Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency.
Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency.
复制标题
DOI：
10.1016/j.cell.2016.04.050
复制
发表时间：
2016-06-16
期刊：
影响因子：
64.5
通讯作者：
Ravetch JV
中科院分区：
文献类型：
--
作者：
Bournazos S;Gazumyan A;Seaman MS;Nussenzweig MC;Ravetch JV
针对HIV - 1包膜糖蛋白（Env）的广泛中和抗体（bNAbs）在HIV - 1动物模型和人类中可抑制病毒血症。为了在不出现病毒逃逸突变体的情况下实现强大的活性，必须共同施用不同的bNAbs以靶向对病毒适应性至关重要的不同表位。在此我们报道了具有强大活性的双特异性抗Env中和抗体（biNAbs）的研发。通过结合一种经过改造的IgG3铰链区来增加Fab区的灵活性（这对于与Env三聚体进行异源二价结合是必需的），同时保留IgG1 - Fc的功能特性，从而实现了biNAbs的协同活性。与未修饰的biNAbs相比，铰链区变体表现出显著提高的中和活性，某些特定组合在体外显示出协同中和效力的证据，并且在感染HIV - 1的人源化小鼠体内治疗活性增强。这些发现为产生具有增强的中和广度和效力的biNAbs提出了创新策略，代表了控制HIV - 1感染的理想候选分子。
Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) suppress viremia in animal models of HIV-1 and humans. To achieve potent activity without the emergence of viral escape mutants, co-administration of different bNAbs is necessary to target distinct epitopes essential for viral fitness. Here we report the development of bispecific anti-Env neutralizing antibodies (biNAbs) with potent activity. Synergistic activity of biNAbs was achieved by combining an engineered hinge domain of IgG3 to increase Fab domain flexibility necessary for hetero-bivalent binding to the Env trimer, while retaining the functional properties of the IgG1-Fc. Compared to unmodified biNAbs, hinge domain variants exhibited substantially improved neutralization activity, with particular combinations showing evidence of synergistic neutralization potency in vitro and enhanced in vivo therapeutic activity in HIV-1-infected humanized mice. These findings suggest innovative strategies for generating biNAbs with enhanced neutralization breadth and potency, representing ideal candidate molecules for the control of HIV-1 infection.