Abstract

In this lecture we will focus on target selection for different types of anti-cancer monoclonal antibody, including those that target cancer cells directly such as rituximab and trastuzumab, and those that target the immune system to promote tumour immunity. This latter group of reagents has become particularly attractive with the recent clinical success of ipilimumab and the anti-PD-1/PD-L1 blockers, such as nivolumab and pembrolizumab, in a number of difficult to treat cancers. It might at first appear that the requirements for these two classes of drug would be very different, with the former acting by recruiting  cytotoxic effectors to kill the unwanted cells and the latter by blocking  inhibitory signals on cytotoxic T cells and thereby reversing  T cell exhaustion. However as we learn more about their respective mechanisms of action we find that in both cases the optimum targets are often key signalling molecules where the antibody is required to either block or in some cases promote transmembrane signalling. The most recent data also suggest that some of the response to checkpoint blockers might be due to cytotoxic activity required to delete regulatory T cells. We will explore these data and how they change our thinking about target molecule selection and antibody engineering to promote efficacy.