Conformation-specific inhibitory anti-MMP-7 monoclonal antibody sensitizes pancreatic ductal adenocarcinoma cells to chemotherapeutic cell kill

Vishnu Mohan, Jean P. Gaffney, Inna Solomonov, Maxim Levin, Mordehay Klepfish, Sophia Akbareian, Barbara Grünwald, Orly Dym, Miriam Eisenstein, Kenneth H. Yu, David P. Kelsen, Achim Krüger, Dylan R. Edwards, Irit Sagi

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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.

Original languageEnglish
Article number1679
JournalCancers
Volume13
Issue number7
DOIs
Publication statusPublished - 2 Apr 2021

Keywords

  • Drug synergy
  • Fas ligand
  • Gemcitabine
  • Matrilysin
  • Matrix metalloproteinase-7
  • Monoclonal antibody
  • Oxaliplatin
  • Pancreatic ductal adeno-carcinoma

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