The preclinical safety evaluation of human monoclonal antibody against cytomegalovirus

Abstract

The human monoclonal antibody against cytomegalovirus (Mab C23) was examined pharmacokinetically and toxicologically as part of the preclinical studies prior to approval for human use. Rats given repeated intravenous administrations of Mab C23 produced no antibodies against Mab C23 and maintained a blood Mab C23 level in a dose-dependent manner. However, pregnant rabbits produced antibodies against Mab C23. The half-life of Mab C23 in plasma was 15.9 days in rats, which was similar to that of normal human serum γ-globulin (NHSG). Neither behavioral effects nor circulatory disturbance was found in mice, rats, and dogs even after a single intravenous injection of 100 or 200 mg/kg, which corresponds to 50 or 100 times the intended clinical dosage. The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasions with 1- or 2-week intervals elicited a transient decrease in leukocyte counts in rats given 10 or 20 mg/kg, but no adverse effects in cynomolgus monkeys. Mab C23 did not cause any reproductive or developmental toxicity when administered to rats and rabbits at dose levels of 20 mg/kg or less. However, pregnant animals showed lower plasma levels of Mab C23 than nonpregnant animals. The chromosomal aberration test disclosed no clastogenicity in human lymphocytes. An immunostaining for Mab C23 revealed no localizations in several tissues of cynomolgus monkeys given intravenous doses of Mab C23. The preclinical safety evaluation in animals other than rabbits, which produced no antibodies against Mab C23, showed that the behavior of Mab C23 is pharmacokinetically similar to that of NHSG and is as safe as NHSG, which has long been used as a biological agent. However, because there was a difference in blood levels of Mab C23 between pregnant and nonpregnant animals, its clinical administration to pregnant patients should differ from that to nonpregnant patients.