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Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease.
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.
Afiliación
  • Crowe JS; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK. Scott.Crowe@vhsquared.com.
  • Roberts KJ; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.
  • Carlton TM; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.
  • Maggiore L; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.
  • Cubitt MF; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.
  • Clare S; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
  • Harcourt K; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
  • Reckless J; RxCelerate Ltd. Babraham Research Campus, Cambridge, CB22 3AT, UK.
  • MacDonald TT; Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, E1 2AT, UK.
  • Ray KP; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.
  • Vossenkämper A; Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, E1 2AT, UK.
  • West MR; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.
Sci Rep ; 8(1): 4941, 2018 03 21.
Article en En | MEDLINE | ID: mdl-29563546
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Inflamatorias del Intestino / Citocinas / Factor de Necrosis Tumoral alfa / Infliximab / Mucosa Intestinal Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Sci Rep Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Inflamatorias del Intestino / Citocinas / Factor de Necrosis Tumoral alfa / Infliximab / Mucosa Intestinal Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Sci Rep Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido