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

作者：Boris Jülg, Kathryn E. Stephenson, Kshitij Wagh, Sabrina C. Tan, Rebecca Zash, Stephen R. Walsh, Jessica L. Ansel, Diane G. Kanjilal, Joseph P. Nkolola, Victoria E. Walker-Sperling, Jasper Ophel, Katherine E. Yanosick, Erica N. Borducchi, Lori F. 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, Lúcio Gama, Richard A. Koup, John R. Mascola, Ana Monczor, Sofia Lupo, Charlotte-Paige Rolle, Roberto C. Arduino, Edwin DeJesus, Georgia D. Tomaras, Michael S. Seaman, Bette Korber, Dan H. Barouch · 发表于：Nature Medicine · 年份：2022 · DOI：10.1038/s41591-022-01815-1 · 被引用次数：144 · 研究领域：HIV Research and Treatment、HIV/AIDS drug development and treatment、HIV/AIDS Research and Interventions

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 log 10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days a...