Abstract：
The potency of antibody neutralization in cell culture has been used as the key criterion for selection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for clinical development. As other aspects may also influence the degree of protection in vivo, we compared the efficacy of two neutralizing monoclonal antibodies (TRES6 and 4C12) targeting different epitopes of the receptor binding domain (RBD) of SARS-CoV-2 in a prophylactic setting in rhesus monkeys. All four animals treated with TRES6 had reduced viral loads in the upper respiratory tract 2 days after naso-oropharyngeal challenge with the Alpha SARS-CoV-2 variant. Starting 2 days after challenge, mutations conferring resistance to TRES6 were dominant in two of the rhesus monkeys, with both animals failing to maintain reduced viral loads. Consistent with its lower serum neutralization titer at the day of challenge, prophylaxis with 4C12 tended to suppress viral load at day 2 less efficiently than TRES6. However, a week after challenge, mean viral loads in the lower respiratory tract in 4C12-treated animals were lower than in the TRES6 group and no mutations conferring resistance to 4C12 could be detected in viral isolates from nasal or throat swabs. Thus, genetic barrier to resistance seems to be a critical parameter for the efficacy of prophylaxis with monoclonal antibodies against SARS-CoV-2. Furthermore, comparison of antibody concentrations in respiratory secretions to those in serum shows reduced distribution of the 4C12 antibody into respiratory secretions and a delay in the appearance of antibodies in bronchoalveolar lavage fluid compared to their appearance in secretions of the upper respiratory tract.IMPORTANCEMonoclonal antibodies are a powerful tool for the prophylaxis and treatment of acute viral infections. Hence, they were one of the first therapeutic agents licensed for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oftentimes, the main criterion for the selection of antibodies for clinical development is their potency of neutralization in cell culture. By comparing two antibodies targeting the Spike protein of SARS-CoV-2, we now observed that the antibody that neutralized SARS-CoV-2 more efficiently in cell culture suppressed viral load in challenged rhesus monkeys to a lesser extent. Extraordinary rapid emergence of mutants of the challenge virus, which had lost their sensitivity to the antibody, was identified as the major reason for the reduced efficacy of the antibody in rhesus monkeys. Therefore, the viral genetic barrier to resistance to antibodies also affects their efficacy.
摘要：
细胞培养物中抗体中和的效力已被用作选择针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗体进行临床开发的关键标准。由于其他方面也可能影响体内保护程度，我们比较了两种针对SARS-CoV-2受体结合域(RBD)不同表位的中和单克隆抗体(TRES6和4C12)在恒河猴预防性治疗中的疗效.用TRES6治疗的所有四只动物在用AlphaSARS-CoV-2变体鼻口咽攻击后2天上呼吸道的病毒载量降低。挑战后2天开始，赋予对TRES6抗性的突变在两只恒河猴中占主导地位，两种动物都无法保持减少的病毒载量。与其在攻击当天较低的血清中和滴度一致，与TRES6相比,使用4C12进行预防在第2天抑制病毒载量的效率较低.然而,挑战一周后，4C12治疗动物下呼吸道的平均病毒载量低于TRES6组,并且在鼻或咽拭子的病毒分离株中未检测到赋予4C12耐药性的突变.因此，抗性的遗传障碍似乎是抗SARS-CoV-2单克隆抗体预防效果的关键参数。此外，呼吸道分泌物中的抗体浓度与血清中的抗体浓度的比较显示,与它们在上呼吸道分泌物中的出现相比,4C12抗体在呼吸道分泌物中的分布减少,并且抗体在支气管肺泡灌洗液中的出现延迟。IMPORTANCE单克隆抗体是预防和治疗急性病毒感染的有力工具。因此，它们是首批获得许可用于治疗严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)的治疗剂之一.通常,选择用于临床开发的抗体的主要标准是它们在细胞培养物中的中和效力。通过比较针对SARS-CoV-2的Spike蛋白的两种抗体，我们现在观察到，在细胞培养物中更有效地中和SARS-CoV-2的抗体在较小程度上抑制了受攻击的恒河猴的病毒载量。攻击病毒的突变体异常迅速出现，失去了对抗体的敏感性，被确定为抗体在恒河猴中功效降低的主要原因。因此,病毒对抗体抗性的遗传障碍也影响其功效。
