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Mark Cragg is Professor of Experimental Cancer Biology in the School of Cancer Sciences at the University of Southampton Faculty of Medicine. His research concerns how therapeutics result in tumour regression with a focus on antibodies and small molecules, with a particular interest in Fc receptors and TNFR family members. The aim is to understand how these therapeutics delete tumour cells, how resistance occurs, and how it might be overcome through antibody engineering.

Immunomodulatory antibodies represent an exciting new modality for immunotherapy. Either by targeting inhibitory immune checkpoints (checkpoint blockers) or stimulatory receptors (agonists) they can elicit powerful responses capable of resolving disease. Whereas checkpoint blockers have been translated successfully into the clinic, agonistic antibodies directed to immunostimulatory receptors have lagged behind and represent an untapped approach for immunotherapy. At least in part this reflects a lack of understanding of what is required for optimal receptor activation and what rules govern the activity of agonistic antibodies. Here we highlight the salient properties of monoclonal antibodies (mAb) required to strongly agonise these receptors and discuss potential strategies for leveraging them for immune activation and anti-tumour efficacy. Through selection and/or engineering, previously inert and even antagonistic antibodies can be rendered powerful immune stimulators. Using TNFR superfamily receptors as a paradigm the role of isotype, epitope, antibody hinge flexibility and affinity will all be discussed.