Oral delivery of the anti-tumor necrosis factor α domain antibody, V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys

Abstract

Objective: V565 is a novel oral anti-tumor necrosis factor (TNF)-a 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 localization of mini-tablet dissolution. V565 distribution in luminal contents and feces was measured by enzyme-linked immunosorbent assay (ELISA). To mimic transit across the damaged intestinal epithelium seen in IBD patients an intravenous (i.v.) 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 0.1 M 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 feces 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 i.v. 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.

Strategic Approaches for Colon Targeted Drug Delivery: An Overview of Recent Advancements

“…This tablet exhibited the sustained drug release at pH ≥ 6 but no drug release during 2-hr incubation in acidic conditions. In vivo studies in monkeys also supported the sustained release of V565 in the intestine for the topical treatment of IBD [44]. In addition, the drug release profiles can be manipulated by using a combination of copolymers with varying the ratios [44].…”

“…In vivo studies in monkeys also supported the sustained release of V565 in the intestine for the topical treatment of IBD [44]. In addition, the drug release profiles can be manipulated by using a combination of copolymers with varying the ratios [44]. This combination system may be superior to tablets coated with a single polymer for colon-targeted drug delivery.…”

“…This system is applicable to macromolecules as well as low molecular synthetic drugs. Recently, Crowe et al [44] developed the Eudragit L100-coated tablets for the colonic delivery of a novel anti-tumor necrosis factor α domain antibody (V565). This tablet exhibited the sustained drug release at pH ≥ 6 but no drug release during 2-hr incubation in acidic conditions.…”

Exosomes derived from T regulatory cells relieve inflammatory bowel disease by transferring miR‐195a‐3p

“…24 Clinical anti-TNF-α treatment can effectively improve intestinal barrier function and ameliorate IBD symptoms. 25,26 In our in vitro study, we used Treg-Exo to culture with colonic epithelial YAMC cells in the presence of TNF-α to investigate the communication between Tregs and intestinal epithelial cells. We found that Treg-Exo could be transferred to YAMC cells where Treg-Exo promoted cell proliferation and inhibited cell apoptosis.…”

Influences of different Fe sources on Fe bioavailability and homeostasis in SD rats

“…In addition, TIBC refers to serum transferrin‐binding iron, and the value of which can indirectly reflect the transferrin content, further proves that the iron supplementation of enteric‐coated Fe‐Gly(1:1) and enteric‐coated Fe‐Gly(2:1) is better than uncoated iron supplements. Some scholars have found that IB‐CP SRCs can maintain the effective blood concentration of the body for a long time by comparing the ibuprofen enteric‐coated sustained‐release pellets (IB‐SRPs) with conventional tablets (Huang, Lu, Li, Luo, & Liu, ); Crowe et al found that the drug passed after the enteric coating, the drug can be released in a specific part of the monkey (intestine) to improve the utilization of the drug; meanwhile (Crowe et al, ); Xu et al also believe that enteric coating treatment can be used as an effective carrier for oral drugs (Xu et al, ).…”