Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV
Year: 2024
Type: article
Abstract: Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.
Source: Pharmaceutics
Authors: Bryan T. Mayer, Lily Zhang, Allan C. deCamp, Chenchen Yu, Alicia Sato, Heather Angier, Kelly E. Seaton, Nicole Yates, Julie E. Ledgerwood, Kenneth Mayer, Marina Caskey, Michel Nussenzweig, Kathryn Stephenson, Boris Julg, Dan H. Barouch, Magdalena E. Sobieszczyk, Srilatha Edupuganti, Colleen F. Kelley, M. Juliana McElrath, Huub C. Gelderblom, Michael Pensiero, Adrian McDermott, Lucio Gama, Richard A. Koup, Peter B. Gilbert, Myron S. Cohen, Lawrence Corey, Ollivier Hyrien, Georgia D. Tomaras, Yunda Huang
Institutions: Fred Hutch Cancer Center, Duke Medical Center, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, Rockefeller University, Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology, Beth Israel Deaconess Medical Center, Columbia University Irving Medical Center, Emory University, University of Washington, University of North Carolina at Chapel Hill
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,296
Awards: G1169301292, Fred Hutchinson Cancer Center - to provide statistical support and a data sharing portal to foundation grantees working to design candidate HIV vaccines and evaluate those vaccine..., G4573240269, G5483201117, G681742546, G690068069, G793395730, G819814859, HIV Vaccine Trials Network Laboratory Center, HIV Prevention Trials Network Leadership and Operations Center, HIV Vaccines Clinical Trials Network Leadership and Operations Center, Columbia Collaborative HIV/AIDS Clinical Trials Unit, LC: HIV PREVENTION TRIALS NETWORK, SDMC: HIV Prevention Trials Network, G95499620, G95938990
OpenAlex ID: W4396585286