Effects of natalizumab, an alpha4 integrin inhibitor, on the development of Hartley guinea pigs.
BACKGROUND
Natalizumab is a humanized monoclonal immunoglobulin G4 antibody directed against the human alpha4 integrin subunit, disrupting interaction with its ligands. Natalizumab inhibits the interaction of alpha4 integrins with fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1, which are of potential importance in development. Two studies were undertaken to evaluate the effects of natalizumab on embryo/fetal development in guinea pigs.


METHODS
In the first study, pregnant guinea pigs were treated with intravenous injections of 3, 10, or 30 mg/kg natalizumab or vehicle every other day from gestational day (GD) 4 to 30. In the second study, females were treated on alternate days starting at least 28 days prior to mating through GD 30. Fetal examinations and histopathologic examination of the liver, heart, thymus, spleen, and intestinal tract were performed following maternal euthanasia on GD 59-62.


RESULTS
Natalizumab had no significant effect on embryo/fetal development in either study. Exposure to natalizumab during organogenesis did not result in treatment-related external, visceral, or skeletal variations or malformations or histopathologic changes.


CONCLUSIONS
No fetotoxicity or teratogenic effects were attributable to natalizumab in these studies.
Wehner
Nancy G
NG
Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. nancy.wehner@elan.com
Shopp
George
G
Rocca
Meredith S
MS
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; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D006168:Guinea Pigs / Q000196:embryology*; D039441:Integrin alpha4 / Q000276:immunology*; D000069442:Natalizumab; D038081:Organogenesis / Q000187:drug effects; D011247:Pregnancy; D011897:Random Allocation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D039441:Integrin alpha4