| Autor: |
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 Godsinia, 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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
EMBO Molecular Medicine, Vol 16, Iss 9, Pp 2233-2261 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1757-4684 |
| DOI: |
10.1038/s44321-024-00121-2 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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