Safety, tolerability, pharmacokinetics, and neutralisation activities of the anti-HIV-1 monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS in adults without HIV in the USA (HVTN 136/HPTN 092): a first-in-human, open-label, randomised controlled phase 1 trial

Srilatha Edupuganti, Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA, USA. Electronic address: sedupug@emory.edu.
Christopher B. Hurt, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Kathryn E. Stephenson, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Yunda Huang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA.
Carmen A. Paez, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Chenchen Yu, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Catherine Yen, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Brett Hanscom, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Zonglin He, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Maurine D. Miner, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Theresa Gamble, FHI 360, HPTN Leadership and Operations Center, Durham, NC, USA.
Jack Heptinstall, Duke University Medical Center, Durham, NC, USA.
Kelly E. Seaton, Duke University Medical Center, Durham, NC, USA.
Elizabeth Domin, Duke University Medical Center, Durham, NC, USA.
Bob C. Lin, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Krisha McKee, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Nicole Doria-Rose, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Stephanie Regenold, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Hans Spiegel, Kelly Government Solutions, Rockville, MD, USA.
Maija Anderson, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Nadia McClosky, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Lily Zhang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Estelle Piwowar-Manning, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Margaret E. Ackerman, Dartmouth College, Hanover, NH, USA.
Michael Pensiero, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Bonnie J. Dye, FHI 360, HPTN Leadership and Operations Center, Durham, NC, USA.
Raphael J. Landovitz, UCLA Center for Clinical AIDS Research and Education, Los Angeles, CA, USA.
Kenneth Mayer, Fenway Health, Harvard Medical School, Boston, MA, USA.
Marc Siegel, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Magdalena Sobieszczyk, Columbia University Irving Medical Center, New York, NY, USA.
Stephen R. Walsh, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Lucio Gama, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.

Document Type

Journal Article

Publication Date

1-1-2025

Journal

The lancet. HIV

Volume

12

Issue

1

DOI

10.1016/S2352-3018(24)00247-9

Abstract

BACKGROUND: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults. METHODS: In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed. FINDINGS: Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86·1% (95% CI 64·0-95·5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups. INTERPRETATION: These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention. FUNDING: US National Institute of Allergy and Infectious Diseases and US National Institutes of Health.

Department

Medicine

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