EMBO Molecular Medicine (Aug 2024)
Novel immunotherapeutics against LGR5 to target multiple cancer types
- Hung-Chang Chen,
- Nico Mueller,
- Katherine Stott,
- Chrysa Kapeni,
- Eilidh Rivers,
- Carolin M Sauer,
- Flavio Beke,
- Stephen J Walsh,
- Nicola Ashman,
- Louise O’Brien,
- Amir Rafati Fard,
- Arman Ghodsinia,
- Changtai Li,
- Fadwa Joud,
- Olivier Giger,
- Inti Zlobec,
- Ioana Olan,
- Sarah J Aitken,
- Matthew Hoare,
- Richard Mair,
- Eva Serrao,
- James D Brenton,
- Alicia Garcia-Gimenez,
- Simon E Richardson,
- Brian Huntly,
- David R Spring,
- Mikkel-Ole Skjoedt,
- Karsten Skjødt,
- Marc de la Roche,
- Maike de la Roche
Affiliations
- Hung-Chang Chen
- University of Cambridge, Cancer Research UK Cambridge Institute
- Nico Mueller
- University of Cambridge, Cancer Research UK Cambridge Institute
- Katherine Stott
- University of Cambridge, Department of Biochemistry
- Chrysa Kapeni
- University of Cambridge, Cancer Research UK Cambridge Institute
- Eilidh Rivers
- University of Cambridge, Department of Biochemistry
- Carolin M Sauer
- University of Cambridge, Cancer Research UK Cambridge Institute
- Flavio Beke
- University of Cambridge, Cancer Research UK Cambridge Institute
- Stephen J Walsh
- University of Cambridge, Yusuf Hamied Department of Chemistry
- Nicola Ashman
- University of Cambridge, Yusuf Hamied Department of Chemistry
- Louise O’Brien
- University of Cambridge, Cancer Research UK Cambridge Institute
- Amir Rafati Fard
- University of Cambridge, Department of Biochemistry
- Arman Ghodsinia
- University of Cambridge, Department of Biochemistry
- Changtai Li
- University of Cambridge, Department of Biochemistry
- Fadwa Joud
- University of Cambridge, Cancer Research UK Cambridge Institute
- Olivier Giger
- University of Cambridge, Department of Pathology
- Inti Zlobec
- Institute of Pathology, University of Bern
- Ioana Olan
- University of Cambridge, Cancer Research UK Cambridge Institute
- Sarah J Aitken
- University of Cambridge, MRC Toxicology Unit
- Matthew Hoare
- University of Cambridge, Cancer Research UK Cambridge Institute
- Richard Mair
- University of Cambridge, Cancer Research UK Cambridge Institute
- Eva Serrao
- University of Cambridge, Cancer Research UK Cambridge Institute
- James D Brenton
- University of Cambridge, Cancer Research UK Cambridge Institute
- Alicia Garcia-Gimenez
- University of Cambridge, Department of Haematology
- Simon E Richardson
- University of Cambridge, Department of Haematology
- Brian Huntly
- University of Cambridge, Department of Haematology
- David R Spring
- University of Cambridge, Yusuf Hamied Department of Chemistry
- Mikkel-Ole Skjoedt
- Rigshospitalet—University Hospital Copenhagen
- Karsten Skjødt
- University of Southern Denmark Campusvej 55
- Marc de la Roche
- University of Cambridge, Department of Biochemistry
- Maike de la Roche
- University of Cambridge, Cancer Research UK Cambridge Institute
- DOI
- https://doi.org/10.1038/s44321-024-00121-2
- Journal volume & issue
-
Vol. 16,
no. 9
pp. 2233 – 2261
Abstract
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.
Keywords
