EFFECTS OF MATRIX METALLOPROTEINASE (MMP)-7, MMP-13 AND CATHEPSIN G ON THE INTEGRITY AND FUNCTION OF ANTI-TUMOUR NECROSIS FACTOR (TNF)-α AND ANTI-INTEGRIN BIOLOGIC AGENTS

JONES SAMANTHA; SOBANDE T; CURCIARELLO RENATA; FERREYRA COMPAGNUCCI MALENA; DOCENA GUILLERMO H.; TREMELLING MARK; WATSON ALASTAIR JM; MACDONALD, THOMAS T.; BIANCHERI PAOLO

Barcelona

Congreso; United European Gastroenterology Week 2019; 2019

United European Gastroenterology

INTRODUCTION: Biologic therapy is highly effectivein inflammatory bowel disease (IBD), however a significant proportion ofpatients fail to respond, and mechanisms underlying primary non-responsivenessare unclear. We have previously observed that proteolytic degradation by MMP(matrix metalloproteinase)-3 and MMP-12, which are up-regulated in IBD inflamedmucosa, may contribute to primary non-responsiveness to anti-tumour necrosisfactor (TNF)-a agents in IBD.1 We hereby investigatedthe effect of other proteases on the integrity and function of anti-TNF-aand anti-integrin agents. AIMS & METHODS: We co-incubated increasingconcentrations of activated recombinant human MMP-7, MMP-13, and Cathepsin Gwith the anti-TNF-a agents Infliximab, Adalimumab, and Etanercept, or with theanti-integrin agent Vedolizumab, and we subsequently analysed the cleavagereaction products by Western blotting. Using a reporter cell line, we evaluatedthe effect of recombinant human proteases on the ability of anti-TNF-a agents to neutralisesoluble TNF-a. RESULTS:Infliximab, Adalimumab and Vedolizumab were not degraded by MMP-7, MMP-13, orCathepsin G. Etanercept was degraded in a concentration-dependent manner byMMP-7 and MMP-13, but not by Cathepsin G. Degradation by MMP-7 and MMP-13 didnot significantly impair the ability of Etanercept to neutralise soluble TNF-a.CONCLUSIONS:Despite being known to cleave immunoglobulins,2 MMP-7 and MMP-13 donot appear to impair the integrity and function of Infliximab and Adalimumab.In keeping with our previous findings, Etanercept appears to be highly susceptibleto the action of proteases.