Systemic radiotherapy for metastatic melanomas: Innovation of a novel radiopharma

描述（由申请人提供）：本快速通道I/II期SBIR提案的最终目标是开发新型药剂131 I-MIP-1145，作为转移性黑色素瘤的分子靶向放射治疗。前一种先导化合物的初步结果在动物肿瘤模型和人类黑素瘤患者中非常成功。在动物安全性研究的纯度检测期间，高放射性浓度下的辐解诱导降解禁止了第一代化合物的开发。化学和临床前评价鉴定化合物MIP-1145具有更高的化学稳定性，在动物中具有更理想的分布特性。131 I-MIP-1145是一种放射性碘化苯甲酰胺分子，与表达黑色素的黑色素瘤具有极高的选择性结合，具有延长的保留和低的非靶器官蓄积。131 I-MIP-1145的分子靶向特异性和高肿瘤蓄积性是有效治疗黑色素瘤转移的药剂的理想性质。初步临床前疗效研究证明，在SK-Mel-3人黑色素瘤异种移植小鼠模型中，131 I-MIP-1145治疗两次后肿瘤完全缓解。该提案的前六个月阶段将集中于开发大剂量（150 mCi）高比活度131 I-MIP-1145的稳定制剂。在进行广泛的临床前安全性和有效性研究之前，必须确定制剂组成。该提案的第二阶段将侧重于开发一种连续流生产工艺，该工艺将在自动化实验室合成系统上得到验证，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。为了生产用于人体试验的材料，必须启动关键组分前体和参比标准品的GMP生产活动。确认前生产的放射性131 I-MIP-1145材料也将用于进行动物安全性和毒性试验。关于工艺开发化学、生产和控制、分析检测、化学稳定性以及临床前毒性研究的数据将是向FDA申请的基础。要求快速通道考虑的理由是，一旦在人黑色素瘤患者中进行成像/剂量测定研究，治疗规模的生产批次就可以用于治疗患者。该提案的创新是转移性黑色素瘤的潜在治愈性治疗的令人兴奋的承诺。在SBIR项目成功完成后，Molecular Insight将为行业申办的IND申请制定临床方案。

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.