Select broadly neutralizing anti-HIV antibodies (bNAbs) are capable of simultaneously engaging gp120/gp41 on the surface of infected CD4+ T-cells, and Fc-gamma receptors (FcγRs) on the surface of innate immune effector cells. Such bNAbs can kill HIV infected cells and may thus be capable of reducing or eliminating the HIV reservoir. PGT121 is a particularly promising bNAb in this class, having demonstrated potent in-vitro cell killing as well as in-vivo efficacy in SHIV infected monkeys (Borducchi et al. Nature, in press). Here we describe GS-9722, an engineered variant of PGT121 with enhanced effector function and improved drug-like-properties.
A panel of PGT121 crystallizable-fragment (Fc) mutations was tested in Fc-receptor (FcR) binding assays, primary cell killing assays and preclinical PK studies in order to optimize effector function and PK properties. In parallel with these efforts, in-silico and in-vitro approaches were used to guide the selection of PGT121 antibody binding fragment (Fab) mutations that reduced immunogenic risk and improved drug-like-properties.
The Fc engineering campaign identified mutations that enhanced binding to activating FcγRs as well as the neonatal Fc-receptor (FcRn). The resulting antibody demonstrated significantly enhanced killing of HIV infected CD4+ T-cells by primary natural killer (NK) cells isolated from multiple human donors (mean values: Emax=71%, EC50=0.23 μg/mL) compared to PGT121 (mean values: Emax=11%, EC50=3.4 μg/mL). The Fab engineering campaign identified mutations that removed immunogenic T-cell epitopes, removed glycosylation motifs and improved thermodynamic stability. The Fab mutations had minimal impact on neutralization breadth or potency when tested on a panel of clade B patient isolates (60% at IC95≤15 µg/mL, median IC95=0.18 µg/mL,) compared to PGT121 (58% at IC95≤15 µg/mL, median IC95=0.33 µg/mL). GS-9722 incorporates all mutations identified in the Fc and Fab engineering campaigns and exhibits a pharmacokinetic profile similar to PGT121 in non-human primate studies.
GS-9722 is a first in class effector-enhanced bNAb for the targeted elimination of HIV infected cells and is currently in Ph1b clinical testing. Future studies will explore GS-9722 in combination with additional effector enhanced bNAbs, immune-modulatory agents (i.e. GS-9620), latency reversal agents and therapeutic vaccines in a multi-pronged approach to reduce or eliminate the HIV reservoir.