P587 Development and Characterization of a Novel Extended Half-life Monoclonal Antibody Drug Candidate Targeting Integrin ɑ4β7 for the Treatment of IBD

Abstract

Abstract Background Antagonism of the interaction between the cellular adhesion integrin ɑ4β7 and endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) is a safe and effective mechanism to treat Crohn’s disease (CD) and ulcerative colitis (UC). Additional benefit may be gained from an ɑ4β7 antagonist given via the subcutaneous (SC) route at extended intervals (eg, every 8 to 12 weeks) during maintenance therapy. Methods The novel humanized monoclonal IgG1 antibody SPY001 binds to the same ɑ4β7 epitope as vedolizumab and includes a YTE modification within the Fc region to increase half-life via increased affinity for the neonatal Fc receptor (FcRn), thereby favoring recycling into the circulation over degradation. Binding affinity of SPY001 to ɑ4β7 was determined by kinetic exclusion assay (KinExA) and flow cytometry, and functional activity was determined by inhibition of addressin-mediated cellular adhesion. Results SPY001 binds specifically to ɑ4β7 and not to the related integrins ɑ4β1 and ɑEβ7. In cellular assays, SPY001 binds ɑ4β7 on the surface of RPMI-8866 cells with an affinity matching that of vedolizumab, but it does not bind to Ramos cells expressing ɑ4β1. It demonstrates high affinity for ɑ4β7, with a KD of 836 pM as determined by KinExA. Functionally, SPY001 potently inhibits MAdCAM-1-mediated cellular adhesion with an IC50 comparable to that of vedolizumab but has no inhibitory activity for VCAM-1-mediated cell adhesion. Conclusion SPY001 is a novel humanized monoclonal IgG1 with high affinity for ɑ4β7 and potent inhibition of the ɑ4β7/MAdCAM-1 interaction. It offers the potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.