Safety, pharmacokinetics, and neutralisation activity of PGDM1400LS, a V2 specific HIV-1 broadly neutralising antibody, infused intravenously or subcutaneously in people without HIV-1 in the USA (HVTN 140/HPTN 101 part A): a first-in-human, phase 1 randomised trial

Kelly E. Seaton, Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA. Electronic address: kelly.seaton@duke.edu.
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.
Shelly T. Karuna, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Theresa Gamble, HPTN Leadership and Operation Center, FHI 360, Durham, NC, USA.
Maurine D. Miner, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Jack Heptinstall, Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA.
Lu Zhang, Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA.
Fei Gao, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Margaret Yacovone, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Hans Spiegel, Kelly Government Solutions, Rockville, MD, USA.
Julie B. Dumond, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Maija Anderson, 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.
Bonnie Dye, HPTN Leadership and Operation Center, FHI 360, Durham, NC, USA.
India Tindale, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Lori Proulx-Burns, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Meg Trahey, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Simbarashe Takuva, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
Azwidihwi Takalani, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Veronique C. Bailey, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Spyros A. Kalams, Division of Infectious Diseases, Department of Medicine, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Hyman Scott, San Francisco Department of Public Health, San Francisco, CA, USA.
Nonhlanhla N. Mkhize, National Institute for Communicable Diseases, Durban, South Africa.
Joshua A. Weiner, Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
Margaret E. Ackerman, Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
M Juliana McElrath, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Michael Pensiero, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
Dan H. Barouch, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
David Montefiori, Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA.
Georgia D. Tomaras, Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA.
Lawrence Corey, Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA.

Document Type

Journal Article

Publication Date

6-1-2025

Journal

The lancet. HIV

Volume

12

Issue

6

DOI

10.1016/S2352-3018(25)00012-8

Abstract

BACKGROUND: PGDM1400LS is a human monoclonal antibody targeting the HIV envelope V2 apex with a lysine-serine modification intended to enhance serum and tissue half-lives and is being considered for use in combination monoclonal antibody trials. We sought to test whether PGDM1400LS was safe and had favourable serum concentration, pharmacokinetics, and neutralising ability in healthy adults. METHODS: HVTN 140/HPTN 101 part A is an open-label, dose escalation, first-in-human phase 1 trial of PGDM1400LS given intravenously or subcutaneously to healthy adults aged 18-50 years without HIV-1. The study enrolled participants at four sites in the USA, across five groups, each receiving one dose of PGDM1400-LS intravenously (group 1: 5 mg/kg; group 2: 20 mg/kg; and group 4: 40 mg/kg) or subcutaneously (group 3: 20 mg/kg; and group 5: 40 mg/kg). Participants in group 1 were enrolled sequentially without random assignment. Participants in groups 2 and 3 were block randomised and enrolled simultaneously after group 1 safety review. Groups 4 and 5 followed the same process, contingent on groups 2 and 3 safety review. The primary endpoints were safety and tolerability of PGDM1400LS, serum concentration of PGDM1400LS, and serum neutralising activity after single administration of PGDM1400LS. Serum PGDM1400LS concentrations collected at seven timepoints (day 0, day 3, day 6, day 28, day 56, day 112, and day 168) were assessed via an anti-idiotype binding assay and characterised via non-compartmental pharmacokinetic analysis. Serum neutralisation activity (ID) was assessed by a TZM-bl assay. The study is registered with ClinicalTrials.gov, NCT05184452. FINDINGS: Between Nov 15, 2021, and March 4, 2022, 15 participants were enrolled into the five study groups (three participants per group) with 6 months of follow-up. Ten of 15 participants were female, 14 of 15 participants were non-Hispanic, and 11 of 15 participants were White, with a median age of 27 years (range 24-47). PGDM1400LS was safe and well tolerated, with mild to moderate solicited symptoms. Serum concentrations showed dose proportionality by administration route, with peak concentrations observed immediately after intravenous infusion (range 95·7-727·4 μg/mL) or on day 6 after subcutaneous infusion (205·6-547·1 μg/mL). The median elimination half-life was 55 days (range 48-59), representing a 2-to-3-times increase versus parental PDGM1400. Estimated subcutaneous (vs intravenous) bioavailability was 50-60%. ID titres showed agreement with concentration-predicted ID titres, indicating maintenance of neutralisation activity in vivo. INTERPRETATION: PGDM1400LS is a promising candidate for combination monoclonal antibody efficacy trials going forward. FUNDING: National Institute of Allergy and Infectious Diseases-National Institutes of Health.

Department

Medicine

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