3rd Supervisor: Prof Sophia Karagiannis
Half of patients with melanoma, the most lethal skin cancer, and a large proportion of patients with aggressive breast cancers such as the triple negative subtypes, do not respond to currently-available antibody immunotherapies. Existing anti-cancer antibody-based therapies are largely-focused on IgG-class antibodies. However, several features of IgG, including low Fc-receptor affinity, inhibitory Fc-receptors downregulating functional signalling, and poor tissue retention, can limit therapeutic response. IgE, the predominant antibody in allergic responses, is emerging as a promising novel anti-cancer therapeutic modality in the field of AllergoOncology. A growing repertoire of pre-clinical studies demonstrate the potential of anti-tumour IgE antibodies to restrict tumour growth and epidemiological studies highlight roles of IgE in tumour immunosurveillance. We have successfully completed a Phase 1 clinical trial of MOv18 IgE, the first-in-class IgE monoclonal antibody for cancer therapy. IgE is a highly-glycosylated antibody, however, there is insufficient understanding of the interplay between glycosylation and anti-tumour function. We have established a platform to generate and characterise IgE antibodies, including those with altered glycan profiles and showed that sialic acid influences the ability of IgE to mediate downstream signalling on immune cells. This project will identify optimal glycoengineered IgEs for cancer immunotherapy. In year 1, we will generate and characterise IgEs and glycovariant forms recognising melanoma-associated and breast cancer-associated antigens. In year 2, we will compare the functional attributes of paired glycoengineered and native IgEs in several in vitro assays. Years 3 and 4 will entail in vivo studies of selected IgE glycoforms in cancer models and tumour organoid models. The study will establish the impact of glycan structures on anti-tumour functions, and the importance of evaluating the glycan profiles of IgE candidates for cancer therapy. Ultimately, selection of optimal IgE glycoforms may lead to new treatment options for patients who do not presently benefit from established immunotherapies.