How Antibody Therapies Cross the Placenta

Monoclonal antibodies can help fight cancer and treat other diseases. These lab-created proteins adhere to specific antigens on cancer cells and other substances, triggering an immune response that can kill cancer cells or perform other functions to help treat some diseases. These targeted treatments are promising, but patients who are pregnant or may become pregnant need a more thorough understanding of how monoclonal antibodies can cross the placenta. A new paper by Exponent's John DeSesso, Ph.D., and coauthors in industry and academia explores how these treatments may cross the placental barrier in multiple animal species and humans in order to guide further research on the safety of antibody therapies.

Published in the journal Birth Defects Research, "Ontogeny of Placental FcRn Protein During Human and Animal Pregnancy to Inform Developmental Toxicity Testing" specifically describes research focused on the neonatal Fc receptor (FcRn), a receptor for a protein that plays an important role in the transfer of monoclonal treatments across the placenta during pregnancy. Building on prior research conducted by Dr. DeSesso and associates, this paper relies on studies coordinated by the Health and Environmental Sciences Institute and Reproductive Toxicology (DART) Technical Committee.

The authors reviewed the results of previous tests on mice, rats, guinea pigs, rabbits, non-human primates, and humans across all stages of gestation. They found increased concentrations of FcRn protein throughout gestation in mice, rats, guinea pigs, and rabbits, indicating that monoclonal antibodies cross the placenta. The research also found the protein in humans, where levels varied based on stage of pregnancy: "In humans, during 1st trimester, FcRn occurred in decidua, maternal endothelium, and maternal and fetal macrophages. During 2nd trimester, fetal FcRn increased in syncytiotrophoblasts and fetal chorionic vessels. FcRn expression decreased in maternal endothelium near term."

The data support that Fc domain-containing molecules can access the embryo-fetus throughout gestation in mammalian species, depending on the concentration of the protein and the size of the placenta. This finding supports the effective use of rodent models to test the safety of antibody-based medicines, as they similarly cross into embryos in all mammalian species. The data may also facilitate the improved use of in silico tools/computational modeling to help reduce animal testing in preclinical safety studies, which U.S. and European health authorities have pledged to do.

From the publication: "Despite this growing body of interspecies information regarding placental FcRn and biodistribution of Fc-containing molecules, the general pharmacokinetics and dynamics of this process are not fully understood and there may be molecule-specific safety and efficacy profiles in pregnant women and fetuses."