Effects of natalizumab,an α4 integrin inhibitor,on fertility in male and female guinea pigs

BACKGROUND : Natalizumab is a humanized monoclonal immunoglobulin G4 antibody directed against the human α4 integrin subunit disrupting interaction with its ligands. As α4 integrins and/or their ligands appear to be involved in reproductive function, the effects of natalizumab on fertility in male and female guinea pigs were investigated. METHODS : Natalizumab was administered by bolus intravenous injection every other day at doses of 0, 3, 10, and 30 mg/kg. Males began treatment at least 28 days prior to mating until necropsy (approximately 3 to 5 days after mating). Dosing in females was done from gestational day (GD) of an existing pregnancy to GD 30 of a second pregnancy. RESULTS : In male guinea pigs, natalizumab treatment had no effect on sperm parameters, reproductive organ weights, organ-weight ratios, or histology of the testis or epididymis. Natalizumab did not affect the ability of treated males to produce pregnancies in untreated females. In female guinea pigs, no treatment-related changes were seen in uterine weights or ovary weights. Pregnancy rates were reduced in females treated with 30 mg/kg natalizumab, but not those treated with 3 or 10 mg/kg. Pregnancy rates were 63.3, 66.7, 66.7, and 29.6% for groups treated with 0, 3, 10, and 30 mg/kg, respectively. Effects observed at 30 mg/kg were at exposures 36-fold those observed in humans. CONCLUSIONS : Natalizumab had no effects on male fertility, but did result in a reduction in pregnancy rates in females treated with the high dose of 30 mg/kg. Birth Defects Res (Part B)86: 108-116, 2009. © 2009 Wiley-Liss, Inc.