title: Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer.
abstract: 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.
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Marshall
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Lyman
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: McCauley
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Kovalenko
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Rhyannon
authors.initials: R
authors.lastname: Spangler
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Chian
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Sullivan
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Vivian
authors.initials: V
authors.lastname: Barry-Hamilton
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Haben
authors.initials: H
authors.lastname: Ghermazien
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mikels-Vigdal
authors.affiliation: Department of Process Development, Gilead Sciences, Inc., Oceanside, California, United States of America.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Garcia
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Brett
authors.initials: B
authors.lastname: Jorgensen
authors.affiliation: Department of Process Development, Gilead Sciences, Inc., Oceanside, California, United States of America.
authors.forename: Arleene C
authors.initials: AC
authors.lastname: Velayo
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Ruth
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Joanne I
authors.initials: JI
authors.lastname: Adamkewicz
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D018604:Epitope Mapping; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D016264:Dextran Sulfate; D020780:Matrix Metalloproteinase 9