Exploratory research on relationships between gene polymorphisms and individual difference of toxicological sensitivity in non-human primate for nonclinical toxicity studies

Abstract

Over the recent years, to select the right medicine for right patients based on the appropriate prediction of efficacy and side effect, namely “personalized medicine”, has been becoming popular. Many clinical studies have reported that gene polymorphism is one of the key factors which influence on patient’s efficacy and toxicity as disease states and lifestyles do. For nonclinical toxicity assessments in pharmaceuticals, cynomolgus monkeys, a primate genetically closed to humans, are widely used. However, inter-individual differences of toxicity are observed in monkeys more often than rodents such as mice and rats. Gene polymorphisms could be one of the reasons, but due to limitations in the number of animals, it is often difficult to analyze the relationships between toxicological sensitivity and mutations.

As macaque monkey genome have been analyzed, genetic diversity has been gradually clarified. Although extrapolation to humans is still largely unknown, the influence of each genetic variation on functions has also been reported. Given these reported data, we have been focusing on mutations of the Fcγ receptors (FcγR), which is well-known as one of the factors causing sensitivity differences to therapeutic antibodies such as trastuzumab in clinical. In our research, through genetic analysis of the FcγR in Cambodian cynomolgus monkeys, we have detected the similarity of gene polymorphism between humans and other macaques. In this session, we would like to introduce the research data and discuss individual differences of toxicological sensitivity in nonclinical studies.