2025 Articles

Pharmacokinetic interaction assessment of an HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 trials in people without HIV

Chawana, Tariro D.; Walsh, Stephen R.; Stranix-Chibanda, Lynda; Chirenje, Zvavahera M.; Yu, Chenchen; Zhang, Lily; Seaton, Kelly E.; Heptinstall, Jack; Zhang, Lu; Paez, Carmen A.; Gamble, Theresa; Karuna, Shelly T.; Andrew, Philip; Hanscom, Brett; Sobieszczyk, Magdalena; Edupuganti, Srilatha; Gay, Cynthia L.; Mannheimer, Sharon B.; Hurt, Christopher B.; Stephenson, Kathryn E.; Polakowski, Laura L.; Spiegel, Hans; Yacovone, Margaret; Regenold, Stephanie; Yen, Catherine; Baumblatt, Jane A.; Gama, Lucio; Barouch, Dan H.; Piwowar-Manning, Estelle; Koup, Richard A.; Tomaras, Georgia D.; Hyrien, Ollivier; Roxby, Alison C.

VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed.

We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone (‘single’; n = 100) or in combination with 1 or 2 other mAbs (‘combined’; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities.

We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups.

These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.