Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in male and female guinea pigs

Birth Defects Res B Dev Reprod Toxicol. 2009 Apr;86(2):108-16. doi: 10.1002/bdrb.20191.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / blood
  • Anti-Inflammatory Agents, Non-Steroidal / immunology
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity*
  • Antibodies, Monoclonal / blood
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / toxicity*
  • Antibodies, Monoclonal, Humanized
  • Antibody Formation
  • Body Weight / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Embryo Implantation / drug effects
  • Embryonic Development / drug effects*
  • Female
  • Fertility / drug effects*
  • Fertilization / drug effects
  • Fetus / drug effects
  • Guinea Pigs / embryology
  • Guinea Pigs / physiology*
  • Infertility, Female / chemically induced*
  • Integrin alpha4 / immunology*
  • Male
  • Natalizumab
  • Pregnancy
  • Pregnancy Rate
  • Random Allocation
  • Sperm Motility / drug effects
  • Spermatogenesis / drug effects


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Natalizumab
  • Integrin alpha4