Cell Research:高福院士课题组研发出预防治疗作用的MERS抗体

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近日，中科院微生物研究所高福课题组与严景华课题组在中东呼吸系统综合征冠状病毒（MERS）抗体研究方面获得新突破。研究团队成功研发出一株人源化的中和抗体，该抗体无论在MERS病毒感染前和感染后使用，都能有效清除小鼠体内病毒，因此有望成为预防和治疗MERS的候选药物。该成果今天在线发表于《细胞研究》。

研究人员通过表达MERS病毒刺突蛋白（S）上与病毒受体相互作用的结构域（MERS-RBD）免疫小鼠，筛选到了两株抗MERS病毒的中和抗体——4C2和2E6。进一步研究表明这两株中和抗体能够竞争病毒S蛋白与受体（CD26）的结合，从而抑制病毒侵入宿主细胞。随后，研究组通过保留4C2抗体分子上一种氨基酸残基，对4C2进行了最大限度的人源化改造。

改造后的抗体保留了接近于鼠源抗体的中和活性。值得关注的是，研究人员用小鼠模型证明了人源化的4C2无论在病毒感染前还是感染后使用均能有效清除病毒。

来源：中国科学报

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A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein

Yan Li1,*, Yuhua Wan1,2,3,*, Peipei Liu1,*, Jincun Zhao4,11, Guangwen Lu5, Jianxun Qi1, Qihui Wang3, Xuancheng Lu6, Ying Wu1, Wenjun Liu1, Buchang Zhang2, Kwok-Yung Yuen7, Stanley Perlman4, George F Gao1,2,8,9,10 and Jinghua Yan1,2,3

The newly-emerging Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe and fatal acute respiratory disease in humans. Despite global efforts, the potential for an associated pandemic in the future cannot be excluded. The development of effective counter-measures is urgent. MERS-CoV-specific anti-viral drugs or vaccines are not yet available. Using the spike receptor-binding domain of MERS-CoV (MERS-RBD) to immunize mice, we identified two neutralizing monoclonal antibodies (mAbs) 4C2 and 2E6. Both mAbs potently bind to MERS-RBD and block virus entry in vitro with high efficacy. We further investigated their mechanisms of neutralization by crystallizing the complex between the Fab fragments and the RBD, and solved the structure of the 4C2 Fab/MERS-RBD complex. The structure showed that 4C2 recognizes an epitope that partially overlaps the receptor-binding footprint in MERS-RBD, thereby interfering with the virus/receptor interactions by both steric hindrance and interface-residue competition. 2E6 also blocks receptor binding, and competes with 4C2 for binding to MERS-RBD. Based on the structure, we further humanized 4C2 by preserving only the paratope residues and substituting the remaining amino acids with the counterparts from human immunoglobulins. The humanized 4C2 (4C2h) antibody sustained similar neutralizing activity and biochemical characteristics to the parental mouse antibody. Finally, we showed that 4C2h can significantly abate the virus titers in lungs of Ad5-hCD26-transduced mice infected with MERS-CoV, therefore representing a promising agent for prophylaxis and therapy in clinical settings.

http://www.nature.com/cr/journal ... ull/cr2015113a.html