A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques.
A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques.
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DOI：
10.1016/j.medj.2022.01.004
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发表时间：
2022-03-11
期刊：
影响因子：
--
通讯作者：
Crowe JE Jr
中科院分区：
文献类型：
--
作者：
Cobb RR;Nkolola J;Gilchuk P;Chandrashekar A;Yu J;House RV;Earnhart CG;Dorsey NM;Hopkins SA;Snow DM;Chen RE;VanBlargan LA;Hechenblaickner M;Hoppe B;Collins L;Tomic MT;Nonet GH;Hackett K;Slaughter JC;Lewis MG;Andersen H;Cook A;Diamond MS;Carnahan RH;Barouch DH;Crowe JE Jr
人单克隆抗体 (mAb) 治疗有望用于预防或治疗 COVID-19。通过突变设计以延长其在人血清中的持久性的中和抗体的暴露前预防功效以及预防 SARS-CoV-2 感染所需的血清中的中和抗体滴度仍不清楚。两种中和单克隆抗体（COV2-2130 和 COV2-2381）的 Fc 区针对 SARS-CoV-2 刺突蛋白受体结合域上的非重叠表位，经过工程设计以延长其在人体中的持久性并减少与 Fc γ 受体的相互作用。我们在 SARS-CoV-2 感染的非人灵长类动物 (NHP) 模型中评估了通过静脉内或肌内途径预防性给予单个抗体或两种抗体组合（指定为 ADM03820）的保护作用。单个 mAb 或 ADM03820 的被动转移以剂量依赖性方式在 NHP 呼吸道中提供病毒学保护，并且 ADM03820 在体外有效中和了令人关注的 SARS-CoV-2 变体。我们为通过直接病毒中和作用的被动转移的人类抗体定义了 NHP 中的保护性血清中和抗体滴度和浓度。总之，我们证明半衰期延长且缺乏 Fc 介导的效应器功能的中和抗体对于 NHP 中 SARS-CoV-2 感染的暴露前预防是有效的。这些结果支持 ADM03820 用于预防 COVID-19 的临床开发。这项研究得到了 JPEO-CBRND 合同的支持 (W911QY-20-9-003, 20-05)；联合科学技术办公室和联合项目执行办公室（MCDC-16-01-002 JSTO、JPEO）； DARPA 拨款 (HR0011-18-2-0001)； NIH 资助 (R01 AI157155)；以及默克公司颁发的 2019 年未来洞察奖。抗体是针对 SARS-CoV-2 感染的保护性免疫的主要介质，人单克隆抗体有望用于 COVID-19 的预防或治疗。定义抗体保护功效并确定保护所需的中和抗体滴度对于开发有效的基于抗体的 COVID-19 疗法至关重要。研究表明，通过静脉内或肌内途径预防性地被动转移个体中和人类单克隆抗体或两者的组合，可以保护非人类灵长类动物免受 SARS-CoV-2 感染。有效的抗体介导的预防保护主要通过直接病毒中和来实现，并确定了血清中中和抗体的保护滴度。这些结果支持将测试的抗体组合作为预防 COVID-19 的生物制剂进行临床开发。在这项工作中，Cobb 等人。描述了两种人类中和抗体的组合，其半衰期延长且缺乏 Fc 效应子功能，当通过静脉内或肌内途径预防性给药时，可保护非人类灵长类动物免受 SARS-CoV-2 感染。定义了病毒学保护所需的血清抗体滴度。
Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized. The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection. Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization. In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention. This research was supported by a contract from the JPEO-CBRND (W911QY-20-9-003, 20-05); the Joint Sciences and Technology Office and Joint Program Executive Office (MCDC-16-01-002 JSTO, JPEO); a DARPA grant (HR0011-18-2-0001); an NIH grant (R01 AI157155); and the 2019 Future Insight Prize from Merck KGaA. Antibodies are a principal mediator of protective immunity to SARS-CoV-2 infections, and human monoclonal antibodies are promising for COVID-19 prophylaxis or therapy. Defining antibody protective efficacy and establishing the titer of neutralizing antibodies required for protection are imperative for the development of efficient antibody-based therapeutics against COVID-19. Here, studies reveal that passive transfer of individual neutralizing human monoclonal antibodies or combinations of the two given prophylactically by an intravenous or intramuscular route protected non-human primates against SARS-CoV-2 infection. Efficient antibody-mediated prophylaxis protection was achieved principally via direct virus neutralization and defined a protective titer of neutralizing antibodies in serum. These results support clinical development of the tested antibody combination as a biologic for COVID-19 prevention. In this work, Cobb et al. described a combination of two human neutralizing antibodies, engineered with extended half-life and lacking Fc effector functions, which protected non-human primates against SARS-CoV-2 infection when given prophylactically by an intravenous or intramuscular route. The serum antibody titer required for virological protection was defined.
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