Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease

TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-b...

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Bibliographic Details
Published in:Scientific reports 2018-03, Vol.8 (1), p.4941-13, Article 4941
Main Authors: Crowe, J Scott, Roberts, Kevin J, Carlton, Timothy M, Maggiore, Luana, Cubitt, Marion F, Clare, Simon, Harcourt, Katherine, Reckless, Jill, MacDonald, Thomas T, Ray, Keith P, Vossenkämper, Anna, West, Michael R
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biomarkers - blood
Cell culture
Chymotrypsin
Colitis
Colon
Colon - metabolism
Colon - pathology
Cytokines
Cytokines - blood
Disease Models, Animal
Drug Evaluation, Preclinical
Enzyme-linked immunosorbent assay
Epithelium
Humans
Ileum - metabolism
Ileum - pathology
Inflammatory bowel disease
Inflammatory bowel diseases
Inflammatory Bowel Diseases - blood
Inflammatory Bowel Diseases - chemically induced
Inflammatory Bowel Diseases - drug therapy
Inflammatory Bowel Diseases - pathology
Infliximab
Infliximab - pharmacokinetics
Infliximab - pharmacology
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Intestine
Male
Mice
Monoclonal antibodies
Mucosa
Necrosis
Oral administration
Pancreatin
Patients
Pepsin
Rodents
Tissue culture
Trypsin
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - blood
Tumor necrosis factor-α
Tumors
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Summary:TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-23277-7