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

基本信息

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
项目类别：
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

项目摘要

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。高血清尿酸盐水平（高尿酸血症）和随后的尿酸钠晶体沉积引起痛风，痛风是男性和绝经后女性最常见的炎症性关节炎。痛风影响据估计，美国有 920 万成年人。高尿酸血症也是糖尿病患者的主要并发症肿瘤溶解综合征。然而，痛风患者高尿酸血症的治疗存在问题。目前，痛风患者采用小分子抑制剂降尿酸药物进行治疗。痛风可进展为破坏性关节病、尿酸钠 (MSU) 晶体沉积（痛风石）以及尿酸盐肾病降药失败。对于这些患者，输注外源尿酸酶，例如重组真菌尿酸酶 (Raburicase) 或用聚乙二醇修饰的重组哺乳动物尿酸酶 (Peloticase/Krystexxa) 是表明可控制高尿酸血症并溶解 MSU 晶体。不幸的是，其免疫原性施用外来尿酸酶和人群中普遍存在的抗 PEG 抗体限制了 Peloticase/Krystexxa 的治疗功效并防止重复治疗。我们建议开发一部小说免疫逃逸尿酸酶，被聚糖盾覆盖并含有免疫逃逸突变。我们有从土壤细菌 Terriglobus saanensis 中鉴定出尿酸酶，在生理 pH 值下具有优异的酶活性，并且可以在酵母和哺乳动物细胞中作为活性酶表达和分泌。使用抗体酶成熟、表面展示和分泌平台，选定的尿酸酶将展示在酵母细胞表面，受到持续的基因进化和免疫选择压力。预计第一阶段结束时多达 2 种独特的功能活性免疫逃逸尿酸酶变体，显着降低或不会分离、表达、纯化和表征与抗尿酸酶多克隆抗体的结合。在第二阶段，最有前途的分子将根据以下标准在诱发痛风的动物模型中进行评估提交启动临床试验的 IND 申请。新型尿酸酶将提供多种治疗优势，包括促进大规模生产和降低免疫原性。