同型对照抗体相比时，如通过qRT-PCR测定的，DZIF-10c治疗在第4天仅导致肺组织中总SARS-CoV-2RNA浓度发生有限变化(图6B)，当通过病毒分离测定时，通过任一途径的DZIF-10c治疗导致不可检测的病毒滴度(图6C)。
在SARS-CoV-2感染的单独小动物模型中，用1x105个空斑形成单位的SARS-CoV-2鼻内攻击黄金叙利亚仓鼠。两天后，用40mg/kg剂量的DZIF-10c或同型对照腹膜内治疗动物，或用3.6mg/kg剂量的DZIF-10c或同型对照鼻内治疗动物。在病毒攻击后3或5天，在拭子样品和/或肺组织中获得病毒RNA和传染性病毒滴度(图7A)。
类似于在hACE2转导的小鼠中的观察，在SARS-CoV-2攻击的仓鼠的呼吸道拭子和肺匀浆中没有检测到SARS-CoV-2RNA水平的变化(图7B-C)。然而，与同型对照治疗的仓鼠相比，在鼻内或腹膜内接受DZIF-10c的仓鼠的肺组织中可以检测到传染性SARS-CoV-2的滴度降低(图7D)。
Fc介导的抗体结合的病毒颗粒的摄取导致感染和疾病增加是对于登革热病毒所观察到的现象，特别是在非-或低水平中和抗体滴度的情况下。为了研究DZIF-10c是否可以增强表达Fc受体的细胞的感染，研究了SARS-CoV-2-/DZIF-10c-共孵育对来自一个供体的人CD14+外周血来源的巨噬细胞的感染的影响。病毒攻击的细胞的qRT-PCR分析表明，类似于Vero E6细胞，这些巨噬细胞可被人类冠状病毒有效地感染。
在将病毒与中和(1μg/ml)或非中和(0.01μg/ml)浓度的IgG1同型对照抗体或DZIF-10c共孵育后，研究了CD14+人巨噬细胞的SARS-CoV-2感染。虽然可以通过分离传染性病毒来检测MERS-CoV感染，但在任何一个测试浓度下均无法分离出SARS-CoV-2(图8A)。此外，在不同条件下测试的CD14+巨噬细胞中测定的SARS-CoV-2基因组拷贝未指示出存在或不存在DZIF-10c的情况下的实质性差异(图8B)。
虽然CD14+人巨噬细胞对SARS-CoV-2的易感性可能有限，但这些观察结果未指示出由DZIF-10c引起的相关Fc受体介导的SARS-CoV-2感染的增强。
为了确定DZIF-10c的药代动力学概况，对大鼠(褐家鼠(Rattus norvegicus)Wistar)静脉内或气管内施用DZIF-10c。使用靶向人类IgG1的配体结合试验来测定DZIF-10c在血浆和支气管肺泡灌洗液(BALF)中的浓度。通过将所测定的BALF稀释因子视为血清和BALF中尿素的比(假设尿素在体内均匀分布)，自BALF测量推导出上皮衬液(Epitheliallining fluid)浓度。
在对四只大鼠静脉内注射10mg/kg体重的剂量的DZIF-10c后，在0.083、0.5、2、8、24、48、72、168、240、312、和336小时后收集血液样品。所有动物中的DZIF-10c血浆浓度非常一致，并且抗体浓度曲线的线性部分揭露了低抗体清除、低分布容积和长终末半衰期(平均t1/2为190小时或7.9天)(参见下表)：
静脉内施用后DZIF-10c的药代动力学特性(大鼠)。
此外，在第13天施用第二10mg/kg静脉内剂量导致血浆浓度从115±6.4nM增加至662±44nM，表明没有发展出抗药抗体(ADA)。
为了确定静脉内施用后上皮衬液中的DZIF-10c浓度，在第14天、第二次10mg/kg静脉内给药后一天进行支气管肺泡灌洗。BALF的分析测定了血浆/ELF比为33.2，表明DZIF-10c的ELF浓度是在血浆中发现的浓度的3％。
为了研究气管内(i.t.)给药1mg/kg的剂量后DZIF-10c的药代动力学特征，在2小时(n＝4)或24小时(n＝4)后在不同的大鼠组群中进行支气管肺泡灌洗。
在气管内施用后，分别在2小时和24小时后，DZIF-10c的平均ELF浓度与血浆相比高～1000倍和高～250倍。ELF中DZIF-10c的平均半衰期确定为～21小时。4小时后达到血浆浓度的时间依赖性增加，所述增加稳定在2.5-5.0nM的浓度(图9)。
在所有剂量组(10mg/kg i.v.，1mg/kg i.t.)中，在下呼吸道和上呼吸道组织中确定了相似的抗体浓度(图10)。
总的来说，Wistar大鼠中不同施用途径的DZIF-10c的血浆和ELF浓度的分析揭露了，分别在2小时和24小时后，气管内给药导致与静脉内给药相比高～1300倍和高～650倍的ELF浓度(剂量标准化)。
人类新生儿Fc受体(huFcRn)减少人类IgG的溶酶体降解并在抗体半衰期中起关键作用。因此，经基因工程化以表达人类新生Fc受体的小鼠可显示出更接近地类似于人类中的药代动力学概况的人类抗体药代动力学特征。
在转基因表达人类新生Fc受体的免疫缺陷scid小鼠(B6.Cg-Fcgrttm1Dcr PrkdcscidTg(FCGRT)32Dcr/DcrJ)中研究了DZIF-10c。在这些小鼠中，在每只小鼠单次静脉内注射0.5mg后，DZIF-10c显示出类似于在人类中具有2-3周的半衰期的两种人类IgG1抗体的有利药代动力学概况。
此外，在免疫缺陷型NRG小鼠中研究了DZIF-10c的药代动力学特征，所述免疫缺陷型NRG小鼠不表达Il2受体共同γ链、在Rag1基因中携带敲除突变、并且不发育鼠淋巴细胞或NK细胞。同样，在临床研究中，DZIF-10c显示出与IgG1抗体相似或相比更长的良好药代动力学特征。
DZIF-10c相对于两种比较抗体的更高亲和力和替代结合模式(alternativebinding mode)
将DZIF-10c的各种性质与自J.Hansen等人,Science10.1126/science.abd0827(2020)重新合成的两种抗体(REGN10987，REGN10933)进行比较。DZIF-10c显示出比比较物显著更高的结合亲和力，以及覆盖抗原的更大面积的结合模式，使其更适合用作单一化合物治疗。
*REGN10987，REGN10933：J.Hansen等人,Science 10.1126/science.abd0827(2020)
治疗方法
作为本发明抗体的一个实例，DZIF-10c可用于治疗SARS-CoV-2感染、预防SARS-CoV-2感染、或作为最近暴露于SARS-CoV-2的个体的暴露后预防。
DZIF-10c可以作为浓度为50mg/mL的一次性无菌溶液提供。每瓶DZIF-10c药物产品可包含20mL的由乙酸、乙酸钠、甘氨酸、海藻糖和聚山梨醇酯20构成的缓冲溶液(参见表)。
在一个优选实施方案中，DZIF-10c以50mg/ml配制于20mM乙酸盐、220mM甘氨酸、20mM海藻糖、pH为5.5的0.4g/L聚山梨醇酯20中。
DZIF-10c可以通过静脉内输注或在使用喷雾器雾化后的吸入施用来给药。
DZIF-10c可以以2.5、10、或40mg/kg的剂量使用0.2μm尼龙在线过滤器(nylon in-line filter)在60分钟(+/-10分钟)内通过在制剂缓冲液中稀释的静脉内输注物来静脉内施用。上述例示的制剂可用制剂缓冲液稀释至合适的体积。
对于吸入施用，在使用筛网雾化器、或射流喷雾器产生气雾剂后，可以通过嘴口件(mouthpiece)用每次治疗50mg、100mg、或250mg的剂量进行治疗。上述例示的制剂可以用制剂缓冲液稀释至合适的体积。
单次吸入后可以接着进行一次静脉内输注。
制剂
在本发明的上下文中，开发了具有若干优点的制剂。重要的是，它代表了可用于多种目的、例如用于静脉内(i.v.)、经口和鼻吸入(inh.)、和皮下(s.c.)施用的溶液。此外，还可以用于儿童用途。特别地，其既可以用于注射给药，也可以用于吸入给药，例如通过喷射雾化器。
此外，所描述的制剂尤其适用于大流行情况或肿瘤学中所需要的高剂量给药(每天每患者>1g)，在这些情况下，常用赋形剂通常超过患者的最大每日暴露水平，并因此达到临界毒理学水平。此外，糖和多元醇通常用于维持已知为例如静脉内和皮下给药所必需的溶液等渗性。然而，对于高剂量施用，糖或多元醇通常超过患者的最大每日暴露水平。
该制剂中使用的特定赋形剂的组合既符合患者的最大日暴露水平，也符合考虑到100kg患者群体针对多至每天每患者5g的高剂量施用所评价的溶液等渗性。
因此，本文提供一种药物组合物，其包含浓度为10-260mg/mL的在水性溶液中的抗体或其抗原结合片段水溶液、10-25mM乙酸盐、172.7-259.1mM甘氨酸、17.3-25.9mM海藻糖、0.2-0.6g/L聚山梨醇酯20(聚氧乙烯(20)-失水山梨糖醇-单月桂酸酯)，渗透压摩尔浓度(osmolality)为240-340mOsmol/kg和pH为5.2-5.8。所提供的制剂已显示适用于不同的抗体。
在一个实施方案中，提供了一种药物组合物，其包含浓度为10-260mg/mL的在水性溶液中的包含序列SEQ ID No:229的重链和序列SEQ ID No:230的轻链的抗体或其抗原结合片段、10-25mM乙酸盐、172.7-259.1mM甘氨酸、17.3-25.9mM海藻糖、0.2-0.6g/L聚山梨醇酯20(聚氧乙烯(20)-失水山梨糖醇-单月桂酸酯)，渗透压摩尔浓度为240-340mOsmol/kg和pH为5.2-5.8。
在另一实施方案中，提供了一种药物组合物，其包含抗体、优选包含序列SEQ IDNO:229的重链和序列SEQ ID NO:230的轻链的抗体、或其结合片段以50mg/ml在20mM乙酸盐、220mM甘氨酸、20mM海藻糖、pH 5.5的0.4g/L聚山梨醇酯20中。
该制剂显示可用作高浓缩液体制剂(HLCF)，这对于向患者通过注射相当低体积(最大1.5–2.0mL)的经由注射器的皮下高剂量施用是必要的。不含活性成分(抗体)的上述溶液可用作专用稀释剂、稀释用溶剂、和安慰剂。进一步显示其与市售临床稀释介质相容。
可证实所描述的药物组合物有效稳定DZIF-10c和其它抗体以使用(i)不同的雾化器系统(例如筛网雾化器、喷射雾化器)、(ii)稀释和未稀释的制剂(不同API浓度)、和(iii)不同的遮罩(口腔和鼻)进行吸入施用。
所述制剂显示在覆盖了宽广范围的技术参数(例如表面/体积比)的不同的容器封闭系统(20mL和6mL I型玻璃瓶)中为稳定的。
表1：本发明的抗体的示例性制剂
当在不同的市售可得的雾化器系统(筛网和喷射雾化器)中测试时，制剂F5显示稳定效果，参见表2。
表2：使用不同雾化器雾化制剂F5时的产物质量参数
将根据表1的不同制剂在Aerogen雾化器中以未稀释和稀释制剂进行测试。
表3：未稀释的制剂的结果(50mg/mL DZIF-10c)
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表4：1:5稀释的制剂的结果(10mg/mL DZIF-10c)
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在长达24周的储存时间内，通过高分子量物质的百分比(A中的HMW(％))或通过单体的百分比(B中的单体(％))测定了制剂F5至F8在预期储存条件(5℃)下的稳定性数据。测量结果如图11所示。
抗体DZIF-10c在食蟹猴中的两次预防性雾化的抗病毒功效的评价
在感染SARS-CoV-2之前，在6只食蟹猴(cynomolgus monkey)中评价了抗体DZIF-10c的两次预防性雾化的抗病毒功效。对于本研究，将6只食蟹猴(食蟹猕猴(Macacafascicularis))分为两个治疗组：在感染前接受抗体的治疗组中包括4只动物，而2只动物仅在感染前接受溶媒。
治疗组的动物在感染前4天(D-4)和2天(D-2)接受10ml DZIF-10c抗体(20mM乙酸盐、220mM甘氨酸、20mM海藻糖、pH 5.5的0,04％(w/v)聚山梨醇酯20中50mg/mL)的两次施用。使用Aerogen雾化器(Aerogen GmbH,Ratingen,Germany)和合适的面罩(LaerdalMedical GmbH,Puchheim,Germany,尺寸S)进行给药。
在感染当日(D0)，通过用连接至具有鲁尔锁(Luer Lock)的1mL安全注射器的微型喷雾器装置(IA-1B型号,)鼻内(IN)给药每鼻孔500μL、和通过使用连接至具有鲁尔锁(Luer Lock)的1mL安全注射器的微型喷雾器装置(IA-1B型号,PennCenturyTM)在气管中喷雾1mL的接种物的气管内(IT)感染，用107TCID50 SARS-CoV-2毒株hCoV-19/France/OCC-NRC02765/2020(登记GISAID"EPI_ISL_640002，刺突取代D614G、K1073N)接种所有动物。
收集每日血液和唾液样品、鼻咽和口咽拭子用于分析。在D2、D4和D6进行支气管肺泡灌洗。临床监测包括体温、食物消耗、和体重。在D6的尸检包括肺的组织病理学和肺、鼻粘膜、口咽、和肾脏的病毒载量测定。
在鼻咽拭子和支气管肺泡灌洗(BAL)中，在感染后的两只对照动物中均可发现病毒拷贝。相比之下，经治疗的动物显示低于检测限(LOD)、或比对照动物的LOD低几个log的水平的结果。所有动物的鼻咽拭子的分析结果示于图12，支气管肺泡灌洗液的分析结果示于图13。
体温：在感染SARS-CoV-2后，两只对照动物均显示明显且长时间的高热。用DZIF-10c进行的预防性治疗延迟高热的发生、缩短其持续时间并降低其强度、或者完全阻止其发作。
肺的宏观和微观观察：两只对照动物肺均显示硬化、深红色区域，类似于在主要公开物中描述的肺实变。四只治疗的动物的肺看起来健康，没有任何肺损伤的迹象。所有这些观察结果都通过显微镜观察得到了证实：两只对照动物的大多数载玻片中有明显的、广泛的、亚急性的支气管间质炎症，和第2组动物的支气管间质炎症非常有限或没有。
总而言之，这些结果指示通过吸入给药的DZIF-10c的预防性治疗降低了病毒拷贝和传染性病毒的病毒载量、减少或防止了临床症状(高热)和预防肺病理学。
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Ser Ser Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 7
<211> 130
<212> PRT
<213> 智人
<220>
<223> 抗体MnC2t2p1_C11的重链
<400> 7
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 Arg Tyr
20 25 30
Thr Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Asp 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 Glu Gly Gly Leu Asp Tyr Phe Gly Ser Arg Asn Ser Gly Trp
100 105 110
Thr Tyr Thr Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 8
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体MnC2t2p1_C11的轻链
<400> 8
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 Asn Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Pro 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 Leu Tyr
85 90 95
Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 9
<211> 118
<212> PRT
<213> 智人
<220>
<223> 抗体FnC1t2p1_D4的重链
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Leu Arg Phe
20 25 30
Ala Met Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Thr Asn Thr Gly Thr Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Thr Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Arg Gly Ala Asn Leu Val Pro Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 10
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体FnC1t2p1_D4的轻链
<400> 10
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 Val Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Gln Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Phe 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 Ser 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
100 105
<210> 11
<211> 118
<212> PRT
<213> 智人
<220>
<223> 抗体FnC1t2p1_G5的重链
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Leu Arg Phe
20 25 30
Ala Met Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Thr Asn Thr Gly Thr Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Thr Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Arg Gly Ala Asn Leu Val Pro Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 12
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体FnC1t2p1_G5的轻链
<400> 12
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 Val Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Gln Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Phe 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 Ser 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
100 105
<210> 13
<211> 123
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC3t1p2_C6的重链
<400> 13
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 Ser 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 Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Met Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Pro Tyr Cys Ser Ser Thr Arg Cys Tyr Asp Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 14
<211> 108
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC3t1p2_C6的轻链
<400> 14
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 Gln Tyr Gly Arg Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 15
<211> 124
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_B3的重链
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly His Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Gly Gly Ile Leu Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu His Met Arg Ser Leu Arg Thr Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu Arg Arg Gln Asp Tyr Tyr Ala Asp Trp Tyr Phe Asp
100 105 110
Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 16
<211> 106
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_B3的轻链
<400> 16
Asp Ile Gln Met Ile Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Leu Ser Ala 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 Gly Asn Ser Phe Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Ile Val Asp Val
100 105
<210> 17
<211> 119
<212> PRT
<213> 智人
<220>
<223> 抗体MnC2t1p1_A3的重链
<400> 17
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 Arg 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 Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Gly Ala Arg Phe Gly Glu Ser Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 18
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体MnC2t1p1_A3的轻链
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala 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 Ala Asn Ser Phe Pro Gly
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 119
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_B4的重链
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Glu Leu Leu Gly Trp Phe Asp Pro Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 20
<211> 110
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_B4的轻链
<400> 20
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 Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Gly 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 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95
Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 21
<211> 120
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC3t1p1_F4的重链
<400> 21
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 Thr Gly Phe Thr Phe Arg Arg Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Leu Phe Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Arg Asn Thr Leu Tyr
65 70 75 80
Leu Gln Leu Asn Ser Leu Arg Arg Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Asp Tyr Glu Trp Glu Leu Leu Glu Ser Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 22
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC3t1p1_F4的轻链
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Gly Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys
100 105
<210> 23
<211> 126
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC2t1p2_D9的重链
<400> 23
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 Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Tyr Tyr Val 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 Ile Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Ala Arg Arg Pro Val Val Thr Asp Thr Met Ala Tyr Tyr
100 105 110
Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 24
<211> 110
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC2t1p2_D9的轻链
<400> 24
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Leu Ser Leu Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Thr Trp Thr Phe Gly Gln Gly Thr Lys Ala Glu Ile Lys Arg
100 105 110
<210> 25
<211> 123
<212> PRT
<213> 智人
<220>
<223> 抗体MnC5t2p1_G1的重链
<400> 25
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 Thr 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 Val Gly Ser Gly Asn Thr Asp Tyr Ala Gln Lys Phe
50 55 60
Gln Glu Arg Val Thr Ile Thr Arg Asp Val 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 Arg Cys Ser Gly Gly Ser Cys Tyr Asp Gly Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 26
<211> 108
<212> PRT
<213> 智人
<220>
<223> 抗体MnC5t2p1_G1的轻链
<400> 26
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 His Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Cys Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 27
<211> 126
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_E12的重链
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Gly Asp Tyr
20 25 30
Ala Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Ser Lys Ala Tyr Gly Gly Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Arg Val Arg Arg Leu Trp Phe Gly Ser Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 28
<211> 112
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_E12的轻链
<400> 28
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Gly Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 29
<211> 126
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_D6的重链
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Gly Asp Tyr
20 25 30
Ala Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Ser Lys Ala Tyr Gly Gly Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Arg Val Arg Arg Leu Trp Phe Gly Ser Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 30
<211> 112
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_D6的轻链
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Gly Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 31
<211> 119
<212> PRT
<213> 智人
<220>
<223> 抗体MnC2t1p1_C5的重链
<400> 31
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 Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Gly Ala Arg Phe Gly Glu Ser Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 32
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体MnC2t1p1_C5的轻链
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala 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 Ala Asn Ser Phe Pro Gly
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 33
<211> 120
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_E8的重链
<400> 33
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Asn Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile His Ser Leu Ser Gly Gly Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Ala Ser Ile Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Gly Ser Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Ala Ser Val Ser Thr Ile Thr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Ala Val Ser Ser
115 120
<210> 34
<211> 110
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_E8的轻链
<400> 34
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 Gly Asp Val Gly Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Val Ile Tyr Glu Ala Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Phe Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Val
85 90 95
Arg Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 35
<211> 120
<212> PRT
<213> 智人
<220>
<223> 抗体MnC1t3p1_G9的重链
<400> 35
Glu Val Gln Leu Leu 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 Phe Arg Asn Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Asp Ser Gly Asp Arg Thr Tyr Asn Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu His
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Ser Gly Ser Tyr Phe Gly Gly Ala Asn Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 36
<211> 109
<212> PRT
<213> 智人
<220>
<223> 抗体MnC1t3p1_G9的轻链
<400> 36
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Pro Val Thr Ser Asp
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Thr Thr
35 40 45
Leu Ile Tyr Asp Thr Asn Asn Lys His Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Tyr Thr Gly
85 90 95
Ala Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 37
<211> 125
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC4t1p1_D5的重链
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Gly Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Asn Tyr Asp Ser Gly Gly Tyr His Lys Asn Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 38
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体HbnC4t1p1_D5的轻链
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Glu 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 Asn Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 122
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_B10的重链
<400> 39
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 Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr 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 Val Ser Gly Tyr Asp Ser Ser Gly Tyr Trp Gly Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 40
<211> 109
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_B10的轻链
<400> 40
Glu Ile Val Leu Thr Gln Ser Pro Ala 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 Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Ala Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 41
<211> 120
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_G6的重链
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile His Ser Leu Ser Gly Gly Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Ala Pro Ile Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Gly Leu Gly Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Ser Val Ala Thr Ile Thr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Ala Val Ser Ser
115 120
<210> 42
<211> 110
<212> PRT
<213> 智人
<220>
<223> 抗体CnC2t1p1_G6的轻链
<400> 42
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 Gly Asp Ile Gly Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln Tyr Pro Gly Lys Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Glu Ala Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Phe Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Val
85 90 95
Arg Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 43
<211> 139
<212> PRT
<213> 智人
<220>
<223> 抗体FnC1t1p2_A5的重链
<400> 43
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile 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 Ala Thr Thr Asp Cys Ser Ser Thr Ser Cys Trp Ser Leu Asp
100 105 110
Phe Trp Ser Gly Tyr Tyr Thr Gly Gly Arg Glu Lys Ile Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 44
<211> 108
<212> PRT
<213> 智人
<220>
<223> 抗体FnC1t1p2_A5的轻链
<400> 44
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 Gln Tyr Gly Ser Ser Pro
85 90 95
Gly Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 128
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_D10的重链
<400> 45
Gln Leu Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Ala Ser Ile Ser Ser Asn
20 25 30
His Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Ala
35 40 45
Trp Ile Gly Ser Met His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Leu
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Val Asn Tyr Tyr Asp Arg Asn Gly Tyr Tyr Arg Asn
100 105 110
Asp Gly Phe Asp Ile Arg Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 46
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_D10的轻链
<400> 46
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Glu Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Thr Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Arg Val Asp Ile Lys
100 105
<210> 47
<211> 118
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p2_A4的重链
<400> 47
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ile Asn Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Thr Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Leu Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Glu Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Gly Ser Arg Asn Ser Leu Gly Val Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 48
<211> 108
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p2_A4的轻链
<400> 48
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 His Ser Val Asp Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Leu 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 Leu Tyr Tyr Cys Gln His Phe Gly Thr Ser Ser
85 90 95
Val Thr Phe Gly Arg Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 49
<211> 128
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t1p1_A10的重链
<400> 49
Gln Leu Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Ala Ser Ile Ser Ser Asn
20 25 30
His Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Ala
35 40 45
Trp Ile Gly Ser Met His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Leu
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Val Asn Tyr Tyr Asp Arg Asn Gly Tyr Tyr Arg Asn
100 105 110
Asp Gly Phe Asp Ile Arg Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 50
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t1p1_A10的轻链
<400> 50
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Glu Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Thr Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Arg Val Asp Ile Lys
100 105
<210> 51
<211> 124
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_E6的重链
<400> 51
Glu Val Gln Leu Val Glu Ser Gly Gly His Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Gly Gly Ile Leu Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Arg Ser Leu Arg Thr Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu Arg Arg Gln Asp Tyr Tyr Ala Asp Trp Tyr Phe Asp
100 105 110
Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 52
<211> 106
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_E6的轻链
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Leu Ser Ala 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 Gly Asn Ser Phe Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Val
100 105
<210> 53
<211> 122
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t1p1_A11的重链
<400> 53
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 Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Ser Asn Thr Arg Tyr Tyr Thr Asp Ser Val
50 55 60
Met Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Ser Lys Gly Phe Cys Ser Gly Gly Ser Cys Ser Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 54
<211> 108
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t1p1_A11的轻链
<400> 54
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 Val 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 Val Val Tyr Tyr Cys His Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 55
<211> 128
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_F5的重链
<400> 55
Gln Leu Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Ala Ser Ile Ser Ser Asn
20 25 30
His Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Ala
35 40 45
Trp Ile Gly Ser Met His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Leu
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Val Asn Tyr Tyr Asp Arg Asn Gly Tyr Tyr Arg Asn
100 105 110
Asp Gly Phe Asp Ile Arg Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 56
<211> 107
<212> PRT
<213> 智人
<220>
<223> 抗体MnC4t2p1_F5的轻链
<400> 56
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Glu Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Thr Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Arg Val Asp Ile Lys
100 105
<210> 57
<211> 1288
<212> PRT
<213> 人工序列
<220>
<223> 如Wrapp 等人, Science (2022) doi:10.1126/science.abb2507中所述病毒分离株Wuhan-Hu-1的融合前稳定变体中SARS-CoV-2的刺突(S)同源三聚体的胞外域
<400> 57
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Gly Ser Ala Ser Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Gly Ser Gly Tyr Ile Pro Glu Ala
1205 1210 1215
Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu
1220 1225 1230
Leu Ser Thr Phe Leu Gly Arg Ser Leu Glu Val Leu Phe Gln Gly Pro
1235 1240 1245
Gly His His His His His His His His Ser Ala Trp Ser His Pro Gln
1250 1255 1260
Phe Glu Lys Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser Ala
1265 1270 1275 1280
Trp Ser His Pro Gln Phe Glu Lys
1285
<210> 58
<211> 223
<212> PRT
<213> 严重急性呼吸综合征相关冠状病毒2
<220>
<223> 如Wrapp等人, Science (2022) doi: 10.1126/science.abb2507中所述的病毒分离株Wuhan-Hu-1的SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)
<400> 58
Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn
1 5 10 15
Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val
20 25 30
Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser
35 40 45
Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val
50 55 60
Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
65 70 75 80
Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln
85 90 95
Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr
100 105 110
Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly
115 120 125
Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys
130 135 140
Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr
145 150 155 160
Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
180 185 190
Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly
195 200 205
Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe
210 215 220
<210> 59
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_C6的CDR-H1
<400> 59
Gly Phe Thr Phe Thr Ser Ser Ala
1 5
<210> 60
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_C6的CDR-H2
<400> 60
Ile Val Val Gly Ser Gly Asn Thr
1 5
<210> 61
<211> 16
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_C6的CDR-H3
<400> 61
Ala Ala Pro His Cys Ser Ser Thr Ile Cys Tyr Asp Gly Phe Asp Ile
1 5 10 15
<210> 62
<211> 7
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_C6的CDR-L1
<400> 62
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 63
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_C6的CDR-L2
<400> 63
Gly Ala Ser
1
<210> 64
<211> 9
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_C6的CDR-L3
<400> 64
Gln Gln Tyr Gly Ser Ser Pro Trp Thr
1 5
<210> 65
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_G4的CDR-H1
<400> 65
Gly Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 66
<211> 7
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_G4的CDR-H2
<400> 66
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 67
<211> 11
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_G4的CDR-H3
<400> 67
Ala Arg Asp Phe Gly Asp Phe Phe Phe Asp Tyr
1 5 10
<210> 68
<211> 6
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_G4的CDR-L1
<400> 68
Gln Ser Val Ser Ser Tyr
1 5
<210> 69
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_G4的CDR-L2
<400> 69
Gly Val Ser
1
<210> 70
<211> 9
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_G4的CDR-L3
<400> 70
Gln Gln Tyr Gly Ser Ser Pro Arg Thr
1 5
<210> 71
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_B10的CDR-H1
<400> 71
Gly Phe Ile Val Ser Ser Asn Tyr
1 5
<210> 72
<211> 7
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_B10的CDR-H2
<400> 72
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 73
<211> 11
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_B10的CDR-H3
<400> 73
Ala Arg Asp Tyr Gly Asp Tyr Phe Phe Asp Tyr
1 5 10
<210> 74
<211> 6
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_B10的CDR-L1
<400> 74
Gln Ser Val Ser Ser Tyr
1 5
<210> 75
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_B10的CDR-L2
<400> 75
Gly Ala Ser
1
<210> 76
<211> 9
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_B10的CDR-L3
<400> 76
Gln Gln Tyr Gly Ser Ser Pro Arg Thr
1 5
<210> 77
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC2t2p1_C11的CDR-H1
<400> 77
Gly Gly Thr Phe Ser Arg Tyr Thr
1 5
<210> 78
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC2t2p1_C11的CDR-H2
<400> 78
Ile Ile Pro Ile Leu Asp Ile Ala
1 5
<210> 79
<211> 23
<212> PRT
<213> 智人
<220>
<223> MnC2t2p1_C11的CDR-H3
<400> 79
Ala Arg Glu Gly Gly Leu Asp Tyr Phe Gly Ser Arg Asn Ser Gly Trp
1 5 10 15
Thr Tyr Thr Trp Phe Asp Pro
20
<210> 80
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC2t2p1_C11的CDR-L1
<400> 80
Gln Asn Ile Ser Ser Tyr
1 5
<210> 81
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC2t2p1_C11的CDR-L2
<400> 81
Ala Ala Ser
1
<210> 82
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC2t2p1_C11的CDR-L3
<400> 82
Gln Gln Ser Tyr Ser Thr Leu Tyr Ser
1 5
<210> 83
<211> 8
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_D4的CDR-H1
<400> 83
Gly Tyr Thr Phe Leu Arg Phe Ala
1 5
<210> 84
<211> 8
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_D4的CDR-H2
<400> 84
Ile Asp Thr Asn Thr Gly Thr Pro
1 5
<210> 85
<211> 11
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_D4的CDR-H3
<400> 85
Ala Arg Ser Leu Arg Gly Ala Asn Leu Val Pro
1 5 10
<210> 86
<211> 6
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_D4的CDR-L1
<400> 86
Gln Asp Val Ser Asn Tyr
1 5
<210> 87
<211> 3
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_D4的CDR-L2
<400> 87
Asp Ala Phe
1
<210> 88
<211> 9
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_D4的CDR-L3
<400> 88
Gln Gln Tyr Asp Asn Leu Pro Leu Thr
1 5
<210> 89
<211> 8
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_G5的CDR-H1
<400> 89
Gly Tyr Thr Phe Leu Arg Phe Ala
1 5
<210> 90
<211> 8
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_G5的CDR-H2
<400> 90
Ile Asp Thr Asn Thr Gly Thr Pro
1 5
<210> 91
<211> 11
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_G5的CDR-H3
<400> 91
Ala Arg Ser Leu Arg Gly Ala Asn Leu Val Pro
1 5 10
<210> 92
<211> 6
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_G5的CDR-L1
<400> 92
Gln Asp Val Ser Asn Tyr
1 5
<210> 93
<211> 3
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_G5的CDR-L2
<400> 93
Asp Ala Phe
1
<210> 94
<211> 9
<212> PRT
<213> 智人
<220>
<223> FnC1t2p1_G5的CDR-L3
<400> 94
Gln Gln Tyr Asp Asn Leu Pro Leu Thr
1 5
<210> 95
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_C6的CDR-H1
<400> 95
Gly Phe Thr Phe Ser Ser Ser Ala
1 5
<210> 96
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_C6的CDR-H2
<400> 96
Ile Val Val Gly Ser Gly Asn Thr
1 5
<210> 97
<211> 16
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_C6的CDR-H3
<400> 97
Ala Ala Pro Tyr Cys Ser Ser Thr Arg Cys Tyr Asp Ala Phe Asp Ile
1 5 10 15
<210> 98
<211> 7
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_C6的CDR-L1
<400> 98
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 99
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_C6的CDR-L2
<400> 99
Gly Ala Ser
1
<210> 100
<211> 9
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p2_C6的CDR-L3
<400> 100
Gln Gln Tyr Gly Arg Ser Pro Trp Thr
1 5
<210> 101
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_B3的CDR-H1
<400> 101
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 102
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_B3的CDR-H2
<400> 102
Ile Ser Trp Asn Gly Gly Ile Leu
1 5
<210> 103
<211> 17
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_B3的CDR-H3
<400> 103
Ala Lys Asp Leu Arg Arg Gln Asp Tyr Tyr Ala Asp Trp Tyr Phe Asp
1 5 10 15
Leu
<210> 104
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_B3的CDR-L1
<400> 104
Gln Gly Ile Ser Ser Trp
1 5
<210> 105
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_B3的CDR-L2
<400> 105
Ala Ala Ser
1
<210> 106
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_B3的CDR-L3
<400> 106
Gln Gln Gly Asn Ser Phe Pro Phe Thr
1 5
<210> 107
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_A3的CDR-H1
<400> 107
Gly Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 108
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_A3的CDR-H2
<400> 108
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 109
<211> 13
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_A3的CDR-H3
<400> 109
Ala Thr Gly Ala Arg Phe Gly Glu Ser Pro Phe Asp Tyr
1 5 10
<210> 110
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_A3的CDR-L1
<400> 110
Gln Gly Ile Ser Ser Trp
1 5
<210> 111
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_A3的CDR-L2
<400> 111
Ala Ala Ser
1
<210> 112
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_A3的CDR-L3
<400> 112
Gln Gln Ala Asn Ser Phe Pro Gly Thr
1 5
<210> 113
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-H1
<400> 113
Gly Tyr Thr Phe Thr Ser Tyr Gly
1 5
<210> 114
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-H2
<400> 114
Ile Ser Ala Tyr Asn Gly Asn Thr
1 5
<210> 115
<211> 12
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-H3
<400> 115
Ala Arg Asp Gly Glu Leu Leu Gly Trp Phe Asp Pro
1 5 10
<210> 116
<211> 9
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-L1
<400> 116
Ser Ser Asp Val Gly Ser Tyr Asn Leu
1 5
<210> 117
<211> 3
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-L2
<400> 117
Glu Gly Ser
1
<210> 118
<211> 10
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-L3
<400> 118
Cys Ser Tyr Ala Gly Ser Ser Thr Trp Val
1 5 10
<210> 119
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_F4的CDR-H1
<400> 119
Gly Phe Thr Phe Arg Arg Tyr Gly
1 5
<210> 120
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_F4的CDR-H2
<400> 120
Ile Leu Phe Asp Gly Ser Asn Lys
1 5
<210> 121
<211> 13
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_F4的CDR-H3
<400> 121
Ala Lys Gly Gly Asp Tyr Glu Trp Glu Leu Leu Glu Ser
1 5 10
<210> 122
<211> 6
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_F4的CDR-L1
<400> 122
Gln Ser Ile Asp Asn Trp
1 5
<210> 123
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_F4的CDR-L2
<400> 123
Lys Ala Ser
1
<210> 124
<211> 9
<212> PRT
<213> 智人
<220>
<223> HbnC3t1p1_F4的CDR-L3
<400> 124
Gln His Tyr His Ser Phe Pro Leu Thr
1 5
<210> 125
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC2t1p2_D9的CDR-H1
<400> 125
Gly Phe Thr Phe Ser Ser Tyr Gly
1 5
<210> 126
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC2t1p2_D9的CDR-H2
<400> 126
Ile Trp Tyr Asp Gly Arg Asn Lys
1 5
<210> 127
<211> 19
<212> PRT
<213> 智人
<220>
<223> HbnC2t1p2_D9的CDR-H3
<400> 127
Ala Arg Ala Ala Arg Arg Pro Val Val Thr Asp Thr Met Ala Tyr Tyr
1 5 10 15
Met Asp Val
<210> 128
<211> 6
<212> PRT
<213> 智人
<220>
<223> HbnC2t1p2_D9的CDR-L1
<400> 128
Leu Ser Leu Ser Ser Tyr
1 5
<210> 129
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC2t1p2_D9的CDR-L2
<400> 129
Asp Ala Ser
1
<210> 130
<211> 11
<212> PRT
<213> 智人
<220>
<223> HbnC2t1p2_D9的CDR-L3
<400> 130
Gln Gln Arg Ser Asn Trp Pro Pro Thr Trp Thr
1 5 10
<210> 131
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC5t2p1_G1的CDR-H1
<400> 131
Gly Phe Thr Phe Thr Ser Ser Ala
1 5
<210> 132
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC5t2p1_G1的CDR-H2
<400> 132
Ile Val Val Gly Ser Gly Asn Thr
1 5
<210> 133
<211> 16
<212> PRT
<213> 智人
<220>
<223> MnC5t2p1_G1的CDR-H3
<400> 133
Ala Ala Pro Arg Cys Ser Gly Gly Ser Cys Tyr Asp Gly Phe Asp Ile
1 5 10 15
<210> 134
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC5t2p1_G1的CDR-L1
<400> 134
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 135
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC5t2p1_G1的CDR-L2
<400> 135
Gly Ala Ser
1
<210> 136
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC5t2p1_G1的CDR-L3
<400> 136
Gln Gln Tyr Gly Ser Ser Pro Trp Thr
1 5
<210> 137
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E12的CDR-H1
<400> 137
Gly Phe Thr Phe Gly Asp Tyr Ala
1 5
<210> 138
<211> 10
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E12的CDR-H2
<400> 138
Ile Arg Ser Lys Ala Tyr Gly Gly Thr Thr
1 5 10
<210> 139
<211> 17
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E12的CDR-H3
<400> 139
Thr Arg Val Arg Arg Leu Trp Phe Gly Ser Tyr Tyr Tyr Gly Met Asp
1 5 10 15
Val
<210> 140
<211> 11
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E12的CDR-L1
<400> 140
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr
1 5 10
<210> 141
<211> 3
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E12的CDR-L2
<400> 141
Leu Gly Ser
1
<210> 142
<211> 9
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E12的CDR-L3
<400> 142
Met Gln Ala Leu Gln Thr Pro Gly Thr
1 5
<210> 143
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_D6的CDR-H1
<400> 143
Gly Phe Thr Phe Gly Asp Tyr Ala
1 5
<210> 144
<211> 10
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_D6的CDR-H2
<400> 144
Ile Arg Ser Lys Ala Tyr Gly Gly Thr Thr
1 5 10
<210> 145
<211> 17
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_D6的CDR-H3
<400> 145
Thr Arg Val Arg Arg Leu Trp Phe Gly Ser Tyr Tyr Tyr Gly Met Asp
1 5 10 15
Val
<210> 146
<211> 11
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_D6的CDR-L1
<400> 146
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr
1 5 10
<210> 147
<211> 3
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_D6的CDR-L2
<400> 147
Leu Gly Ser
1
<210> 148
<211> 9
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_D6的CDR-L3
<400> 148
Met Gln Ala Leu Gln Thr Pro Gly Thr
1 5
<210> 149
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_C5的CDR-H1
<400> 149
Gly Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 150
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_C5的CDR-H2
<400> 150
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 151
<211> 13
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_C5的CDR-H3
<400> 151
Ala Thr Gly Ala Arg Phe Gly Glu Ser Pro Phe Asp Tyr
1 5 10
<210> 152
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_C5的CDR-L1
<400> 152
Gln Gly Ile Ser Ser Trp
1 5
<210> 153
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_C5的CDR-L2
<400> 153
Ala Ala Ser
1
<210> 154
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC2t1p1_C5的CDR-L3
<400> 154
Gln Gln Ala Asn Ser Phe Pro Gly Thr
1 5
<210> 155
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E8的CDR-H1
<400> 155
Gly Tyr Ile Phe Thr Asn Tyr Tyr
1 5
<210> 156
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E8的CDR-H2
<400> 156
Ile His Ser Leu Ser Gly Gly Thr
1 5
<210> 157
<211> 13
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E8的CDR-H3
<400> 157
Ala Arg Ala Ser Val Ser Thr Ile Thr Asp Phe Asp Tyr
1 5 10
<210> 158
<211> 9
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E8的CDR-L1
<400> 158
Ser Gly Asp Val Gly Ser Tyr Asn Leu
1 5
<210> 159
<211> 3
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E8的CDR-L2
<400> 159
Glu Ala Thr
1
<210> 160
<211> 10
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_E8的CDR-L3
<400> 160
Cys Ser Tyr Ala Gly Val Arg Thr Val Val
1 5 10
<210> 161
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC1t3p1_G9的CDR-H1
<400> 161
Gly Phe Thr Phe Arg Asn Tyr Ala
1 5
<210> 162
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC1t3p1_G9的CDR-H2
<400> 162
Ile Ser Asp Ser Gly Asp Arg Thr
1 5
<210> 163
<211> 13
<212> PRT
<213> 智人
<220>
<223> MnC1t3p1_G9的CDR-H3
<400> 163
Ala Leu Ala Ser Gly Ser Tyr Phe Gly Gly Ala Asn Tyr
1 5 10
<210> 164
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC1t3p1_G9的CDR-L1
<400> 164
Thr Gly Pro Val Thr Ser Asp His Tyr
1 5
<210> 165
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC1t3p1_G9的CDR-L2
<400> 165
Asp Thr Asn
1
<210> 166
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC1t3p1_G9的CDR-L3
<400> 166
Leu Leu Ser Tyr Thr Gly Ala Arg Val
1 5
<210> 167
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC4t1p1_D5的CDR-H1
<400> 167
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 168
<211> 8
<212> PRT
<213> 智人
<220>
<223> HbnC4t1p1_D5的CDR-H2
<400> 168
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 169
<211> 18
<212> PRT
<213> 智人
<220>
<223> HbnC4t1p1_D5的CDR-H3
<400> 169
Ala Lys Asp Ile Asn Tyr Asp Ser Gly Gly Tyr His Lys Asn Tyr Phe
1 5 10 15
Asp Tyr
<210> 170
<211> 6
<212> PRT
<213> 智人
<220>
<223> HbnC4t1p1_D5的CDR-L1
<400> 170
Gln Ser Ile Ser Ser Tyr
1 5
<210> 171
<211> 3
<212> PRT
<213> 智人
<220>
<223> HbnC4t1p1_D5的CDR-L2
<400> 171
Ala Ala Ser
1
<210> 172
<211> 9
<212> PRT
<213> 智人
<220>
<223> HbnC4t1p1_D5的CDR-L3
<400> 172
Gln Gln Ser Tyr Ser Asn Pro Leu Thr
1 5
<210> 173
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B10的CDR-H1
<400> 173
Gly Gly Thr Phe Ser Ser Tyr Ala
1 5
<210> 174
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B10的CDR-H2
<400> 174
Ile Ile Pro Ile Phe Gly Thr Ala
1 5
<210> 175
<211> 15
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B10的CDR-H3
<400> 175
Ala Arg Val Ser Gly Tyr Asp Ser Ser Gly Tyr Trp Gly Asp Tyr
1 5 10 15
<210> 176
<211> 6
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B10的CDR-L1
<400> 176
Gln Ser Val Ser Ser Tyr
1 5
<210> 177
<211> 3
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B10的CDR-L2
<400> 177
Asp Ala Ser
1
<210> 178
<211> 11
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B10的CDR-L3
<400> 178
Gln Gln Arg Ser Asn Trp Pro Pro Ala Leu Thr
1 5 10
<210> 179
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_G6的CDR-H1
<400> 179
Gly Tyr Ile Phe Thr Asn Tyr Tyr
1 5
<210> 180
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_G6的CDR-H2
<400> 180
Ile His Ser Leu Ser Gly Gly Thr
1 5
<210> 181
<211> 13
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_G6的CDR-H3
<400> 181
Ala Arg Ala Ser Val Ala Thr Ile Thr Asp Phe Asp Tyr
1 5 10
<210> 182
<211> 9
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_G6的CDR-L1
<400> 182
Ser Gly Asp Ile Gly Ser Tyr Asn Leu
1 5
<210> 183
<211> 3
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_G6的CDR-L2
<400> 183
Glu Ala Ser
1
<210> 184
<211> 10
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_G6的CDR-L3
<400> 184
Cys Ser Tyr Ala Gly Val Arg Thr Val Val
1 5 10
<210> 185
<211> 8
<212> PRT
<213> 智人
<220>
<223> FnC1t1p2_A5的CDR-H1
<400> 185
Gly Tyr Thr Phe Thr Ser Tyr Asp
1 5
<210> 186
<211> 8
<212> PRT
<213> 智人
<220>
<223> FnC1t1p2_A5的CDR-H2
<400> 186
Met Asn Pro Asn Ser Gly Asn Thr
1 5
<210> 187
<211> 32
<212> PRT
<213> 智人
<220>
<223> FnC1t1p2_A5的CDR-H3
<400> 187
Ala Arg Ala Thr Thr Asp Cys Ser Ser Thr Ser Cys Trp Ser Leu Asp
1 5 10 15
Phe Trp Ser Gly Tyr Tyr Thr Gly Gly Arg Glu Lys Ile Phe Asp Tyr
20 25 30
<210> 188
<211> 7
<212> PRT
<213> 智人
<220>
<223> FnC1t1p2_A5的CDR-L1
<400> 188
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 189
<211> 3
<212> PRT
<213> 智人
<220>
<223> FnC1t1p2_A5的CDR-L2
<400> 189
Gly Ala Ser
1
<210> 190
<211> 9
<212> PRT
<213> 智人
<220>
<223> FnC1t1p2_A5的CDR-L3
<400> 190
Gln Gln Tyr Gly Ser Ser Pro Gly Thr
1 5
<210> 191
<211> 10
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_D10的CDR-H1
<400> 191
Gly Ala Ser Ile Ser Ser Asn His Tyr Phe
1 5 10
<210> 192
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_D10的CDR-H2
<400> 192
Met His Tyr Ser Gly Ser Thr
1 5
<210> 193
<211> 20
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_D10的CDR-H3
<400> 193
Ala Arg Gly Val Asn Tyr Tyr Asp Arg Asn Gly Tyr Tyr Arg Asn Asp
1 5 10 15
Gly Phe Asp Ile
20
<210> 194
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_D10的CDR-L1
<400> 194
Gln Gly Ile Arg Asn Asp
1 5
<210> 195
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_D10的CDR-L2
<400> 195
Ala Ala Ser
1
<210> 196
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_D10的CDR-L3
<400> 196
Leu Gln His Asn Thr Tyr Pro Phe Thr
1 5
<210> 197
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t2p2_A4的CDR-H1
<400> 197
Gly Tyr Ile Phe Ile Asn Tyr Ala
1 5
<210> 198
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t2p2_A4的CDR-H2
<400> 198
Ile Asn Thr Asn Thr Gly Asn Pro
1 5
<210> 199
<211> 11
<212> PRT
<213> 智人
<220>
<223> MnC4t2p2_A4的CDR-H3
<400> 199
Ala Lys Ile Gly Ser Arg Asn Ser Leu Gly Val
1 5 10
<210> 200
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC4t2p2_A4的CDR-L1
<400> 200
His Ser Val Asp Arg Ser Tyr
1 5
<210> 201
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t2p2_A4的CDR-L2
<400> 201
Gly Ala Ser
1
<210> 202
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t2p2_A4的CDR-L3
<400> 202
Gln His Phe Gly Thr Ser Ser Val Thr
1 5
<210> 203
<211> 10
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A10的CDR-H1
<400> 203
Gly Ala Ser Ile Ser Ser Asn His Tyr Phe
1 5 10
<210> 204
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A10的CDR-H2
<400> 204
Met His Tyr Ser Gly Ser Thr
1 5
<210> 205
<211> 20
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A10的CDR-H3
<400> 205
Ala Arg Gly Val Asn Tyr Tyr Asp Arg Asn Gly Tyr Tyr Arg Asn Asp
1 5 10 15
Gly Phe Asp Ile
20
<210> 206
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A10的CDR-L1
<400> 206
Gln Gly Ile Arg Asn Asp
1 5
<210> 207
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A10的CDR-L2
<400> 207
Ala Ala Ser
1
<210> 208
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A10的CDR-L3
<400> 208
Leu Gln His Asn Thr Tyr Pro Phe Thr
1 5
<210> 209
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_E6的CDR-H1
<400> 209
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 210
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_E6的CDR-H2
<400> 210
Ile Ser Trp Asn Gly Gly Ile Leu
1 5
<210> 211
<211> 17
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_E6的CDR-H3
<400> 211
Ala Lys Asp Leu Arg Arg Gln Asp Tyr Tyr Ala Asp Trp Tyr Phe Asp
1 5 10 15
Leu
<210> 212
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_E6的CDR-L1
<400> 212
Gln Gly Ile Ser Ser Trp
1 5
<210> 213
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_E6的CDR-L2
<400> 213
Ala Ala Ser
1
<210> 214
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_E6的CDR-L3
<400> 214
Gln Gln Gly Asn Ser Phe Pro Phe Thr
1 5
<210> 215
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A11的CDR-H1
<400> 215
Gly Phe Thr Phe Ser Ser Tyr Ser
1 5
<210> 216
<211> 8
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A11的CDR-H2
<400> 216
Ile Ser Ser Ser Ser Asn Thr Arg
1 5
<210> 217
<211> 15
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A11的CDR-H3
<400> 217
Ala Ser Ser Lys Gly Phe Cys Ser Gly Gly Ser Cys Ser Asp Tyr
1 5 10 15
<210> 218
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A11的CDR-L1
<400> 218
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 219
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A11的CDR-L2
<400> 219
Gly Val Ser
1
<210> 220
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t1p1_A11的CDR-L3
<400> 220
His Gln Tyr Gly Ser Ser Pro Trp Thr
1 5
<210> 221
<211> 10
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_F5的CDR-H1
<400> 221
Gly Ala Ser Ile Ser Ser Asn His Tyr Phe
1 5 10
<210> 222
<211> 7
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_F5的CDR-H2
<400> 222
Met His Tyr Ser Gly Ser Thr
1 5
<210> 223
<211> 20
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_F5的CDR-H3
<400> 223
Ala Arg Gly Val Asn Tyr Tyr Asp Arg Asn Gly Tyr Tyr Arg Asn Asp
1 5 10 15
Gly Phe Asp Ile
20
<210> 224
<211> 6
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_F5的CDR-L1
<400> 224
Gln Gly Ile Arg Asn Asp
1 5
<210> 225
<211> 3
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_F5的CDR-L2
<400> 225
Ala Ala Ser
1
<210> 226
<211> 9
<212> PRT
<213> 智人
<220>
<223> MnC4t2p1_F5的CDR-L3
<400> 226
Leu Gln His Asn Thr Tyr Pro Phe Thr
1 5
<210> 227
<211> 8
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-H2的衍生物
<400> 227
Ile Ser Ala Tyr Ser Gly Asn Thr
1 5
<210> 228
<211> 10
<212> PRT
<213> 智人
<220>
<223> CnC2t1p1_B4的CDR-L3的衍生物
<400> 228
Gln Ser Tyr Ala Gly Ser Ser Thr Trp Val
1 5 10
<210> 229
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体DZIF-10c的完整重链(HbnC3t1p1_F4(-K))
<400> 229
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 Thr Gly Phe Thr Phe Arg Arg Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Leu Phe Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Arg Asn Thr Leu Tyr
65 70 75 80
Leu Gln Leu Asn Ser Leu Arg Arg Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Asp Tyr Glu Trp Glu Leu Leu Glu Ser 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 Arg 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 Glu Glu Met 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
<210> 230
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体DZIF-10c的完整轻链(HbnC3t1p1_F4(-K))
<400> 230
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Gly Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Asp 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
Claims (36)
1.一种针对SARS相关冠状病毒的抗体或其结合片段，
其中所述抗体或其结合片段包含来自包括以下的组的一种抗体的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6(具有SEQ ID No.1的可变区重链氨基酸序列和SEQ ID No.2的可变区轻链氨基酸序列)，HbnC3t1p1_G4(具有SEQ ID No.3的可变区重链氨基酸序列和SEQ ID No.4的可变区轻链氨基酸序列)，HbnC3t1p2_B10具有SEQ ID No.5的可变区重链氨基酸序列和SEQ ID No.6的可变区轻链氨基酸序列)，MnC2t2p1_C11(具有SEQID No.7的可变区重链氨基酸序列和SEQ ID No.8的可变区轻链氨基酸序列)，FnC1t2p1_D4(具有SEQ ID No.9的可变区重链氨基酸序列和SEQ IDNo.10的可变区轻链氨基酸序列)，FnC1t2p1_G5(具有SEQ ID No.11的可变区重链氨基酸序列和SEQ ID No.12的可变区轻链氨基酸序列)，HbnC3t1p2_C6(具有SEQ ID No.13的可变区重链氨基酸序列和SEQ ID No.14的可变区轻链氨基酸序列)，MnC4t2p1_B3(具有SEQ ID No.15的可变区重链氨基酸序列和SEQ ID No.16的可变区轻链氨基酸序列)，MnC2t1p1_A3(具有SEQ ID No.17的可变区重链氨基酸序列和SEQ ID No.18的可变区轻链氨基酸序列)，CnC2t1p1_B4(具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列)，HbnC3t1p1_F4(具有SEQ ID No.21的可变区重链氨基酸序列和SEQ ID No.22的可变区轻链氨基酸序列)，HbnC2t1p2_D9(具有SEQ ID No.23的可变区重链氨基酸序列和SEQ ID No.24的可变区轻链氨基酸序列)，MnC5t2p1_G1(具有SEQ ID No.25的可变区重链氨基酸序列和SEQ ID No.26的可变区轻链氨基酸序列)，CnC2t1p1_E12(具有SEQ ID No.27的可变区重链氨基酸序列和SEQ ID No.28的可变区轻链氨基酸序列)，CnC2t1p1_D6(具有SEQ ID No.29的可变区重链氨基酸序列和SEQ ID No.30的可变区轻链氨基酸序列)，MnC2t1p1_C5(具有SEQ ID No.31的可变区重链氨基酸序列和SEQ ID No.32的可变区轻链氨基酸序列)，CnC2t1p1_E8(具有SEQ ID No.33的可变区重链氨基酸序列和SEQ ID No.34的可变区轻链氨基酸序列)，MnC1t3p1_G9(具有SEQ ID No.35的可变区重链氨基酸序列和SEQ ID No.36的可变区轻链氨基酸序列)，HbnC4t1p1_D5(具有SEQ ID No.37的可变区重链氨基酸序列和SEQ ID No.38的可变区轻链氨基酸序列)，CnC2t1p1_B10(具有SEQ ID No.39的可变区重链氨基酸序列和SEQ ID No.40的可变区轻链氨基酸序列)，CnC2t1p1_G6(具有SEQ ID No.41的可变区重链氨基酸序列和SEQ ID No.42的可变区轻链氨基酸序列)，FnC1t1p2_A5(具有SEQ ID No.43的可变区重链氨基酸序列和SEQ ID No.44的可变区轻链氨基酸序列)，MnC4t2p1_D10(具有SEQ ID No.45的可变区重链氨基酸序列和SEQ ID No.46的可变区轻链氨基酸序列)，MnC4t2p2_A4(具有SEQ ID No.47的可变区重链氨基酸序列和SEQ ID No.48的可变区轻链氨基酸序列)，MnC4t1p1_A10(具有SEQ ID No.49的可变区重链氨基酸序列和SEQ ID No.50的可变区轻链氨基酸序列)，MnC4t2p1_E6(具有SEQ ID No.51的可变区重链氨基酸序列和SEQ ID No.52的可变区轻链氨基酸序列)，MnC4t1p1_A11(具有SEQ ID No.53的可变区重链氨基酸序列和SEQ ID No.54的可变区轻链氨基酸序列)，和MnC4t2p1_F5(具有SEQ IDNo.55的可变区重链氨基酸序列和SEQ ID No.56的可变区轻链氨基酸序列)，优选其中所述抗体或其结合片段包含选自包括以下的组的抗体之一的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，FnC1t2p1_D4，FnC1t2p1_G5，HbnC3t1p2_C6，MnC4t2p1_B3，MnC2t1p1_A3，CnC2t1p1_B4，HbnC3t1p1_F4，和HbnC2t1p2_D9，更优选来自包括以下的组的一种抗体的重链CDR1至CDR3和轻链CDR1至CDR3氨基酸序列：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，和FnC1t2p1_D4。
2.根据权利要求1所述的抗体或结合片段，其中所述抗体或其结合片段包含选自包括以下的组的一种抗体的可变区重链序列和可变区轻链序列的组合：HbnC3t1p1_C6(具有SEQID No.1的可变区重链氨基酸序列和SEQ IDNo.2的可变区轻链氨基酸序列)，HbnC3t1p1_G4(具有SEQ ID No.3的可变区重链氨基酸序列和SEQ ID No.4的可变区轻链氨基酸序列)，HbnC3t1p2_B10具有SEQ ID No.5的可变区重链氨基酸序列和SEQ ID No.6的可变区轻链氨基酸序列)，MnC2t2p1_C11(具有SEQ ID No.7的可变区重链氨基酸序列和SEQ ID No.8的可变区轻链氨基酸序列)，FnC1t2p1_D4(具有SEQ ID No.9的可变区重链氨基酸序列和SEQ IDNo.10的可变区轻链氨基酸序列)，FnC1t2p1_G5(具有SEQ ID No.11的可变区重链氨基酸序列和SEQ ID No.12的可变区轻链氨基酸序列)，HbnC3t1p2_C6(具有SEQ ID No.13的可变区重链氨基酸序列和SEQ ID No.14的可变区轻链氨基酸序列)，MnC4t2p1_B3(具有SEQ IDNo.15的可变区重链氨基酸序列和SEQ ID No.16的可变区轻链氨基酸序列)，MnC2t1p1_A3(具有SEQ ID No.17的可变区重链氨基酸序列和SEQ ID No.18的可变区轻链氨基酸序列)，CnC2t1p1_B4(具有SEQ ID No.19的可变区重链氨基酸序列和SEQ ID No.20的可变区轻链氨基酸序列)，HbnC3t1p1_F4(具有SEQ ID No.21的可变区重链氨基酸序列和SEQ ID No.22的可变区轻链氨基酸序列)，HbnC2t1p2_D9(具有SEQ ID No.23的可变区重链氨基酸序列和SEQ ID No.24的可变区轻链氨基酸序列)，MnC5t2p1_G1(具有SEQ ID No.25的可变区重链氨基酸序列和SEQ ID No.26的可变区轻链氨基酸序列)，CnC2t1p1_E12(具有SEQ ID No.27的可变区重链氨基酸序列和SEQ ID No.28的可变区轻链氨基酸序列)，CnC2t1p1_D6(具有SEQ ID No.29的可变区重链氨基酸序列和SEQ ID No.30的可变区轻链氨基酸序列)，MnC2t1p1_C5(具有SEQ ID No.31的可变区重链氨基酸序列和SEQ ID No.32的可变区轻链氨基酸序列)，CnC2t1p1_E8(具有SEQ ID No.33的可变区重链氨基酸序列和SEQ ID No.34的可变区轻链氨基酸序列)，MnC1t3p1_G9(具有SEQ ID No.35的可变区重链氨基酸序列和SEQ ID No.36的可变区轻链氨基酸序列)，HbnC4t1p1_D5(具有SEQ ID No.37的可变区重链氨基酸序列和SEQ ID No.38的可变区轻链氨基酸序列)，CnC2t1p1_B10(具有SEQ ID No.39的可变区重链氨基酸序列和SEQ ID No.40的可变区轻链氨基酸序列)，CnC2t1p1_G6(具有SEQ ID No.41的可变区重链氨基酸序列和SEQ ID No.42的可变区轻链氨基酸序列)，FnC1t1p2_A5(具有SEQ ID No.43的可变区重链氨基酸序列和SEQ ID No.44的可变区轻链氨基酸序列)，MnC4t2p1_D10(具有SEQ ID No.45的可变区重链氨基酸序列和SEQ ID No.46的可变区轻链氨基酸序列)，MnC4t2p2_A4(具有SEQ ID No.47的可变区重链氨基酸序列和SEQ ID No.48的可变区轻链氨基酸序列)，MnC4t1p1_A10(具有SEQ ID No.49的可变区重链氨基酸序列和SEQ ID No.50的可变区轻链氨基酸序列)，MnC4t2p1_E6(具有SEQ ID No.51的可变区重链氨基酸序列和SEQ ID No.52的可变区轻链氨基酸序列)，MnC4t1p1_A11(具有SEQ ID No.53的可变区重链氨基酸序列和SEQ ID No.54的可变区轻链氨基酸序列)，和MnC4t2p1_F5(具有SEQ ID No.55的可变区重链氨基酸序列和SEQ ID No.56的可变区轻链氨基酸序列)，优选来自包括以下的组的一种抗体的可变区重链序列和可变区轻链序列的组合：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，FnC1t2p1_D4，FnC1t2p1_G5，HbnC3t1p2_C6，MnC4t2p1_B3，MnC2t1p1_A3，CnC2t1p1_B4，HbnC3t1p1_F4，和HbnC2t1p2_D9，更优选来自包括以下的组的一种抗体的可变区重链序列和可变区轻链序列的组合：HbnC3t1p1_C6，HbnC3t1p1_G4，HbnC3t1p2_B10，MnC2t2p1_C11，和FnC1t2p1_D4。
3.根据权利要求1或2所述的抗体或其结合片段，其中所述SARS相关冠状病毒毒株是严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。
4.根据前述权利要求中任一项所述的抗体或其结合片段，其中所述抗体或结合片段针对SARS-CoV-2的刺突(S)蛋白的胞外域，优选针对如Wrapp等人,Science(2020)doi:10.1126/science.abb2507中所描述的病毒分离株Wuhan-Hu-1的融合前稳定化变体中SARS-CoV-2的刺突(S)同源三聚体的胞外域(SEQ ID NO.57)，更优选针对SARS-CoV-2的刺突(S)蛋白的受体结合结构域(RBD)(SEQ ID NO.58)。
5.根据前述权利要求中任一项所述的抗体或其结合片段，其中根据Koch等人,LancetInfect.Dis.(2020)doi:10.1016/s1473-3099(20)30248-6，当在37℃下共培养病毒和抗体1h后使用100TCID50的SARS-CoV-2施用至VeroE6细胞在病毒中和试验中进行测试时，所述抗体或其结合片段表现小于10μg/ml的针对VeroE6细胞上的真实SARS-CoV-2分离株BavPat1/2020的中和效力(IC100；导致完全不存在细胞病变效应的最低抗体剂量)。
6.根据权利要求5所述的抗体或其结合片段，其中所述抗体或其结合片段表现小于1μg/ml的中和效力。
7.根据权利要求5所述的抗体或其结合片段，其中所述抗体或其结合片段表现小于0.5μg/ml的中和效力。
8.根据权利要求5所述的抗体或其结合片段，其中所述抗体或其结合片段表现0.25μg/ml以下的中和效力。
9.根据前述权利要求中任一项所述的抗体或其结合片段，其中所述抗体或其结合片段与SARS-CoV-2的刺突(S)蛋白的胞外域的区域1和区域2二者结合。
10.根据前述权利要求中任一项所述的抗体或其结合片段，其中当使用浓度为100μg/ml的抗体或其结合片段的抗核抗体(ANA)测试试剂盒(NOVA-Lite HEp-2 ANA试剂盒；InovaDiagnostics)针对透化HEp-2细胞进行测试时，所述抗体或其结合片段不表现定义为可检测的结合的自身反应性。
11.根据前述权利要求中任一项所述的抗体，其中所述抗体的重链具有SEQ ID No.229的氨基酸序列，和所述抗体的轻链具有SEQ ID No.230的氨基酸序列。
12.一种药物组合物，其包含根据权利要求1至11中任一项所述的抗体或其结合片段和至少一种药学上可接受的赋形剂。
13.根据权利要求12所述的药物组合物，其中所述药物组合物是用于人类受试者的疫苗接种组合物。
14.一种试剂盒，其包含根据权利要求1至11中任一项所述的抗体或其结合片段和容器。
15.根据权利要求1至11中任一项所述的抗体或其结合片段、根据权利要求12或13所述的药物组合物、或根据权利要求14所述的试剂盒，其用作药物，优选用作疫苗。
16.根据权利要求1至11中任一项所述的抗体或其结合片段、根据权利要求12或13所述的药物组合物、或根据权利要求14所述的试剂盒，其用于治疗或预防人类受试者中由SARS相关冠状病毒引起的疾病的用途，优选用于治疗或预防人类受试者中由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)引起的疾病的用途。
17.根据权利要求1至11中任一项所述的抗体或其结合片段、根据权利要求12或13所述的药物组合物、或根据权利要求14所述的试剂盒，其用于预防人类受试者感染SARS相关冠状病毒的用途，优选用于预防人类受试者感染严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的用途。
18.一种治疗人类和/或动物受试者中SARS相关冠状病毒的方法，所述方法包括向所述受试者施用治疗有效量的至少一种根据权利要求1至11中任一项所述的抗体和/或其结合片段。
19.根据权利要求18所述的方法，其中所述SARS相关冠状病毒是SARS-CoV-2。
20.一种预防人类和/或动物受试者感染SARS相关冠状病毒的方法，所述方法包括向所述受试者施用治疗有效量的至少一种根据权利要求1至11中任一项所述的抗体和/或其抗原结合片段。
21.一种降低患有SARS相关冠状病毒的人类和/或动物受试者中的疾病的严重程度的方法，所述方法包括向所述受试者施用治疗有效量的至少一种根据权利要求1至11中任一项所述的抗体和/或其抗原结合片段。
22.根据权利要求15至17中任一项所述的用于用途的抗体或根据权利要求18至21中任一项所述的方法，其中所述抗体通过静脉内输注来施用。
23.根据权利要求22所述的用于用途的抗体或根据权利要求22所述的方法，其中所述抗体以1mg/kg患者体重至100mg/kg患者体重的剂量施用。
24.根据权利要求23所述的用于用途的抗体或根据权利要求23所述的方法，其中所述抗体以2,5mg/kg、5mg/kg、10mg/kg、20mg/kg、25mg/kg、30mg/kg、40mg/kg、50mg/kg、或100mg/kg患者体重的剂量施用。
25.根据权利要求15至17中任一项所述的用于用途的抗体或根据权利要求18至21中任一项所述的方法，其中所述抗体通过吸入给药来施用。
26.根据权利要求25所述的用于用途的抗体或根据权利要求25所述的方法，其中所述抗体以液体药物组合物提供，所述液体药物组合物在施用前通过筛网雾化器或喷射雾化器进行雾化。
27.根据权利要求25或26中任一项所述的用于用途的抗体或根据权利要求25或26中任一项所述的方法，其中所述抗体以50mg、100mg、200mg、250mg、300mg、400mg、500mg、750mg、或1000mg的剂量施用。
28.一种针对SARS相关冠状病毒2(SARS-CoV-2)的抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：包含序列SEQ ID NO:119的CDR1、序列SEQ ID NO:120的CDR2、和序列SEQ ID NO:121的CDR3的重链可变区，还包含：包含序列SEQ ID NO:122的CDR1、SEQ IDNO:123的CDR2、和序列SEQ ID NO:124的CDR3的轻链可变区。
29.根据权利要求28所述的抗体或其抗原结合片段，其包含序列SEQ IDNO:21的重链可变区和序列SEQ ID NO:22的轻链可变区。
30.根据权利要求28或29所述的抗体，其包含序列SEQ ID NO:229的重链和序列SEQ IDNO:230的轻链。
31.根据权利要求28至30中任一项所述的抗体，其由序列SEQ ID NO:229的两条重链和序列SEQ ID NO:230的两条轻链组成。
32.一种核酸，其编码根据权利要求1至11或28至31中任一项所述的抗体。
33.一种表达载体，其包含根据权利要求32所述的核酸，所述核酸与表达控制序列功能性缔合。
34.一种宿主细胞，其包含根据权利要求32所述的核酸或根据权利要求33所述的表达载体。
35.一种产生根据权利要求1至11或28至31中任一项所述的抗体的方法，所述方法包括
(a)在允许所述抗体表达的条件下培养根据权利要求34所述的宿主细胞，和
(b)回收所述抗体。
36.根据权利要求1至11或28至31中任一项所述的抗体，其与至少一种针对SARS相关冠状病毒2(SARS-CoV-2)的其它抗体组合用于药物中，其中所述其它抗体具有不同的结合特异性。
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| PCT/EP2021/064326 WO2021239935A1 (en) | 2020-05-29 | 2021-05-28 | Neutralizing antibodies against sars-related coronavirus |
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