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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.
Zikos, Joanna; Webb, Gabriela M; Wu, Helen L; Reed, Jason S; Watanabe, Jennifer; Usachenko, Jodie L; Shaqra, Ala M; Schiffer, Celia A; Van Rompay, Koen K A; Sacha, Jonah B; Magnani, Diogo M.
Afiliação
  • Zikos J; Nonhuman Primate Reagent Resource (NHPRR), Department of Medicine - Innate Immunity, UMass Chan Medical School, Worcester, MA, USA.
  • Webb GM; Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
  • Wu HL; Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
  • Reed JS; Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
  • Watanabe J; California National Primate Research Center (CNPRC), University of California, Davis, CA, USA.
  • Usachenko JL; California National Primate Research Center (CNPRC), University of California, Davis, CA, USA.
  • Shaqra AM; Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA, USA.
  • Schiffer CA; Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA, USA.
  • Van Rompay KKA; California National Primate Research Center (CNPRC), University of California, Davis, CA, USA.
  • Sacha JB; Department of Pathology, Microbiology and Immunology, University of California, Davis, CA, USA.
  • Magnani DM; Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
MAbs ; 16(1): 2406788, 2024.
Article em En | MEDLINE | ID: mdl-39324549
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Fc / Antígenos de Histocompatibilidade Classe I / Receptores CCR5 / Feto / Macaca mulatta Limite: Animals / Female / Humans / Pregnancy Idioma: En Revista: MAbs Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Fc / Antígenos de Histocompatibilidade Classe I / Receptores CCR5 / Feto / Macaca mulatta Limite: Animals / Female / Humans / Pregnancy Idioma: En Revista: MAbs Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos