Abstact

IgE antibodies exert strong immunostimulatory effects and their anti-tumour effectiveness is currently being assessed in clinical trials. The high affinity of IgE for FcepsilonRI may result in the binding of exogenously delivered antibody to effector cells prior to antigen engagement, potentially leading to IgE being presented multivalently to cancer cells. With the presumed higher avidity of antigen binding it is unclear whether increasing monovalent affinity of IgE improves anti-tumour functionality. To address this, we affinity-matured an anti-HER2 IgE, generating 12 clones with increased affinity for HER2. These clones were more potent than the parental antibody in inducing mast cell degranulation, with the most potent, EPS 232, achieving enhanced antibody-dependent cytotoxicity and phagocytosis of HER2-expressing cancer cells. EPS 232 delivered superior tumour growth inhibition in vivo, including in models expressing ultra-low levels of HER2, and it promoted greater infiltration of T cells and macrophages into tumours. These findings suggest that for therapeutic IgE, increasing antigen-binding affinity can lead to functional enhancements.