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
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
Affiliations
Bryan T. Mayer
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Lily Zhang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Allan C. deCamp
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Chenchen Yu
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Alicia Sato
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Heather Angier
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Kelly E. Seaton
Duke University Medical Center, Durham, NC 27705, USA
Nicole Yates
Duke University Medical Center, Durham, NC 27705, USA
Julie E. Ledgerwood
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
Kenneth Mayer
The Fenway Institute, Boston, MA 02215, USA
Marina Caskey
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
Michel Nussenzweig
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
Kathryn Stephenson
Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA 02139, USA
Boris Julg
Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA 02139, USA
Dan H. Barouch
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Magdalena E. Sobieszczyk
Columbia University Irving Medical Center, New York, NY 10032, USA
Srilatha Edupuganti
Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA
Colleen F. Kelley
Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA
M. Juliana McElrath
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Huub C. Gelderblom
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Michael Pensiero
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
Adrian McDermott
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
Lucio Gama
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
Richard A. Koup
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
Peter B. Gilbert
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Myron S. Cohen
Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Lawrence Corey
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Ollivier Hyrien
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Georgia D. Tomaras
Duke University Medical Center, Durham, NC 27705, USA
Yunda Huang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
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.
