# An oral TNFα inhibitor for inflammatory bowel disease

> **NIH NIH R43** · D BIOTHERAPEUTICS, LLC · 2022 · $299,981

## Abstract

Project Summary
Inflammatory bowel disease is a group of disorders (Crohn’s disease and Ulcerative Colitis) that are associated
with substantial morbidity and disability for millions of people worldwide. Although multiple biologic agents and
small molecules are approved for the treatment, anti-TNF 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 to
develop gut-restricted oral anti-TNF antibodies (for convenience and to avoid systemic toxicity) have shown
treatment benefit but have not been clinically feasible due to the high doses required to overcome proteolytic gut
enzyme digestion. DBT178 is a trimerized 14 D-amino acid cyclic peptide that binds with exceptional affinity to
the TNF trimer. It blocks both soluble and membrane-bound TNF activity and is 400-fold more potent than the
leading TNF 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, orally
administered DBT178 should transit intact to sites of IBD (jejunum, ileum and colon), permitting clinically effective
dosing. In addition, DBT178 has ~5% the mass of therapeutic anti-TNF mAbs and should have a greater
penetration from gut luminal mucosa to submucosal tissues. Oral DBT178 is expected to minimize absorption
from gut to portal and systemic circulation (thereby limiting potential systemic toxicity), and its resistance to
proteolytic antigen processing will reduce the potential for developing neutralizing anti-DBT178 antibodies. The
goal of this Phase I SBIR is to demonstrate DBT178 efficacy following oral delivery in two mouse models of
colitis. However, since this inhibitor binds human TNF, but not mouse TNF it will not be effective in
conventional IBD models. Accordingly, Aim 1 optimizes DBT178 for oral delivery and tests its inhibition of GI
toxicity and systemic inflammation following a single IP injection of high dose hTNF. Aim 2 tests oral DBT178
delivery in a specialized model of DSS-induced acute colitis using B-hTNFA mice, where the human TNFα gene
is expressed under normal physiological control following its insertion into the deleted mouse TNF locus. This
work plan has a 1-year timeline.

## Key facts

- **NIH application ID:** 10603230
- **Project number:** 1R43DK135253-01
- **Recipient organization:** D BIOTHERAPEUTICS, LLC
- **Principal Investigator:** GRANT H RISDON
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,981
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10603230

## Citation

> US National Institutes of Health, RePORTER application 10603230, An oral TNFα inhibitor for inflammatory bowel disease (1R43DK135253-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10603230. Licensed CC0.

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