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-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 postdose 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 infammatory cytokine biomarkers was similar to infiximab, demonstrating efcacy when present at
the disease site. Taken together, results of these studies provide confdence that oral V565 dosing will
be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.

Scientific Reports