Host: The Japanese Society of Toxicology
Here I present cases where results of toxicology studies using monkeys were efficiently used for labeling in some regulatory agencies as well as for establishing potential safety biomarkers. All of those examples of labeling are from immune check point inhibition and the resultant immune-related pregnancy risks. These include the cases of CTLA-4 inhibition that exhibits premature births and decreased birth weight (PMDA), PD-1 inhibition mAb that exhibits increased abortion and premature infant death (FDA), and PD-L1 inhibition that exhibits irregular menstrual cycle pattern (EMA), all of which have been observed in ePPND studies of cynomolgus monkeys. Since blockade of PD1/PDL1 (+CTLA-4) pathway may result in a decrease in the efficiency of Tregs and an increase in inflammatory Th17 cells leading to loss of tolerance at the feto maternal interface, the above finding are described as basis of clinical risks in respective labeling. In the course of monkey studies, etc, there are also recent research papers that have raised out Th17/Treg ratio, Th1/Th2 ratio, or NK cell activity in maternal peripheral blood as the potential predictive biomarkers for spontaneous abortion, preterm or preeclampsia. Thus, as far as drug-related immunological pregnancy risks, monkey studies appear to serve as a good translational model to clinical.
