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Significance Antibodies blocking inhibitory checkpoints on T cells have been a major advance in cancer treatment. However, agonistic antibodies have had less success due to toxicity concerns. Harnessing the knowledge that agonistic antibodies require the inhibitory Fc receptor (FcR), we engineered a CD40 antibody with improved in vivo activity. Because current models fail to recapitulate important dose-limiting toxicities in patients, we developed a mouse model carrying human CD40 and FcRs. This model mirrors human toxicities and allowed for the development of an in situ vaccination approach leading to durable tumor control. These results support the rational design of immune modulating antibodies as well as stress the importance, and possible reconsiderations needed, for optimal preclinical models allowing parallel efficacy and toxicity analyses.

Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity