FcRn-enhancing mutations lead to increased and prolonged levels of the HIV CCR5-blocking monoclonal antibody leronlimab in the fetuses and newborns of pregnant rhesus macaques
Joanna Zikos,
Gabriela M. Webb,
Helen L. Wu,
Jason S. Reed,
Jennifer Watanabe,
Jodie L. Usachenko,
Ala M. Shaqra,
Celia A. Schiffer,
Koen K. A. Van Rompay,
Jonah B. Sacha,
Diogo M. Magnani
Affiliations
Joanna Zikos
Nonhuman Primate Reagent Resource (NHPRR), Department of Medicine – Innate Immunity, UMass Chan Medical School, Worcester, MA, USA
Gabriela M. Webb
Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Helen L. Wu
Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Jason S. Reed
Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Jennifer Watanabe
California National Primate Research Center (CNPRC), University of California, Davis, CA, USA
Jodie L. Usachenko
California National Primate Research Center (CNPRC), University of California, Davis, CA, USA
Ala M. Shaqra
Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA, USA
Celia A. Schiffer
Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA, USA
Koen K. A. Van Rompay
California National Primate Research Center (CNPRC), University of California, Davis, CA, USA
Jonah B. Sacha
Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Diogo M. Magnani
Nonhuman Primate Reagent Resource (NHPRR), Department of Medicine – Innate Immunity, UMass Chan Medical School, Worcester, MA, USA
Prenatal administration of monoclonal antibodies (mAbs) is a strategy that could be exploited to prevent viral infections during pregnancy and early life. To reach protective levels in fetuses, mAbs must be transported across the placenta, a selective barrier that actively and specifically promotes the transfer of antibodies (Abs) into the fetus through the neonatal Fc receptor (FcRn). Because FcRn also regulates Ab half-life, Fc mutations like the M428L/N434S, commonly known as LS mutations, and others have been developed to enhance binding affinity to FcRn and improve drug pharmacokinetics. We hypothesized that these FcRn-enhancing mutations could similarly affect the delivery of therapeutic Abs to the fetus. To test this hypothesis, we measured the transplacental transfer of leronlimab, an anti-CCR5 mAb, in clinical development for preventing HIV infections, using pregnant rhesus macaques to model in utero mAb transfer. We also generated a stabilized and FcRn-enhanced form of leronlimab, termed leronlimab-PLS. Leronlimab-PLS maintained higher levels within the maternal compartment while also reaching higher mAb levels in the fetus and newborn circulation. Further, a single dose of leronlimab-PLS led to complete CCR5 receptor occupancy in mothers and newborns for almost a month after birth. These findings support the optimization of FcRn interactions in mAb therapies designed for administration during pregnancy.
