Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients

Abstract

V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn’s disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn’s patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.

Structural features of bovine colostral immunoglobulin that confer proteolytic stability in a simulated intestinal fluid

“…Oral delivery of anti-CD3 monoclonal antibodies has been shown to have a biological effect in both preclinical (36,37) and clinical (38) settings, although a relatively small fraction of the dosed antibody reached the small intestine in an active form (36). A llama domain antibody engineered for enhanced protease stability has shown promising anti-inflammatory activity in a small cohort of IBD patients (39). There remains a major unmet need to be able to orally administer antibody therapeutics.…”

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

“…Serum concentrations of V565 were also observed in this study, showing that V565 is partly absorbed after oral administration. V565 has been investigated in a clinical study [ 104 ] and is discussed in Section 4 .…”

“…[ 92 , 94 ]. Results from a clinical trial [ 104 ] showed that active V565 could be recovered in the ileal fluids of patients with a terminal ileostomy after oral administration of enteric-coated tablets with a pH threshold ≥ 6. In CD patients, high active V565 concentrations could be recovered in fecal samples.…”

Oral Delivery of Biologics in Inflammatory Bowel Disease Treatment

“…Eudragit-coated V565 was encapsulated in hydroxypropyl methylcellulose (HPMC) capsules. Overall, this study showed that oral-delivered active V565 reaches IBD disease sites in high concentrations and can bind to V565 TNF-α + cells in UC lesions (Nurbhai et al, 2019). In another phase I clinical study, 47 patients with CD were involved in investigating tolerability and safety of oral V565, and V565 is currently under phase II clinical study in Europe and North America (Crowe et al, 2017).…”

“…V565 is a 12.6-kDa anti-TNF-α heavy chain variable domain antibody. It is isolated from a phage library produced from lymphocytes of a human TNF-α hyperimmunized llama and engineered to be resistant to intestinal and inflammatory proteases while retaining the TNF-α neutralizing potency against both soluble and membrane forms of human TNF-α ( Crowe et al, 2017 ; Nurbhai et al, 2019 ). Opposite to AVX-470, V565 is unable to survive in acidic stomach environment and requires sustenance from oral delivery vehicles.…”