5th Annual BMRP Investigator Meeting - Abstract

Therapy of Inflammatory Bowel Disease Using LMP-420
 
Laura P. Hale

Department of Pathology, Duke University Medical Center (Durham, North Carolina, U.S.A.)

Systemic therapy with anti-TNF drugs such as infliximab has proven to be beneficial for a number of inflammatory bowel disease (IBD) patients, particularly those with Crohn’s disease. However infliximab therapy also has significant disadvantages, including its high cost, need for intravenous infusion, development of anti-chimeric antibodies, and the potential for opportunistic infections.  A drug that could interfere with the TNF pathway yet overcome these disadvantages could represent a major advance in the therapy of patients with IBD. LMP-420 is a purine-based small molecule containing boronic acid that is a non-cytotoxic transcriptional inhibitor of TNF production. The purpose of this project is to determine the efficacy of LMP-420 as an anti-inflammatory agent in murine models of IBD. The degree of systemic and colonic TNF blockade that resulted from different LMP-420 dosing protocols was initially assessed using a bacterial lipopolysaccharide (LPS) challenge model. Intraperitoneal (i.p.) pre-treatment with LMP-420 significantly decreased serum and colonic TNF (-42% and -28%, respectively) 2 hours after i.p. challenge with 0.5 mg LPS. Similar decreases in serum (-43%) and colonic TNF levels (-29%) were also seen when LMP-420 was administered in food prior to LPS challenge. C57BL/6 mice with acute colitis following 7 days of exposure to 3% dextran sulfate sodium (DSS) in their drinking water had significantly decreased colonic TNF levels on day 7 when LMP-420 therapy was initiated on day 4 (66±30 pg/100 mg tissue for no DSS; 409±107 pg/100 mg for DSS + vehicle; 117±8 pg/100 mg for DSS + i.p. LMP-420, p = 0.05 vs. vehicle). Studies are currently in progress to determine the efficacy of a dose range of LMP-420 in chronic colitis elicited by 3 cycles of DSS in wild type C57BL/6 mice and in piroxicam-accelerated colitis in IL-10^-/- mice.