Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency

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. [Display omitted] •Bispecific anti-HIV-1 antibodies combine the breadth and potency of two bNAbs•IgG3 hinge domain engineering increases Fab flexibility and improves neutralization•Particular bispecific antibody combinations exhibit synergistic activity•Hinge-modified bispecific antibodies display enhanced in vivo therapeutic activity A new generation of bispecific anti-HIV-1 antibodies combines the breadth and potency of previous broadly neutralizing antibodies in a synergistic manner, producing enhanced in vitro viral neutralization and better control of viremia in vivo.