Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are debilitating disorders thatafflict ~1.3% of the U.S. population. Blockade of TNFα-driven inflammation with approved anti-TNFα biologicshas been an effective IBD treatment for many patients. However, loss of efficacy due to anti-drug antibodies(ADAs) and toxicities such as serious infections often lead to discontinuation of anti-TNFα biologics. We have developed a stable, protease-resistant, anti-TNFα D-peptide, DBT178, that is designed to be takenorally and delivered intact to gastrointestinal (GI) sites of inflammation characteristic of IBD. Other therapeuticcandidates evaluated by other sponsors have already demonstrated proof of activity for orally administered anti-TNFα biologics in IBD patients. However, these agents have not been feasible as oral IBD therapeutics primarilydue to high dosing requirements resulting from low potency and sensitivity to GI proteases. DBT178 is an ~8 kDa highly potent and specific anti-TNFα D-peptide that was discovered via mirror-imagephage display. Multiple in vitro assays have demonstrated that DBT178 is substantially more potent thanadalimumab (Humira®) antibody at blocking TNFα ligand:receptor binding and TNFα-mediated cell killing. Unlike natural peptides composed of L-amino acids, D-peptides are composed of mirror-image D-aminoacids and are the enantiomers of their natural counterparts. Proteolytic enzymes, including those found in thegut, are known to exhibit chiral specificity, thus D-peptides demonstrate remarkable stability to proteases. In rats,when administered by oral gavage, a "model" D-peptide closely related to DBT178 was excreted intact in stooland was not absorbed into systemic circulation. Therefore, we hypothesize that orally administered DBT178 willinhibit TNFα -induced mucosal and submucosal inflammation characteristic of IBD without associated absorptioninto the portal circulation, systemic distribution, or systemic immunosuppression. Furthermore, D-peptides are also minimally immunogenic since they are resistant to the proteolytic antigenprocessing carried out by antigen presenting cells that is necessary for successful immune responses. Expectedgut restriction and low immunogenicity suggest that DBT178 is unlikely to induce anti-drug antibodies (ADA) orthe associated loss of efficacy observed in ~30% of IBD patients treated with current anti-TNFα biologics. DBT178 is a promising product candidate with the potential to disrupt the multi-billion-dollar anti-TNFαtherapeutics landscape for treatment of psoriasis, inflammatory forms of arthritis, uveitis and IBD. For thisapplication we have focused on its potential to provide a convenient, gut restricted and non-immunogenic oralalternative to the currently approved anti-TNFα parenteral biologics. In this proposal, we request funding to manufacture and formulate a non-GMP batch of DBT178, characterizeits stability and activity in simulated gastric and intestinal fluids, and assess its pharmacokinetics and GI tissuepenetration when given orally to mice. We will also characterize its immunogenicity in non-human primates.
Public Health Relevance Statement: PROJECT NARRATIVE
Crohn's disease and ulcerative colitis (IBD) are debilitating inflammatory disorders. Blockade of TNFα-driven
inflammation with anti-TNFα biologics is an effective treatment; however, chronic parenteral administration and
loss of efficacy due to anti-drug antibodies (ADAs) and side effects due to systemic immunosuppression (e.g.,
opportunistic infections) are significant problems. We have designed a synthetic, protease-stable anti-TNFα
inhibitor of outstanding potency that can be taken orally, which is expected to act only locally at gastrointestinal
sites of inflammation, thus potentially overcoming the major limitations of marketed anti-TNFα biologics.
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