Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

Abstract Anti-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...

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Autores principales:	Kevin J. Roberts, Marion F. Cubitt, Timothy M. Carlton, Lurdes Rodrigues-Duarte, Luana Maggiore, Ray Chai, Simon Clare, Katherine Harcourt, Thomas T. MacDonald, Keith P. Ray, Anna Vossenkämper, Michael R. West, J. Scott Crowe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1e2fe779b63b4101b684f9f331edf0fd
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spelling	oai:doaj.org-article:1e2fe779b63b4101b684f9f331edf0fd2021-12-02T17:37:28ZPreclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease10.1038/s41598-021-97236-02045-2322https://doaj.org/article/1e2fe779b63b4101b684f9f331edf0fd2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97236-0https://doaj.org/toc/2045-2322Abstract Anti-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.Kevin J. RobertsMarion F. CubittTimothy M. CarltonLurdes Rodrigues-DuarteLuana MaggioreRay ChaiSimon ClareKatherine HarcourtThomas T. MacDonaldKeith P. RayAnna VossenkämperMichael R. WestJ. Scott CroweNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kevin J. Roberts Marion F. Cubitt Timothy M. Carlton Lurdes Rodrigues-Duarte Luana Maggiore Ray Chai Simon Clare Katherine Harcourt Thomas T. MacDonald Keith P. Ray Anna Vossenkämper Michael R. West J. Scott Crowe Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
description	Abstract Anti-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.
format	article
author	Kevin J. Roberts Marion F. Cubitt Timothy M. Carlton Lurdes Rodrigues-Duarte Luana Maggiore Ray Chai Simon Clare Katherine Harcourt Thomas T. MacDonald Keith P. Ray Anna Vossenkämper Michael R. West J. Scott Crowe
author_facet	Kevin J. Roberts Marion F. Cubitt Timothy M. Carlton Lurdes Rodrigues-Duarte Luana Maggiore Ray Chai Simon Clare Katherine Harcourt Thomas T. MacDonald Keith P. Ray Anna Vossenkämper Michael R. West J. Scott Crowe
author_sort	Kevin J. Roberts
title	Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
title_short	Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
title_full	Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
title_fullStr	Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
title_full_unstemmed	Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
title_sort	preclinical development of a bispecific tnfα/il-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1e2fe779b63b4101b684f9f331edf0fd
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Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

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