Generation of anti-human MAdCAM-1 antibodies and bispecifics as gut-targeted anti-inflammatory biologics 3100

Description Inflammatory bowel disease (IBD) is a term that encompasses highly prevalent conditions characterized by chronic sites of inflammation present along the gastrointestinal track. The local delivery of biologics to manage symptoms associated with IBD would improve the quality of life of patients by limiting off-target events. Here, we report the development of monoclonal antibodies that target the human Mucosal Addressin-Cell Adhesion Molecule 1 (MAdCAM-1), a cell surface antigen predominantly expressed on endothelial cells of venules located in the lamina propria of the small intestine and colon. We postulate that these antibodies and related bispecifics harboring a therapeutic protein domain represent an attractive strategy to focus biologics to inflamed areas of the gut. As such, mAbs derived from eight hybridoma clones, bound to human MAdCAM-1 with dissociation constants in the low to sub-nanomolar range. Four of these 8 mAbs were able to detect MAdCAM-1 on the venules of human small intestinal tissue by immunohistochemistry and blocked MAdCAM-1 co-stimulation of primary human CD4+ T-cells, causing a shift in their ex vivo differentiation from central memory (CD45RA-, CD27+) cells to a more differentiated CD45RA–CD27- phenotype. These antagonistic antibodies as well as bispecifics linking a scFv derived from one of these mAbs to known biologics may represent potential therapeutic reagents for the localized treatment of gastrointestinal inflammation.