Lais C G F Palhares, Melanie Grandits, Katie Stoker, Jitesh Chauhan, Heng Sheng Sow, Gilbert O Fruhwirth, Sophia Tsoka, James Birtley, Leanne Partington, Tim Wilson, Elizabeth Hardaker, Sophia N Karagiannis, Heather J Bax, Kevin FitzGerald
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引用次数: 0
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
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