Conformation-specific inhibitory anti-MMP-7 monoclonal antibody sensitizes pancreatic ductal adenocarcinoma cells to chemotherapeutic cell kill Journal Article
| Authors: | Mohan, V.; Gaffney, J. P.; Solomonov, I.; Levin, M.; Klepfish, M.; Akbareian, S.; Grünwald, B.; Dym, O.; Eisenstein, M.; Yu, K. H.; Kelsen, D. P.; Krüger, A.; Edwards, D. R.; Sagi, I. |
| Article Title: | Conformation-specific inhibitory anti-MMP-7 monoclonal antibody sensitizes pancreatic ductal adenocarcinoma cells to chemotherapeutic cell kill |
| Abstract: | Matrix metalloproteases (MMPs) undergo post-translational modifications including pro-domain shedding. The activated forms of these enzymes are effective drug targets, but generating potent biological inhibitors against them remains challenging. We report the generation of anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with an active site mimicry antigen and the activated enzyme. Our protocol yielded highly selective anti-MMP-7 monoclonal antibody, which specifically inhibits MMP-7′ s enzyme activity with high affinity (IC50 = 132 ± 10 nM). The atomic model of the MMP-7-GSM-192 Fab complex exhibited antibody binding to unique epitopes at the rim of the enzyme active site, sterically preventing entry of substrates into the catalytic cleft. In human PDAC biopsies, tissue staining with GSM-192 showed characteristic spatial distribution of activated MMP-7. Treatment with GSM-192 in vitro induced apoptosis via stabilization of cell surface Fas ligand and retarded cell migration. Co-treatment with GSM-192 and chemotherapeutics, gemcitabine and oxaliplatin elicited a synergistic effect. Our data illustrate the advantage of precisely targeting catalytic MMP-7 mediated disease specific activity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. |
| Keywords: | controlled study; unclassified drug; drug efficacy; nonhuman; gemcitabine; antineoplastic agent; mouse; animal tissue; fas ligand; animal experiment; animal model; tumor biopsy; enzyme activity; monoclonal antibody; cancer cell; pancreas adenocarcinoma; conformational transition; oxaliplatin; antigen binding; antibody production; matrilysin; female; article; drug synergy; ic50; matrix metalloproteinase-7; pancreatic ductal adeno-carcinoma; gsm 192 |
| Journal Title: | Cancers |
| Volume: | 13 |
| Issue: | 7 |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Date Published: | 2021-04-01 |
| Start Page: | 1679 |
| Language: | English |
| DOI: | 10.3390/cancers13071679 |
| PROVIDER: | scopus |
| PMCID: | PMC8038143 |
| PUBMED: | 33918254 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 May 2021 -- Source: Scopus |
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