Engineering a Potent Immune-evading Uricase

设计一种有效的免疫逃避尿酸酶

• 批准号: 9908607
• 负责人: Chris Bailey-Kellogg
• 金额: $ 29.99万
• 依托单位: STEALTH BIOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-18 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908607
• 关键词: Acute; Acute Disease; Acute Pain; Address; American; Anaphylaxis; Antibodies; Antibody titer measurement; Antigens; Biological; Biological Assay; Blood; Cells; Chronic; Chronic Disease; Clinical; Complement; Country; Deposition; Development; Disease; Engineering; Enzymes; Excretory function; Exhibits; Face; General Population; Genotype; Goals; Gout; Health; Human; Hyperuricemia; Immune; Immune response; Immunoassay; Immunologic Surveillance; Immunologics; Individual; Infection; Kinetics; Lead; Libraries; Lysostaphin; Modeling; Molecular; Mutation; Nature; Outcome; Pain; Pathologic; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Plant Roots; Production; Protein Engineering; Proteins; Quality of life; Rasburicase; Refractory; Risk; Small Business Technology Transfer Research; Source; Stream; T-Lymphocyte; Technology; Therapeutic; Time; Tissues; Transgenic Organisms; Treatment Efficacy; Tumor Lysis Syndrome; Urate Oxidase; Uric Acid; Urinary tract; Variant; acute symptom; base; bioprocess; clinical development; de-immunization; design; effective therapy; functional disability; high throughput screening; humanized mouse; immunoengineering; immunogenic; immunogenicity; immunoreaction; in vivo; indexing; lead candidate; member; peripheral blood; pre-clinical; response; stem; symptom treatment; thermostability

Abstract The accumulation of uric acid in the urinary tract, blood stream, or tissues causes a pathological condition known as hyperuricemia, which leads to a variety of acute and chronic diseases including gout. Gout alone afflicts more than 8 million Americans, causing acute pain and potentially even chronic functional impairment. While a number of drugs have been developed to treat symptoms and to limit production or increase excretion of uric acid, these drugs do not suffice for the majority of gout patients. A powerful alternative therapeutic approach is to directly attack uric acid deposits, using the enzyme uricase to degrade uric acid into products that are readily excreted. Unfortunately, while one uricase variant (pegloticase, or Krystexxa®) has been approved for treatment of chronic refractory gout, it suffers from severe immunogenicity-associated problems. In particular it carries black box warnings for anaphylaxis and other detrimental outcomes, along with a fairly short period of therapeutic efficacy for many patients, who have to discontinue treatment due to the development of antidrug antibodies. Stealth Biologics® has developed a leading-edge immuno engineering platform, integrating computational protein design, high-throughput protein engineering, and exquisitely sensitive immunoassays. We have a proven track record of using this platform to render non-human enzymes (among other types of proteins) “stealth”y, evading immune recognition while still maintaining potent therapeutic function. We propose here to systematically overcome uricase’s immunogenicity problems by addressing the root sources of immune recognition, using our platform to develop a high-function, low-immunogenicity candidate. This molecule will then serve as the basis for a phase II project to further advance the lead candidate towards IND-enabling studies and ultimately an effective treatment for gout and other hyperuricemia-associated diseases.

抽象的 尿酸在尿道、血流或组织中积聚会导致病理状况 称为高尿酸血症，可导致多种急性和慢性疾病，包括痛风。 超过 800 万美国人遭受这种疾病的困扰，造成急性疼痛，甚至可能造成慢性功能障碍。 虽然已经开发了许多药物来治疗症状并限制产生或增加排泄 尿酸，这些药物不足以为大多数痛风患者提供强有力的替代治疗。 方法是直接攻击尿酸沉积物，利用尿酸酶将尿酸降解为产物 不幸的是，虽然一种尿酸酶变体（pegloticase，或 Krystexxa®）已被排出体外。 它被批准用于治疗慢性难治性痛风，但存在严重的免疫原性相关问题。 特别是它带有针对过敏反应和其他不利结果的黑框警告，以及相当 不少患者因疗效不佳而不得不中止治疗。 抗药物抗体的开发。 Stealth Biologics® 开发了一个领先的免疫工程平台，集成了计算 蛋白质设计、高通量蛋白质工程和极其灵敏的免疫分析。 使用该平台渲染非人类酶（以及其他类型的蛋白质）的良好记录 “隐形”，逃避免疫识别，同时仍保持有效的治疗功能。 通过解决免疫的根源，明显克服了尿酸酶的免疫原性问题 识别，使用我们的平台开发一种高功能、低免疫原性的候选分子。 然后作为第二阶段项目的基础，以进一步推动主要候选药物实现 IND 启用 研究并最终有效治疗痛风和其他高尿酸血症相关疾病。