Research Project
9202065
Abstract Inflammatory Bowel Disease (IBD), including primarily Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, debilitating condition with no effective treatment. The economic impact is disproportionally high because it affects primarily young individuals (10-40 years old), and the characteristic periods of remission and relapse necessitate frequent hospitalizations. Furthermore, some 20-30% of patients with total bowel involvement will have colectomy, and 70%-80% of patients with CD require some type of surgical intervention during their lifetime. Symptoms like bloody diarrhea, abdominal pain, general malaise, and fever significantly compromise quality of life. IBD affects 1.4 million Americans with annual healthcare costs approaching $2 billion. Current therapies (anti-inflammatory drugs, immunosuppressants, antibiotics, and drugs for symptomatic relief) are only modestly effective, and often cause unacceptable adverse events, particularly with long-term use. A new generation of biologics targets pathways of immune activation to block proinflammatory signaling. All seven biologics showing clinical benefits in IBD are monoclonal antibodies, including TNF-?, ?4 integrin, and IL-12/23 blockers. Mucosal healing and long-term remission occur in only a minority of patients. Significantly, rare but life-threatening conditions, including increased risk for serious infections, non-Hodgkin's lymphoma, and melanoma, have been associated with chronic exposure to anti-TNF?. therapies The pharmaceutical management of IBD, despite the revolutionizing use of biological therapies, remains problematic. Recent data support the hypothesis that melanin-concentrating hormone (MCH) is a crucial link in inflammatory events affecting the mucosa. Results from four animal models support a pivotal role for MCH signaling in IBD. Both MCH and MCH receptor (MCHR1) expression levels are elevated in biopsies of inflamed mucosa from IBD patients relative to non-involved mucosa from the same patients. A polyclonal rabbit anti-MCH antibody attenuates chronic colitis and fibrosis in two animal models of colitis. Further supporting a role for MCH in IBD, MCH-knock-out mice are protected from experimental colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). During this Phase I project, we will identify and characterize a neutralizing anti-MCH human monoclonal antibody (humAb). Evaluation in both in vitro cellular and in vivo rodent models will be carried out. We are optimistic that this work will result in a new therapeutic for CD and UC. This biological therapy will reduce inflammation, fibrosis and prolong periods of remission among patients suffering from IBD.
