Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an α4 integrin inhibitor

BACKGROUND: Natalizumab is a humanized monoclonal immunoglobulin G4 antibody to human alpha 4 integrin that binds to the alpha 4 subunit of alpha 4 beta 1 and alpha 4 beta 7 integrins, where it blocks the interaction of these integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha 4 integrins and their ligands appear to be involved in mammalian fetal development, it is possible that natalizumab may interfere with these processes. METHODS: The effects of natalizumab on fetal development were assessed in cynomolgus monkeys at doses of 0, 3, 10, and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70. Pregnancies were terminated by Cesarean section at GD 100. RESULTS: Natalizumab treatment was not associated with increased abortions. All fetuses were alive. No external, visceral, or skeletal abnormalities were seen that were considered to be related to treatment with natalizumab. No histopathological findings were seen in the heart, a target organ of developmental toxicity with a small molecule inhibitor of alpha 4 integrin. At dose levels >= 10 mg/kg, hematological and/or lymphoid effects were observed in some fetuses, consisting of slight thymic atropy, increased extramedullary hematopoiesis in the spleen With a corresponding decrease in the liver, increases in WBC and nucleated RBC, decreases in RBC parameters, and decreases in lymphoid CD20 staining. CONCLUSION: Natalizumab had no abortifacient or teratogenic effects, but was associated with changes in fetal hematopoiesis and leukocyte trafficking. Birth Defects Res (Part B) 86:117-130, 2009. (C) 2009 Wiley-Liss, Inc.