Combination Therapy of Selective MMP9 Inhibitor and JAK Inhibitor Is Effective to Induce Disease Control in Mouse DSS Model of Colitis

Abstract

Introduction: MMP9 (matrix metalloproteinase-9) promotes tissue destruction by degrading the basement membrane of epithelia and vasculature, in addition to driving inflammation via activation of cytokines and chemokines. MMP9 knock out animals were protected in DSS (dextran sulfate sodium)-induced colitis. A functional murine analog of the selective anti-MMP9 inhibitory antibody reduced disease activity index (DAI: stool consistency, hemoccults, body weight change) in established chronic DSS colitis. A potent, selective, allosteric antibody that inhibits MMP9 is currently being investigated in clinical trials. Here, a combination therapy treatment with systemic anti-inflammatory agent JAK (janus kinase) inhibitor was investigated. Methods: Colitis was induced in female C57BL/6 (n=15/group) and treatments were administered after the disease induction. Efficacy was assessed via metrics of colitis including DAI and histopathological assessment. Results: All animals were included in the evaluation. Treatment with each therapeutic agent, on its own or in combination, resulted in efficacy with respect to body weight change, stool consistency, hemoccults, colon length and weight, and histopathological assessment. Disease-induced body weight loss was improved in combination as compared to single agents (48% vs. 21-32%, relative to sham; p < 0.05 combination vs. single agents). DAI score was lower in combination vs. single agents (48% vs. 73-63%, relative to vehicle, p < 0.05). Normal stool consistency was better maintained in combination vs. single agents throughout the study period (205% vs. 139-159%, relative to vehicle, p < 0.05). Drug treatment induced early disease control, with no disease at day 12 vs. consistent disease symptoms in control-treated animals. The median ratio of colon weight/ length (mg/ cm) was 29 in combination vs. 32-38 in single agents (40-42 in controls, p < 0.05). The median surface affected by erosion or atrophy inflammation was 19% in combination vs. 38-41% in single agents (relative to vehicle, p < 0.05). Conclusion: The combination of anti-MMP9 inhibitory antibody with JAK inhibitor was significantly more effective than single agents to induce and maintain disease control by slowing disease progression and promoting mucosal healing. Further studies are required to examine combination therapy of selective anti-MMP9 antibody and JAK inhibitor in a clinical setting.