Novel immune-escape uricase for treatment of hyperuricemia

治疗高尿酸血症的新型免疫逃逸尿酸酶

• 批准号: 10696609
• 负责人: Hiep T Tran
• 金额: $ 30万
• 依托单位: ABZYME THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-22 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696609
• 关键词: Adult; Affect; Affinity Chromatography; Animal Model; Antibodies; Bacteria; Binding; Biological Assay; Biological Products; Catalytic Antibodies; Cell Culture Techniques; Cell Separation; Cell surface; Cells; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Complication; Crystal Formation; DNA sequencing; Data; Deposition; Diploidy; Engineering; Enzyme-Linked Immunosorbent Assay; Enzymes; Escherichia coli; Evolution; Galactose; Generations; Genes; Genetic; Goat; Gout; Hyperuricemia; Immune; Immune system; Immunoglobulin G; Immunologic Surveillance; Individual; Inflammatory Arthritis; Infusion procedures; Kidney Diseases; Letters; Libraries; Mammalian Cell; Measures; Molecular Weight; Monitor; Mus; Mutagens; Mutate; Mutation; Nature; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Physiological; Polyethylene Glycols; Polysaccharides; Population; Postmenopause; Production; Proteins; Recombinants; Refractory; Risk; Serum; Signal Transduction; Soil; Sorting; Stains; Surface; System; T-Lymphocyte; Technology; Therapeutic; Treatment Efficacy; Tumor Lysis Syndrome; United States; Universities; Urate; Urate Oxidase; Uric Acid; Utah; Variant; Woman; Yeasts; activation-induced cytidine deaminase; analog; arthropathies; base; effective therapy; enzyme activity; expression vector; genetic variant; glycosylation; human disease; immunogenicity; improved; in vivo; innovation; large scale production; medical schools; men; novel; polyclonal antibody; pressure; prevent; scale up; small molecule inhibitor

Abstract. High serum urate levels (hyperuricemia) and subsequent monosodium urate crystal deposition cause gout, the most common inflammatory arthritis in men and postmenopausal women. Gout affects an estimated 9.2 million adults in the United States. Hyperuricemia is also a major complication in patients with tumor lysis syndrome. However, the management of hyperuricemia in gout patients is problematic. Currently, gout patients are treated with small molecule inhibitor urate-lowering drugs. Gout can progress to destructive arthropathy, deposition of monosodium urate (MSU) crystals (tophi), and nephropathy if urate- lowering drugs fail. For those patients, infusion of foreign uricases such as a recombinant fungal uricase (Raburicase) or recombinant mammalian uricase modified with polyethylene glycol (Pegloticase/Krystexxa) is indicated to control hyperuricemia and dissolve the MSU crystals. Unfortunately, the immunogenicity of the administered foreign uricase and the ubiquitous presence of anti-PEG antibodies in the population limit the therapeutic efficacy of Pegloticase/Krystexxa and prevent repeated treatment. We propose to develop a novel immune-escape uricase that is covered with a glycan shield and contains immune escape mutations. We have identified uricase from soil bacteria Terriglobus saanensis with excellent enzyme activity at physiological pH, and that can be expressed and secreted as an active enzyme in yeast and mammalian cells. Using Abzyme's maturation, surface display and secretion platform, a selected uricase will be displayed on yeast cell surfaces, subjected to continuous gene evolution and immune selection pressure. At the end of phase I, it is anticipated that as many as 2 unique functionally-active immune escape uricase variants with a significant reduction in or no binding to anti-uricase polyclonal antibodies will be isolated, expressed, purified, and characterized. In Phase II, the most promising molecules will be evaluated in animal models of induced gout pursuant to the submission of an IND application for the initiation of clinical trials. The novel uricase will offer a number of therapeutic advantages, including the facilitation of large-scale production and reduced immunogenicity.

抽象的。高血清尿酸含水平（高尿酸血症）和随后的单钠晶体沉积 导致痛风，这是男性和绝经后女性中最常见的炎症性关节炎。痛风会影响一个 估计在美国有920万成年人。高尿酸血症也是患者的主要并发症 肿瘤裂解综合征。但是，痛风患者高尿酸血症的治疗是有问题的。 目前，痛风患者接受了小分子抑制剂尿酸尿酸尿素药物的治疗。痛风可以进步 破坏性关节炎，单钠菌酸（MSU）晶体（TOPHI）的沉积和肾病，如果尿酸 降低药物失败。对于那些患者，输注外国尿液（例如重组真菌尿酶） （兔）或重组哺乳动物尿酶用聚乙烯甘氨酸（pegloticass/krystexxa）进行的重组哺乳动物尿布酶是 指示可以控制高尿酸血症并溶解MSU晶体。不幸的是， 施用外国尿液酶和人口中无处不在的抗PEG抗体的存在限制 葡萄糖酶/krystexxa的治疗功效并防止重复治疗。我们建议开发小说 免疫散发尿液酶，覆盖有聚糖屏蔽并包含免疫逃生突变。我们有 从土壤细菌saanensis中鉴定出具有出色酶活性的尿素菌群在生理pH中， 并且可以在酵母和哺乳动物细胞中表达并分泌为活性酶。使用abzyme 成熟，表面显示和分泌平台，选定的尿布将显示在酵母细胞表面上， 受到连续的基因演化和免疫选择压力。在第一阶段结束时，预计 多达2个独特的功能性免疫逃生尿酶变体，显着降低或显着降低 不会与抗尿酶多克隆抗体结合，将分离，表达，纯化和表征。在 第二阶段，最有希望的分子将在诱发痛风的动物模型中评估 提交IND申请启动临床试验。新颖的尿素将提供许多 治疗优势，包括促进大规模生产和降低免疫原性。