Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor.
BACKGROUND
Natalizumab is a humanized monoclonal immunoglobulin G4 antibody to human alpha4 integrin that binds to the alpha4 subunit of alpha4beta1 and alpha4beta7 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 alpha4 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 alpha4 integrin. At dose levels > or = 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.


CONCLUSIONS
Natalizumab had no abortifacient or teratogenic effects, but was associated with changes in fetal hematopoiesis and leukocyte trafficking.
Wehner
Nancy G
NG
Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. nancy.wehner@elan.com
Shopp
George
G
Oneda
Satoru
S
Clarke
Janet
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000917:Antibody Formation; D001284:Atrophy; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects*; D039441:Integrin alpha4 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects; D008252:Macaca fascicularis / Q000196:embryology*; D000069442:Natalizumab; D038081:Organogenesis / Q000187:drug effects; D011247:Pregnancy; D011897:Random Allocation; D013950:Thymus Gland / Q000187:drug effects / Q000196:embryology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D039441:Integrin alpha4