Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
The first-in-human (FiH) dose for monoclonal antibodies (mAb) is generally determined based on the no observed adverse effect level (NOAEL) or pharmacologically active dose (PAD). However, after the tragedy of an anti-CD28 agonist mAb (TGN1412), which resulted in severe life-threatening adverse events directly related to the exaggerated pharmacology, regulatory agencies have provided guidance that recommend using the minimal anticipated biological effect level (MABEL) to select a safe FiH dose for certain classes of drugs (e.g. T-cell engagers). However, this could result in inefficient clinical development as the starting dose can be significantly lower than the efficacious dose level. In this presentation, we will discuss case studies of T-cell engager antibodies where a FiH starting dose was determined collectively by pharmacology (MABEL derived from the in vitro tumor cell killing assay) and toxicology (NOAEL derived from the pre-clinical toxicity study).
