851 Targeted Intracecal Anti-Α4β7 Integrin Antibody Results in Reduce Accumulation of Α4β7 Memory T-cells in Gut Tissue in DSS-induced Colitis Mice

INTRODUCTION: Systemically administered anti-α4β7 integrin antibodies such as Vedolizumab have been approved for the treatment of Crohn's disease and ulcerative colitis. The objective of this study was to assess whether intracecally (IC) delivered anti-mouse α4β7 integrin antibody (DATK32) might penetrate the mucosa and confer efficacy compared with systemic intraperitoneal (IP) injection in DSS-induced colitis mice. METHODS: Animals underwent implantation of a cecal cannula for topical bolus delivery in the IC groups. Acute colitis was induced by exposure to 3% DSS drinking water from Day 0-5. DATK32 was administrated via IP (25 mg/kg) every 3 days (Q3D), IC (25 mg/kg) Q3D, or IC (25 or 5 mg/kg) every day (QD) from Day 0 to 14. At Day 14, plasma, colon content and tissue were collected for DATK32 measurement; and Peyer’s patches (PP), mesenteric lymph nodes (mLN), and whole blood were collected for α4β7 memory T-cell counts. RESULTS: Significantly higher colon content and tissue exposure but limited blood exposure of DATK32 were found in IC QD groups compared to IP Q3D group. Immunohistochemistry staining of DATK32 was found in all layers of colon tissue, and as deep as tunica muscularis when delivered IC. The α4β7 memory T-cell count was significantly reduced in mLN in all IC groups compared to vehicle control and IP groups. Similar findings were observed in PP with IC QD treatment. Finally, the α4β7 memory T-cell count in blood was significantly increased in IC QD but not IC Q3D groups compared to vehicle control and IP group. CONCLUSION: In this study, we demonstrated that targeted IC anti-α4β7 integrin antibody lead to significantly higher drug exposure in colon contents and tissues with limited blood exposure compared to IP. Targeted IC QD treatment showed a significantly reduced α4β7 memory T-cell counts in PP and mLN representing populations within inflamed jejunal and colon tissues. Additionaly, an increased number of α4β7 memory T-cells was found in blood with targeted IC DATK32 compared to IP, suggesting T cells that have trafficked from blood to tissue can undergo reverse trafficking. Recent publications have reported a dose dependent increase in efficacy with systemically delivered anti-α4β7 despite full T-cell receptor occupancy in blood. Results of this study point to the potential for increased efficacy with high concentrations in local inflamed tissues. Although the mechanism of action is unclear, results suggest topically delivered anti-α4β7 may be an efficacious treatment in IBD.