Insights from the bottom-up development of LGR5-targeting immunotherapeutics.

Abstract

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a transcriptional target gene of the Wnt signalling pathway, is overexpressed in multiple cancers, including colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) and has emerged as a promising therapeutic target. Here, we reflect on the bottom-up development of a novel α-LGR5 therapeutic antibody we have recently reported, into a palette of LGR5-targeting immunotherapeutic modalities: antibody-drug conjugates (ADCs), bispecific T cell engagers (bispecific engagers), and chimeric antigen receptor (CAR) T cells. The α-LGR5 antibody is highly specific and accurately detects LGR5 protein expression levels, enabling its use as a prognostic biomarker for identifying LGR5⁺ tumour types. Preclinical studies road-testing the various α-LGR5-based modalities established potent and safe elimination of LGR5-expressing cancer cells in vitro and efficacy in a mouse model of human cancer in vivo. In this review, we discuss the utility of our antibody as the building block for a novel set of immunotherapeutics and highlight the importance of matching specific α-LGR5-based therapeutic modalities to individual tumour type and patient characteristics.