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

Autor: Nurbhai S; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK. Suhail.Nurbhai@vhsquared.com., Roberts KJ; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Carlton TM; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Maggiore L; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Cubitt MF; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Ray KP; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Reckless J; RxCelerate Ltd. Babraham Research Campus, Cambridge, CB22 3AT, UK., Mohammed H; RxCelerate Ltd. Babraham Research Campus, Cambridge, CB22 3AT, UK., Irving P; Guy's and St Thomas' Hospital, London, UK., MacDonald TT; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Vossenkämper A; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., West MR; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK., Parkes GC; Royal London Hospital, London, UK., Crowe JS; VHsquared Ltd., 1 Lower Court, Copley Hill, Cambridge Road, Babraham, Cambridge, CB22 3GN, UK.; VHsquared Ltd., Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Oct 01; Vol. 9 (1), pp. 14042. Date of Electronic Publication: 2019 Oct 01.
DOI: 10.1038/s41598-019-50545-x
Abstrakt: 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.
Databáze: MEDLINE
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