Arginine deiminase as an Anti-Cancer Therapy

描述：肝细胞癌对精氨酸的独特需求 恶性黑色素瘤为新的潜在化疗提供了基础。 正如急性淋巴细胞白血病细胞需要天冬酰胺和E。杆菌 天冬酰胺酶可用于治疗这种疾病，我们建议 使用支原体衍生的精氨酸脱亚胺酶（ADI）治疗肝细胞癌 癌和恶性黑色素瘤。由于第一阶段的资金，我们有 发现了一种方法，ADI可以与聚乙二醇一起配制 (PEG)使得它在小鼠中具有更长的循环半衰期， 免疫原性。当用PEG配制的ADI注射到小鼠体内时， 降低精氨酸的血浆水平并使人黑色素瘤饥饿， 肝细胞癌植入这些动物。这种治疗也是 在患有自发性黑色素瘤的狗中进行测试（根据从 FDA），并迅速被证明是治疗 自发性黑色素瘤，即使有副作用也很少。我们已经要求， 在IND前会议上获得了本项目的孤儿药认定 与FDA和孤儿药办公室合作，描述了需要进行的实验， 申请I期IND以允许对该药物进行人体试验。建议的研究 在这个补助金反映FDA的要求，并完成时，将允许 用PEG配制的ADI在人体中的检测。建议的研究包括 用于生产（在GMP条件下）3批 ADI-PEG，采用经验证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 预测的人类剂量，并进行必要的免疫学和 本项目进入人体临床所需的毒理学试验 试验. 拟议商业应用：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