Mark Cragg

Engineering antibodies for immune stimulation

Agonistic antibodies directed to immunostimulatory receptors are a currently untapped source for immunotherapy. Whereas checkpoint blockers have translated into the clinic, the rules for agonistic antibodies have been more difficult to discern and these reagents await further optimisation. 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. Using TNFR superfamily receptors as a paradigm the following key aspects will be discussed: The role of isotype; properties of the epitope; the importance of antibody hinge flexibility and the impact of affinity on delivering receptor agonism.

References:
Yu et al. (2023) Reducing affinity as a strategy to boost immunomodulatory antibody agonism. Nature. doi.org/10.1038/s41586-022-05673-2
Orr et al. (2022) Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility. Sci Immunol 7(73):eabm3723.
Yu et al. (2020) Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity. Cancer Cell. 37(6):850-866.
Yu et al. (2018) Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies. Cancer Cell. 33(4):664-675.