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

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.

• Authors: Boris Julg, Kathryn E Stephenson, Kshitij Wagh, Sabrina C Tan, Rebecca Zash, Stephen Walsh, Jessica Ansel, Diane Kanjilal, Joseph Nkolola, Victoria E K Walker-Sperling, Jasper Ophel, Katherine Yanosick, Erica N Borducchi, Lori Maxfield, Peter Abbink, Lauren Peter, Nicole L Yates, Martina S Wesley, Tom Hassell, Huub C Gelderblom, Allen deCamp, Bryan T Mayer, Alicia Sato, Monica W Gerber, Elena E Giorgi, Lucio Gama, Richard A Koup, John R Mascola, Ana Monczor, Sofia Lupo, Charlotte-Paige Rolle, Roberto Arduino, Edwin DeJesus, Georgia D Tomaras, Michael S Seaman, Bette Korber, Dan H Barouch
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 6 Pg. 1288-1296 (06 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35551291 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: © 2022. The Author(s).

Chemical References

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

Topics

• 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)