Antibody engineering to identify optimal expression systems and glycoforms of IgE class antibodies for cancer therapy

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Design strategies for cancer therapy have largely focused on one of nine human antibody classes, IgG1. We have designed an alternative approach by engineering anti-cancer antibodies bearing IgE Fc class regions. IgE antibodies are known to support immune defences against parasites and to be associated with allergies. These activities may be harnessed against cancer as a novel cancer immunotherapy strategy, exemplified by our first-in-class IgE antibody recognising a tumour-associated antigen undergoing a Phase I clinical trial at Guy's Hospital. IgEs are highly glycosylated antibodies, yet the precise effects of IgE glycan moieties on the potency and immune cell-activating mechanisms of IgE against cancer remain unclear. In this study, we aim to explore optimal engineering and glycoengineering strategies for the generation of anti-tumour IgE class antibodies in order to identify optimised antibodies for immuno-oncology. We will generate IgEs of the same specificity expressed in different mammalian expression systems and we will characterise their carbohydrate profiles in relation to function. Furthermore, we will generate different IgE glycoforms by administering inhibitors of glycan biosynthesis (Wagner). Antibody variant generation and pharmacological evaluations will be conducted in Year 1. Years 2-3 will focus on elucidating antibody biological functions, potency and ex vivo safety studies in patient blood and sera. Furthermore, glycoprofiling analyses (Ludger Ltd) will be conducted and correlated with antibody functional profiles. The study is designed to aid the identification of IgE antibodies and glycovariants with defined functional profiles and harbours considerable potentialto deliver optimised antibody immunotherapies for clinical testing in oncology.Project Aims: We will apply our established expression cloning methodologies to produce anti-tumour IgE antibody clones in different mammalian expression systems and as different glycoforms using glycosyltransferase inhibitors. We will interrogate the functional and glycosylation profiles of antibody variants. A panel of characterised antibodies with defined attributes will be selected for downstream translation and clinical testing.