Arginine deiminase as an Anti-Cancer Therapy

精氨酸脱亚胺酶作为抗癌疗法

• 批准号: 6338099
• 负责人: MIKE A CLARK
• 金额: $ 38.36万
• 依托单位: PHOENIX PHARMACOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-20 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338099
• 关键词: Mycoplasma; amidinohydrolase; antineoplastics; chemical synthesis; drug design /synthesis /production; drug screening /evaluation; hepatocellular carcinoma; immunity; laboratory mouse; orphan disease /drug; pharmacokinetics; polyethylene glycols; recombinant proteins

DESCRIPTION: The distinctive arginine requirement of hepatocellular carcinomas and malignant melanomas provides the basis for a new potential chemotherapy. Just as acute lymphocytic leukemia cells require asparagine and E. coli asparaginase enzyme can be used to effect a cure for this disease, we propose using a mycoplasma derived arginine deiminase (ADI) to treat hepatocellular carcinoma and malignant melanomas. As a result of Phase I funding we have discovered a method where by ADI can be formulated with polyethylene glycol (PEG) such that it has a much longer circulating half-life in mice and is less immunogenic. When ADI formulated with PEG is injected into mice it selectively reduces the plasma levels of arginine and starves human melanomas and hepatocellular carcinomas implanted into these animals. This treatment is also being tested in dogs with spontaneous melanoma (under an INAD received from the FDA) and is quickly being proven to be an effective means of treating spontaneous melanoma with very few, if any, side effects. We have requested and received an Orphan Drug Designation for this project and in a Pre-IND meeting with the FDA and the Orphan drug Office, delineated the experiments needed to file a Phase I IND to permit human testing of this drug. The studies proposed in this grant reflect the FDA requirements and when completed will allow for the testing of ADI formulated with PEG in humans. The studies proposed include the validation of the process used to make (under GMP conditions) 3 lots of ADI-PEG, characterize these lots with validated procedures, obtain pharmacodynamic and pharmacokinetic data that will allow allometric modeling of the predicted human dosing and perform the necessary immunological and toxicological testing needed for this project to progress into human clinical testing. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：肝细胞癌的独特精氨酸需求 恶性黑色素瘤为新的潜在化疗提供了基础。 就像急性淋巴细胞性白血病细胞需要天冬酰胺和大肠杆菌 天冬氨酸酶可用于实现这种疾病的治疗，我们建议 使用支原体衍生的精氨酸脱节酶（ADI）治疗肝细胞 癌和恶性黑色素瘤。由于第一阶段资金，我们拥有 发现了一种可以用聚乙烯乙二醇配制ADI的方法 （钉）使其在鼠标中具有更长的循环半衰期，并且较少 免疫原性。当将用PEG配制的ADI注入小鼠中时， 降低精氨酸的血浆水平，并饿死人类黑色素瘤 植入这些动物的肝细胞癌。这种治疗也是 在患有自发黑色素瘤的狗中测试 FDA），很快被证明是治疗的有效手段 自发黑色素瘤几乎没有副作用。我们已要求 在此项目和预定会议上收到了孤儿的名称 使用FDA和孤儿药办公室，描述了所需的实验 提交I阶段IND，以允许对该药物进行人体测试。研究提出 在这笔赠款中，反映了FDA要求，完成后将允许 在人类中用PEG配制的ADI的测试。提出的研究包括 用于制造（在GMP条件下）的过程的验证3个很多 adi-peg，用经过验证的程序来表征这些批次，获得 药效和药代动力学数据将允许进行异态建模 预测的人类给药并执行必要的免疫学和 该项目进入人类临床所需的毒理学测试 测试。 拟议的商业应用程序：不可用