Novel immunotherapeutics against LGR5 to target multiple cancer types 2423

Abstract Description Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a target gene of Wnt signalling. LGR5 is overexpressed in multiple cancers, including colorectal cancer, hepatocellular carcinoma and pre-B acute lymphoblastic leukaemia, with no to low expression levels in healthy human tissues. In our study we developed novel immunotherapeutics based on highly specific monoclonal antibodies against human LGR5 (α-LGR5). Antibody-Drug Conjugates (ADCs): We show that α-LGR5 is rapidly internalised and trafficked into lysosomal vesicles, making it a suitable target for ADC development. Our α-LGR5-ADCs effectively eliminate LGR5+ tumour cells in vitro, and in a murine model of human pre-B-ALL, where α-LGR5-ADC treatment reduces tumour burden to less than 1% of the control treatment. Bispecific T cell Engagers: α-LGR5 bispecifics efficiently activate human T cells and redirect them to eliminate LGR5+ cancer cells. In vivo studies show a 50% reduction of tumour burden following treatment. Chimeric Antigen Receptor (CAR): α-LGR5-CAR T cells exhibit potent and specific killing of LGR5+ cancer cells in vitro and a significant 80% reduction of tumour burden in vivo. Finally, we show that LGR5high cancer lines and PDXs are more susceptible to our α-LGR5-directed therapies compared to LGR5low expressors. Thus, we generated safe and potent immunotherapeutics against LGR5, with the potential to uniquely direct immunotherapeutic modalities to different LGR5+ cancers and patient profiles. Funding Sources Supported by several CRUK (A22257, C67279/A27957, RCCCSF-May23/100001, C52489/A19924, C63389/A30462, C18873/A26813), and Wellcome Trust Awards (227432/Z/23/Z, 222062/Z/20/Z), a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (107609/Z/15/Z, 203151/Z/16/Z), the Medical Research Council (RG94521), and the Pathological Society (3903171). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)