Immunomodulatory mAb, led by the checkpoint blockers against CTLA-4 and PD-1/PD-L1, are changing the outlook for a number of difficult to manage cancers, such as melanoma and non-small cell lung cancer, and look set to become blockbuster drugs in the near future. While there is still some uncertainty concerning how these reagents work, it is generally agreed that they target exhausted effector T cells and Tregs within the tumour tissue. An alternative way to regulate anti-cancer T cells is using immunostimulatory mAb which trigger activatory T-cell co-receptors, often of the TNF receptor superfamily. Interestingly, most preclinical models show that immunostimulatory mAb are as good if not better than checkpoint blockers in terms of therapeutic potency. However, other than some limited success with anti-CD40 mAb in pancreatic cancer, immunostimulatory mAb have yet to display the level of clinical success seen with the checkpoint blockers. In this lecture we will discuss the mechanisms of action of these two groups of reagents and explore how differences in the rodent and human antibody effector functions might explain why immunostimulatory mAb have not performed as well in patients. We will show how the mouse inhibitory Fc gamma Receptor (FcγR), FcγRIIB, plays a critical role in hyper-crosslinking agonistic anti-TNFR mAb, yet in humans the equivalent receptor is less available to perform this function. We will also discuss how this knowledge is being used to engineer new immunostimulatory mAb which can exploit human FcγR effectively, or even mAb which can operate independently of FcγR with the opportunity of potent agonistic function regardless of bio-availability of FcγR.

Citation Format: Martin J. Glennie, Aymen Al-Shamkhani, Stephen A. Beers, Ann L. White, Peter W. Johnson, Ruth R. French, Mark S. Cragg. Designing immunostimulatory antibodies for cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA06.