Studying how structural modification of the TNFα inhibitor Enbrel affects its therapeutic efficacy in IBD

Inflammatory bowel disease (IBD) is a class of chronic inflammatory disorders, that are characterized by chronic inflammation of the gastrointestinal tract and affects millions of people worldwide. Although vastly studied, treatment options remain limited and are associated with multiple adverse effects. Initially, IBD patients are treated with general anti-inflammatory drugs such as corticosteroids, and when these fail, are offered biological treatments such as monoclonal antibodies, in particular anti-TNFα antibodies. TNFα is a pro-inflammatory cytokine that plays a crucial role in intestinal inflammation in IBD patients.

Enbrel™ (Etanercept) is an anti-TNFα Fc fusion protein that has FDA approval for treatment of rheumatoid arthritis (RA), another chronic inflammatory disease. Although Enbrel™ neutralizes TNFα, it was shown to be ineffective for treating IBD patients. This phenomenon raises questions about the mechanism and the immune response to different anti-TNFα agents in different TNFα- driven pathologies.

This research aimed to study how structural modification of the TNFα inhibitor Enbrel affects its therapeutic efficacy in IBD. To investigate the differences in the immune response to different anti-TNFα agents, a DSS-colitis model in mice was established. A murine version of Enbrel (named “mEnbrel) was developed for evaluation in a murine in vivo model. Modification of the mEnbrel molecule allows examining different features of anti-TNFα agents in a murine colitis model.

Our results showed differences between the murine version of Enbrel in their effects in the mouse model in some IBD disease indexes and in the leukocyte infiltration to the colon.