Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus
Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus
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DOI：
10.1371/journal.ppat.1003312
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发表时间：
2013-04-01
期刊：
影响因子：
6.7
通讯作者：
Diamond, Michael S.
中科院分区：
文献类型：
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作者：
Pal, Pankaj;Dowd, Kimberly A.;Diamond, Michael S.
基孔肯雅病毒（CHIKV）是一种由蚊子传播的甲病毒，可在人类中引发全球性的使人衰弱的多发性关节炎流行。由于迫切需要开发治疗药物，我们筛选了230种新的小鼠抗基孔肯雅病毒单克隆抗体（MAb），以检测它们抑制所有三种基孔肯雅病毒基因型感染的能力。36种中和性单克隆抗体中的4种（CHK - 102、CHK - 152、CHK - 166和CHK - 263）在缺乏I型干扰素受体（Ifnar(-/-)）的高度易感免疫缺陷小鼠中作为预防措施可提供完全的抗致死保护，并定位在E1和E2结构蛋白上的不同表位。最具保护作用的单克隆抗体CHK - 152已人源化，被证明可阻断病毒融合，且在体内需要Fc效应功能以达到最佳活性。在暴露后治疗试验中，在基孔肯雅病毒诱导死亡前24至36小时给予单剂量的两种中和性单克隆抗体组合（CHK - 102 + CHK - 152或CHK - 166 + CHK - 152）可限制耐药性的产生，并保护免疫缺陷小鼠免受疾病侵害。所选的高度中和性单克隆抗体对可能是人类基孔肯雅病毒的一种有前景的治疗选择。
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-)) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans.