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

Publication ,  Journal Article
Julg, B; Stephenson, KE; Wagh, K; Tan, SC; Zash, R; Walsh, S; Ansel, J; Kanjilal, D; Nkolola, J; Walker-Sperling, VEK; Ophel, J; Yanosick, K ...
Published in: Nature medicine
June 2022

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.

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Published In

Nature medicine

DOI

EISSN

1546-170X

ISSN

1078-8956

Publication Date

June 2022

Volume

28

Issue

6

Start / End Page

1288 / 1296

Related Subject Headings

  • Viremia
  • Immunology
  • Humans
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
  • HIV Antibodies
  • Broadly Neutralizing Antibodies
  • Antiviral Agents
  • Antibodies, Neutralizing
 

Citation

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Julg, B., Stephenson, K. E., Wagh, K., Tan, S. C., Zash, R., Walsh, S., … Barouch, D. H. (2022). Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nature Medicine, 28(6), 1288–1296. https://doi.org/10.1038/s41591-022-01815-1
Julg, Boris, Kathryn E. Stephenson, Kshitij Wagh, Sabrina C. Tan, Rebecca Zash, Stephen Walsh, Jessica Ansel, et al. “Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.Nature Medicine 28, no. 6 (June 2022): 1288–96. https://doi.org/10.1038/s41591-022-01815-1.
Julg B, Stephenson KE, Wagh K, Tan SC, Zash R, Walsh S, et al. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nature medicine. 2022 Jun;28(6):1288–96.
Julg, Boris, et al. “Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.Nature Medicine, vol. 28, no. 6, June 2022, pp. 1288–96. Epmc, doi:10.1038/s41591-022-01815-1.
Julg B, Stephenson KE, Wagh K, Tan SC, Zash R, Walsh S, Ansel J, Kanjilal D, Nkolola J, Walker-Sperling VEK, Ophel J, Yanosick K, Borducchi EN, Maxfield L, Abbink P, Peter L, Yates NL, Wesley MS, Hassell T, Gelderblom HC, deCamp A, Mayer BT, Sato A, Gerber MW, Giorgi EE, Gama L, Koup RA, Mascola JR, Monczor A, Lupo S, Rolle C-P, Arduino R, DeJesus E, Tomaras GD, Seaman MS, Korber B, Barouch DH. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nature medicine. 2022 Jun;28(6):1288–1296.

Published In

Nature medicine

DOI

EISSN

1546-170X

ISSN

1078-8956

Publication Date

June 2022

Volume

28

Issue

6

Start / End Page

1288 / 1296

Related Subject Headings

  • Viremia
  • Immunology
  • Humans
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
  • HIV Antibodies
  • Broadly Neutralizing Antibodies
  • Antiviral Agents
  • Antibodies, Neutralizing