Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.
Клиническое исследование I фазыСтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.