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

一种有效的 TNFα D 肽抑制剂，用于治疗类风湿性关节炎

• 批准号: 10822182
• 负责人: GRANT H RISDON
• 金额: $ 29.59万
• 依托单位: D BIOTHERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822182
• 关键词: Address; Adult; American; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Avidity; Binding; Biological; Biological Products; Chronic; Clinical; Cultured Cells; Cyclic Amino Acids; Cyclic Peptides; Deformity; Development; Disease; Disease model; Dose; Drug Costs; Drug Kinetics; Economic Burden; Enzymes; Etanercept; Exhibits; Fatigue; Formulation; Generations; Goals; Grant; Half-Life; Human; Humira; Image; Immune response; Implant; Improve Access; In Vitro; Inflammation; Inflammatory; Intellectual Property; Job loss; Life; Life Expectancy; Major Histocompatibility Complex; Medical Care Costs; Membrane; Microspheres; Modeling; Mole the mammal; Monoclonal Antibodies; Mus; Organic solvent product; Osmosis; Outcome; Pain; Pathology; Patients; Penetration; Peptide Fragments; Peptide Hydrolases; Peptide Receptor; Peptide Synthesis; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Polyarthritides; Polymers; Process; Production; Productivity; Proteolysis; Pump; Quality of life; Recommendation; Resistance; Rheumatoid Arthritis; Sales; Sampling; Serum; Small Business Innovation Research Grant; Solid; Solubility; Solvents; Specificity; Surface; System; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Treatment Cost; Variant; adalimumab; antagonist; biodegradable polymer; chronic inflammatory disease; cost; cost comparison; cytokine; design; disability; disorder control; effective therapy; efficacy testing; experience; immunogenic; immunogenicity; improved; in vitro Assay; in vivo; infliximab; inhibitor; innovation; insight; joint inflammation; manufacture; manufacturing cost; novel; optimal treatments; overexpression; peptide L; receptor; response; societal costs; synthetic peptide; timeline; treatment guidelines

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.

风湿性关节炎（RA）是一种慢性、使人衰弱的炎症性疾病，具有很高的医疗和社会成本 超过160万美国人受到影响。用获批的抗TNF α药物阻断TNFα驱动的炎症 生物制剂（如Humira®、Remicade®、Escheroni ®和Enbrel®）是许多患者的有效治疗方法 患RA。然而，至少部分由于这些抗TNF α生物制剂的免疫原性， 50%的RA患者最初对这些药物反应良好，后来由于抗药抗体而失去益处 （ADA）。 我们设计了一种稳定的、抗蛋白酶的抗TNF α肽DBT 178，它有可能克服 治疗限制性ADA DBT 178是通过镜像噬菌体发现的高度有效和特异性的D肽 显示. DBT 178阻断可溶性和膜结合的TNFα活性，其效力是 领先的抗TNF α生物制剂Humiraâ在各种体外试验中的应用。 D-肽是天然L-肽的手性镜像。由于酶具有手性特异性， 对蛋白水解基本上是惰性的。作为蛋白水解降解和表面展示的肽片段， 抗原提呈细胞（APC）是产生生产性免疫应答的关键步骤， 对蛋白质水解的抗性使D肽的免疫原性最低。 这项为期1年的SBIR资助的目标是证明DBT 178在经验证的RA疾病模型中的疗效。 目的1旨在评估通过渗透泵全身递送DBT 178在健康人中的药代动力学。 小鼠目的2应用来自目的1的见解来评估DBT 178在慢性炎症模型中的全身递送。 过表达人TNFα的转基因小鼠中自发性和进行性RA。目标3侧重于 微球制剂的开发，在单剂量后，将提供有效的，持续的药物 DBT 178水平持续一个月或更长时间。 开发一种新的、对治疗限制性ADA耐药的疾病缓解性抗TNF α药物， 通过延长反应持续时间使RA患者受益。除了这一潜在的临床获益外， 商业规模，DBT 178的预计生产成本预计是抗TNF α成本的十分之一 生物制品这一好处可以降低总体治疗成本，并大大改善获得最佳治疗的机会。 RA患者