EFFECTS OF MATRIX METALLOPROTEINASE RMMPS-T, MMP-UV AND CATHEPSIN G ON THE INTEGRITY AND FUNCTION OF ANTI-TUMOUR NECROSIS FACTOR RTNFS-􀄮 AND ANTI-INTEGRIN BIOLOGIC AGENTS

SAMANTHA JONES; SOBANDE TONI; CURCIARELLO RENATA; COMPAGNUCCI FERREYRA MALENA; TREMELLING MARK; WATSON A; DOCENA GUILLERMO; MACDONALD THOMAS; BIANCHERI PAOLO

Barcelona

Congreso; 27th UEG Week 2019; 2019

Introduction: Biologic therapy is highly eSective in inoammatory boweldisease (IBD), however a signiJcant proportion of patients fail to respond,and mechanisms underlying primary non-responsiveness are unclear. Wehave previously observed that proteolytic degradation by MMP (matrix metalloproteinase)-3 and MMP-12, which are up-regulated in IBD inoamedmucosa, may contribute to primary non-responsiveness to anti-tumournecrosis factor (TNF)-􀄮 agents in IBD.1 We hereby investigated the eSectof other proteases on the integrity and function of anti-TNF-􀄮 and antiintegrinagents.Aims & Methods: We co-incubated increasing concentrations of activatedrecombinant human MMP-7, MMP-13, and Cathepsin G with the anti-TNF-􀄮􀀃agents Inoiximab, Adalimumab, and Etanercept, or with the anti-integrinagent Vedolizumab, and we subsequently analysed the cleavage reactionproducts by Western blotting. Using a reporter cell line, we evaluated theeSect of recombinant human proteases on the ability of anti-TNF-􀄮 agentsto neutralise soluble TNF-􀄮.Results: Inoiximab, Adalimumab and Vedolizumab were not degraded byMMP-7, MMP-13, or Cathepsin G. Etanercept was degraded in a concentration-dependent manner by MMP-7 and MMP-13, but not by Cathepsin G.Degradation by MMP-7 and MMP-13 did not significantly impair the abilityof Etanercept to neutralise soluble TNF-􀄮.Conclusion: Despite being known to cleave immunoglobulins,2 MMP-7 andMMP-13 do not appear to impair the integrity and function of Inoiximaband Adalimumab. In keeping with our previous Jndings, Etanercept appearsto be highly susceptible to the action of proteases.