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.

摘要 尿酸在泌尿道、血液或组织中的积累会导致病理状态 称为高尿酸血症，导致包括痛风在内的各种急性和慢性疾病。痛风单 超过800万的美国人深受其害，导致急性疼痛，甚至可能导致慢性功能障碍。 虽然已经开发了许多药物来治疗症状并限制生产或增加排泄 痛风患者的饮食习惯是什么？一种强有力的替代疗法 一种方法是直接攻击尿酸沉积物，使用尿酸酶将尿酸降解为产物 很容易被排出体外不幸的是，虽然一种尿酸酶变体（pegloticase或Krystexxa®）已经被发现， 它被批准用于治疗慢性难治性痛风，但它存在严重的免疫原性相关问题。 特别是它带有过敏反应和其他有害结果的黑框警告，沿着相当 对于许多患者来说，治疗效果持续时间短，他们不得不因治疗而停止治疗 产生抗药抗体。 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灵敏度极高的免疫测定。我们有一个 使用该平台提供非人类酶（以及其他类型的蛋白质）的良好记录 "隐身"，逃避免疫识别，同时仍然保持有效的治疗功能。我们在此提议， 通过解决免疫的根源，系统地克服尿酸酶的免疫原性问题， 识别，使用我们的平台开发高功能，低免疫原性的候选物。这种分子将 然后作为第二阶段项目的基础，以进一步推动领先候选人实现IND 研究并最终成为痛风和其他高尿酸血症相关疾病的有效治疗方法。