PGDM-1400

In this study, all preexisting HIV-1 s rains prior to immunotherapy initiation were sensitive in vitro to VRC07-523LS and mostly sensitive to both PGT121 and PGDM1400.However, rebounded viruses during immunotherapy were still ensitive in vitro to VRC07-523LS but partially or completely resistant to PGT121 and PGDM1400.Similar to VRC01, VRC07-523LS targets the CD4bs.And, hence, high concentrations of two bnAbs (VRC01 and VRC07-523LS) that target the HIV-1 Env CD4bs are associated with existence of sensitive, replicating strains in the serum of some treated individuals, whereas coadministration of PGT121 and PGDM1400 (with VRC07- 523LS) led to the development of HIV-1 strains with defined direct resistance against these two bnAbs.

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg−1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg−1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml−1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.