Human Monoclonal Antibodies Against Clostridium Difficile Toxin A And B Inhibit Inflammatory Responses And Epithelial Cell Damage To Toxins A And B In Human Peripheral Blood Monocytes And Human Colonic Tissues

Background and Aims: Inflammatory bowel disease (IBD) is characterized by the failure to repair mucosal damage resulting from chronic inflammation in the intestinal tract.Macrophage Stimulating Protein (MSP) is a soluble growth factor that is the ligand for the receptor tyrosine kinase, RON.Genome-wide association studies (GWAS) have identified a nonsynonymous single nucleotide polymorphism (rs3197999) in MSP that is associated with elevated susceptibility to IBD, thus linking the MSP/RON pathway to disease pathogenesis.We have demonstrated that RON is preferentially expressed on epithelial cells in the intestine of normal individuals and IBD patients, implicating the MSP/RON pathway in the regulation of epithelial responses during IBD.We hypothesized that the MSP risk allele impacts RON signaling activity in IBD patients and that therapeutic activation of the RON pathway could promote an epithelial wound repair response that would have relevance for treatment of IBD.Methods: rs3197999 genotype and serum MSP levels were analyzed in matched samples from 204 donors, including normal individuals and IBD patients.RON agonist antibodies were developed, characterized, and tested in pre-clinical models of epithelial wound healing.Results: We found that carriers of the MSP risk allele had up to 50 percent lower quantities of serum MSP, indicating that, in these individuals, decreased RON signaling may impact the efficiency of wound repair, thereby affecting IBD susceptibility.A novel panel of RON agonist antibodies was generated, and they were found to be potent inducers of RON signaling and wound repair responses in vitro.Additionally, these antibodies were capable of inducing RON signaling in the colon of mice following systemic administration, demonstrating that antibodies could reach the intestinal parenchyma in a functional state.Furthermore, agonist antibodies stimulated wound repair in a mouse model of epithelial tissue damage.In diabetic db/db mice that received punch-biopsy skin wounds, RON agonist antibodies induced healing to the point of wound closure.In controls, wound size decreased by only 50 percent.Conclusions: These results indicate that diminished RON activity may increase genetic risk for development of IBD and that activation of the RON pathway with agonist antibodies can induce epithelial repair.Thus, a RON agonist approach may benefit IBD patients by stimulating repair of damaged intestinal tissues.