Systemic radiotherapy for metastatic melanomas: Innovation of a novel radiopharma

描述(由申请人提供)：这项快速通道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方法。前一种先导化合物在动物肿瘤模型和人类黑色素瘤患者中的初步结果非常成功。在动物安全性研究的纯度测试期间，高放射性浓度下的辐射分解导致的降解阻止了第一代化合物的开发。化学和临床前评估证实，化合物MIP-1145具有更大的化学稳定性和更理想的动物分布特性。131I-MIP-1145是一种放射性碘标记的苯甲酰胺分子，与表达黑色素瘤的黑色素具有极高的选择性结合，具有长期滞留和低非靶器官蓄积的特点。131I-MIP-1145的分子靶向性和高肿瘤蓄积性是有效治疗黑色素瘤转移的理想药物。初步的临床前疗效研究显示，在SK-Mel-3人黑色素瘤移植小鼠模型中，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侧重于开发大剂量(150mCI)高比活度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，必须牢固地确定该制剂的组成。该提案的第二阶段将侧重于开发一种连续的流动生产过程，该过程将在自动化实验室合成系统上得到验证，以减少对人员的辐射暴露，并为治疗性临床试验提供足够的活动水平。为了生产用于人体试验的材料，必须启动关键成分前体和参考标准的GMP生产活动。来自预验证产品的放射性131I-MIP-1145材料也将用于进行动物安全和毒性测试。有关过程开发化学、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FDA申请的基础。申请Fast Track考虑的理由是，一旦对人类黑色素瘤患者进行成像/剂量学研究，就可以准备好治疗规模的生产批次，以治疗患者。这项提案的创新是为转移性黑色素瘤的潜在根治性治疗提供了令人兴奋的前景。在成功完成SBIR计划后，分子洞察公司将为向FDA提交的行业赞助的IND申请开发一种临床方案。

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.