Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in male and female guinea pigs.
BACKGROUND
Natalizumab is a humanized monoclonal immunoglobulin G4 antibody directed against the human alpha4 integrin subunit disrupting interaction with its ligands. As alpha4 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.
Wehner
Nancy G
NG
Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. nancy.wehner@elan.com
Skov
Michael
M
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; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D010064:Embryo Implantation / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005306:Fertilization / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D006168:Guinea Pigs / Q000196:embryology / Q000502:physiology*; D007247:Infertility, Female / Q000139:chemically induced*; D039441:Integrin alpha4 / Q000276:immunology*; D008297:Male; D000069442:Natalizumab; D011247:Pregnancy; D018873:Pregnancy Rate; D011897:Random Allocation; D013081:Sperm Motility / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D039441:Integrin alpha4