Human Neutrophil Elastase Degrades The Therapeutic Monoclonal Antibodies Effective in IBD

CURCIARELLO RENATA; PAOLO GIUFFRIDA; KOK KLAARTJE; DOCENA GUILLERMO H.; ANTONIO DI SABATINO; MACDONALD, THOMAS T.

Washington DC

Congreso; International Congress of Mucosal Immunology 2017; 2017

Society of Mucosal Immunology

Therapeutic monoclonal antibodies which are effective in other inflammatory diseases such as rheumatoid arthritis are less effective inflammatory bowel disease (IBD). Human Neutrophil Elastase (HNE) is highly expressed in IBD mucosa, especially ulcerative colitis. The aim of this study was to determine if HNE degrades biologics, rendering them ineffective, and whether its action can be reversed by its natural inhibitor, Elafin. Biologics (Infliximab, Adalumimab, Etanercept) were digested using different concentrations of recombinant HNE in the absence or present of Elafin overnight. Neutrophils where isolated from human blood (UC patients and HC patients) by gradient centrifugation with Na-Dextran solution. Neutrophils where lysed and elastase activity was quantified. Antibody integrity after recombinant or natural HNE digestion was then analysed by western blot, and the functional capacity of the antibodies to neutralise TNF-alpha was tested using recombinant TNF-alpha and a TNFR reporter cell line. Recombinant and HNE from blood cells fully degrades all anti-TNF-alpha agents in a dose-dependent manner. This activity is inhibited by recombinant Elafin. Treatment with HNE also partially prevented the ability of the biologicals to inhibit TNF-alpha bioactivity. These results may explain some of the reasons for primary non-responsiveness to anti-TNF alpha therapy in IBD.