Oral delivery of the anti-TNFα domain antibody, V565, results in high intestinal and faecal concentrations with minimal systemic exposure in cynomolgus monkeys.

OBJECTIVE: V565 is a novel oral anti-TNFα domain antibody being developed for topical treatment of inflammatory bowel disease (IBD) patients. Protein engineering rendered the molecule resistant to intestinal proteases. Here we investigate the formulation of V565 required to provide gastro-protection and enable optimal delivery to the lower intestinal tract in monkeys.

METHODS: Enteric coated V565 mini-tablets were prepared and dissolution characteristics tested in vitro. Oral dosing of monkeys with enteric coated mini-tablets containing V565 and methylene blue dye enabled in vivo localisation of mini-tablet dissolution. V565 distribution in luminal contents and faeces was measured by ELISA. To mimic transit across the damaged intestinal epithelium seen in IBD patients an intravenous bolus of V565 was given to monkeys and pharmacokinetic parameters of V565 measured in serum and urine by ELISA.

RESULTS: Enteric coated mini-tablets resisted dissolution in 0.1M HCl, before dissolving in a sustained release fashion at neutral pH. In orally dosed monkeys methylene blue intestinal staining indicated the jejunum and ileum as sites for mini-tablet dissolution. Measurements of V565 in monkey faeces confirmed V565 survival through the intestinal tract. Systemic exposure after oral dosing was very low consistent with limited V565 mucosal penetration in healthy monkeys. The rapid clearance of V565 after intravenous dosing was consistent with renal excretion as the primary route for elimination of any V565 reaching the circulation.

CONCLUSIONS: These results suggest that mini-tablets with a 24% Eudragit® enteric coating are suitable for targeted release of orally delivered V565 in the intestine for topical treatment of IBD.