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
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...
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2406788 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Joanna Zikos |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c3903556c3ab42faabeedc9cf418281c |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-c3903556c3ab42faabeedc9cf418281c2025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2406788FcRn-enhancing mutations lead to increased and prolonged levels of the HIV CCR5-blocking monoclonal antibody leronlimab in the fetuses and newborns of pregnant rhesus macaquesJoanna Zikos0Gabriela M. Webb1Helen L. Wu2Jason S. Reed3Jennifer Watanabe4Jodie L. Usachenko5Ala M. Shaqra6Celia A. Schiffer7Koen K. A. Van Rompay8Jonah B. Sacha9Diogo M. Magnani10Nonhuman Primate Reagent Resource (NHPRR), Department of Medicine – Innate Immunity, UMass Chan Medical School, Worcester, MA, USADivision of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USADivision of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USADivision of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USACalifornia National Primate Research Center (CNPRC), University of California, Davis, CA, USACalifornia National Primate Research Center (CNPRC), University of California, Davis, CA, USADepartment of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA, USADepartment of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA, USACalifornia National Primate Research Center (CNPRC), University of California, Davis, CA, USADivision of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USANonhuman Primate Reagent Resource (NHPRR), Department of Medicine – Innate Immunity, UMass Chan Medical School, Worcester, MA, USAPrenatal 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.https://www.tandfonline.com/doi/10.1080/19420862.2024.2406788Antibody optimizationentry inhibitorHIVleronlimabMother-to-child transmission (MTCT)nonhuman primate |
| spellingShingle | 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 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 mAbs Antibody optimization entry inhibitor HIV leronlimab Mother-to-child transmission (MTCT) nonhuman primate |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Antibody optimization entry inhibitor HIV leronlimab Mother-to-child transmission (MTCT) nonhuman primate |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2406788 |
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