Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants
Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants
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DOI：
10.1128/jvi.79.10.5900-5906.2005
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发表时间：
2005-05-01
影响因子：
5.4
通讯作者：
Marasco, WA
中科院分区：
文献类型：
--
作者：
Sui, JH;Li, WH;Marasco, WA
在这份报告中，80 R免疫球蛋白G1（IgG 1），一种抗严重急性呼吸综合征冠状病毒（SARS冠状病毒）刺突蛋白的人单克隆抗体，在体外作为病毒进入抑制剂，在小鼠模型中的体内抗病毒活性进行了研究。当80 R IgG 1以人类治疗上可达到的剂量对小鼠进行免疫给药时，病毒复制降低了4个数量级以上，低于测定限值。80 R结合所需的S蛋白的核心区域被鉴定为与受体ACE 2结合结构域重叠的构象敏感片段（残基324至503）。鉴定了80 R结合的关键氨基酸。此外，各种80 R结合域氨基酸取代发生在SARS样冠状病毒从果子狸，并在2002/2003年爆发和2003/2004年广东指数患者的演变，进行了分析。结果表明，绝大多数SARS-CoV对80 R敏感。我们建议，通过建立新出现的SARS-CoV的敏感性和耐药谱，通过80 R的核心180个氨基酸的中和表位的早期S1基因分型，一个有效的免疫预防策略与80 R应该是可能的，在爆发设置。我们的研究还警告说，对于任何基于中和抗体应答的预防策略，无论是被动免疫还是主动免疫，有效使用基因分型监测是必要的。
In this report, the antiviral activity of 80R immunoglobulin G1 (IgG1), a human monoclonal antibody against severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein that acts as a viral entry inhibitor in vitro, was investigated in vivo in a mouse model. When 80R IgG1 was given prophylactically to mice at doses therapeutically achievable in humans, viral replication was reduced by more than 4 orders of magnitude to below assay limits. The essential core region of S protein required for 80R binding was identified as a conformationally sensitive fragment (residues 324 to 503) that overlaps the receptor ACE2-binding domain. Amino acids critical for 80R binding were identified. In addition, the effects of various 80R-binding domain amino acid substitutions which occur in SARS-like-CoV from civet cats, and which evolved during the 2002/2003 outbreak and in a 2003/2004 Guangdong index patient, were analyzed. The results demonstrated that the vast majority of SARS-CoVs are sensitive to 80R. We propose that by establishing the susceptibility and resistance profiles of newly emerging SARS-CoVs through early S1 genotyping of the core 180-amino-acid neutralizing epitope of 80R, an effective immunoprophylaxis strategy with 80R should be possible in an outbreak setting. Our study also cautions that for any prophylaxis strategy based on neutralizing antibody responses, whether by passive or active immunization, a genotyping monitor will be necessary for effective use.