CN115057938A - 抗新型冠状病毒人源化多价结合蛋白及其应用 - Google Patents
抗新型冠状病毒人源化多价结合蛋白及其应用 Download PDFInfo
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- CN115057938A CN115057938A CN202210724686.3A CN202210724686A CN115057938A CN 115057938 A CN115057938 A CN 115057938A CN 202210724686 A CN202210724686 A CN 202210724686A CN 115057938 A CN115057938 A CN 115057938A
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Abstract
本发明涉及抗体技术领域，具体而言，涉及抗新型冠状病毒人源化多价结合蛋白及其应用。本发明提供的多价结合蛋白包括至少两个抗原表位结合结构域，所述抗原表位结合结构域为VHH；所述VHH的氨基酸序列如SEQ ID NO:1或SEQ ID NO:2所示，或如与SEQ ID NO:1或SEQ ID NO:2具有至少95％相似性的氨基酸序列所示。该多价结合蛋白能有效阻断野生株、Delta变异株和Omicron变异株SARS‑COV‑2RBD蛋白与人ACE2受体蛋白的结合，且相比单价结合蛋白，其具有更显著的新型冠状病毒中和活性，可广泛用于新型冠状病毒的预防和治疗。
Description
技术领域
本发明属于抗体技术领域。更具体地，涉及抗新型冠状病毒人源化多价结合蛋白及其应用。
背景技术
传统的单克隆抗体分子质量过大(150kD)，难穿透组织，造成肿瘤区域的有效浓度较低，治疗效果不充分；另外，传统的抗体具有很高的免疫原性，而改造的抗体很难达到原来的亲和力，限制了其在临床上的广泛应用。
新型冠状病毒(SARS-COV-2)在全世界各地广泛传播；另外，陆续发现了多种类型的新型冠状病毒变异株，如2020年10月在印度首次发现新型冠状病毒Delta变异株，2021年11月24日首次从南非发现了新型冠状病毒Omicron变异株。变异株是指在原有病毒的基因组基础上发生了某一个基因碱基的突变、或者某些碱基的缺失，发生突变或者碱基缺失会导致病毒的性质发生变化，病毒可能会出现比如传染性、宿主范围、传播力度、毒力、致病力、病情的严重程度、预后以及免疫原性的改变。这样就会导致临床整个发病过程以及流行病学发生变化，甚至对于免疫原性以及免疫的预防也可能会出现影响，造成了严重的经济损失、社会负担和其他负面影响。因此，亟需开发对新型冠状病毒野生株和突变株有特异性疗效的药物。
发明内容
本发明的目的是提供抗新型冠状病毒人源化多价结合蛋白及其应用。本发明提供的多价结合蛋白能有效阻断野生株、Delta变异株和Omicron变异株 SARS-COV-2 RBD蛋白与人ACE2受体蛋白的结合，且相比单价结合蛋白，本发明人源化多价结合蛋白具有更显著的新型冠状病毒中和活性。
本发明上述目的通过以下技术方案实现：
第一方面，本发明提供了抗新型冠状病毒人源化多价结合蛋白，其包括至少两个抗原表位结合结构域，所述抗原表位结合结构域为VHH；所述VHH的氨基酸序列如SEQ IDNO:1或SEQ ID NO:2所示，或如与SEQ ID NO:1或SEQ ID NO:2具有至少95％相似性的氨基酸序列所示。
第二方面，本发明提供了融合蛋白，其包含所述多价结合蛋白。
第三方面，本发明提供了缀合物，其包含所述多价结合蛋白。
第四方面，本发明提供了核酸，所述核酸编码所述多价结合蛋白、或编码所述融合蛋白、或编码所述缀合物。
第五方面，本发明提供了重组载体，所述重组载体携带所述核酸。
第六方面，本发明提供了宿主细胞，所述宿主细胞携带所述核酸、或包含所述重组载体。
第七方面，本发明提供了药物组合物，所述药物组合物含有所述多价结合蛋白、所述融合蛋白、所述缀合物、所述核酸、所述重组载体、或所述宿主细胞。
第八方面，本发明提供了所述多价结合蛋白、所述融合蛋白、所述缀合物、所述核酸、所述重组载体、或所述宿主细胞在制备治疗和/或预防新型冠状病毒的药物中的应用。
第九方面，本发明提供了一种制备所述多价结合蛋白的方法，其包括：培养所述的宿主细胞，从培养产物中分离纯化获得所述多价结合蛋白。
附图说明
图1是本发明多价结合蛋白R1406、R1407、R1475、R1464的结构图。
图2是R1382、R1406、R1407对野生株新型冠状病毒的中和活性结果图。
图3是R1463、R1475、R1464对野生株新型冠状病毒的中和活性结果图。
图4是R1382、R1406、R1407对Delta变异株新型冠状病毒的中和活性结果图。
图5是R1463、R1475、R1464对Delta变异株新型冠状病毒的中和活性结果图。
图6是R1382、R1406、R1407对Omicron变异株新型冠状病毒的中和活性结果图。
图7是R1463、R1475、R1464对Omicron变异株新型冠状病毒的中和活性结果图。
具体实施方式
以下结合具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
本发明中，术语“氨基酸”表示天然存在或非天然存在的羧基α-氨基酸。术语“氨基酸”用在本申请中可以包括天然存在的氨基酸和非天然存在的氨基酸。天然存在的氨基酸包括丙氨酸(三字母密码：Ala，单字母密码：A)，精氨酸(Arg，R)，天冬酰胺(Asn，N)，天冬氨酸(Asp，D)，半胱氨酸(Cys，C)，谷氨酰胺(Gln，Q)，谷氨酸(Glu，E)，甘氨酸(Gly，G)，组氨酸(His，H)，异亮氨酸(Ile，I)，亮氨酸 (Leu，L)，赖氨酸(Lys，K)，甲硫氨酸(Met，M)，苯丙氨酸(Phe，F)，脯氨酸(Pro， P)，丝氨酸(Ser，S)，苏氨酸(Thr，T)，色氨酸(Trp，W)，酪氨酸(Tyr，Y)，和缬氨酸(Val，V)。非天然存在的氨基酸包括但不限于α-氨基己二酸，氨基丁酸，瓜氨酸，高瓜氨酸，高亮氨酸，高精氨酸，羟基脯氨酸，正亮氨酸，吡啶基丙氨酸，肌氨酸等。
本发明中，术语“氨基酸序列”是指氨基酸相互连接形成肽链(或多肽)的顺序，氨基酸序列只能按照一个方向读取。氨基酸有100多种不同类型，其中20 种常用，本发明不排除氨基酸链上有其他物质，例如糖类、脂类等修饰，本发明也不限于20中常用的氨基酸。
本发明中，术语“Fc区”是指免疫球蛋白的C端区域，该区域是由重链恒定结构域中仅CH2和CH3组成的功能性结构单元。Fc区没有结合抗原的能力，然而其具有半衰期延长的性质，并且具有恒定的氨基酸序列。
本发明提供了抗新型冠状病毒人源化多价结合蛋白，其特征在于，其包括至少两个抗原表位结合结构域，所述抗原表位结合结构域为VHH。
在一些实施方式中，所述VHH的氨基酸序列如SEQ ID NO:1或SEQ ID NO:2 所示，或如与SEQ ID NO:1或SEQ ID NO:2具有至少95％相似性的氨基酸序列所示。
在一些实施方式中，所述抗原表位结合结构域的数量为2-6个。
在一些实施方式中，所述抗原表位结合结构域通过连接肽连接。本领域常用的连接肽均可用于本发明中。
在优选实施方式中，所述连接肽的氨基酸序列为：GGGGSGGGGSGGGGS。
在优选实施方式中，所述连接的方式为串联。
在一些实施方式中，所述多价结合蛋白还包括半衰期延长结构域。
在优选实施方式中，所述半衰期延长结构域选自免疫球蛋白Fc区或血清白蛋白结合结构域。
在优选实施方式中，所述免疫球蛋白选自IgA、IgD、IgE、IgG和IgM
在一些实施方式中，所述半衰期延长结构域为免疫球蛋白Fc区，所述抗原表位结合结构域连接至所述Fc区的N端或C端。
在一些实施方式中，所述多价结合蛋白通过所述Fc区的链间二硫键形成二聚体结构。
在优选实施方式中，所述Fc区的氨基酸序列如SEQ ID NO:3所示。
在一些实施方式中，所述多价结合蛋白的氨基酸序列如SEQ ID NO:6～9任一所示。
在一些实施方式中，所述多价结合蛋白的氨基酸序列可以不含有His标签，也可以含有His标签。
本发明还提供了融合蛋白，其包含所述多价结合蛋白。
本发明中，术语“融合蛋白”是指本发明多价结合蛋白与其他功能性蛋白片段等融合在一起得到的融合蛋白。
本发明还提供了缀合物，其包含所述多价结合蛋白。
本发明中，术语“缀合物”是指本发明多价结合蛋白与酶相(如辣根过氧化物酶、碱性磷酸酶等)、放射性同位素、荧光化合物或化学发光化合物、治疗剂等中的一种或多种相偶联得到的缀合物，这些缀合物可用于检测新冠病毒、制备治疗和/或预防新型冠状病毒的药物、或治疗新冠病毒感染疾病。
本发明还提供了核酸，所述核酸编码所述多价结合蛋白、或编码所述融合蛋白、或编码所述缀合物。
本发明中，核酸通常是RNA或DNA，核酸分子可以是单链或双链的。当将核酸与另一个核酸序列置于功能关系中时，核酸是“有效连接的”。例如，如果启动子或增强子影响编码序列的转录，那么启动子或增强子有效地连接至所述编码序列。当其连入载体时采用DNA核酸。
目前，已经可以完全通过化学合成来得到编码本发明蛋白的核酸分子序列。
本发明还提供了重组载体，所述重组载体携带所述核酸。
在本发明中，术语“载体”包括质粒、表达载体、克隆载体、病毒载体等。可选用本领域已知的各种载体。比如，选用市售的载体，然后将编码本发明多价结合蛋白的核酸序列可操作地连于表达调控序列，可以形成重组载体。
本发明还提供了宿主细胞，所述宿主细胞携带所述核酸、或包含所述重组载体。
在本发明中，术语“宿主细胞”包括原核细胞和真核细胞。常用的原核宿主细胞的例子包括大肠杆菌、枯草杆菌等。用于表达多价结合蛋白的宿主细胞包括大肠杆菌、酵母细胞、昆虫细胞、COS细胞、CHO细胞等。在获得转化的宿主细胞后，可在适合表达本发明多价结合蛋白的条件下培养该细胞，从而表达出多价结合蛋白；然后再分离出表达的多价结合蛋白。
本发明还提供了药物组合物，所述药物组合物含有所述多价结合蛋白、所述融合蛋白、所述缀合物、所述核酸、所述重组载体、或所述宿主细胞。
在一些实施方式中，所述药物组合物还包含可药用载体。作为可药用载体，黏合剂、助流剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、助悬剂、色素、矫味剂等可用于经口施用；缓冲剂、防腐剂、疼痛减轻剂、增溶剂、等张剂、稳定剂等可用于注射用混合物；以及基质、赋形剂、润滑剂、防腐剂等可用于表面施用。
在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
本发明还提供了所述多价结合蛋白、所述融合蛋白、所述缀合物、所述核酸、所述重组载体、或所述宿主细胞在制备治疗和/或预防新型冠状病毒的药物中的应用。
本发明还提供了一种制备所述多价结合蛋白的方法，其包括：培养所述的宿主细胞，从培养产物中分离纯化获得所述多价结合蛋白。
实施例1抗新型冠状病毒人源化多价结合蛋白的设计构建
利用Fc区或His标签，结合VHH结构域串联设计不同结构的人源化多价结合蛋白。改造后的人源化多价结合蛋白的结构如图1所示，具体氨基酸序列如表 1所示：
其中，R1406、R1407的母本序列为RX011(氨基酸序列如SEQ ID NO:1所示)，序列结构依次为：R1406:VHH-Linker-VHH-Linker-VHH-Fc区，R1407:Fc 区-VHH-Linker-VHH-Linker-VHH；R1475、R1464的母本序列为RX017(氨基酸序列如SEQ ID NO:2所示)，序列结构依次为：R1475:VHH-Linker-VHH-His标签， R1464:His标签-VHH-Linker-VHH-Linker-VHH；Fc区的氨基酸序列如SEQ ID NO:3所示，His标签的氨基酸序列为HHHHHH。
并以R1382(氨基酸序列如SEQ ID NO:4所示)、R1463(氨基酸序列如SEQ ID NO:5所示):作为对照，序列结构依次为：R1382：RX011 VHH-Fc区，R1463： RX017 VHH-His标签。
SEQ ID NO:1：
QVQLVESGGGPVQAGGSLRLSCTCSRCTFNWDGMGWFRQAPGKEREFVATISWSGQ EPAYADSVKGRFTISRDKPKNTVYLQMTSLKSEDTAVYYCAAAQYTGASYSILRDQVGYD YWGQGTRVTVSA
SEQ ID NO:2：
QVQLVESGGGVVQPGGSLRLSCTCSRCTFNWDGMGWFRQAPGKGLEFVATISWSGQ EPAYADSVKGRFTISRDNSKNTLYLQMTSLRAEDTAVYYCAAAQYTGASYSILRDQVGYD YWGQGTLVTVSS
SEQ ID NO:3：
EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:4：
QVQLVESGGGPVQAGGSLRLSCTCSRCTFNWDGMGWFRQAPGKEREFVATISWSGQ EPAYADSVKGRFTISRDKPKNTVYLQMTSLKSEDTAVYYCAAAQYTGASYSILRDQVGYD YWGQGTRVTVSAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK
SEQ ID NO:5：
QVQLVESGGGVVQPGGSLRLSCTCSRCTFNWDGMGWFRQAPGKGLEFVATISWSGQ EPAYADSVKGRFTISRDNSKNTLYLQMTSLRAEDTAVYYCAAAQYTGASYSILRDQVGYD YWGQGTLVTVSSHHHHHH
表1人源化多价结合蛋白的氨基酸序列
实施例2抗新型冠状病毒人源化多价结合蛋白的制备
蛋白瞬转表达：
将含有目的基因的质粒通过与转染试剂PEI形成阳离子复合物后，导入到宿主细胞Expi293，质粒在细胞内期间，质粒上的外源基因在细胞内发生转录翻译，从而得到目的蛋白。
Expi293在37℃、8％二氧化碳、130rpm条件培养，并在转染前通过细胞计数，将2E6的细胞接种至1L摇瓶中，培养体系约为300ml。配制转染复合物准备转染：首先将750μg目标质粒加入到含有15ml Opti-MEM试剂的50ml离心管中，轻轻混匀，标记为A管；将1.5mg转染试剂PEI加入到含有15ml Opti-MEM 试剂的50ml离心管中，轻轻混匀后，室温孵育5min，标记为B管；将B管PEI 稀释液逐滴加入到A管DNA稀释液中，轻轻混匀后，室温孵育15min，孵育结束后，将PEI-目标质粒复合物加入到Expi293细胞，置于37℃摇床中继续培养。直到D7-D10后收样。
复合物样品的纯化：
瞬转细胞表达液经过9000rpm/20min离心，收集上清，再经过0.22μm滤膜除菌过滤。纯化采用ProA亲和层析。过程如下，使用AKTA avant 150层析设备，用至少5CV平衡缓冲液(10mM PBS)平衡层析柱(如MabSelectSuRe LX，GE)，加载样品至层析柱，使目标蛋白吸附在层析柱上而其他杂质穿透分离。完成上样后使用至少5CV平衡缓冲液(10mM PBS)再次冲洗层析柱，随后使用洗脱缓冲液(20mM NaAc，pH＝3.4)洗脱目标蛋白，收集管中预先加入中和缓冲液(1M Tris，pH8.0)，中和缓冲液的加入体积根据洗脱样品的预估含量而定，一般加入 10％洗脱体积量。
常规方法进行结合蛋白的制备，表达上清采用ProA亲和层析纯化。过程如下，使用AKTA avant 150层析设备，用至少5CV平衡缓冲液(10mM PBS)平衡层析柱(如MabSelectSuRe LX，GE)，加载样品至层析柱，使目标蛋白吸附在层析柱上而其他杂质穿透分离。完成上样后使用至少5CV平衡缓冲液(10mM PBS)再次冲洗层析柱，随后使用洗脱缓冲液(20mM NaAc，pH＝3.4)洗脱目标蛋白，收集管中预先加入中和缓冲液(1M Tris，pH8.0)，中和缓冲液的加入体积根据洗脱样品的预估含量而定，一般加入10％洗脱体积量。
样品使用Biotek-Epoch-Take-3进行浓度测定，利用A280方法检测结合蛋白浓度，即以消光系数E.C.＝1.37(根据氨基酸序列预测)，光程＝0.05mm(Take-3 板不同孔光程有细微差异，会自动校正)，通过设备检测样品吸光值，按照 Lambert-Beer law计算待测结合蛋白的浓度。样品浓度过低则需要进行超滤浓缩，使用超滤浓缩管(
Ultra-15Centrifugal Filter Devices，30kD)按照说明书提供的通用操作方法，将样品浓度浓缩至＞0.5mg/ml；收集浓缩端样品，0.22um 无菌针头滤器除菌过滤(科百特，PES，0.22um，直径13mm)后分装冻存备用。
抗新型冠状病毒人源化多价结合蛋白的滴度和纯度结果如表2所示，结果显示，人源化多价结合蛋白的滴度和纯度数据都很理想。
表2抗新型冠状病毒人源化多价结合蛋白的滴度和纯度结果
| 编号 | 滴度mg/L | 纯度 |
| R1382 | 255.78 | 99.18％ |
| R1406 | 187.44 | 95.95％ |
| R1407 | 179.61 | 94.74％ |
| R1463 | 81.51 | 88.69％ |
| R1475 | 124.06 | 87.95％ |
| R1464 | 137.76 | 78.89％ |
实施例3人源化多价结合蛋白对野生株新型冠状病毒的中和活性
使用竞争法检测实施例2制备得到的人源化多价结合蛋白对野生株 SARS-COV-2RBD蛋白的中和活性，以R1382、R1463作为对照，具体实验步骤如下：
包被条件：
病毒蛋白：野生株SARS-COV-2RBD蛋白(Ag27)，2ug/ml；
包被液：50mm pH 9.51CB；
包被体积：100ul/孔；
包被温度：2℃-8℃；
包被时间：18小时；
封闭液：含1％BSA+1×PBS；
封闭温度：37℃；
封闭时间：3小时；
加样：加50ul待测结合蛋白(所有结合蛋白起始浓度是5ug/mL，并按照5 倍进行系列梯度稀释)，孵育30min，使用洗板液(1 x PBS)清洗5次后，加入 50ul ACE2蛋白，使用洗板液(1 x PBS)清洗3次后，显色检测。
人源化多价结合蛋白对野生株新型冠状病毒的中和活性结果如表3、图2和图3所示，表3、图2和图3的结果显示，实施例2制备得到的人源化多价结合蛋白具有新型冠状病毒中和活性，能有效阻断野生株SARS-COV-2RBD蛋白与人ACE2受体蛋白的结合；其中，与对照组相比，R1406、R1407、R1475、R1464 显示出显著的野生株新型冠状病毒中和活性。
表3人源化多价结合蛋白对野生株新型冠状病毒的中和活性结果
| 编号 | 野生株SARS-COV-2 IC50(nM) |
| R1382 | 0.05192 |
| R1406 | 0.06306 |
| R1407 | 0.04783 |
| R1463 | 0.03591 |
| R1475 | 0.0206 |
| R1464 | 0.02724 |
实施例4人源化多价结合蛋白对Delta变异株新型冠状病毒的中和活性
使用竞争法检测实施例2制备得到的人源化多价结合蛋白对Delta变异株 SARS-COV-2 RBD蛋白的中和活性，以R1382、R1463作为对照，实验中包被的病毒蛋白为：Delta变异株SARS-COV-2RBD蛋白(Ag101)，2ug/ml，具体实验步骤同实施例3。
人源化多价结合蛋白对Delta变异株新型冠状病毒的中和活性结果如表4、图4和图5所示，表4、图4和图5的结果显示，实施例2制备得到的人源化多价结合蛋白能有效阻断Delta变异株SARS-COV-2RBD蛋白与人ACE2受体蛋白的结合，都有新型冠状病毒中和活性；其中，与对照组相比，R1406、R1407、 R1475、R1464显示出显著的Delta变异株新型冠状病毒中和活性。
表4人源化多价结合蛋白对Delta变异株新型冠状病毒的中和活性结果
| 编号 | Delta变异株SARS-COV-2 IC50(nM) |
| R1382 | 0.01369 |
| R1406 | 0.01476 |
| R1407 | 0.01582 |
| R1463 | 0.01805 |
| R1475 | 0.003341 |
| R1464 | 0.004316 |
实施例5人源化多价结合蛋白对Omicron变异株新型冠状病毒的中和活性
使用竞争法检测实施例2制备得到的人源化多价结合蛋白对Omicron变异株SARS-COV-2 RBD蛋白的中和活性，以R1382、R1463作为对照，实验中包被的病毒蛋白为：Omicron变异株SARS-COV-2RBD蛋白(covsK20)，2ug/ml，具体实验步骤同实施例3。
人源化多价结合蛋白对Omicron变异株新型冠状病毒的中和活性结果如表 5、图6和图7所示，结果显示，实施例2制备得到的人源化多价结合蛋白能有效阻断Omicron变异株SARS-COV-2RBD蛋白与人ACE2受体蛋白的结合，都有新型冠状病毒中和活性；其中，与对照组相比，R1406、R1407、R1475、R1464 显示出显著的Omicron变异株新型冠状病毒中和活性。
表5人源化多价结合蛋白对Omicron变异株新型冠状病毒的中和活性结果
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
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<110> 广东菲鹏制药股份有限公司
<120> 抗新型冠状病毒人源化多价结合蛋白及其应用
<130> 2022
<160> 9
<170> PatentIn version 3.5
<210> 1
<211> 128
<212> PRT
<213> 人工序列
<400> 1
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Pro Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys Pro Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ala
115 120 125
<210> 2
<211> 128
<212> PRT
<213> 人工序列
<400> 2
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 3
<211> 232
<212> PRT
<213> 人工序列
<400> 3
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 4
<211> 360
<212> PRT
<213> 人工序列
<400> 4
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Pro Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys Pro Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ala
115 120 125
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
130 135 140
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
145 150 155 160
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
165 170 175
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
180 185 190
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
195 200 205
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
210 215 220
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
225 230 235 240
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
245 250 255
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
260 265 270
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
275 280 285
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
290 295 300
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
305 310 315 320
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
325 330 335
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
340 345 350
Ser Leu Ser Leu Ser Pro Gly Lys
355 360
<210> 5
<211> 128
<212> PRT
<213> 人工序列
<400> 5
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 6
<211> 646
<212> PRT
<213> 人工序列
<400> 6
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Pro Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys Pro Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ala
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
130 135 140
Val Gln Leu Val Glu Ser Gly Gly Gly Pro Val Gln Ala Gly Gly Ser
145 150 155 160
Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp Gly
165 170 175
Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
180 185 190
Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Lys Pro Lys Asn Thr Val Tyr Leu
210 215 220
Gln Met Thr Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
225 230 235 240
Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln Val
245 250 255
Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ala Gly
260 265 270
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
275 280 285
Gln Leu Val Glu Ser Gly Gly Gly Pro Val Gln Ala Gly Gly Ser Leu
290 295 300
Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp Gly Met
305 310 315 320
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Thr
325 330 335
Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val Lys Gly
340 345 350
Arg Phe Thr Ile Ser Arg Asp Lys Pro Lys Asn Thr Val Tyr Leu Gln
355 360 365
Met Thr Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
370 375 380
Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln Val Gly
385 390 395 400
Tyr Asp Tyr Trp Gly Gln Gly Thr Arg Val Thr Val Ser Ala Glu Pro
405 410 415
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
420 425 430
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
435 440 445
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
450 455 460
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
465 470 475 480
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
485 490 495
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
500 505 510
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
515 520 525
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
530 535 540
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
545 550 555 560
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
565 570 575
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
580 585 590
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
595 600 605
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
610 615 620
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
625 630 635 640
Ser Leu Ser Pro Gly Lys
645
<210> 7
<211> 661
<212> PRT
<213> 人工序列
<400> 7
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Pro Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Thr Cys Ser
260 265 270
Arg Cys Thr Phe Asn Trp Asp Gly Met Gly Trp Phe Arg Gln Ala Pro
275 280 285
Gly Lys Glu Arg Glu Phe Val Ala Thr Ile Ser Trp Ser Gly Gln Glu
290 295 300
Pro Ala Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Lys Pro Lys Asn Thr Val Tyr Leu Gln Met Thr Ser Leu Lys Ser Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Gln Tyr Thr Gly Ala Ser
340 345 350
Tyr Ser Ile Leu Arg Asp Gln Val Gly Tyr Asp Tyr Trp Gly Gln Gly
355 360 365
Thr Arg Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly
385 390 395 400
Pro Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg
405 410 415
Cys Thr Phe Asn Trp Asp Gly Met Gly Trp Phe Arg Gln Ala Pro Gly
420 425 430
Lys Glu Arg Glu Phe Val Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro
435 440 445
Ala Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys
450 455 460
Pro Lys Asn Thr Val Tyr Leu Gln Met Thr Ser Leu Lys Ser Glu Asp
465 470 475 480
Thr Ala Val Tyr Tyr Cys Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr
485 490 495
Ser Ile Leu Arg Asp Gln Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr
500 505 510
Arg Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Pro
530 535 540
Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys
545 550 555 560
Thr Phe Asn Trp Asp Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys Pro
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Thr Ser Leu Lys Ser Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser
625 630 635 640
Ile Leu Arg Asp Gln Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Arg
645 650 655
Val Thr Val Ser Ala
660
<210> 8
<211> 271
<212> PRT
<213> 人工序列
<400> 8
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
130 135 140
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser
145 150 155 160
Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp Gly
165 170 175
Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val Ala
180 185 190
Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
210 215 220
Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
225 230 235 240
Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln Val
245 250 255
Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
260 265 270
<210> 9
<211> 414
<212> PRT
<213> 人工序列
<400> 9
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp
20 25 30
Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val
35 40 45
Ala Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln
100 105 110
Val Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
130 135 140
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser
145 150 155 160
Leu Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp Gly
165 170 175
Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val Ala
180 185 190
Thr Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
210 215 220
Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
225 230 235 240
Ala Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln Val
245 250 255
Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
260 265 270
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
275 280 285
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu
290 295 300
Arg Leu Ser Cys Thr Cys Ser Arg Cys Thr Phe Asn Trp Asp Gly Met
305 310 315 320
Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val Ala Thr
325 330 335
Ile Ser Trp Ser Gly Gln Glu Pro Ala Tyr Ala Asp Ser Val Lys Gly
340 345 350
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
355 360 365
Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
370 375 380
Ala Gln Tyr Thr Gly Ala Ser Tyr Ser Ile Leu Arg Asp Gln Val Gly
385 390 395 400
Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
405 410
Claims (14)
1.抗新型冠状病毒人源化多价结合蛋白，其特征在于，其包括至少两个抗原表位结合结构域，所述抗原表位结合结构域为VHH；
所述VHH的氨基酸序列如SEQ ID NO:1或SEQ ID NO:2所示，或如与SEQ ID NO:1或SEQID NO:2具有至少95％相似性的氨基酸序列所示。
2.根据权利要求1所述多价结合蛋白，其特征在于，所述抗原表位结合结构域的数量为2-6个。
3.根据权利要求1或2所述多价结合蛋白，其特征在于，所述抗原表位结合结构域通过连接肽连接；
优选地，所述连接的方式为串联。
4.根据权利要求1～3任一项所述多价结合蛋白，其特征在于，所述多价结合蛋白还包括半衰期延长结构域；
优选地，所述半衰期延长结构域选自免疫球蛋白Fc区或血清白蛋白结合结构域；
优选地，所述免疫球蛋白选自IgA、IgD、IgE、IgG和IgM。
5.根据权利要求1～4任一项所述多价结合蛋白，其特征在于，所述半衰期延长结构域为免疫球蛋白Fc区，所述抗原表位结合结构域连接至所述Fc区的N端或C端；
所述多价结合蛋白通过所述Fc区的链间二硫键形成二聚体结构；
优选地，所述Fc区的氨基酸序列如SEQ ID NO:3所示。
6.根据权利要求1～5任一项所述多价结合蛋白，其特征在于，所述多价结合蛋白的氨基酸序列如SEQ ID NO:6～9任一所示。
7.融合蛋白，其特征在于，其包含权利要求1～6任一项所述多价结合蛋白。
8.缀合物，其特征在于，其包含权利要求1～6任一项所述多价结合蛋白。
9.核酸，其特征在于，所述核酸编码权利要求1～6任一项所述多价结合蛋白、或编码权利要求7所述融合蛋白、或编码权利要求8所述缀合物。
10.重组载体，其特征在于，所述重组载体携带权利要求9所述核酸。
11.宿主细胞，其特征在于，所述宿主细胞携带权利要求9所述核酸、或包含权利要求10所述重组载体。
12.药物组合物，其特征在于，所述药物组合物含有权利要求1～6任一项所述多价结合蛋白、权利要求7所述融合蛋白、权利要求8所述缀合物、权利要求9所述核酸、权利要求10所述重组载体、或权利要求11所述宿主细胞。
13.权利要求1～6任一项所述多价结合蛋白、权利要求7所述融合蛋白、权利要求8所述缀合物、权利要求9所述核酸、权利要求10所述重组载体、或权利要求11所述宿主细胞在制备治疗和/或预防新型冠状病毒的药物中的应用。
14.一种制备权利要求1～6任一项所述多价结合蛋白的方法，其特征在于，其包括：培养权利要求11所述的宿主细胞，从培养产物中分离纯化获得所述多价结合蛋白。
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| CN202211668151.5A CN117327174A (zh) | 2022-06-24 | 2022-06-24 | 抗新型冠状病毒人源化多价结合蛋白及其应用 |
| CN202210724686.3A CN115057938B (zh) | 2022-06-24 | 2022-06-24 | 抗新型冠状病毒人源化多价结合蛋白及其应用 |
| PCT/CN2023/101644 WO2023246853A1 (zh) | 2022-06-24 | 2023-06-21 | 抗新型冠状病毒人源化多价结合蛋白及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023246853A1 (zh) * | 2022-06-24 | 2023-12-28 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化多价结合蛋白及其应用 |
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| CN114369172A (zh) * | 2021-03-01 | 2022-04-19 | 中国科学院微生物研究所 | 一种新型冠状病毒多价抗原、其制备方法和应用 |
| WO2022105772A1 (zh) * | 2020-11-18 | 2022-05-27 | 三优生物医药(上海)有限公司 | 针对冠状病毒具有中和活性的双特异性抗体及其用途 |
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| WO2022032660A1 (zh) * | 2020-08-14 | 2022-02-17 | 武汉友微生物技术有限公司 | 新型冠状病毒rbd融合蛋白 |
| CN114106162A (zh) * | 2020-08-28 | 2022-03-01 | 安源医药科技（上海）有限公司 | 一种新型冠状病毒Spike蛋白抗体及其用途 |
| CN112707968B (zh) * | 2020-12-17 | 2023-10-20 | 苏州科锐迈德生物医药科技有限公司 | 一种用于检测新冠病毒中和抗体的重组的受体结合蛋白、重组的受体蛋白 |
| CN113018427B (zh) * | 2021-03-10 | 2023-09-19 | 江苏健安生物科技有限公司 | 基于新冠病毒中和抗原表位的多价融合蛋白疫苗 |
| CN114349851B (zh) * | 2021-12-22 | 2023-08-15 | 上海纳为生物技术有限公司 | 新冠病毒中和抗体及其制备方法和应用 |
| CN117327174A (zh) * | 2022-06-24 | 2024-01-02 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化多价结合蛋白及其应用 |
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| CN112513076A (zh) * | 2020-09-23 | 2021-03-16 | 深圳市因诺赛生物科技有限公司 | 新型冠状病毒(sars-cov-2)刺突蛋白结合分子及其应用 |
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| CN114369172A (zh) * | 2021-03-01 | 2022-04-19 | 中国科学院微生物研究所 | 一种新型冠状病毒多价抗原、其制备方法和应用 |
| CN114634556A (zh) * | 2022-04-01 | 2022-06-17 | 中国科学院微生物研究所 | 一种新冠病毒Delta和Omicron变异株嵌合抗原、其制备方法和应用 |
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| WO2023246853A1 (zh) * | 2022-06-24 | 2023-12-28 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化多价结合蛋白及其应用 |
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| CN115057938B (zh) | 2023-01-06 |
| CN117327174A (zh) | 2024-01-02 |
| WO2023246853A1 (zh) | 2023-12-28 |
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