Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease, is a debilitating autoimmune condition that can be clinically challenging to manage effectively. Many IBD patients are diagnosed early in life, and as a result of chronic gut inflammation, experience higher risks of colorectal cancer. Presently, other than general suppression of immunity or inflammatory signals, there is little specific knowledge about how to limit or prevent IBD flare-ups.
Building on their expertise in tissue barrier functions of the gastrointestinal tract, LIMR scientists have now developed an antibody-based therapy that inactivates a molecule that facilitates gut inflammation in the setting of IBD. This therapeutic technology tightens the poor gut-barrier function found in IBD patients, thereby attenuating multiple sources of inflammation that are associated with a leaky gut barrier.
LIMR’s technology focuses on Bin1, a cell signaling molecule that, among its various roles, acts to modify the intensity of stress and the inflammatory responses of cells under stress. In genetic studies in mice, we discovered that Bin1 ablation dramatically attenuated colonic inflammation and risks of colon carcinogenesis. In exploring therapeutic directions to mimic this effect, we discovered a cell-permeable anti-Bin1 antibody that was safe and effective when delivered systemically. Human colon tissue studies confirm observations in colon cell culture systems that antibody uptake is sufficient to tighten barrier functions, as measured physiologically or molecularly at the level of tight junction protein expression.
Thus, the technology focuses on a novel and tractable mechanism of action for IBD control that targets a nodal modifier of tight junction-mediated barrier function, thereby coordinating a reduction in mucosal lesions, crypt loss, lymphoid follicle rupture, and infiltration of neutrophils and lymphocytes into the mucosal and submucosal areas of the colon.
Current work is at a preclinical stage of development, including ongoing mechanism studies and antibody humanization.
The incidence of IBD in developed countries has been skyrocketing, and the disorder is now becoming a global disease in newly industrialized countries as societies become more Westernized in diet and other factors. In the U.S., the CDC estimates that 1.3 percent of adults (about three million) have been diagnosed with IBD. Foundations that support the annual World IBD Day (held in May) estimate the number of affected individuals at 10 million.
In distinguishing IBD cases from the far larger number of individuals presenting with irritable bowel syndrome, an accurate blood test would enable more rapid focus on the IBD-affected population. The global market for gastrointestinal therapeutics is set to grow from US $35.7 billion in 2015 to US $48.4 billion by 2022, according to the business intelligence provider GBI Research.
Intellectual property position
Bin1 antibody uses for inflammatory disease therapy: Patents pending.
Chang MY, Boulden J, Valenzano MC, Soler AP, Muller AJ, Mullin JM and Prendergast GC. (2012). Bin1 attenuation suppresses inflammatory colitis by enforcing intestinal barrier function. Dig Dis Sci 57: 1813-1821.
Thomas S, Mercado JM, DuHadaway J, DiGuilio K, Mullin JM and Prendergast GC. (2016). Novel colitis immunotherapy targets Bin1 and improves colon cell barrier function. Dig Dis Sci 61: 423-432.
Thomas S, Hoxha K, Alexander W, Gilligan J, Dilbarova R, Whittaker K, Kossenkov A, Prendergast GCP and Mullin JM. (2018). Intestinal barrier tightening by a cell penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis. J Cell Biochem (in press).