Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory disease with high medical and societal costs afflicting more than 1.6 million Americans. Blockade of TNF?-driven inflammation with approved anti-TNF? 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-TNF? 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-TNF? 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 TNF? activity and is 6 - 400-fold more potent than the leading anti-TNF? 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 TNF?. 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-TNF? 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-TNF? biologics. This benefit could lower overall treatment costs and greatly improve access to optimal treatment for patients with RA.
Public Health Relevance Statement
Rheumatoid arthritis is a debilitating, chronic inflammatory disease, though blockade of TNF? driven inflammation with anti-TNF? biologics is a highly effective treatment for many patients. Unfortunately, TNF? biologics are costly (currently >$68,000/year) and repeated administration of anti-TNF? biologics leads to loss of efficacy due, in part, to anti-drug antibodies. To address these limitations, we have developed a fully synthetic, protease resistant TNF? inhibitor with outstanding potency, designed to have minimal immunogenicity and 10% of the manufacturing cost compared to current anti-TNF? biologics.
Project Terms: 21+ years old; Adult Human; adulthood; Adult; cyclic aminoacid; Cyclic Amino Acids; Animals; inhibitor; Antibodies; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; accessory cell; Antigen-Presenting Cells; Rheumatoid Arthritis; Atrophic Arthritis; rheumatic arthritis; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Cultured Cells; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Exhibits; Fatigue; Lack of Energy; Goals; Grant; Half-Life; Human; Modern Man; In Vitro; Inflammation; Life Expectancy; Major Histocompatibility Complex; Histocompatibility Complex; Histocompatibility Complices; Major Histocompatibility Complices; Transgenic Mice; Microspheres; Microbeads; Mole the mammal; Moles; Mus; Mice; Mice Mammals; Murine; Osmosis; Pain; Painful; Pathology; Patients; Peptide Fragments; Peptide Hydrolases; Esteroproteases; Peptidases; Protease Gene; Proteases; Proteinases; Proteolytic Enzymes; Peptides; Cyclic Peptides; Drug Kinetics; Pharmacokinetics; Polymers; polymer; polymeric; Production; Productivity; Quality of life; QOL; Recommendation; Sales; Solubility; Solvents; Specificity; Tissues; Body Tissues; cytokine; Generations; Drug Costs; medical costs; Medical Care Costs; Treatment Cost; timeline; polyarthritis; Polyarthritides; Pump; improved; Surface; Chronic; Solid; Clinical; Penetration; Phase; Variation; Variant; biologic; Biological; Peptide Receptor; Blood Serum; Serum; disability; insight; Intellectual Property; Immunological response; host response; immune system response; immunoresponse; Immune response; Anatomic Abnormality; Anatomical Abnormality; Deformity; Therapeutic; Inflammatory; Organic solvent product; Organic Solvents; Life; System; American; experience; Membrane; membrane structure; Proteolysis; Protein Cleavage; receptor; Receptor Protein; synthetic peptide; biodegradable polymer; bioresorbable polymer; degradable polymer; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; peptide L; infliximab; MAb cA2; Remicade; monoclonal antibody cA2; novel; Disease model; disorder model; Etanercept; Enbrel; Modeling; Sampling; response; immunogenic; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; disorder control; disease control; D2E7 antibody; adalimumab; Molecular Interaction; Binding; Humira; Address; Dose; Avidity; Economic Burden; Improve Access; in vitro Assay; in vivo; Peptide Synthesis; Phage Display; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; Development; developmental; Image; imaging; cost; immunogenicity; designing; design; Outcome; innovate; innovative; innovation; resistant; Resistance; Implant; overexpress; overexpression; effective treatment; effective therapy; efficacy testing; Formulation; societal costs; treatment guidelines; optimal therapies; optimal treatments; inflamed joint; joint swelling; joint inflammation; chronic inflammatory disease; Job loss; antagonist; antagonism; cost comparison; compare cost; manufacture; manufacturing cost; fabrication cost
