HVTN 140/HPTN 101

HVTN 140/HPTN 101: Advancing HIV Prevention with Novel Antibody Therapy

Overview

The HVTN 140/HPTN 101 study is a Phase 1 dose-escalation clinical trial investigating the safety, tolerability, and pharmacokinetics of PGDM1400LS alone and in combination with VRC07-523LS and PGT121.414.LS. Conducted among healthy, HIV-uninfected adults, the trial aims to evaluate the potential of these novel monoclonal antibodies (mAbs) to offer effective and innovative HIV prevention strategies.

Study Rationale

With current HIV prevention methods presenting challenges related to accessibility and adherence, this study explores a groundbreaking approach involving lab-made antibodies delivered through intravenous (IV) or subcutaneous (SC) infusion. By directly introducing these antibodies, the trial seeks to understand immune responses and pave the way for expanding HIV prevention and treatment options.

Primary Objectives

1. Safety and Tolerability: Evaluate the safety and tolerability of PGDM1400LS administered alone and in combination with other mAbs via IV or SC routes.
2. Pharmacokinetics: Assess serum concentrations and pharmacokinetics of the mAbs to understand their behavior in the body post-administration.
3. Neutralizing Activity: Measure the antibodies’ capacity to neutralize HIV across a range of viral strains after single or combination dosing.

Study Population

This multicenter, randomized, open-label study enrolled 95 healthy, HIV-1–uninfected volunteers aged 18 to 50 years.

Investigators

• Principal Investigator: Prof Sinead Delany-Moretlwe
• Sub-Investigator: Dr Carrie-Anne Mathew and
• Sub-Investigator: Dr Juliet Vimbai Rundogo

Abstract

Phase 1 dose-escalation trial to evaluate the safety, tolerability, pharmacokinetics and neutralization activity of PGDM1400LS in combination with VRC07-523LS and PGT121.414.LS in healthy participants without HIV (HVTN 140/HPTN 101)

S. Mahomed, K. E. Seaton, C. A. Paez, C. Yu, K. Gillespie, S. T. Karuna, T. Gamble, J. Heptinstall, L. Zhang, F. Gao, M. Yacovone, H. Spiegel, J. Dumond, M. Anderson, E. Piwowar-Manning, B. Dye, I. Tindale, L. Proulx-Burns, M. Trahey, S. Takuva, A. Takalani, V. C. Bailey, S. Kalams, H. Scott, J. Kosgei, S. Delany-Moretlwe, S. Kassim, F. Laher, Z.M. Chirenje, Y. Musodza, F. Mhlanga, N. Mkhize, J. Weiner, M. Ackerman, M.J. McElrath, M. Pensiero, L. Gama, D.H Barouch, D. Montefiori, G. D. Tomaras, L. Corey, M. Cohen, Y. Huang, M. Siegel, C. Kelley, HVTN 140/HPTN 101 study team. HIVR4P 2024, the 5th HIV Research for Prevention Conference. Lima, Peru, 06-10 October 2024.

Background: Passive immunization with broadly neutralizing antibodies (bNAbs) presents a promising HIV prevention modality. Studies suggest that bNAb combinations targeting multiple HIV-1 epitopes and clades are necessary for effective prevention. HVTN140/HPTN101 evaluated the safety, tolerability, pharmacokinetics, and neutralization activity of PGDM1400LS (V2 apex) administered in combination with VRC07-523LS (CD4 binding site) and PGT121.414.LS (V3 glycan) in healthy adults, without HIV.

Methods: The study was a multicenter, randomized, open-label study conducted in Africa and the United States. After establishing the safety of a single administration of PGDM1400LS in Part A (n=15), Part B (n=80) enrolled adults aged 18-50 years without HIV who received two doses of PGDM1400LS, VRC07-523LS and PGT121.414.LS four months apart. In the five bNAb combination groups, each bNAb was administered at weight-based doses of 20mg/kg or 40mg/kg intravenously, 20mg/kg subcutaneously or a fixed dose of 1.4g either intravenously or subcutaneously. Safety was evaluated through solicited and unsolicited adverse events. Pharmacokinetic parameters were estimated using a two-compartment population pharmacokinetic model. BNAb serum concentrations were measured by anti-idiotypic binding antibody assays. Serum neutralization was assessed against viruses sensitive to each of the three bNAbs administered and a panel of recently circulating HIV-1 strains.

Results: Median age was 25.5 years, and 50.5% were assigned female sex at birth. Most participants reported mild-to-moderate solicited local and systemic symptoms. The median estimated elimination half-life of PGDM1400LS was 54 days, not significantly influenced by co-administration with VRC07-523LS and PGT121.414.LS. Compared to IV administration, the bioavailability of PGDM1400LS administered subcutaneously was 75.5%. The median estimated elimination half-life of PGT121.414.LS was 66 days, with subcutaneous bioavailability of 77.7%. The median estimated elimination half-life of VRC07-523LS was 45 days, with subcutaneous bioavailability of 80.1%. Weight-based and fixed-dose regimens showed similar pharmacokinetic patterns. ID80 neutralization titers aligned with predicted values, indicating sustained neutralization activity in vivo, with broad and potent neutralization against both bNAb-sensitive isolates and recently circulating HIV-1 strains. No treatment-induced anti-drug-antibody responses were observed.

Conclusions: The bNAb combination of PGDM1400LS, PGT121.414.LS, and VRC07-523LS was safe and well-tolerated, with no pharmacokinetic interactions or loss of complementary neutralization. These findings strongly support the evaluation of this triple combination in future efficacy trials.

Latest Update

December 2024

For more information about HVTN 140/HPTN 101, please email rhicomms@wrhi.ac.za