Preclinical Studies

A number of preclinical studies have been conducted with efalizumab to evaluate its pharmacodynamic and pharmacokinetic properties, as well as its toxicity.

In vitro studies performed with efalizumab have shown that it is able to bind to human and chimpanzee leucocytes, inhibit lymphocyte binding to ICAM-1 on keratinocytes and inhibit T-cell proliferation. In murine and chimpanzee in vivo models, efalizumab was able to down-regulate LFA-1 expression on lymphocytes, while efalizumab has been shown to have two-compartment kinetics with non-linear elimination in monkeys.

Anti-mouse CD11a antibodies have been used to study developmental toxicity in mice. In these studies, doses were administered at up to 30 times the equivalent recommended clinical dose of 1 mg/kg. No adverse effects were observed on mating, fertility or reproductive parameters. There was also no evidence of maternal toxicity, embryotoxicity or teratogenicity.

Similarly to other immunoglobulins, anti-mouse CD11a antibody is secreted in the milk of lactating mice that are exposed to the antibody during gestation and lactation. Furthermore, a significant reduction was observed in the ability of their offspring to generate an antibody response at 11 weeks of age, which was - at least partially - reversible at week 25. There were, however, no adverse effects on behaviour, growth and reproductive function of the offspring.

Immunization of chimpanzees exposed to high doses of efalizumab (>10 times the clinical dose) with tetanus toxoid produced an impaired antibody response compared with control animals. However, there have been no animal reproduction studies and long-term carcino-genicity studies conducted with efalizumab.

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