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Julg, Boris; Stephenson, Kathryn E; Wagh, Kshitij; Tan, Sabrina C; Zash, Rebecca; Walsh, Stephen; Ansel, Jessica; Kanjilal, Diane; Nkolola, Joseph; Walker-Sperling, Victoria E K; Ophel, Jasper; Yanosick, Katherine; Borducchi, Erica N; Maxfield, Lori; Abbink, Peter; Peter, Lauren; Yates, Nicole L; Wesley, Martina S; Hassell, Tom; Gelderblom, Huub C; deCamp, Allen; Mayer, Bryan T; Sato, Alicia; Gerber, Monica W; Giorgi, Elena E; Gama, Lucio; Koup, Richard A; Mascola, John R; Monczor, Ana; Lupo, Sofia; Rolle, Charlotte-Paige; Arduino, Roberto; DeJesus, Edwin; Tomaras, Georgia D; Seaman, Michael S; Korber, Bette; Barouch, Dan H
Nature medicine, 06/2022, Volume: 28, Issue: 6Journal Article
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 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log 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 . 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.
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