Novel immunotherapeutics against LGR5 to target multiple cancer types

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (alpha-LGR5). alpha-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (alpha-LGR5-ADC), Bispecific T-cell Engager (alpha-LGR5-BiTE) and Chimeric Antigen Receptor (alpha-LGR5-CAR). alpha-LGR5-ADC was the most effective modality for targeting LGR5(+) cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. alpha-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. alpha-LGR5-CAR-T cells also showed specific and potent LGR5(+) cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that alpha-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.