Novel immunotherapeutics against LGR5 to target multiple cancer types.

Autor:	Chen HC; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.; Astra Zeneca, Cambridge, UK., Mueller N; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Stott K; University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge, CB2 1QW, UK., Kapeni C; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Rivers E; University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge, CB2 1QW, UK.; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK., Sauer CM; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Beke F; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Walsh SJ; University of Cambridge, Yusuf Hamied Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK.; Bicycle Therapeutics, Cambridge, UK., Ashman N; University of Cambridge, Yusuf Hamied Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK.; Charles River Laboratories, Saffron Walden, UK., O'Brien L; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Rafati Fard A; University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge, CB2 1QW, UK., Ghodsinia A; University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge, CB2 1QW, UK., Li C; University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge, CB2 1QW, UK., Joud F; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Giger O; University of Cambridge, Department of Pathology, Tennis Court Road, Cambridge, CB2 1QP, UK., Zlobec I; Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008, Bern, Switzerland., Olan I; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Aitken SJ; University of Cambridge, MRC Toxicology Unit, Tennis Court Road, Cambridge, CB2 1QR, UK.; Department of Histopathology, Cambridge University Hospitals, NHS Foundation Trust, Main Drive, Cambridge, CB2 0QQ, UK., Hoare M; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Mair R; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Serrao E; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Brenton JD; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK., Garcia-Gimenez A; University of Cambridge, Department of Haematology, Puddicombe Way, Cambridge, CB2 0AW, UK., Richardson SE; University of Cambridge, Department of Haematology, Puddicombe Way, Cambridge, CB2 0AW, UK., Huntly B; University of Cambridge, Department of Haematology, Puddicombe Way, Cambridge, CB2 0AW, UK., Spring DR; University of Cambridge, Yusuf Hamied Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK., Skjoedt MO; Rigshospitalet-University Hospital Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.; Institute of Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.; Novo Nordisk, Måløv, Denmark., Skjødt K; University of Southern Denmark Campusvej 55, Odense M, DK-5230, Denmark., de la Roche M; University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge, CB2 1QW, UK. mad58@cam.ac.uk., de la Roche M; University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK. maike.delaroche@cruk.cam.ac.uk.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Sep; Vol. 16 (9), pp. 2233-2261. Date of Electronic Publication: 2024 Aug 21.
DOI:	10.1038/s44321-024-00121-2
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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