Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Antibody Generation and Purification
2.2. Antibody Digestion with Papain for Fab Generation
2.3. MMP-7 Elisa Binding Assay
2.4. MMP-7 Enzymatic Kinetic Assay
2.5. Antibody Sequencing
2.6. Protein Crystallography of GSM-192 Fab
2.7. Computational Modeling and Docking
2.8. Constructing and Analyzing, MMP Ortholog-Based Multiple Sequence Alignment (MSA)
2.9. Structural Alignment and Analysis
2.10. Cell Culture
2.11. MMP-7 Lentiviral Silencing and FACS Analysis
2.12. MTT Cell Proliferation Assay
2.13. FACS Annexin-V Apoptosis Detection Assay
2.14. Western Blots
2.15. Wound Healing Assay (Scratch Assay)
2.16. Trans-Well Migration Assay
2.17. Immunohistochemistry
2.18. Co-Treatment with Chemotherapeutics
2.19. In Vitro Dose Response Matrix and Synergistic Effect
2.20. Statistics
3. Results
3.1. Alternating Antigen Immunization Strategy Yields High Affinity Monoclonal Antibody (mAb) Selectively Targeting Active MMP-7
3.2. GSM-192 Selectively Binds to the Active form of Human MMP-7 and Inhibits its Catalytic Activity
3.3. Fab Fragment Crystal Structure and Docking Model Show Antibody’s Affinity to Bind Sites Close to the Conserved Active Site
3.4. Anti MMP-7 Fab Inhibits Fas Ligand Shedding Leading to Pancreatic Tumor Cell Death via Apoptosis
3.5. GSM-192 Fab Reduces Cell Motility In Vitro
3.6. Co-Treatment with GSM-192 Decreases IC50 of Gemcitabine (GEM) and Oxaliplatin (OX)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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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. Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill. Cancers 2021, 13, 1679. https://doi.org/10.3390/cancers13071679
Mohan V, Gaffney JP, Solomonov I, Levin M, Klepfish M, Akbareian S, Grünwald B, Dym O, Eisenstein M, Yu KH, Kelsen DP, Krüger A, Edwards DR, Sagi I. Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill. Cancers. 2021; 13(7):1679. https://doi.org/10.3390/cancers13071679
Chicago/Turabian StyleMohan, Vishnu, 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, and Irit Sagi. 2021. "Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill" Cancers 13, no. 7: 1679. https://doi.org/10.3390/cancers13071679