Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill
نویسندگان
چکیده
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 anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with active site mimicry antigen and enzyme. Our protocol yielded highly selective antibody, which specifically inhibits MMP-7′s enzyme activity high affinity (IC50 = 132 ± 10 nM). atomic model MMP-7-GSM-192 Fab complex exhibited binding to unique epitopes at rim site, sterically preventing entry substrates into catalytic cleft. In human PDAC biopsies, tissue staining GSM-192 showed characteristic spatial distribution MMP-7. Treatment in vitro induced apoptosis via stabilization cell surface Fas ligand retarded migration. Co-treatment chemotherapeutics, gemcitabine oxaliplatin elicited a synergistic effect. data illustrate advantage precisely targeting MMP-7 mediated disease specific activity.
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ژورنال
عنوان ژورنال: Cancers
سال: 2021
ISSN: ['2072-6694']
DOI: https://doi.org/10.3390/cancers13071679