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

基本信息

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
项目类别：
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

项目摘要

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.

类风湿性关节炎 (RA) 是一种慢性、使人衰弱的炎症性疾病，具有高昂的医疗和社会成本用批准的抗 TNFα 药物阻断 TNFα 驱动的炎症困扰着超过 160 万美国人。生物制剂（例如 Humira®、Remicade®、Simponi® 和 Enbrel®）对许多患者来说是一种有效的治疗方法然而，至少部分由于这些抗 TNFα 生物制剂的免疫原性， 50% 的 RA 患者最初对这些药物有良好反应，但后来由于抗药物抗体而失去益处（美国残疾人协会）。我们设计了一种稳定的、耐蛋白酶的抗 TNFα 肽 DBT178，具有克服以下问题的潜力： DBT178 是一种通过镜像噬菌体发现的高效且特异性的 D 肽。 DBT178 阻断可溶性和膜结合 TNFα 活性，其效力比 display 强 6 - 400 倍。领先的抗 TNFα 生物制剂 Humiraâ，已在各种体外试验中进行了测试。 D-肽是天然L-肽的手性镜像，因为酶具有手性特异性，所以D-肽。作为蛋白水解降解和肽片段的表面展示，其本质上是惰性的。抗原呈递细胞 (APC) 是产生高效免疫反应的关键步骤，是免疫反应的固有特征对蛋白水解的抗性使得 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 DBT178 在经过验证的 RA 疾病模型中的功效。目标 1 旨在评估健康人体内通过渗透泵全身输送 DBT178 的药代动力学目标 2 应用目标 1 的见解来评估 DBT178 在慢性模型中的全身递送。过度表达人 TNFα 的转基因小鼠中的自发性和进行性 RA 目标 3 重点关注开发微球制剂，单剂量后可提供有效、持续的药物 DBT178 水平持续一个月或更长时间。开发一种新型的、缓解疾病的抗 TNFα 药物，对限制治疗的 ADA 具有耐药性，可以极大地促进除了这种潜在的临床益处外，还可以通过延长反应持续时间使 RA 患者受益。商业规模化后，DBT178的预计生产成本预计为抗TNFα成本的十分之一这种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