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

Journal Article · · Nature Medicine
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  1. Ragon Institute, Cambridge, MA (United States); Beth Israel Deaconess Medical Center, Boston, MA (United States)
  2. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); New Mexico Consortium, Los Alamos, NM (United States)
  3. Beth Israel Deaconess Medical Center, Boston, MA (United States)
  4. Duke University, Durham, NC (United States)
  5. International AIDS Vaccine Initiative, New York, NY (United States)
  6. International AIDS Vaccine Initiative, New York, NY (United States); Icosavax Inc., Seattle, WA (United States)
  7. Fred Hutchinson Cancer Research Center, Seattle, WA (United States)
  8. National Institutes of Health (NIH), Bethesda, MD (United States)
  9. University of Texas Health Science Center, Houston, TX (United States)
  10. Orlando Immunology Center, FL (United States)
+ Show Author Affiliations
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. 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.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)
Grant/Contract Number:
89233218CNA000001
OSTI ID:
2005803
Report Number(s):
LA-UR--21-25866
Journal Information:
Nature Medicine, Journal Name: Nature Medicine Journal Issue: 6 Vol. 28; ISSN 1078-8956
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
Antibodies
Biological Science
HIV infections
Retrovirus