Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice
Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice
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DOI：
10.1086/427242
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发表时间：
2005-02-15
影响因子：
6.4
通讯作者：
Ambrosino, DM
中科院分区：
文献类型：
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作者：
Greenough, TC;Babcock, GJ;Ambrosino, DM
背景严重急性呼吸系统综合症（SARS）在2003年流行之后仍然是一个重大的公共卫生问题。中和SARS相关冠状病毒（SARS-CoV）的人单克隆抗体（MAbs）可以为暴露个体提供保护。用重组SARS-CoV主要表面糖蛋白（S）胞外域免疫转人免疫球蛋白基因小鼠。在SARS-CoV感染的小鼠模型中对来自这些小鼠的2种中和性单克隆抗体的表位进行了定位和评估。这两种单克隆抗体结合的S糖蛋白表达的转染细胞，但不同的能力，以阻止S糖蛋白的Vero E6细胞的结合。免疫沉淀分析显示2个抗体结合表位：一个MAb（201）结合在aa 490-510的受体结合结构域内，另一个MAb（68）结合在aa 130-150的结构域外部。在用SARS-CoV攻击之前接受40 mg/kg单克隆抗体的小鼠完全免受肺部病毒复制的影响，并且低至1.6 mg/kg的剂量提供了显著的保护。针对SARS-CoV S糖蛋白的单克隆抗体确定了两个中和表位。针对这两个表位的抗体保护小鼠免受SARS-CoV攻击。临床试验计划测试MAb 201，一种对受体结合区内的表位具有特异性的全人源MAb。
Background. Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARS-CoV) could provide protection for exposed individuals.Methods. Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection.Results. Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb ( 201) bound within the receptor-binding domain at aa 490-510, and the other MAb ( 68) bound externally to the domain at aa 130-150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection.Conclusions. Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region.