CN113307865A - 新型冠状病毒的全人源单域抗体及应用 - Google Patents
新型冠状病毒的全人源单域抗体及应用 Download PDFInfo
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Abstract
本发明公开了针对新型冠状病毒(SARS‑CoV‑2)的全人源单域抗体及其抗原结合片段。其主要特征在于这些单域抗体是由存在于抗体重链基因可变区中的互补决定区(complementarity‑determining region,CDR)特异性基因序列决定的,并在原核和真核细胞中获得有效表达的特异性结合SARS‑CoV‑2病毒表面糖蛋白上的受体结合域的抗体。利用此抗体CDR区或部分或全基因,可在原核和真核细胞及任何表达系统中改造和生产不同形式的基因工程抗体,在临床上诊断或治疗新型冠状病毒感染相关的疾病。
Description
技术领域
本发明属于生物技术领域,具体涉及了结合新型冠状病毒(SARS-CoV-2)全人源单域抗 体及其应用,特别是在治疗和/或预防、或诊断SARS-CoV-2相关疾病中的应用。
背景技术
通过抗体分子基因水平的重组可获得多种多样的特异性鼠源、人源化及全人源抗体,使 对单克隆抗体的研究有了突破性进展并越来越显示出其重要意义及实际应用前景。上世纪80 年代末90年代初兴起的噬菌体抗体基因库技术兴起和整个基因工程抗体技术研究领域的发 展,使当今世界全人源单克隆抗体及新结构抗体的开发研究取得很大进展并已由基础研究阶 段步入实质性应用研究和开发阶段。含有特异性抗体的人源或动物血清免疫球蛋白用以预防 和治疗传染病已历史悠久。而全人源单克隆抗体的发展,给这一领域的生物制品发展带来了 新的希望和远大前景。单克隆抗体的体外抗病毒中和活性和体内保护机体抵抗病毒攻击已获 得许多实验证明,如抗甲肝病毒、汉坦病毒、RSV病毒、SARS病毒、亨尼帕病毒、埃博拉病 毒等单克隆抗体可以在体内100%保护动物免受病毒攻击(NatBiotechnol,2005.23(9):p. 1126-1136.)。因此,鉴定出针对SARS-CoV-2的抗体,用于紧急预防和治疗是十分必要和可 行的。
虽然单抗类药物在防治传染病上效果显著,但全长的单抗IgG分子量过大(约150kDa), 从而导致单抗药物生产成本高、价格昂贵,阻碍了其在经济欠发达地区特别是疟疾流行地区 (如东南亚和非洲区域)的大规模临床应用。长期以来,人们都在探索用具有更小分子量、 可在原核细胞中可溶表达的“抗体片段”(antibody fragment)代替IgG形式的单克隆抗体, 作为生产成本低、组织渗透能力强的新一代抗体药物(Nat Biotechnol,2005.23(9):p. 1126-1136;Current Opinion in Pharmacology,2008.8(5):p.600-608)。近年来,人们 在羊驼血清中发现了一类仅含重链可变区的抗体,它是自然界存在的具有与抗原结合性能的 最小抗体片段,称为纳米抗体(nanobody,VHH)或单域抗体(sdAb)(Protein Engineering, 1994.7(9):p.1129-1135.)。这些纳米抗体的抗原亲和力和特异性很高,与全长IgG单抗 相类似。更重要的是,这些抗体更易于改造并且能在原核系统中表达,因此制备成本很低廉 (Front Immunol,2017.8:p.1802.)。然而,这些小分子抗体目前主要来源于骆驼或鲨鱼, 在人体内容易产生免疫反应从而限制了其在临床上的应用。虽然动物源的纳米抗体可以通过 基因工程技术进行人源化,但此过程中抗体容易失去热稳定性以及很难保持抗体的亲和力。 最近发现,人的某一重链可变区亚家族也具有较优异的稳定性、可溶性、低聚集性、优异的 表达和纯化产率以及适用于噬菌体展示系统的特性(JMol Biol,2008.382(3):p. 779-789.)。基于这些发现,我们以该重链可变区亚家族为骨架,引入源于健康成年人与新生 儿的所有抗体亚家族的重链CDR区(CDR1,CDR2,CDR3),构建了全人源纳米抗体噬菌体展示 库。利用此抗体库可从中筛选到针对癌症(Front Oncol,2018.8:p.539.)、病毒(J Virol, 2017.91(20):p.e00937-17.)以及免疫细胞(Sci Rep,2017.7(1):p.9130.)相关靶 点的特异性全人源单域抗体。
因此,筛选针对SARS-CoV-2表面糖蛋白受体结合域的高亲和力、高特异性、高稳定性的 全人源单域抗体,为COVID-19的临床治疗及防控疫情蔓延提供重要保障,也为疫苗的研制提 供新思路。
发明内容
本发明为解决上述技术问题,利用噬菌体展示技术,通过筛选获得了特异性结合SARS-CoV-2表面糖蛋白受体结合域的全人源单域抗体。本发明提供了结合SARS-CoV-2RBD区的全人源单域抗体包括n3010,n3021,n3055和n3063。本发明还涉及了制备本文所述SARS-CoV-2RBD结合分子的方法。本发明还涉及这些单域抗体的抗原结合片段,双特异性抗体,免疫偶联物以及融合蛋白的应用。本发明涉及的单域抗体可开发为SARS-CoV-2感染的诊 断产品或候选治疗药物。
本发明提供了一种结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,包含至 少一个免疫球蛋白单一可变结构域,所述免疫球蛋白单一可变结构域包含:
(1)SEQ ID NO:5所示的CDR1,SEQ ID NO:6所示的CDR2,SEQ ID NO:7所示的CDR3;
或
(2)SEQ ID NO:8所示的CDR1,SEQ ID NO:9所示的CDR2,SEQ ID NO:10所示的CDR3;
或
(3)SEQ ID NO:11所示的CDR1,SEQ ID NO:12所示的CDR2,SEQ ID NO:13所示的CDR3;
或
(4)SEQ ID NO:14所示的CDR1,SEQ ID NO:15所示的CDR2,SEQ ID NO:16所示的CDR3。
优选的,所述的免疫球蛋白单一可变结构域包含与SEQ ID NO:1-4中任一氨基酸序列具 有至少90%、更优选地至少95%、甚至更优选地至少99%序列相同的氨基酸序列。
优选的,所述的免疫球蛋白单一可变结构域是重链可变区(VH)。
优选的,所述的重链可变区(VH)是全人源的。
优选的,所述结合新型冠状病毒(SARS-CoV-2)的抗体分子与新型冠状病毒(SARS-CoV-2) 表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
本发明提供了一种双特异性抗体,其特征在于,含有上述所述的任一抗体分子。
优选的,所述双特异性抗体能够特异性结合新型冠状病毒(SARS-CoV-2),或与新型冠状 病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
本发明提供了一种融合蛋白,其特征在于,包含上述所述的任一抗体分子,或上述所述 的任一双特异性抗体,和一种异源蛋白融合。
优选的,其中的异源蛋白是人免疫球蛋白Fc,更优选的是人IgG1的Fc。
优选的,所述的任一融合蛋白能够特异性结合新型冠状病毒(SARS-CoV-2),或与新型冠 状病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
本发明提供了一种偶联物,其特征在于,该偶联物包含上述所述的任一抗体分子,或上 述所述的任一双特异性抗体,或上述所述的任一融合蛋白,与一种效应分子偶联。
优选的,其中的效应分子是可检测标记。
优选的,可检测标记是荧光标记,放射性标记,亲和素,生物素,或酶。
优选的,所述的任一偶联物能够特异性结合新型冠状病毒(SARS-CoV-2),或与新型冠状 病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
本发明提供了编码上述所述的任一抗体的核酸。本发明提供了包含所述核酸的质粒,任 选地,可操作地连接调控序列。本发明提供了包含该载体的宿主细胞,以及用于生产和任选 地回收该抗体或抗原结合片段的方法。本发明所述宿主细胞可以是任何原核细胞或真核细胞, 包括但不限于细菌细胞(例如大肠杆菌)、昆虫细胞(例如利用杆状病毒表达系统)、酵母或 哺乳动物细胞(例如CHO或BHK细胞系)。其它合适的宿主细胞为本领域技术人员所知。优选 宿主细胞为大肠杆菌细胞,其培养周期短且生产成本较低。
本发明提供的抗体或双特异性抗体,能够特异性结合对应的抗原,所述抗原指所有能诱 导机体发生免疫应答的物质。所述抗原包括但不限于小分子化合物。所述抗原包括但不限于 如下所列的蛋白质、属于下列蛋白质的亚基、结构域、基序和表位:CD2,CD3,CD3E,CD4, CD11,CD11a,CD14,CD16,CD18,CD19,CD20,CD22,CD23,CD25,CD28,CD29,CD30,CD32, CD33(p67蛋白),CD38,CD40,CD40L,CD52,CD54,CD56,CD80,CD147,GD3,IL-1,IL-1R,IL-2,IL-2R,IL-4,IL-5,IL-6,IL-6R,IL-8,IL-12,IL-15,IL-18,IL-23,α-干扰素、 β-干扰素、γ-干扰素;TNF-α,TNFβ2,TNFc,TNFαβ,TNF-RI,TNF-RII,FasL,CD27L, CD30L,4-1BBL,TRAIL,RANKL,TWEAK,APRIL,BAFF,LIGHT,VEGI,OX40L,TRAIL受体-1, A1腺苷受体,淋巴毒素β受体,TACI,BAFF-R,EPO;LFA-3,ICAM-1,ICAM-3,EpCAM,β1- 整联蛋白、β2-整联蛋白、α4/β7-整联蛋白、α2-整联蛋白、α3-整联蛋白、α4-整联蛋 白、α5-整联蛋白、α6-整联蛋白、αv-整联蛋白、αVβ3-整联蛋白、FGFR-3,角质化细胞 生长因子、VLA-1,VLA-4,L-选择蛋白,抗独特型抗体(anti-id),E-选择蛋白,HLA,HLA-DR, CTLA-4,T细胞受体,B7-1,B7-2,VNR整联蛋白(VNR integrin),TGF-β1,TGF-β2,嗜 酸细胞活化趋化因子1,BLyS(B-淋巴细胞刺激物),补体C5,IgE,因子VII,CD64,CBL, NCA 90,EGFR(ErbB-1),Her2/neu(ErbB-2),Her3(ErbB-3),Her4(ErbB-4),组织因子, VEGF,VEGFR,内皮素受体,VLA-4,半抗原NP-加帽或NIP-加帽蛋白,T细胞受体α/β,E- 选择蛋白,地高辛,胎盘碱性磷酸酶(PLAP)和睾丸类PLAP-样碱性磷酸酶,铁传递蛋白受 体,癌胚抗原(CEA),CEACAM5,HMFG PEM,粘蛋白MUC1,MUC18,类肝素酶(heparanase) I,人心脏肌球蛋白,肿瘤相关糖蛋白-72(TAG-72),肿瘤相关抗原CA125,前列腺特异性膜 抗原(PSMA),高分子量黑色素瘤相关抗原(HMW-MAA),癌相关抗原,Gcoprotein IIb/IIIa (GPIIb/IIIa),表达LewisY相关糖的肿瘤相关抗原(tumor-associated antigen expressing Lewis Y related carbohydrate),人巨细胞病毒(HCMV)gH包膜糖蛋白,HIV gp120,HIV gp140, HCMV,呼吸合胞病毒RSVF,RSVF Fgp,VNR整联蛋白,IL-8,细胞角蛋白肿瘤相关抗原,Hep B gp120,CMV,gpIIbIIIa,HIV IIIB gp120V3环,呼吸合胞病毒(RSV)Fgp,单纯疱疹病 毒(HSV)gD糖蛋白,HSV gB糖蛋白,HCMV gB包膜糖蛋白和产气荚膜梭菌(Clostridium perfrmgens)毒素、程序性死亡蛋白(Programmeddeath-1,PD-1)。
本领域技术人员应当理解上述列出的靶不仅指特定的蛋白质及生物分子,而且还指包含 它们的生化途径或各种途径。例如,当提及的CTLA-4作为靶抗原时,意味着配体和受体组成 了T细胞共刺激途径,包括CTLA-4、B7-1、B7-2、CD28,并且任何其它未被发现的配体或受 体也是靶对象。因此本文中使用的靶不仅指特定的生物分子,也指与所述靶以及所述靶所属 的生化途径的成员相互作用的一组蛋白。本领域技术人员应当进一步理解任一上述的靶抗原、 连接它们的配体或受体,或它们相应的生化途径的其它成员能可操作地与本发明的单域抗体 或抗原结合片段连接以便产生融合体。因而,事实上任何多肽,无论是配体、受体或一些其 它蛋白质或蛋白质结构域,包括但不限于上述靶和组成它们相应的生化途径的蛋白质,能可 操作地与本发明的单域抗体或抗原结合片段连接形成融合体。
更优选的,所述抗原来源包括但不限于癌症、感染性疾病(如病毒、细菌、真菌、寄生 虫感染等)、自身免疫性疾病、炎症紊乱性疾病。
所述抗原可来自病毒。本发明所述的病毒,例如来自以下家族之一的病毒:逆转录病毒 科(例如,人免疫缺陷病毒(HIV)、人T细胞白血病病毒(HTLV));小核糖核酸病毒科(例如,脊髓灰质炎病毒、甲型肝炎病毒、丙型肝炎病毒、肠道病毒、人类柯萨奇病毒、鼻病毒、埃可病毒、口蹄疫病毒);钙粘病毒科(如引起胃肠炎的病毒株);披膜病毒科(例如马脑炎病毒、风疹病毒);黄病毒科(例如,登革病毒、黄热病病毒、西尼罗河病毒、圣路易斯脑炎 病毒、日本脑炎病毒和其他脑炎病毒);冠状病毒科(例如冠状病毒、严重急性呼吸道综合征(SARS)病毒);弹状病毒科(例如,水疱性口炎病毒、狂犬病病毒);副粘病毒科(例如, 副流感病毒、腮腺炎病毒、麻疹病毒、呼吸道合胞病毒(RSV));正粘病毒科(例如,流感病 毒);布尼亚病毒科(例如汉坦病毒、Sin Nombre病毒、裂谷热病毒、bunya病毒、phleboviruses 和Nairo病毒);沙粒病毒科(例如出血热病毒、Machupo病毒、Junin病毒);呼肠孤病毒科 (例如呼肠孤病毒、orbiviurse和轮状病毒);双核糖核酸病毒科;嗜肝病毒科(例如乙型 肝炎病毒);细小病毒科(例如细小病毒);乳多空病毒科(例如乳头瘤病毒、多瘤病毒、BK 病毒);腺病毒科(例如,大多数腺病毒,如腺相关病毒);疱疹病毒科(例如,单纯疱疹病 毒(HSV-1和HSV-2)、巨细胞病毒(CMV)、爱泼斯坦-巴尔病毒(EBV)、水痘带状疱疹病毒(VZV)、 和其他疱疹病毒、包括HSV-6);痘病毒科(例如天花病毒、痘苗病毒、痘病毒);和虹膜病 毒科(如非洲猪瘟病毒);病毒科(例如,埃博拉病毒、马尔堡病毒);杯状病毒科(例如, 诺沃克病毒)和未分类的病毒(例如,海绵状脑病的病原体、三角洲肝炎的病原体(被认为 是乙型肝炎病毒的有缺陷的卫星)和星状病毒)。
所述抗原可来自细菌。本发明所述的细菌如幽门螺杆菌、Borelia burgdorferi、嗜肺军 团菌、分枝杆菌(如M.tuberculosis,M.avium,M.intracellulare,M.kansaii,M.gordonae)、金黄色葡萄球菌、淋病奈瑟菌,脑膜炎奈瑟菌、单核细胞增生李斯特菌、化脓 性链球菌(A组链球菌)、无乳链球菌(B组链球菌)、链球菌(草绿蝇群)、粪链球菌、牛链 球菌、链球菌(厌氧菌)、肺炎链球菌、致病性弯曲杆菌、肠球菌、流感嗜血杆菌、炭疽芽孢 杆菌、白喉棒状杆菌、棒状杆菌、猪瘟病毒、产气荚膜梭菌、破伤风梭菌、产气肠杆菌、肺 炎克雷伯菌、多杀巴斯德氏菌、拟杆菌属、梭状芽孢杆菌、麦芽链霉菌、梅毒螺旋体、密螺 旋体、钩端螺旋体或放线菌(Actinomyces israelli)。
所述抗原可来自真菌。本发明所述的真菌如新型隐球菌、夹膜组织胞浆菌(Histoplasma capsulatum)、粗球孢子菌(Coccidioides immitis)、皮炎芽生菌(Blastomyces dermatitidis)、沙眼衣原体(Chlamydia trachomatis)或白念珠菌(Candida albicans)。
所述抗原可来自寄生虫。本发明所述的寄生虫例如恶性疟原虫(Plasmodiumfalciparum) 或弓形虫(Toxoplasma gondii)。
所述抗原可以是癌症抗原,例如实体瘤或血源性癌抗原。本发明所述的实体瘤是肉瘤或 癌,例如纤维肉瘤,粘液肉瘤,脂肪肉瘤,软骨肉瘤,成骨肉瘤,或另一种肉瘤,滑膜瘤, 间皮瘤,尤文氏瘤,平滑肌肉瘤,横纹肌肉瘤,结肠癌,淋巴恶性肿瘤,胰腺癌,乳腺癌,肺癌,卵巢癌,前列腺癌,肝细胞癌,鳞状细胞癌,基底细胞癌,腺癌,汗腺癌,皮脂腺癌, 乳头状癌,乳头状腺癌,髓样癌,支气管癌,肾细胞癌,肝细胞癌,胆管癌,绒毛膜癌,肾 母细胞瘤,宫颈癌,睾丸肿瘤,膀胱癌或中枢神经系统肿瘤(如胶质瘤,星形细胞瘤,成神 经管细胞瘤,颅咽管瘤,室管膜瘤,松果体,血管母细胞瘤,听神经瘤,少突神经胶质瘤, 血管瘤,黑素瘤,神经母细胞瘤或视网膜母细胞瘤)。本发明所述的血源性癌症是白血病,如 急性白血病(如急性淋巴细胞白血病,急性髓细胞白血病,急性髓性白血病和成髓细胞,早 幼粒细胞,髓单核细胞,单核细胞和红白血病);慢性白血病(如慢性粒细胞性(粒细胞)白 血病,慢性粒细胞白血病和慢性淋巴细胞白血病),真性红细胞增多症,淋巴瘤,霍奇金病, 非霍奇金淋巴瘤(惰性和高级形式),多发性骨髓瘤,瓦尔登斯特伦巨球蛋白血症,重链性疾 病,骨髓增生异常综合征,多毛细胞白血病或骨髓增生异常。肿瘤抗原是本领域公知的,包 括例如癌胚抗原(CEA),β-人绒毛膜促性腺激素(β-HCG),甲胎蛋白(AFP),凝集素反应 性AFP,(AFP-L3),甲状腺球蛋白,RAGE-1,MN-CA IX,人端粒酶逆转录酶(hTERT),RU1, RU2(AS),肠道羧基酯酶,mut hsp70-2,M-CSF,前列腺素酶,前列腺特异性抗原(PSA), PAP,NY-ESO-1,LAGE-1a,p53,prostein,PSMA,Her2/neu,存活蛋白和端粒酶,前列腺 癌肿瘤抗原-1(PCTA-1),黑色素瘤相关抗原(MAGE),ELF2M,中性粒细胞弹性蛋白酶,ephrinB2 和CD22。还可以是任何癌症相关蛋白,例如IGF-I,IGF-II,IGR-IR或间皮素。
本发明提供了一种药用组合物,由含有有效预防或治疗剂量的本发明所述的抗体或抗原 结合片段、双特异性抗体、融合蛋白、偶联物、抗体或抗原结合片段的核酸分子、质粒和生 理学上或药学上可接受的载体、赋形剂或稳定剂混合制备而成,所述组合物包括但不限于冻 干剂型、水溶液剂型、脂质体或胶囊剂型等。本发明所述的抗体或抗原结合片段、双特异性 抗体、融合蛋白、偶联物、抗体或抗原结合片段的核酸分子、质粒的浓度可从约0.1%变化为 100%(重量)。
附图说明
图1:利用ELISA检测单域抗体与SARS-CoV-2表面糖蛋白受体的结合。
图2:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3001的结合。
图3:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3002的结合。
图4:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3003的结合。
图5:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3004的结合。
图6:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3008的结合。
图7:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3009的结合。
图8:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3010的结合。
图9:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3011的结合。
图10:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3014的结合。
图11:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3020的结合。
图12:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3021的结合。
图13:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3025的结合。
图14:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3026的结合。
图15:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3047的结合。
图16:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3051的结合。
图17:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3055的结合。
图18:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3063的结合。
图19:利用ForteBio检测SARS-CoV-2RBD与单域抗体n3065的结合。
图20:利用ForteBio检测单域抗体与SARS-CoV RBD的交叉结合。
图21:利用ForteBio检测单域抗体与SARS-CoV RBD的交叉结合。
图22:利用ForteBio检测单域抗体与SARS-CoV RBD的交叉结合。
图23:利用ForteBio检测单域抗体与TIM3-Fc的结合。
图24:利用ForteBio检测单域抗体与TIM3-Fc的结合。
图25:利用ForteBio检测单域抗体与TIM3-Fc的结合。
图26:利用ForteBio检测n3055抗体和17个单域抗体与SARS-CoV-2RBD的竞争结合。
图27:利用ForteBio检测n3055抗体和17个单域抗体与SARS-CoV-2RBD的竞争结合。
图28:利用ForteBio检测n3063抗体和n3010与SARS-CoV-2RBD的竞争结合。
图29:利用ForteBio检测ACE2与单域抗体对SARS-CoV-2RBD与无关对照单域抗体(anti-5T4 抗体)的竞争性结合。
图30:利用ForteBio检测ACE2与单域抗体对SARS-CoV-2RBD的竞争性结合。
图31:利用ForteBio检测ACE2与单域抗体对SARS-CoV-2RBD的竞争性结合。
发明详述
为了能更彻底地理解发明,以下列出一些定义。上述定义意在包含语法等同成分。
本文中“抗体分子”意指由基本上为公认的免疫球蛋白基因的全部或部分所编码的一种 或多种结构域组成的蛋白质。所述公认的免疫球蛋白基因,例如在人中,包括kappa(κ)、 lambda(λ)和重链基因座,其中包含了无数的可变区基因,以及分别编码IgM、IgD、IgG、 IgE和IgA同种型的恒定区基因mu(μ)、delta(δ)、gamma(γ)、epsilon(ε)、alpha (α)。本文中的抗体意指包括全长抗体、其单个的链以及其所有部分、结构域或片段,以及 来自任意生物体的天然抗体,工程抗体,或为试验、治疗目的或其它如下所进一步规定的目 的而重组产生的抗体。术语“抗体”包括抗体片段,为本领域所公知,诸如Fab、Fab’、F(ab’)2、Fv,scFv或抗体的抗原结合域(例如VHH结构域或VH/VL结构域),或通过修饰完整抗体或 使用重组DNA技术重新合成的那些抗体而产生的抗体片段。术语“抗体”包括单克隆以及多 克隆抗体。抗体可以是拮抗剂、激动剂、中和性抗体、或抑制性抗体、或刺激性抗体。本发 明的抗体可以是非人抗体,嵌合抗体,人源化抗体或完全人抗体。
具体地包括于“抗体”定义范围内的是非糖基化抗体。优选的,本文使用的为“非糖基 化抗体”,意指在Fc区297位缺少糖附着的抗体,其中编号方式依照Kabat的EU系统。非糖基化的抗体可以是去糖基化的抗体,其是一种Fc糖已去除的抗体,例如以化学或酶的方法去 除。可选地,所述非糖基化抗体可以是非糖基化或未糖基化的抗体,其是一种无Fc糖表达的 抗体,例如通过突变一种或多种编码糖基化型的残基或通过在不将糖附着到蛋白质上的生物 体诸如细菌中表达。
本文中使用的“IgG”意指一种属于抗体类的多肽,其基本上为公认的免疫球蛋白γ基 因所编码。在人类中,该类包含IgG1、IgG2、IgG3和IgG4。在小鼠中,该类包含IgG1、IgG2a、 IgG2b、IgG3。本文中“免疫球蛋白(Ig)”意指由基本上为免疫球蛋白基因所编码的一个或 多个多肽组成的蛋白质。免疫球蛋白包括但不限于抗体。免疫球蛋白可具有许多结构型,包 括但不限于全长抗体、抗体片段和单个免疫球蛋白结构域。抗体IgG类中已知的Ig结构域 VH、Cγi、Cγ2、Cγ3、VL以及CL。
本文中使用的“抗原”意指可以在动物体内刺激抗体产生或T细胞反应的化合物、组合 物或物质,包括注射或吸收到动物体内的组合物,可以是蛋白质、糖类、脂质或其它病原体。
本文中所使用的“免疫球蛋白单一可变结构域”意指能够在不与其他免疫球蛋白可变结 构域配对的情况下特异性结合抗原表位的免疫球蛋白可变结构域。本发明含义中的免疫球蛋 白单一可变结构域的一个实例为“结构域抗体”,如本文中的VH结构域抗体。
本文中所使用的“重链可变区(VH)”意指免疫球蛋白重链靠近N端氨基酸序列变化较大 的区域,是常规4链抗体中的的重链可变区结构域。特别用于区分骆驼科的VHH抗体。
本文中使用的“相同性”意指核苷酸或氨基酸序列之间的相似性,或者称为序列同一性。 序列同一性通常根据百分比同一性(或相似性或同源性)来衡量;百分比越高,两个序列越 相似。当使用标准方法比对时,同源物或变体将具有相对高程度的序列同一性。用于比较的 序列比对方法是本领域熟知的。各种程序和对准算法描述于:Smith andWaterman,Adv Appl. Math.,2:482,1981;Needlema and Wunsch,J.Mol.Biol.48:443,1970;Pearson and Lipman,Proc.Natl.Acad.Sci.U.S.A.85:2444,1988;Higgins andSharp,Gene 73: 237-244,1988;Higgins and Sharp,CABIOS 5:151-153,1989;Corpet等,Nucleic Acids Research 16:10881-10890,1988;和Altschul等,Nature Genet.,1994,6:119-129。
可从若干来源获得NCBI基本局部比对搜索工具(BLAST TM)(Altschul等,J.Mol.Biol., 215:403-410,1990。),包括国家生物技术信息中心(NCBI,Bethesda,Md.)和在因特网上 有关用于序列分析程序blastp,blastn,blastx,tblastn和tblastx。
本文中使用的“双特异性抗体”意指含有两种特异性抗原结合位点的人工抗体。
本文中使用的“全人源”意指抗体全部由人类抗体基因所编码。
本文中使用的“融合蛋白”意指融合基因的表达产物,或通过生物学或化学方法融合的 两个或两个以上蛋白质。
本文中使用的“偶联物”意指抗体或蛋白质分子通过生物或化学方法与另一小分子或大 分子连接。
本文中使用的“氨基酸”意指20种天然存在的氨基酸之一或任一非天然类似物,它们可 位于具体规定的位置。本文中“蛋白质”意指至少两个共价连接的氨基酸,其包括蛋白质、 多肽、寡肽和肽。蛋白质可由天然存在的氨基酸和肽键构成,或由合成的肽模拟物结构构成, 该肽模拟物即“类似物”。因此本文中使用的“氨基酸”或“肽残基”意指天然存在和合成的 氨基酸。举例来说,对于本发明目的而言,高苯基丙氨酸、瓜氨酸和降亮氨酸被认为是用于 本发明目的的氨基酸。“氨基酸”也包括诸如脯氨酸和羟脯氨酸的亚氨基酸残基。侧链可以是 (R)或(S)构型。在优选的实施方案中,氨基酸以(S)或L-构型存在。如果使用非天然存在的侧链,可使用非氨基酸取代,例如以阻止或延迟体内降解。
本文中使用的“多肽”意指一种聚合物,其中单体是通过酰胺键连接在一起的氨基酸残 基。当氨基酸是α-氨基酸时,可以使用L-光学异构体或D-光学异构体。如本文所用的术语 “多肽”或“蛋白质”旨在涵盖任何氨基酸序列并包括修饰的序列,例如糖蛋白。术语“多 肽”特别旨在涵盖天然存在的蛋白质,以及重组或合成产生的蛋白质。
本文所使用的“核酸”意指由核苷酸单元(核糖核苷酸,脱氧核糖核苷酸,相关的天然 存在的结构变体及其合成的非天然存在的类似物)通过磷酸二酯键组成的聚合物。因此,该 术语包括核苷酸聚合物,其中核苷酸和它们之间的键包括非天然存在的合成类似物,例如但 不限于硫代磷酸酯,氨基磷酸酯,甲基磷酸酯,手性甲基磷酸酯,2'-O-甲基核糖核苷酸,肽 核酸(PNA)等。例如,可以使用自动DNA合成仪合成这些多核苷酸。术语“寡核苷酸”通常 是指短多核苷酸,通常不大于约50个核苷酸。应当理解,当核苷酸序列由DNA序列(即A, T,G,C)表示时,这也包括其中“U”取代“T”的RNA序列(即A,U,G,C)。
本文使用常规符号来描述核苷酸序列:单链核苷酸序列的左手末端5'末端;双链核苷酸 序列的左手方向称5'方向。向新生RNA转录物添加5'至3'核苷酸的方向称为转录方向。具 有与mRNA相同序列的DNA链被称为编码链。
本文中使用的“质粒”意指在天然质粒的基础上为适应实验室操作而进行人工构建的质 粒。可将核酸分子导入宿主细胞,从而产生转化的宿主细胞。载体可包括允许其在宿主细胞 中复制的核酸序列,例如复制起点,还可以包括一种或多种选择标记基因和本领域已知的其 他遗传元件。
本文所使用的“宿主细胞”也称为受体细胞,是指在转化和转导(感染)中接受外源基 因的宿主细胞。
本文中使用的“药学可接受载体”意指常规的药学上可接受的载体。Remington'sPharmaceutical Sciences,EWMartin,Mack Publishing Co.,Easton,Pa.,第15版(1975),描述了适用于药物递送一种或多种治疗化合物或分子(例如一种或多种抗体)的组合物和制 剂,以及另外的药剂。
本文中“有效预防或治疗剂量”意指足以在用该药剂治疗的受试者中达到所需效果的一 定量的特定药剂。精确的剂量将依赖于治疗的目的,并可为本领域技术人员通过使用公知技 术所确定。剂量范围可为0.01-100mg/kg体重或更大,例如0.1、1、10或50mg/kg体重, 优选1-10mg/kg。如本领域所公知,对于抗体或Fc融合体降解、全身性或局部性递药和新蛋 白酶合成速率,以及年龄、体重、大致健康状况、性别、饮食、给药时间、药物相互作用以 及病症的严重程度而言,调整可以是必需的,并可由本领域那些技术人员通过常规的实验方 法来确定。理想地,治疗有效量的抗体是足以预防,治疗或改善感染或疾病的量。用于预防, 改善和/或治疗受试者的治疗有效量的药剂将取决于所治疗的受试者,痛苦的类型和严重程 度,以及治疗组合物的施用方式。
本文中所使用的“编码”意指多核苷酸中特定核苷酸序列的固有特性,例如基因,cDNA 或mRNA,用作在具有确定的核苷酸序列的生物过程中合成其他聚合物和大分子的模板,或确 定的氨基酸序列和由此产生的生物学特性。因此,如果由该基因产生的mRNA的转录和翻译在 细胞或其他生物系统中产生蛋白质,则基因编码蛋白质。编码链(其核苷酸序列与mRNA序列 相同并且通常在序列表中提供)和非编码链(用作转录模板,基因或cDNA)可以被称为编码 蛋白质。或该基因或cDNA的其他产物。除非另有说明,否则“编码氨基酸序列的核苷酸序列” 包括彼此简并形式且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质和RNA的核苷酸序 列可包括内含子。
除非另外说明,否则本文使用的所有技术和科学术语具有与本公开所属领域的普通技术 人员通常理解的含义相同的含义。除非上下文另有明确说明,否则单数术语“一”,“一个” 和“该”包括复数指示物。还应理解,对于核酸或多肽给出的所有碱基大小或氨基酸大小, 以及所有分子量或分子量值是近似的,并且提供用于描述。尽管与本文描述的那些类似或等 同的方法和材料可用于本公开的实践或测试,但下文描述了合适的方法和材料。术语“包含” 表示“包括”。本文提及的所有出版物、专利申请、专利和其他参考文献均通过引用整体并入。 如果发生冲突,将以本说明书(包括术语解释)为准。另外,材料,方法和实施例仅是说明 性的而不是限制性的。
具体实施方式
实施例中使用的标准的重组DNA技术和分子克隆技术是本领域所熟知的(Ausubel,F.M 等人,Current Protocols in Molecular Biology,Greene PublishingAssoc.和 Wiley-Interscience出版),适用于微生物生长的材料和方法是本领域熟知的。主要化学、 生物试剂购自KAPA Biosystems,New England Biolabs,TransGen Biotech,Thermo Fisher Scientific,OMEGA bio-tek等。
下面结合具体实施例对本发明进行详细说明。
实施例1 SARS-CoV-2表面糖蛋白受体结合域(RBD)蛋白的生产。
编码SARS-CoV-2受体结合域(RBD)(GISAID accession no.EPI_ISL_402124)的319-541 位氨基酸的基因于Genscript公司合成,并构建到带有IgG1的Fc标签以及其C末端带有一 段Avi-tag(GLNDIFEAQKIEWHE)的pSecTag2B表达载体(Thermo Fisher,产品号:V90020) 中。重组质粒转染Expi293细胞(Thermo Fisher,产品号:A14635)进行瞬时表达并用Protein G(GE Healthcare,产品号:17061805)纯化。将纯化的RBD重组蛋白利用生物素蛋白连接 酶将生物素特异性连接到重组蛋白的Avi-tag序列上。
实施例2针对SARS-CoV-2表面糖蛋白受体结合域筛选高亲和力的单域抗体
利用CDR移植技术,将实验室已有的噬菌体抗体库(Cell Host Microbe.2017. 22(4):471-483.e5.;Emerg Microbes Infect.2017.6(10):e89.)中的重链可变区包括CDR1、CDR2和CDR3克隆到人的IGHV胚系家族1-66*01骨架上,最后巢式PCR扩增编码全长 的重链可变区的核酸片段。重链单域抗体的核酸片段随后克隆到噬菌体展示用载体pComb3x(Addgene,产品号:63891)中,连接产物电转化至大肠杆菌电转感受态TG1中,构建库容 量超上千亿的重链单域抗体噬菌体展示库。然后针对生物素标记的SARS-CoV-2RBD来筛选抗体。具体步骤如下:将生物素标记的SARS-CoV-2RBD蛋白固定在链亲和素包被的磁珠上,1012个展示抗体的噬菌体在常温下于1,2,3,4轮分别与5,4,2,1微克抗原孵育两小时,每 轮的筛选所用的噬菌体均为1012个。选用第3、4轮筛选获得的噬菌体,感染TG1细胞并随机 挑选克隆进行单克隆噬菌体ELISA,进一步测序鉴定与SARS-CoV-2RBD蛋白结合的单域抗体。
实施例3抗体的制备、表达与纯化
根据测序结果选择了20个克隆,它们的可溶性表达产物的制备基本按文献进行(Cell Host Microbe.2017.22(4):471-483.e5.)。具体为:将20个克隆的质粒转入HB2151感受 态细胞,从过夜生长的氨苄平皿中挑取单个菌落,接种SB细菌培养液,在30度IPTG诱导条 件下表达12-14小时。收获细菌并用Ni-TNA从中纯化出单域抗体。
实施例4单域抗体与SARS-CoV-2RBD蛋白的结合能力的检测
将100ng SARS-CoV-2RBD蛋白包被在ELISA板上4度过夜,加入浓度梯度稀释的单域 抗体孵育,用抗FLAG-HRP抗体(购自SIGMA)来检测单域抗体与SARS-CoV-2RBD蛋白的结合能力,其中n501是靶向肿瘤表面抗原的单域抗体作为无关对照。结果显示,大部分单域抗体能非常强的结合SARS-CoV-2RBD蛋白(图1)。
实施例5单域抗体与SARS-CoV-2RBD的结合动力学检测
使用BLI技术(Emerg Microbes Infect.2017.6(10):e89.)测定单域抗体n3001,n3002, n3003,n3004,n3008,n3009,n3010,n3011,n3014,n3020,n3021,n3025,n3026,n3047, n3051,n3055,n3063,以及n3065与SARS-CoV-2RBD的结合活性。将生物素标记的SARS-CoV-2 RBD固定于SA传感器(SA biosensor)(Pall Fortebio),浓度梯度稀释的抗体溶液作为分 析样品。步骤如下:将生物素标记的SARS-CoV-2RBD用含有0.02%Tween-20的PBS缓冲液 (PBST)稀释至10μg/ml,然后固化到SA biosensor上,与3倍梯度稀释的抗体溶液(浓 度范围为1500~18.5nM)在running buffer(PBST)中进行结合,其中空白对照孔中不加入 抗体。程序设定为:Association,300s;Dissociation,300s,温度设定为37℃。应用ForteBio Data analysis 10.1软件对数据进行分析。以对应的空白对照孔作为对照扣减背 景,各浓度的曲线按照Mass Transport结合模式进行拟合,得到动力学分析结果,报告中显 示结合的平衡常数(KD)值以及结合速率常数(kon)和解离速率常数(koff)(图2-图19)。
实施例6单域抗体与SARS-CoV RBD的结合动力学检测
利用BLI技术(Emerg Microbes Infect.2017.6(10):e89.)测定单域抗体n3001,n3002, n3003,n3004,n3008,n3009,n3010,n3011,n3014,n3020,n3021,n3025,n3026,n3047, n3051,n3055,n3063,以及n3065与SARS-CoV RBD的结合活性。将生物素标记的SARS-CoV RBD(购自义翘神州)固定于SA传感器(SA biosensor),抗体溶液作为分析样品。步骤如下: 将生物素标记的SARS-CoV用含有0.02%Tween-20的PBS缓冲液(PBST)稀释至10μg/ml, 然后固化到SA biosensor上,与500nM的抗体在running buffer(PBST)中进行结合。结 果显示,这些单域抗体不跟SARS-CoV RBD具有交叉反应(图20-图22)。
实施例7单域抗体的结合特异性检测
利用BLI技术(Emerg Microbes Infect.2017.6(10):e89.)测定单域抗体n3001,n3002, n3003,n3004,n3008,n3009,n3010,n3011,n3014,n3020,n3021,n3025,n3026,n3047, n3051,n3055,n3063,以及n3065是否特异性结合SARS-CoV-2RBD,选取无关抗原TIM3-Fc 蛋白(购自Novoprotein)进行结合动力学检测。将生物素标记的TIM3-Fc固定于SA传感器 (SA biosensor),抗体溶液作为分析样品。步骤如下:将生物素标记的TIM3-Fc用含有0.02% Tween-20的PBS缓冲液(PBST)稀释至10μg/ml,然后固化到SA biosensor上,与500nM 的抗体在running buffer(PBST)中进行结合。结果显示,这些单域抗体不能与TIM3-Fc蛋 白结合,说明具有很好的SARS-CoV-2RBD结合特异性(图23-图25)。
实施例8竞争实验检测18个单域抗体是否在SARS-CoV-2RBD上具有相似的结合表位
以n3055抗体作为竞争对象,将17个单域抗体与n3055抗体进行与SARS-CoV-2RBD的 竞争结合。步骤如下:首先将生物素标记的SARS-CoV-2RBD固定于SA传感器(SAbiosensor) 上,与500nM的第一抗体溶液(n3001,n3002,n3003,n3004,n3008,n3009,n3010,n3011, n3014,n3020,n3021,n3025,n3026,n3047,n3051,n3063和n3065)反应300s,然后 再与含有500nM的n3055抗体和500nM的第一抗体的混合溶液反应,绘制动力学曲线。结 果显示单域抗体n3010和n3063均与n3055抗体的结合表位不同(图26-图27)。
实施例9竞争实验检测n3010与n3063单域抗体是否在SARS-CoV-2RBD上具有相似的结合 表位
步骤如下:首先将生物素标记的SARS-CoV-2RBD固定于SA传感器(SA biosensor)上, 与500nM的第一抗体溶液(n3010)反应300s,然后再与含有500nM的n3063抗体和500nM的第一抗体的混合溶液反应,绘制动力学曲线。结果显示单域抗体n3010和n3063的结合表位不同(图28)。
实施例10检测18个单域抗体对ACE2和SARS-CoV-2RBD的结合竞争
步骤如下:首先将生物素标记的SARS-CoV-2RBD固定于SA传感器(SA biosensor)上, 与500nM的第一抗体溶液(n3001,n3002,n3003,n3004,n3008,n3009,n3010,n3011,n3014,n3020,n3021,n3025,n3026,n3047,n3051,n3063和n3065)反应300s,然后 再与含有200nM的ACE2蛋白和500nM的第一抗体的混合溶液反应,绘制动力学曲线。其中 n3001,n3002,n3003,n3004,n3008,n3009,n3011,n3014,n3020,n3021,n3025,n3026, n3047,n3051,n3063和n3065均能部分竞争ACE2和SARS-CoV-2RBD的结合,n3010完全 不竞争ACE2和SARS-CoV-2RBD的结合(图29-图31)。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使用本发明。以上所 述仅是本发明的优选实施方式,应当指出,对于本领域的技术人员,在不脱离本发明原理的 前提下,还可以做出若干改进和补充,这些改进和补充也应当视为本发明的保护范围。对这 些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原 理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会 被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽 的范围。
SEQUENCE LISTING
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Claims (21)
1.一种结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,包含至少一个免疫球蛋白单一可变结构域,所述免疫球蛋白单一可变结构域包含:
(1)SEQ ID NO:5所示的CDR1,SEQ ID NO:6所示的CDR2,SEQ ID NO:7所示的CDR3;或
(2)SEQ ID NO:8所示的CDR1,SEQ ID NO:9所示的CDR2,SEQ ID NO:10所示的CDR3;或
(3)SEQ ID NO:11所示的CDR1,SEQ ID NO:12所示的CDR2,SEQ ID NO:13所示的CDR3;或
(4)SEQ ID NO:14所示的CDR1,SEQ ID NO:15所示的CDR2,SEQ ID NO:16所示的CDR3。
2.如权利要求1所述的结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,其中所述的免疫球蛋白单一可变结构域包含与SEQ ID NO:1-4中任一氨基酸序列具有至少90%序列相同的氨基酸序列。
3.如权利要求1所述的结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,其中所述的免疫球蛋白单一可变结构域包含与SEQ ID NO:1-4中任一氨基酸序列具有至少95%序列相同的氨基酸序列。
4.如权利要求1所述的结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,其中所述的免疫球蛋白单一可变结构域包含与SEQ ID NO:1-4中任一氨基酸序列具有至少99%序列相同的氨基酸序列。
5.如权利要求1所述的结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,其中所述的免疫球蛋白单一可变结构域是重链可变区(VH)。
6.如权利要求5所述的结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,其中所述的重链可变区(VH)是全人源的。
7.如权利要求1-6所述的任一结合新型冠状病毒(SARS-CoV-2)的抗体分子,其特征在于,与新型冠状病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
8.一种双特异性抗体,其特征在于,含有权利要求1-7中任一项所述的抗体分子。
9.如权利要求8所述的双特异性抗体,其特征在于,能够特异性结合新型冠状病毒(SARS-CoV-2),或与新型冠状病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
10.一种融合蛋白,其特征在于,包含权利要求1-7中任一项所述的抗体分子,或权利要求8-9中任一项所述的双特异性抗体,和一种异源蛋白融合。
11.如权利要求10所述的融合蛋白,其特征在于,其中的异源蛋白是人免疫球蛋白Fc。
12.如权利要求10所述的融合蛋白,其特征在于,其中的异源蛋白是人IgG1的Fc。
13.如权利要求10-12所述的任一融合蛋白,其特征在于,能够特异性结合新型冠状病毒(SARS-CoV-2),或与新型冠状病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
14.一种偶联物,其特征在于,由权利要求1-7中任一项所述的抗体分子,或权利要求8-9中任一项所述的双特异性抗体,或权利要求10-13中任一项所述的融合蛋白,与一种效应分子偶联。
15.如权利要求14所述的偶联物,其特征在于,其中的效应分子是可检测标记。
16.如权利要求15所述的偶联物,其特征在于,其中的可检测标记是荧光标记,放射性标记,亲和素,生物素,或酶。
17.如权利要求14-16所述的任一偶联物,其特征在于,能够特异性结合新型冠状病毒(SARS-CoV-2),或与新型冠状病毒(SARS-CoV-2)表面糖蛋白受体结合域(RBD)结合的KD值小于1×10-7M。
18.一种核酸分子,其特征在于编码权利要求1-7中所述的抗体分子。
19.一种质粒,其特征在于含有权利要求18所述的核酸分子。
20.一种宿主细胞,其特征在于含有权利要求19所述的质粒。
21.一种药用组合物,含有有效预防或治疗剂量的权利要求1-7中任一项所述的抗体分子,或权利要求8-9中任一项所述的双特异性抗体,或权利要求10-13中任一项所述的融合蛋白,或权利要求14-17中任一项所述的偶联物,或权利要求18所述的核酸分子,或权利要求19所述的质粒,和一种药学可接受载体。
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US11732030B2 (en) | 2020-04-02 | 2023-08-22 | Regeneron Pharmaceuticals, Inc. | Anti-SARS-CoV-2-spike glycoprotein antibodies and antigen-binding fragments |
US11999777B2 (en) | 2020-06-03 | 2024-06-04 | Regeneron Pharmaceuticals, Inc. | Methods for treating or preventing SARS-CoV-2 infections and COVID-19 with anti-SARS-CoV-2 spike glycoprotein antibodies |
WO2022056171A1 (en) * | 2020-09-10 | 2022-03-17 | Bighat Biosciences, Inc. | Sars-cov(-2) spike glycoprotein-binding domains and polypeptides comprising the same and use of the same |
CN114028539A (zh) * | 2021-09-13 | 2022-02-11 | 北京大学 | 粘蛋白1在抑制冠状病毒中的应用 |
CN114028539B (zh) * | 2021-09-13 | 2024-04-26 | 北京大学 | 粘蛋白1在抑制冠状病毒中的应用 |
WO2023058762A1 (ja) * | 2021-10-08 | 2023-04-13 | 国立研究開発法人理化学研究所 | 蛍光vhh抗体 |
CN116041498A (zh) * | 2021-10-13 | 2023-05-02 | 中国医学科学院病原生物学研究所 | 特异性结合SARS-CoV-2刺突蛋白的单域抗体及其应用 |
CN116041498B (zh) * | 2021-10-13 | 2024-01-02 | 中国医学科学院病原生物学研究所 | 特异性结合SARS-CoV-2刺突蛋白的单域抗体及其应用 |
CN114702576A (zh) * | 2022-03-01 | 2022-07-05 | 武汉科技大学 | 抗新型冠状病毒s蛋白受体结合区的单域抗体及其编码基因和应用 |
CN114702576B (zh) * | 2022-03-01 | 2023-09-01 | 武汉科技大学 | 抗新型冠状病毒s蛋白受体结合区的单域抗体及其编码基因和应用 |
CN116396382A (zh) * | 2023-04-27 | 2023-07-07 | 中国海洋大学 | 一种靶向幽门螺杆菌HpaA的鲨鱼单域抗体及其应用 |
CN116396382B (zh) * | 2023-04-27 | 2024-08-27 | 中国海洋大学 | 一种靶向幽门螺杆菌HpaA的鲨鱼单域抗体及其应用 |
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