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Clinical Trial
. 2025 Jun;12(6):e405-e415.
doi: 10.1016/S2352-3018(25)00012-8.

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  1 , Carmen A Paez  2 , Chenchen Yu  2 , Shelly T Karuna  2 , Theresa Gamble  3 , Maurine D Miner  2 , Jack Heptinstall  4 , Lu Zhang  4 , Fei Gao  2 , Margaret Yacovone  5 , Hans Spiegel  6 , Julie B Dumond  7 , Maija Anderson  2 , Estelle Piwowar-Manning  8 , Bonnie Dye  3 , India Tindale  2 , Lori Proulx-Burns  2 , Meg Trahey  2 , Simbarashe Takuva  9 , Azwidihwi Takalani  2 , Veronique C Bailey  2 , Spyros A Kalams  10 , Hyman Scott  11 , Nonhlanhla N Mkhize  12 , Joshua A Weiner  13 , Margaret E Ackerman  13 , M Juliana McElrath  2 , Michael Pensiero  5 , Dan H Barouch  14 , David Montefiori  4 , Georgia D Tomaras  4 , Lawrence Corey  4 , Myron S Cohen  7 , Yunda Huang  2 , Sharana Mahomed  15 , Marc Siegel  16 , Colleen F Kelley  17 ; HVTN 140/HPTN 101 study team
Affiliations
Clinical Trial

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 et al. Lancet HIV. 2025 Jun.

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 (ID80) 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%. ID80 titres showed agreement with concentration-predicted ID80 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.

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Conflict of interest statement

Declaration of interests CFK receives research grant support from her institution from Moderna, Novavax, Humanigen, Gilead, and ViiV Healthcare. YH reports funding to her institution from National Institutes of Health (NIH) and WHO and sits on the advisory board of Worcester HIV Vaccine. JH reports funding from the NIH to his institution. HSc reports serving on the HIV Vaccine Trials Network (HVTN) executive management team and having travel expenses paid for conference travel. MJM reports funding from the NIH-National Institute of Allergy and Infectious Diseases (NIAID), Consortia for HIV/AIDS Vaccine Development, Comprehensive Cellular Vaccine Immune Monitoring Consortium, and Bill & Melinda Gates Foundation paid to their institution, travel support for the Conference on Retroviruses and Opportunistic Infections, and serving on boards at NIH Vaccine Research Centre and Ragon Institute. JBD reports paid registration to the International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs 2024. MEA reports funding from NIAID, Bill & Melinda Gates Foundation, NIH, Moderna, and Be Bio paid to their institution, Elsevier book royalties, consulting for Seromyx Systems, support for attending meetings, and patents not related to monoclonal antibody therapy. KES reports funding from NIAID-HVTN to their institution and for travel. MSC reports funding from NIH-HIV Prevention Trials Network and consulting fees from Aerium, AstraZeneca, Atea, GSK, Merck, ModeX, and Opko Pharma. All other authors declare no competing interests.

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