A Potent D-peptide Inhibitor of TNFα for Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory disease with high medical and societal costs afflicting more than 1.6 million Americans. Blockade of TNFα-driven inflammation with approved anti-TNFα biologics (such as Humira®, Remicade®, Simponi®, and Enbrel®) is an effective treatment for many patients suffering from RA. However, due at least in part to the immunogenicity of these anti-TNFα biologics, upwards of 50% of RA patients initially responding favorably to these agents later lose benefit due to anti-drug antibodies (ADA). We have designed a stable, protease-resistant anti-TNFα peptide, DBT178, with potential to overcome treatment-limiting ADA. DBT178 is a highly potent and specific D-peptide discovered via mirror-image phage display. DBT178 blocks both soluble and membrane-bound TNFα activity and is 6 - 400-fold more potent than the leading anti-TNFα biologic, Humiraâ, in various in-vitro assays. D-peptides are the chiral mirror images of natural L-peptides. Since enzymes exhibit chiral specificity, D-peptides are essentially inert to proteolysis. As proteolytic degradation and surface display of peptide fragments on antigen-presenting cells (APC) are critical steps in the generation of a productive immune response, the inherent resistance to proteolysis renders D-peptides minimally immunogenic. The goal of this 1-year SBIR grant is to demonstrate the efficacy of DBT178 in a validated disease model of RA. Aim 1 seeks to evaluate the pharmacokinetics of systemic delivery of DBT178 via osmotic pumps in healthy mice. Aim 2 applies the insights from Aim 1 to evaluate the systemic delivery of DBT178 in a chronic model of spontaneous and progressive RA in transgenic mice overexpressing human TNFα. Aim 3 focuses on the development of microsphere formulations which, following a single dose, would provide effective, sustained drug levels of DBT178 for a period of one month or longer. The development of a novel, disease-modifying anti-TNFα agent resistant to treatment-limiting ADA could greatly benefit RA patients by increasing the duration of response. In addition to this potential clinical benefit, at commercial scale, the projected production cost of DBT178 is anticipated to be one-tenth the cost of anti-TNFα biologics. This benefit could lower overall treatment costs and greatly improve access to optimal treatment for patients with RA.