An IgE antibody targeting HER2 identified by clonal selection restricts breast cancer growth via immune-stimulating...

Tumor-targeting IgE antibodies have elicited potent tumor-restricting effects by recruiting immune effector mechanisms. However, a dedicated platform for the generation, selection and evaluation of novel IgEs based on target antigen recognition and functional profiles has not been reported.

By establishing an IgE class antibody therapeutic design platform to allow selection of lead candidates, we generated a panel of IgEs recognising the human epidermal growth factor receptor 2 (HER2), overexpressed in 15-20% of breast cancers. From 1840 phage display-generated variable region sequences panned against HER2, we engineered 30 full length IgE antibodies. We selected three clones based on biophysical properties, reactivity to HER2 + cancer cells, epitope reactivity and Fc-mediated anti-tumor profiles in vitro. Clones with cross-reactivity to rat HER2 were selected to allow functional evaluations in a fully immunocompetent syngeneic HER2 + rat breast cancer model.

IgE antibodies induced degranulation and antibody-dependent cellular cytotoxicity against human and rat HER2-expressing tumor cells in vitro. IgE antibody 26 demonstrated anti-tumor activity in a syngeneic HER2 + rat model, and a human HER2 + breast cancer xenograft model in mice reconstituted with human immune cells. Treatment was associated with enhanced immune cell infiltration and pro-inflammatory immune signatures, and downregulated cancer progression signaling pathways, in the tumor microenvironment.

This study pioneers the design and generation of anti-HER2 IgE lead antibody candidates with immune-stimulating and tumor-restricting effects. The present work may pave the way for antibody engineering therapeutic opportunities for challenging-to-treat HER2-expressing cancers.