MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
PLoS Pathog. 2019 Jun 26;15(6):e1007836. doi: 10.1371/journal.ppat.1007836. eCollection 2019 Jun.
Dengue is the most widespread vector-borne viral disease caused by dengue virus (DENV) for which there are no safe, effective drugs approved for clinical use. Here, by using sequential antigen panning of a yeast antibody library derived from healthy donors against the DENV envelop protein domain III (DIII) combined with depletion by an entry defective DIII mutant, we identified a cross-reactive human monoclonal antibody (mAb), m366.6, which bound with high affinity to DENV DIII from all four DENV serotypes. Immunogenetic analysis indicated that m366.6 is a germline-like mAb with very few somatic mutations from the closest VH and Vλ germline genes. Importantly, we demonstrated that it potently neutralized DENV both in vitro and in the mouse models of DENV infection without detectable antibody-dependent enhancement (ADE) effect. The epitope of m366.6 was mapped to the highly conserved regions on DIII, which may guide the design of effective dengue vaccine immunogens. Furthermore, as the first germline-like mAb derived from a naïve antibody library that could neutralize all four DENV serotypes, the m366.6 can be a tool for exploring mechanisms of DENV infection, and is a promising therapeutic candidate.
登革热是由登革病毒（DENV）引起的最广泛传播的虫媒病毒病，目前尚无安全、有效的药物批准用于临床。在这里，我们通过对来自健康供体的针对登革病毒包膜蛋白结构域 III（DIII）的酵母抗体文库进行连续抗原淘选，并结合使用进入缺陷型 DIII 突变体进行耗尽，鉴定出一种具有交叉反应性的人源单克隆抗体（mAb）m366.6，该抗体与来自所有 4 种登革病毒血清型的 DENV DIII 具有高亲和力。免疫遗传分析表明，m366.6 是一种类似于胚系的 mAb，与最近的 VH 和 Vλ 胚系基因相比，体细胞突变很少。重要的是，我们证明它能够在体外和登革热感染的小鼠模型中有效中和 DENV，而没有可检测到的抗体依赖性增强（ADE）作用。m366.6 的表位被映射到 DIII 上高度保守的区域，这可能为设计有效的登革热疫苗免疫原提供指导。此外，作为首个能够中和所有 4 种登革病毒血清型的源自天然抗体文库的胚系样 mAb，m366.6 可用于探索 DENV 感染的机制，是一种有前途的治疗候选药物。
