Systemic radiotherapy for metastatic melanomas: Innovation of a novel radiopharma

转移性黑色素瘤的全身放疗：新型放射性药物的创新

• 批准号: 8146128
• 负责人: JAMES F KRONAUGE
• 金额: $ 72.27万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146128
• 关键词: Acute; Animal Model; Animal Testing; Animals; Attention; Benzamides; Binding; Biological; Biological Assay; Canis familiaris; Cardiac; Cardiovascular system; Cell Death; Cells; Chemicals; Chemistry; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cyclic GMP; Data; Data Reporting; Development; Disease; Disease remission; Documentation; Dose; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Electrocardiogram; Excipients; Exposure to; Eye; Favorable Clinical Outcome; Free Radical Scavengers; Generations; Genes; Goals; High Pressure Liquid Chromatography; Human; Human Resources; I131 isotope; Image; Imagery; Incidence; Industry; Label; Laboratories; Lead; Life; Measures; Melanins; Melanoma Cell; Metastatic Melanoma; Methods; Micronucleus Tests; Modeling; Molecular; Molecular Target; Monitor; Mus; Neoplasm Metastasis; Organ; Oryctolagus cuniculus; Osmolar Concentration; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Preclinical Testing; Process; Prodrugs; Production; Property; Protocols documentation; Pyrogens; Qualifying; Quality Control; Radiation; Radiation therapy; Radio; Radioactive; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Rattus; Reaction; Reagent; Records; Reference Standards; Reporting; Research; Risk; Running; Safety; Small Business Innovation Research Grant; Solubility; Specificity; Sterility; Sterilization; System; Targeted Radiotherapy; Techniques; Test Result; Testing; Texas; Therapeutic; Therapeutic Clinical Trial; Therapeutic Radiology specialty; Time; Tissues; Toxic effect; Toxicity Tests; Trace metal; Treatment Efficacy; United States; United States National Institutes of Health; Validation; Vertebral column; Vial device; Xenograft Model; Xenograft procedure; analog; analytical method; cancer type; chemical stability; design; dosimetry; effective therapy; follow-up; innovation; insight; intravenous injection; meetings; melanoma; mouse model; nonhuman primate; novel; pre-clinical; pre-clinical therapy; preclinical efficacy; preclinical evaluation; preclinical safety; preclinical study; programs; prospective; quality assurance; radiochemical; radiotracer; research clinical testing; response; safety study; safety testing; scale up; stability testing; tumor; uptake

DESCRIPTION (provided by applicant): The ultimate goal of this Fast Track Phase I/II SBIR proposal is to develop the novel pharmaceutical agent 131I-MIP-1145, as a molecular targeting radio-therapeutic treatment for metastatic melanoma. Preliminary results with the former lead compound were highly successful in animal tumor models and human melanoma patients. During purity testing for animal safety studies, radiolysis induced degradation at high radioactive concentrations prohibited development of the first generation compound. Chemical and preclinical evaluation identified the compound MIP-1145 to have greater chemical stability with more desirable distribution properties in animals. 131I-MIP-1145 is a radio-iodinated benzamide molecule with extremely high selective binding to melanin expressing melanomas with prolonged retention and low non-target organ accumulation. The molecular target specificity and high tumor accumulation of 131I-MIP-1145 are ideal properties for an agent to effectively treat melanoma metastasis. Preliminary preclinical efficacy studies demonstrated complete tumor remission after two treatments with 131I-MIP-1145 in a SK-Mel-3 human melanoma xenograft mouse model. The first six month phase of this proposal will focus on developing a stable formulation for large doses (150 mCi) of high specific activity 131I-MIP-1145. The formulation composition must be firmly established prior to conducting extensive pre-clinical safety and efficacy studies. The second phase of the proposal will focus on developing a continuous flow production process that will be validated on an automated laboratory synthesis system, to reduce radiation exposure to personnel and provide sufficient levels of activity for therapeutic clinical trials. To produce material for human testing, a GMP production campaign for the critical component precursor and reference standard must be initiated. Radioactive 131I-MIP-1145 material from pre-validation productions will also be used to perform animal safety and toxicity testing. The data on process development chemistry, manufacturing and controls, analytical testing, chemical stability as well as pre-clinical toxicity studies will be the backbone of an application to the FDA. The justification for requesting Fast Track consideration is to have the therapeutic scale production batch ready to treat patients as soon as the imaging / dosimetry study is performed in human melanoma patients. The innovation in this proposal is the exciting promise for a potential curative therapeutic treatment of metastatic melanoma. Following successful completion of the SBIR program, Molecular Insight will develop a clinical protocol for an industry sponsored IND application to the FDA.

描述（由申请人提供）：该快速通道 I/II 期 SBIR 提案的最终目标是开发新型药剂 131I-MIP-1145，作为转移性黑色素瘤的分子靶向放射治疗。前先导化合物的初步结果在动物肿瘤模型和人类黑色素瘤患者中非常成功。在动物安全研究的纯度测试中，高放射性浓度下的辐射分解引起的降解阻碍了第一代化合物的开发。化学和临床前评估确定化合物 MIP-1145 具有更高的化学稳定性和更理想的动物分布特性。 131I-MIP-1145 是一种放射性碘化苯甲酰胺分子，对表达黑色素的黑色素瘤具有极高的选择性结合，具有较长的保留时间和较低的非靶器官积累。 131I-MIP-1145 的分子靶点特异性和高肿瘤积累是有效治疗黑色素瘤转移的药物的理想特性。初步临床前疗效研究表明，在 SK-Mel-3 人黑色素瘤异种移植小鼠模型中使用 131I-MIP-1145 两次治疗后，肿瘤完全缓解。该提案的前六个月阶段将重点开发大剂量 (150 mCi) 高比活性 131I-MIP-1145 的稳定配方。在进行广泛的临床前安全性和有效性研究之前，必须牢固地确定制剂成分。该提案的第二阶段将重点开发连续流动生产工艺，该工艺将在自动化实验室合成系统上进行验证，以减少人员的辐射暴露并为治疗性临床试验提供足够的活性水平。为了生产用于人体测试的材料，必须启动关键成分前体和参考标准的 GMP 生产活动。预验证产品中的放射性 131I-MIP-1145 材料也将用于进行动物安全和毒性测试。有关工艺开发化学、制造和控制、分析测试、化学稳定性以及临床前毒性研究的数据将成为向 FDA 申请的支柱。请求快速通道考虑的理由是，一旦在人类黑色素瘤患者中进行成像/剂量测定研究，就可以准备好治疗规模的生产批次来治疗患者。该提案的创新之处在于为转移性黑色素瘤的潜在治愈性治疗带来了令人兴奋的希望。在成功完成 SBIR 计划后，Molecular Insight 将为行业赞助的向 FDA 提交的 IND 申请制定临床方案。