P098 Novel drug candidate for the treatment of Inflammatory Bowel Disease with unique mechanisms of action
Lee, J.(1)*;Kim, G.(1);Kim, J.C.(1);Park, J.H.(1);Han, C.(1);Kim, M.(1);
(1)NEXEL Co.-Ltd., Department of New Drug Development, Seoul, Korea- Republic Of;
Background
Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation and severe dysfunction of the gastrointestinal tract. Despite significant improvements in therapeutic agents targeting IBD, many subjects with IBD fail to achieve recovery or do not respond to current medication. Moreover, current therapy has been limited to the management of inflammation, while almost no progress has been made in the development of anti-fibrotic therapies for IBD. NEXEL's novel protein NP-011, targeting αVβ3 and αVβ5 integrins and phosphatidylserine, has shown anti-inflammatory and anti-fibrotic effects in various in vivo models with fibrosis. This study was designed to evaluate the therapeutic potential of NP-011 for the treatment of IBD using mice models.
Methods
Acute ulcerative colitis was induced by exposure to 2% dextran sodium sulfate (DSS)-treated drinking water from Day 1 to Day 7; Normal control animals did not receive DSS. Animals were then dosed with vehicle (NP-011 storage buffer, n=10), comparative protein, MFG-E8 (n=10), or NP-011 (n=10) daily for five days (IV) from Day 7 to Day 11. All animals were sacrificed on Day 14. The chronic colitis model was induced by exposure to 2% DSS-treated drinking water (initial three consecutive days of each week) and recovered by providing normal water (four days each from Day 3 and Day 10). Animals were dosed with the vehicle, three commercial drugs (n=10, 1.03 mg/kg, on Day 3), and NP-011 (n=10, 320, and 640 ug/kg, on Day 3 and Day 10) by intravenous injection. All animals were sacrificed on Day 18. Colon length and histological changes (inflammation and crypt damage) were analyzed.
Results
The induction of colitis was characterized by weight loss. Treatment with comparative protein or NP-011 improved body weight gain during recovery. Both proteins suppressed the shortening of the colon and reduced histological score, including intestinal inflammation and crypt damage. Notably, the administration of NP-011 showed higher efficiency than the same dose of the comparative protein in improving these pathologic parameters. NP-011 was also effective in the chronic model of colitis. Colon shortening, inflammation reactions, and crypt damage were markedly attenuated in NP-011-administered mice with comparable efficacy to commercial drugs.
Conclusion
Treatment with NP-011 demonstrated substantial improvement in histological characteristics of bowel pathology and suppression of colon shortening in the IBD mice model. Taken together, this novel protein, NP-011, could be a promising drug candidate for the treatment of IBD with unique mechanisms of action, including anti-inflammation and anti-fibrosis
*JL, GK, and JCK have equally contributed to this study.