Introduction

Antagonism of the interaction between the cellular adhesion integrin ɑ4β7 and endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) has proven to be relatively safe and effective in the treatment of 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.

Aims & Methods

The humanized monoclonal IgG1 antibody SPY001 binds to the same ɑ4β7 epitope as vedolizumab and includes a YTE modification within the Fc region to increase its serum half-life via increased affinity for the neonatal Fc receptor (FcRn), thereby favoring recycling into the circulation over degradation. The binding affinity of SPY001 to ɑ4β7 was determined by kinetic exclusion assay (KinExA), surface plasmon resonance, and flow cytometry. In vitro functional activity was determined by inhibition of MAdCAM-1-mediated cell adhesion. In vivo half-life extension was evaluated via pharmacokinetic analysis in Tg276 transgenic mice (hemizygous for human FcRn) and in non-human primates (NHP). PK simulations in humans were based on allometric scaling of SPY001 clearance observed in NHP. Safety was assessed via a good laboratory practice toxicity (GLP-tox) study in NHP.

Results

SPY001 binds specifically to ɑ4β7 and not to the related integrins ɑ4β1 and ɑEβ7. In cell-based binding assays, SPY001 binds ɑ4β7 expressed on the surface of RPMI-8866 cells with an affinity matching that of vedolizumab, but does not bind to Ramos cells expressing ɑ4β1. It demonstrates high affinity for ɑ4β7, with a K_D of <1 nM. Functionally, SPY001 potently inhibits MAdCAM-1-mediated cell adhesion with an IC₅₀ comparable to that of vedolizumab but has no inhibitory activity for VCAM-1-mediated cell adhesion.

In Tg276 mice, the half-life of SPY001 was approximately 12 days compared to approximately 4 days for vedolizumab. In cynomolgus monkeys, the half-life of SPY001 was approximately 22 days following a single SC infusion, substantially longer than the half-life of vedolizumab (~6 days) in the same study. Based on allometric scaling of SPY001 clearance observed in this study, predictive simulations of SPY001 PK in humans suggest that Q8W-Q12W SC dosing will achieve therapeutic exposure in patients across a wide range of body weights and albumin concentrations. In a repeat-dose GLP toxicity study in NHP no adverse or dose limiting toxicities were observed even at the highest dose tested. Both SC and IV administration were well-tolerated and observations related to the administration procedure were similar across doses including controls.

Conclusion

SPY001 is a novel humanized monoclonal IgG1 with an extended half-life relative to that of vedolizumab in Tg276 mice and cynomolgus monkeys. Repeat-dose toxicity studies at doses up to 160 mg/kg showed no SPY001-related adverse events and a safety profile supportive of progression into clinical development. SPY001 offers the potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Clinical studies are warranted to demonstrate this potential.

Disclosure

EZ, DR, RV, JO, and HS are employees of Paragon Therapeutics.
JF, DN, AS, MR, and OB are employees of Spyre Therapeutics.