Inflammatory bowel disease is a group of disorders (Crohn's disease and Ulcerative Colitis) that are associatedwith substantial morbidity and disability for millions of people worldwide. Although multiple biologic agents andsmall molecules are approved for the treatment, anti-TNFï¡ monoclonal antibodies remain first line therapy. Yet,clinical benefit from these agents is lost in ~30% of patients due to neutralizing anti-drug antibodies (ADAs).Systemic administration results in immunosuppression with heightened risk for serious infections. Efforts todevelop gut-restricted oral anti-TNFï¡ antibodies (for convenience and to avoid systemic toxicity) have showntreatment benefit but have not been clinically feasible due to the high doses required to overcome proteolytic gutenzyme digestion. DBT178 is a trimerized 14 D-amino acid cyclic peptide that binds with exceptional affinity tothe TNFï¡ trimer. It blocks both soluble and membrane-bound TNFï¡ activity and is 400-fold more potent than theleading TNFï¡ mAb, adalimumab (Humira®), in vitro. D-peptides are chiral mirror images of natural L-peptides;thus, they are essentially inert to enzymatic proteolysis and are stable over a broad pH range. Thus, orallyadministered DBT178 should transit intact to sites of IBD (jejunum, ileum and colon), permitting clinically effectivedosing. In addition, DBT178 has ~5% the mass of therapeutic anti-TNFï¡ mAbs and should have a greaterpenetration from gut luminal mucosa to submucosal tissues. Oral DBT178 is expected to minimize absorptionfrom gut to portal and systemic circulation (thereby limiting potential systemic toxicity), and its resistance toproteolytic antigen processing will reduce the potential for developing neutralizing anti-DBT178 antibodies. Thegoal of this Phase I SBIR is to demonstrate DBT178 efficacy following oral delivery in two mouse models ofcolitis. However, since this inhibitor binds human TNFï¡, but not mouse TNFï¡ it will not be effective inconventional IBD models. Accordingly, Aim 1 optimizes DBT178 for oral delivery and tests its inhibition of GItoxicity and systemic inflammation following a single IP injection of high dose hTNFï¡. Aim 2 tests oral DBT178delivery in a specialized model of DSS-induced acute colitis using B-hTNFA mice, where the human TNFα geneis expressed under normal physiological control following its insertion into the deleted mouse TNFï¡ locus. Thiswork plan has a 1-year timeline.
Public Health Relevance Statement: Project Narrative
Inflammatory bowel diseases (Crohn's disease and Ulcerative Colitis) are associated with substantial morbidity
and disability for millions of people worldwide. Although multiple biologic agents and small molecules have been
approved for these indications, they can be inefficient, inconvenient, and sometimes toxic. The goal of this Phase
I SBIR is to demonstrate the efficacy of a new anti-TNF inhibitor in two mouse models of colitis.
Project Terms: <(TNF)-α>
