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 (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<sup>+</sup> 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<sup>+</sup> 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
- Chrysa Kapeni (ORCID: https://orcid.org/0000-0003-0408-2106)
- Amir Rafati Fard (ORCID: https://orcid.org/0000-0003-1804-2586)
- Eva Serrão (ORCID: https://orcid.org/0000-0002-1402-3444)
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Ioana Olan (ORCID: https://orcid.org/0000-0003-0692-1831)
- Eilidh Rivers
- Katherine Stott (ORCID: https://orcid.org/0000-0002-4014-1188)
- Louise M. O’Brien (ORCID: https://orcid.org/0000-0002-8121-5374)
- Carolin M. Sauer (ORCID: https://orcid.org/0000-0003-2168-6630)
- Arman Ghodsinia
- James D. Brenton (ORCID: https://orcid.org/0000-0002-5738-6683)
- Matthew Hoare (ORCID: https://orcid.org/0000-0001-5990-9604)
- Stephen J. Walsh (ORCID: https://orcid.org/0000-0002-3164-1519)
- Marc de la Roche (ORCID: https://orcid.org/0000-0002-3757-082X)
- Sarah J. Aitken (ORCID: https://orcid.org/0000-0002-1897-4140)
- Nicola Ashman (ORCID: https://orcid.org/0000-0003-4907-058X)
- David R. Spring (ORCID: https://orcid.org/0000-0001-7355-2824)
- Fadwa Joud
- Inti Zlobec (ORCID: https://orcid.org/0000-0001-6741-3000)
- Simon Richardson (ORCID: https://orcid.org/0000-0003-4343-4784)
- Hung‐Chang Chen (ORCID: https://orcid.org/0000-0002-2849-6752)
- Flavio Beke (ORCID: https://orcid.org/0000-0002-2294-0306)
- Maike de la Roche (ORCID: https://orcid.org/0000-0002-0558-4119)
- Karsten Skjødt (ORCID: https://orcid.org/0000-0002-9161-8185)
- Richard James Mair (ORCID: https://orcid.org/0000-0001-8235-5689)
- Olivier Giger (ORCID: https://orcid.org/0000-0003-3390-6397)
- Alícia Giménez (ORCID: https://orcid.org/0000-0003-0604-3215)
- Changtai Li (ORCID: https://orcid.org/0000-0002-9372-9452)
- Mikkel‐Ole Skjoedt
- Nico Mueller
Institutions
- AstraZeneca (United Kingdom) (GB)
- University of Bern (CH)
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Novo Nordisk (Denmark) (DK)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- Charles River Laboratories (United Kingdom) (GB)
- Bicycle Therapeutics (United Kingdom) (GB)
- MRC University of Glasgow Centre for Virus Research (GB)
- MRC Epidemiology Unit (GB)
- IT University of Copenhagen (DK)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s44321-024-00121-2
- Citations
- 12
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 3.39
Funders
- Wellcome Trust
- Cancer Research UK
- Pathological Society of Great Britain and Ireland
- Medical Research Council