Abstract Body

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. Complementary viral coverage resulting in extended breadth and potency has been modeled for multiple bNAb combinations and the combination of the CD4bs antibody VRC07-523LS, the V3-glycan antibody PGT121 and the V2-apex antibody PGDM1400 has been identified to cover 99% of cross clade strains of which 82% would be covered with at least 2 active antibodies (at IC80 of <10ug/ml).

To determine whether the triple combination of PGDM1400, PGT121 and VRC07-523LS is safe and active against HIV in humans, we initiated a two-step phase 1 study: Part 1 was a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial to evaluate three intravenous doses of PGDM1400 alone or in combination with PGT121 (3, 10, and 30 mg/kg per antibody, respectively) in adults without HIV. Part 2 was a multi-center, open-label trial of a single intravenous (IV) administration of 20 mg/kg of PGDM1400, PGT121 and VRC07-523LS each or a single infusion of 30 mg/kg of PGDM1400+PGT121 each, in viremic adults with HIV not on ART. Clinicaltrials.gov #: NCT03205917

PGDM1400 was safe and well tolerated at doses up to 30 mg/kg and when given in combination with PGT121 and VRC07-523LS. A single infusion of 20 mg/kg of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a mean of 2.04 log10 copies/ml, however, viral rebound occurred within a median of 20 days post nadir. Viruses present before antibody administration were all susceptible to VRC07-523-LS and in many cases were susceptible to PGT121 and PGDM1400. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121, while susceptibility to VRC07-523-LS was largely preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg/ml.

To our knowledge, this is the first report of a triple antibody combination in humans for the treatment of HIV. While PGDM1400 and the combination of all three bNAbs were safe and well tolerated, our data highlight the critical requirement of broad antiviral activity and high serum concentrations that bNAb combinations need to achieve in order to maintain control over the virus.