Scientific Abstract
Proposal No. IBD-0021
Principal Investigator: Hudson Freeze, Ph.D.
Applicant Organization: The Burnham Institute (La Jolla, California, U.S.A.)
Project Title: An anti-glycan antibody (mAbGB3.1) as a novel therapy for Crohn's disease and ulcerative colitis
Period of Award: August 1, 2002 - March 31, 2005
We recently discovered a group of novel, carboxylated N-linked sugar chains that are primarily expressed on the surface of mammalian endothelial cells. An IgG monoclonal antibody against these sugar chains identified the receptor for advanced glycation end-products (RAGE) as a major carrier of antibody-binding oligosaccharides. The carboxylated sugar chains specifically bind four proteins: amphoterin, annexin-I, S100A9 and S-100A12, which are all involved in inflammation.
We found that our antibody blocks acute peritoneal inflammation in the mouse by blocking the transmigration of adherent neutrophils into the tissue. Others had already shown that RAGE binds to S100A12 and that preventing the binding blocks the onset of IBD in IL-10 knockout mice. Based on these results, we hypothesized that our antibody, mAbGB3.1, would block the development of inflammatory bowel disease (IBD)-like symptoms in susceptible mice. Our preliminary experiments strongly support this idea: the antibody blocked both weight loss and development of typical histopathology in IBD-prone mice. mAbGB3.1 might be a useful therapeutic for IBD-like inflammatory disorders.
To test this hypothesis, we will use three murine models of IBD: dextran sodium sulfate model, transfer of CD4+ CD45RBhigh T cells to immune deficient recipients, and IL-10 knockout mice. Each system has distinct advantages and limitations, necessitating the use of all to obtain a full picture. Mice in each model will be given mAbGB3.1 or a control antibody to determine whether our antibody blocks the onset, rate of development, or severity of IBD. Once disease is established in these models, we will also see whether our antibody improves the extent or rate of recovery from disease. Quantitation will be done by assessment of general health, weight loss/gain, intestinal histology, localized increases of cytokines such as TNF-a, IL-1, IL-6, IL-12, and identification of lymphocyte phenotype and function. A successful outcome will provide a new therapeutic approach for IBD and offer a new role for sugar chains in the development and resolution of inflammation.