Arginine deiminase as an Anti-Cancer Therapy

描述：肝细胞癌独特的精氨酸需求 恶性黑色素瘤为新的潜在化疗提供了基础。 就像急性淋巴细胞白血病细胞需要天冬酰胺和大肠杆菌一样 我们建议，可以使用天冬酰胺酶来治愈这种疾病。 应用支原体来源的精氨酸脱亚氨酶治疗肝细胞癌 癌症和恶性黑色素瘤。作为第一阶段资金的结果，我们有 发现了一种方法，在这种方法中，可以用聚乙二醇制得ADI (聚乙二醇胺)使其在小鼠体内有更长的循环半衰期和更少的 免疫原性。当用聚乙二醇配制的ADI注射到小鼠体内时，它选择性地 降低血浆精氨酸水平，饥饿人类黑色素瘤和 植入这些动物体内的肝细胞癌。这种治疗也是 在患有自发性黑色素瘤的狗身上进行测试(在从 FDA)，并迅速被证明是一种有效的治疗手段 自发性黑色素瘤，副作用极少。我们已经要求并 在IND前会议上获得了该项目的孤儿药物称号 与FDA和孤儿药物办公室合作，描述了需要进行的实验 申请第一阶段IND，以允许对该药物进行人体试验。这项研究建议 在这笔赠款中反映了FDA的要求，完成后将允许 用聚乙二醇配制的ADI在人体内的测试。建议的研究包括 用于生产(在GMP条件下)3批产品的工艺验证 ADI-PEG，用有效的程序表征这些批次，获得 药效学和药代动力学数据将允许异速生长建模 预测的人体剂量，并进行必要的免疫学和 该项目进入人体临床所需的毒理学测试 测试。 建议的商业应用：不可用

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