Background/Purpose: Matrix metalloproteinase-9 (MMP9), highly expressed by infiltrating inflammatory cells, pannus tissue, and multinucleated cells in the synovium and subchondral bone tissue, including osteoclasts, participates in joint destruction, drives inflammation via activation of cytokines and chemokines, and promotes tissue destruction by degrading the basement membrane of epithelia and vasculature. MMP9 knockout mice are protected from collagen-induced arthritis (CIA) disease progression. A potent, allosteric antibody that inhibits MMP9 is currently being investigated in clinical trials{Marshall et al 2015}. The ability of a functional murine analog of this antibody to reduce disease signs and symptoms in established, chronic mouse CIA model both as a single agent and in combination with anti-TNF, was investigated.

Methods: CIA was induced in male DBA/1J mice (n=15/group) and treatments were administered after disease establishment. Efficacy was assessed via metrics of joint injury including clinical score (erythema/ paw swelling, score 0-4) in addition to histopathological assessment of destructive joint remodeling (soft tissue changes: edema, necrosis, inflammatory cell infiltration, and fibroplasia, sum score 0-16; bone changes: cartilage damage, bone erosion, periosteal bone formation, synovitis, pannus formation, and joint destruction, sum score 0-24).

Results: All animals were included in the evaluation. In all endpoints assessed, treatment with each therapeutic agent, on its own or in combination, resulted in efficacy with respect to body weight change, clinical score, and histopathological measures. The combination group provided the best overall trend for therapeutic benefit, although statistical significance as compared to each single agent alone was not met in most parameters. Body weight recovery was superior in combination as compared to single agent therapies (52% vs. 12-34%, relative to sham; p<0.05 combination vs. single agents). Clinical score and histopathology measures in soft tissue and bone changes were most improved in the combination therapy group, although it did not achieve statistical significance as compared to each single agent (26% vs. 17-21%; 1.5 vs. 1.5-1.8; and 7 vs. 7-9, respectively). Importantly, combination therapy resulted in a significant number of limbs with zero or mild disease as compared to single agents (no disease sign: 256% vs. 172-223%; mild disease sign: 178% vs. 138-141%). Analysis of complete blood count at the end of study revealed no abnormalities in any treatment group.

Conclusion: Selective inhibition of MMP9 was effective in reducing disease severity in CIA models of RA. The combination of anti-MMP9 with anti-TNF was well tolerated and increased the number of limbs with no or mild disease compared to anti-TNF alone. Further studies are required to examine combination therapy of selective anti-MMP9 and anti-TNF therapies in a clinical setting.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-inhibition-of-mmp9-using-a-monoclonal-antibody-as-a-therapeutic-strategy-for-rheumatoid-arthritis/