Author:
Roberts Kevin J.,Cubitt Marion F.,Carlton Timothy M.,Rodrigues-Duarte Lurdes,Maggiore Luana,Chai Ray,Clare Simon,Harcourt Katherine,MacDonald Thomas T.,Ray Keith P.,Vossenkämper Anna,West Michael R.,Crowe J. Scott
Abstract
AbstractAnti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.
Publisher
Springer Science and Business Media LLC
Reference58 articles.
1. Torres, J., Mehandru, S., Colombel, J.-F. & Peyrin-Biroulet, L. Crohn’s disease. Lancet (Lond., Engl.) 389, 1741–1755 (2017).
2. Ungaro, R., Mehandru, S., Allen, P. B., Peyrin-Biroulet, L. & Colombel, J. F. Ulcerative colitis. Lancet 389, 1756–1770 (2017).
3. Lamb, C. A. et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 68, s1–s106 (2019).
4. Ho, G. T., Porter, R. J. & Kalla, R. Ulcerative colitis: Recent advances in the understanding of disease pathogenesis. Research 9, 294 (2020).
5. Adegbola, S. O., Sahnan, K., Warusavitarne, J., Hart, A. & Tozer, P. Anti-TNF therapy in Crohn’s disease. Int. J. Mol. Sci. 19, 1–21 (2018).
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