PROTEOLYTIC ACTIVITY OF MATRIX METALLOPROTEINASE (MMP)-7, MMP-13 AND CATHEPSIN G IMPAIRS INTEGRITY AND FUNCTION OF THERAPEUTIC MONOCLONAL ANTIBODIES USED IN INFLAMMATORY BOWEL DISEASES

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

San Miguel de Tucumán

Congreso; LXVII Reunión Anual de la Sociedad Argentina de Inmunología; 2019

Sociedad Argentina de Inmunología

INTRODUCTION:Biologic therapy is highly effective in inflammatory bowel diseases (IBD). However,a significant proportion of patients fail to respond, and mechanisms underlyingprimary non-responsiveness are unclear. We have previously observed thatproteolytic degradation by Human Neutrophil Elastase (HNE), MMP-3 and MMP-12,which are up-regulated in IBD inflamed mucosa, may contribute to primarynon-responsiveness to anti-tumour necrosis factor (TNF)-aagents in IBD. We hereby investigated the effect of other proteases onanti-TNF-a and anti-integrin biological agents. METHODS:We co-incubated increasing concentrations of activated recombinant human MMP-7,MMP-13, and Cathepsin G with anti-TNF-a agents Infliximab(IFX), Adalimumab (ADA), and Etanercept (ETA), or with anti-integrin agentVedolizumab (Vedo). Digestions with pepsin and papain were performed as controlfor immunoglobulin´s proteolytic cleavage. We analysed the cleavage reactionproducts by western blot. The TNF-αneutralising ability of degraded biological agents was evaluated using areporter cell line.RESULTS: IFX, ADA andVedo were not degraded by MMP-7, MMP-13, nor Cathepsin G. ETA was degraded in aconcentration-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 ability ofEtanercept to neutralise soluble TNF-a. Even though pepsincleavage site in the lower hinge region of IgG is similar for MMP-7, pepsindigestion impaired TNF neutralisation ability of IFX and ETA.CONCLUSIONS:Despite being known to cleave immunoglobulins, MMP-7 and MMP-13 did not impairthe integrity and function of Infliximab and Adalimumab. In keeping with ourprevious findings, Etanercept appears to be highly susceptible to proteases.