Preclinical Development of Uricase-PEG 20

Uricase-PEG 20 的临床前开发

• 批准号: 6480514
• 负责人: JOHN S BOMALASKI
• 金额: $ 10万
• 依托单位: PHOENIX PHARMACOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6480514
• 关键词: antigen antibody reaction; drug screening /evaluation; enzyme linked immunosorbent assay; gout; gout drug; histopathology; hyperuricemia; laboratory mouse; laboratory rabbit; miscellaneous oxidoreductase; nonhuman therapy evaluation; polyethylene glycols; tetracyclines; urate

Hyperuricemia (elevated serum uric acid) results in gouty arthritis and chronic renal disease. Severe hyperuricemia can occur following cancer chemotherapy (tumor lysis syndrome) and organ transplantation (most common in heart and kidney transplant patients) which may result in acute uric acid nephropathy with resultant metabolic disorders and death. Moreover, in addition to pain, hyperuricemia can result in destructive gouty arthritis, with concomitant permanent damage to joints and connective tissue. Elevated uric acid levels (hyperuricemia) do not develop in most mammals because they have the gene which encodes urate oxidase which metabolizes the less soluble uric acid into a much more soluble metabolite, allantoin. However, in humans, the urate oxidase gene has evolved to contain a nonsense codon which results in a complete loss of enzyme activity. Many different groups of investigators have administered uricase, purified from micro organisms, to patients. Although these treatments lower plasma uric acid levels, all of the enzymes used are highly immunogenic and cause allergic reactions and anaphylaxis. Formulation of other therapeutic proteins with polyethylene glycol (PEG) has been shown to reduce their anti-genicity and prolong their circulating half-life. We have initiated Phase I clinical testing of a PEG modified uricase termed Uricase-PEG20. In this proposal we seek funding to perform the additional studies requested by the FDA in order for this drug to move into Phase 2 human clinical testing. PROPOSED COMMERCIAL APPLICATIONS: This proposal focuses on performing the additional preclinical experiments requested by the FDA in order for this drug to enter Phase 2 human testing. Although non-PEG formulated uricase is used in Europe, it has not been approved in the USA because of the high incidence of allergic reactions associated with its use. uricase-PEG 20 is formulated with polyethylene glycol (PEG), a technology known to reduce the antigenicity of heterologous proteins.

高尿酸血症（血清尿酸升高）会导致痛风性关节炎和慢性肾脏疾病。癌症化疗（肿瘤溶解综合征）和器官移植（最常见于心脏和肾脏移植患者）后可能会出现严重的高尿酸血症，这可能导致急性尿酸性肾病，从而导致代谢紊乱和死亡。此外，除了疼痛之外，高尿酸血症还可导致破坏性痛风性关节炎，并伴随对关节和结缔组织的永久性损伤。大多数哺乳动物不会出现尿酸水平升高（高尿酸血症），因为它们具有编码尿酸氧化酶的基因，该酶将溶解度较低的尿酸代谢为溶解度更高的代谢物尿囊素。然而，在人类中，尿酸氧化酶基因已进化为包含无义密码子，导致酶活性完全丧失。许多不同的研究小组已经向患者施用从微生物中纯化的尿酸酶。尽管这些治疗方法可以降低血浆尿酸水平，但所使用的所有酶都具有高度免疫原性，并会引起过敏反应和过敏反应。使用聚乙二醇 (PEG) 配制其他治疗性蛋白质已被证明可以降低其抗原性并延长其循环半衰期。我们已经启动了 PEG 修饰尿酸酶（称为 Uricase-PEG20）的 I 期临床测试。在本提案中，我们寻求资金来执行 FDA 要求的额外研究，以便该药物进入第二阶段人体临床测试。拟议的商业应用：该提案的重点是执行 FDA 要求的额外临床前实验，以便该药物进入 2 期人体测试。尽管非 PEG 配制的尿酸酶已在欧洲使用，但由于与其使用相关的过敏反应发生率很高，因此在美国尚未获得批准。 uricase-PEG 20 采用聚乙二醇 (PEG) 配制而成，这是一种已知可降低异源蛋白质抗原性的技术。