Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial

Nat Med. 2022 Jun;28(6):1288-1296. doi: 10.1038/s41591-022-01815-1. Epub 2022 May 12.

Abstract

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Neutralizing
  • Antiviral Agents / therapeutic use
  • Broadly Neutralizing Antibodies
  • HIV Antibodies
  • HIV Infections*
  • HIV Seropositivity*
  • HIV-1*
  • Humans
  • Viremia / drug therapy

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antiviral Agents
  • Broadly Neutralizing Antibodies
  • HIV Antibodies

Associated data

  • ClinicalTrials.gov/NCT03205917