Chen, Hung-Chang; Mueller, Nico; Stott, Katherine; Kapeni, Chrysa; Rivers, Eilidh; Sauer, Carolin M; Beke, Flavio; Walsh, Stephen J; Ashman, Nicola; O'Brien, Louise; Rafati Fard, Amir; Godsinia, Arman; Li, Changtai; Joud, Fadwa; Giger, Olivier; Zlobec, Inti; Olan, Ioana; Aitken, Sarah J; Hoare, Matthew; Mair, Richard; ... (2024). Novel immunotherapeutics against LGR5 to target multiple cancer types. EMBO molecular medicine, 16(9), pp. 2233-2261. EMBO Press 10.1038/s44321-024-00121-2
Full text not available from this repository.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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology |
UniBE Contributor: |
Zlobec, Inti |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1757-4684 |
Publisher: |
EMBO Press |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
22 Aug 2024 09:16 |
Last Modified: |
14 Sep 2024 00:16 |
Publisher DOI: |
10.1038/s44321-024-00121-2 |
PubMed ID: |
39169164 |
Uncontrolled Keywords: |
ADC BiTE CAR Cancer Immunotherapeutics LGR5 |
URI: |
https://boris.unibe.ch/id/eprint/199910 |
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