Novel immunotherapeutics against LGR5 to target multiple cancer types.

Abstract:: We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-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 (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-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. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-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 α-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.

Authors:: H-C Chen, N Mueller, K Stott, C Kapeni, E Rivers, CM Sauer, F Beke, SJ Walsh, N Ashman, L O'Brien, A Rafati Fard, A Godsinia, C Li, F Joud, O Giger, I Zlobec, I Olan, SJ Aitken, M Hoare, R Mair, E Serrao, JD Brenton, A Garcia-Gimenez, SE Richardson, B Huntly, DR Spring, M-O Skjoedt, K Skjødt, M de la Roche, M de la Roche

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