Safety, pharmacokinetics, and neutralisation activity of PGDM1400LS, VRC07-523LS, and PGT121.414.LS infused intravenously or subcutaneously (HVTN 140/HPTN 101 part B): a phase 1, randomised trial.

BACKGROUND: Passive immunisation with a combination of broadly neutralising monoclonal antibodies (mAbs) presents a potential HIV-1 prevention modality. This study (HVTN 140/HPTN 101) sought to evaluate PGDM1400LS (targeting V3-glycan) administered alone (part A, previously reported), and in combination (part B) with VRC07-523LS (targeting CD4 binding site) and PGT121.414.LS (targeting V2-apex) in healthy adults without HIV-1. METHODS: The study was a phase 1, multicentre, randomised, open-label trial done across the USA (five sites), Kenya (one site), South Africa (four sites), and Zimbabwe (three sites). Part B participants were randomly assigned to five groups (n=16 each), all receiving the three mAbs at months 0 and 4: infusion group T6 (20 mg/kg each mAb intravenously), T7 (20 mg/kg each mAb subcutaneously), T8 (1·4 g each mAb intravenously), T9 (1·4 g each mAb subcutaneously), and T10 (40 mg/kg each mAb intravenously). Primary endpoints were safety and tolerability throughout the study, and pharmacokinetics and neutralising activity on days 0, 3, 6, 28, 56, 112, 168, 224, and 280. Serum mAb concentrations over time were assessed via a validated anti-idiotype binding assay and analysed with two-compartment population pharmacokinetics models. Serum neutralisation titres were assessed by a validated TZM-bl assay. The study is registered at ClinicalTrials.gov (NCT05184452) and is complete. FINDINGS: For the 80 part B participants enrolled from March 21 to Oct 5, 2022, the median age was 27·0 years, with 47·5% females. Most participants had mild-to-moderate solicited local and systemic symptoms. No serious adverse events were reported. On the basis of pharmacokinetics data from part A and part B combined, the estimated elimination half-life of PGDM1400LS was 53 days (51·4-55·3). Subcutaneous administration of PGDM1400LS exhibited bioavailability of 73·0% (67·5-78·5%) relative to intravenous administration of the same dose. PGT121.414.LS had an estimated elimination half-life of 65 days (61·8-68·1) with subcutaneous bioavailability of 77·7% (71·2-84·1), and VRC07-523LS had an estimated elimination half-life of 44 days (41·6-45·7) with a subcutaneous bioavailability of 80·1% (71·4-88·8). Both weight-based and fixed-dose regimens showed similar pharmacokinetic profiles. Observed neutralisation titres were consistent with those predicted on the basis of concentrations and in vitro neutralisation. No treatment-induced anti-drug antibody responses were detected. INTERPRETATION: The mAb combination of PGDM1400LS, PGT121.414.LS, and VRC07-523LS was safe and well tolerated, with no antagonistic pharmacokinetic interactions or loss of neutralisation activity. These findings support further evaluation of this combination in future efficacy trials. FUNDING: National Institute of Allergy and Infectious Diseases-National Institutes of Health.