Journal Article

Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer

Lyman, Susan K., Barry-Hamilton, Vivian, Smith, Victoria, Mikels-Vigdal, Amanda, Wang, Ruth, Lee, Michael, O’Sullivan, Christopher, Jorgensen, Brett, Adamkewicz, Joanne I., Liu, Chian, McCauley, Scott, Kovalenko, Maria, Spangler, Rhyannon, Velayo, Arleene C., Garcia, Carlos A., Marshall, Derek C., Ghermazien, Haben

2015

Overview

Expression of matrix metalloproteinase 9 (MMP9) is elevated in a variety of inflammatory and oncology indications, including ulcerative colitis and colorectal cancer. MMP9 is a downstream effector and an upstream mediator of pathways involved in growth and inflammation, and has long been viewed as a promising therapeutic target. However, previous efforts to target matrix metalloproteinases (MMPs), including MMP9, have utilized broad-spectrum or semi-selective inhibitors. While some of these drugs showed signs of efficacy in patients, all MMP-targeted inhibitors have been hampered by dose-limiting toxicity or insufficient clinical benefit, likely due to their lack of specificity. Here, we show that selective inhibition of MMP9 did not induce musculoskeletal syndrome (a characteristic toxicity of pan-MMP inhibitors) in a rat model, but did reduce disease severity in a dextran sodium sulfate-induced mouse model of ulcerative colitis. We also found that MMP9 inhibition decreased tumor growth and metastases incidence in a surgical orthotopic xenograft model of colorectal carcinoma, and that inhibition of either tumor- or stroma-derived MMP9 was sufficient to reduce primary tumor growth. Collectively, these data suggest that selective MMP9 inhibition is a promising therapeutic strategy for treatment of inflammatory and oncology indications in which MMP9 is upregulated and is associated with disease pathology, such as ulcerative colitis and colorectal cancer. In addition, we report the development of a potent and highly selective allosteric MMP9 inhibitor, the humanized monoclonal antibody GS-5745, which can be used to evaluate the therapeutic potential of MMP9 inhibition in patients.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Allosteric properties / Allosteric Regulation / Animal models / Animals / Antibodies, Monoclonal, Humanized - biosynthesis / Antibodies, Monoclonal, Humanized - isolation & purification / Antibodies, Monoclonal, Humanized - pharmacology / Antineoplastic Agents - isolation & purification / Antineoplastic Agents - metabolism / Antineoplastic Agents - pharmacology / Apoptosis / Biochemistry / Biology / Cancer / Cancer metastasis / Colitis, Ulcerative - chemically induced / Colitis, Ulcerative - drug therapy / Colitis, Ulcerative - enzymology / Colitis, Ulcerative - genetics / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - enzymology / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Cytokines / Dextran / Dextran Sulfate / Disease / Disease Models, Animal / Drug development / Drug Evaluation, Preclinical / Drug therapy / Drugs / Epitope Mapping / Female / Gelatinase B / Gene Expression Regulation, Neoplastic / Growth factors / Health aspects / Humans / Hybridomas - immunology / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Inhibition / Inhibitors / Kinases / Male / Matrix metalloproteinase / Matrix Metalloproteinase 9 - administration & dosage / Matrix Metalloproteinase 9 - genetics / Matrix Metalloproteinase 9 - metabolism / Matrix Metalloproteinase Inhibitors - isolation & purification / Matrix Metalloproteinase Inhibitors - metabolism / Matrix Metalloproteinase Inhibitors - pharmacology / Matrix metalloproteinases / Medical research / Metabolism / Metalloproteinase / Metastases / Metastasis / Mice / Mice, Nude / Monoclonal antibodies / Neutrophils / Patients / Rats / Rats, Inbred Lew / Recombinant Proteins - administration & dosage / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Rodents / Signal Transduction / Sodium / Sodium sulfate / Stroma / Sulfates / Surgery / Toxicity / Tumorigenesis / Tumors / Ulcerative colitis / Xenograft Model Antitumor Assays / Xenografts