Preferential antibody and drug conjugate targeting of the ADAM10 metalloprotease in tumours Journal Article
| Authors: | Yan, H.; Vail, M. E.; Hii, L.; Guo, N.; McMurrick, P. J.; Oliva, K.; Wilkins, S.; Saha, N.; Nikolov, D. B.; Lee, F. T.; Scott, A. M.; Janes, P. W. |
| Article Title: | Preferential antibody and drug conjugate targeting of the ADAM10 metalloprotease in tumours |
| Abstract: | ADAM10 is a transmembrane metalloprotease that sheds a variety of cell surface proteins, including receptors and ligands that regulate a range of developmental processes which re-emerge during tumour development. While ADAM10 is ubiquitously expressed, its activity is normally tightly regulated, but becomes deregulated in tumours. We previously reported the generation of a monoclonal antibody, 8C7, which preferentially recognises an active form of ADAM10 in human and mouse tumours. We now report our investigation of the mechanism of this specificity, and the preferential targeting of 8C7 to human tumour cell xenografts in mice. We also report the development of novel 8C7 antibody–drug conjugates that preferentially kill cells displaying the 8C7 epitope, and that can inhibit tumour growth in mice. This study provides the first demonstration that antibody– drug conjugates targeting an active conformer of ADAM10, a widely expressed transmembrane metalloprotease, enable tumour-selective targeting and inhibition. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. |
| Keywords: | controlled study; protein expression; unclassified drug; histopathology; nonhuman; drug targeting; flow cytometry; mouse; animal tissue; tumor volume; animal experiment; animal model; antineoplastic activity; tumor xenograft; monoclonal antibody; cancer inhibition; drug distribution; colon cancer; antibody specificity; brain cancer; mouse model; molecularly targeted therapy; therapeutic antibody; adam10 endopeptidase; adam metalloprotease; article; nod scid gamma mouse; antibody drug conjugate; lim1215 cell line; antibody–drug conjugate; 8c7 antibody; balb/c nude mouse; u-251mg cell line |
| Journal Title: | Cancers |
| Volume: | 14 |
| Issue: | 13 |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Date Published: | 2022-07-01 |
| Start Page: | 3171 |
| Language: | English |
| DOI: | 10.3390/cancers14133171 |
| PROVIDER: | scopus |
| PMCID: | PMC9264901 |
| PUBMED: | 35804938 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
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