Treatment and Prevention of Inflammatory Bowel Disease (IBD) using Mutant and Chimeric IL-13 Molecules
Posted Oct 20 2010 8:00pm
Description of Invention: Ulcerative colitis (UC) is a chronic inflammatory disease of the colorectum and affects approximately 400,000 people in the United States. The cause of UC is not known, although an abnormal immunological response to bacterial antigens in the gut microflora is thought to be involved. Present treatments for UC include anti-inflammatory therapy using aminosalicylates or corticosteroids, as well as immunomodulators and diet. However, 25-40% of ulcerative colitis patients must eventually have their colons removed due to massive bleeding, severe illness, rupture of the colon, risk of cancer or due to side effects of corticosteroids and novel treatments are still actively being sought. NIH scientists and their collaborators have used a mouse model of experimental colitis (oxazolone colitis, OC) to show that IL-13, a Th2 cytokine, is a significant pathologic factor in OC and that neutralizing IL-13 in these animals effectively prevents colitis.
OC is a colitis induced by intrarectal administration of a relatively low dose of the haptenating agent oxazolone subsequent to skin sensitization with oxazolone. A highly reproducible and chronic colonic inflammation is obtained that is histologically similar to human ulcerative colitis. Studies show that Natural Killer T (NKT) cells, rather than conventional CD4+T cells, mediate oxazolone colitis and are the source of IL-13 as well as being activated by CD1- expressing intestinal epithelial cells. Tissue removed from ulcerative colitis patients were also shown to contain increased numbers of nonclassical NKT cells that produce markedly increased amounts of IL-13 and that in keeping with epithelial damage being a key factor in UC, these NKT cells are cytotoxic for epithelial cells. Building on their previous work, scientists at NIAID and FDA have shown that an Il-13 chimeric fusion protein linked to an effector molecule was able to prevent colitis in a mouse model of ulcerative colitis.
Available for licensing are methods for treating or preventing the inflammatory response of IBD by inhibiting the binding of IL-13 to IL-13 receptors on NKT cells. Additionally, these mutant and chimeric Il-13 molecules are able to block the chronic inflammatory response that results in fibrosis as seen in Crohn's disease. Preventing the inflammatory response of colitis by either modulating or blocking IL-13 and NKT cell activity continues to be an effective therapeutic approach in animal models of colitis with implications for the treatment of human ulcerative colitis and for the treatment of fibrosis associated with Crohn's disease.
Inventors: Atsushi Kitani (NIAID) Stefan Fichtner-Feigl (NIAID) Warren Strober (NIAID) Ivan J Fuss (NIAID) Koji Kawakami (FDA) Raj K Puri (FDA) Jan Preiss (NIAID) Peter J Mannon (NIAID)
Patent Status: HHS, Reference No. E-003-2005/0 US, Application No. 11/918,711 filed 14 Apr 2006 and related international filings
Related Technologies: US, Patent No. 7,666,411, Issued 23 Feb 2010, Reference No. E-131-2002/0 US, Application No. 12/709,029 filed 19 Feb 2010, Reference No. E-131-2002/0 US, Application No. 11/920,214 filed 09 Nov 2007, Reference No. E-108-2005/0
F Heller, IJ Fuss, EW Nieuwenhuis, RS Blumberg, W Strober. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 2002 Nov;17(5):629-628. [ PubMed: 12433369 ]
IJ Fuss, F Heller, M Boirivant, F Leon, M Yoshida, S Fichtner-Feigl, Z Yang, M Exley, A Kitani, RS Blumberg, P Mannon, W Strober. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004 May 15;113(10):1490-1497. [ PubMed: 15146247 ]
Licensing Status: Available for licensing.
Portfolios: Internal Medicine Internal Medicine - Therapeutics Miscellaneous
For Licensing Information Please Contact: Betty Tong Ph.D. NIH Office of Technology Transfer 6011 Executive Blvd. Suite 325, Rockville, MD 20852 United States Email: firstname.lastname@example.org Phone: 301-594-6565 Fax: 301-402-0220