G-109 Special lecture: Engineering anti-HIV antibodies for optimal control of HIV infection

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Broadly neutralizing antibodies (bNAbs) against the envelope glycoprotein of HIV-1 (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, non-overlapping epitopes essential for viral fitness. In addition to Fab mediated neutralizing activity, Fc effector activity resulting from selective FcγR binding is required to mediate clearance of viral particles, elimination of infected cells and induction of cellular responses. I will discuss the development and evaluation of new classes of anti-HIV antibodies, in which engineering of the Fab, hinge and Fc domains has resulted in antibodies with remarkable breadth, potency, half-life and effector activity. Bispecific anti-Env neutralizing antibodies (biNAbs) with potent in vitro and in vivo activity was achieved by engineering the hinge domain of IgG1 to increase Fab domain flexibility necessary for hetero-bivalent binding to the Env trimer. 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. Combining these biNAbs with Fc’s modified to enhance FcRn and FcγR binding has resulted in molecules with extended half-life, enhanced effector activity. These findings suggest innovative strategies for generating anti-HIV antibodies with remarkable neutralization breadth, potency, half-life and effector activities, representing ideal candidate molecules for the control of HIV-1 infection.

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