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

基本信息

批准号：
7613567
负责人：
JAMES F KRONAUGE
金额：
$ 33.14万
依托单位：
MOLECULAR INSIGHT PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-16 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7613567
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 Condition Cyclic GMP Data Data Reporting Development Disease Disease regression Disease remission Documentation Dose Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Electrocardiogram Evaluation Excipients Exposure to Eye Favorable Clinical Outcome Free Radical Scavengers Generations Genes Goals Guanosine Monophosphate High Pressure Liquid Chromatography Human Human Resources I131 isotope Image Imagery Immunohistochemistry Incidence Industry Label Laboratories Lead Life MCC protocol Macrophage Inflammatory Proteins Malignant - descriptor 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 Prohibit Property Protocols documentation Public Health Pyrogens Qualifying Quality Control Radiation Radiation therapy Radio Radioactive Radioisotopes Radiolabeled Radiopharmaceuticals Range Rate Rattus Reaction Reagent Records Reference Standards Reporting Research Risk Room, Clean Running Safety Small Business Funding Mechanisms Small Business Innovation Research Grant Solubility Specificity Standards of Weights and Measures Sterility Sterilization for infection control System Targeted Radiotherapy Techniques Test Result Testing Texas Therapeutic Therapeutic Clinical Trial Therapeutic Radiology specialty Time Tissues Title Toxic effect Toxicity Tests Trace metal Treatment Efficacy United States United States Food and Drug Administration United States National Institutes of Health Validation Vertebral column Vial device Week Xenograft Model Xenograft procedure analog analytical method cancer type chemical stability day design dosimetry follow-up human study innovation insight intravenous injection melanocyte melanoma mouse model nonhuman primate novel pre-clinical pre-clinical therapy preclinical study programs prospective quality assurance radiochemical radiotracer research clinical testing response scale up size tumor uptake

项目摘要

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. PUBLIC HEALTH RELEVANCE: Systemic radiotherapy for metastatic melanomas: Innovation of a novel radiopharmaceutical agent exclusively targeting melanin in malignant melanocytes. The incidence of malignant melanoma is rising faster than that of any other types of cancer in the United States. A radiopharmaceutical, capable of being labeled with cell destroying radioisotopes and exclusively targeted to melanoma tissue, would provide a drug specific for the treatment of metastatic disease. The successful development of an I-131 labeled molecular targeting radiotherapeutic agent for malignant melanoma would introduce this therapeutic technique to a now incurable disease and bring considerable attention to the field of therapeutic radiology. Molecular Insights potential new drug: 131I-MIP-1145 would enable systemic radiotherapy target to melanin positive metastatic melanomas combined with personalized dose administration and therapeutic follow-up. The rising incidence of malignant melanomas, the early and wide-spread occurrence of metastases, and the poor response rates for current therapies, represents a life saving and valuable commercial opportunity for an effective treatment for patients with metastatic melanomas.

描述（由申请人提供）：这种快速轨道I/II SBIR提案的最终目标是开发新型的药物131I-MIP-1145，作为一种分子靶向转移性黑色素瘤的射线治疗。前铅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取得了非常成功。在进行动物安全研究的纯度测试中，放射分解在高放射性浓度下诱导降解，禁止第一代化合物的发展。化学和临床前评估确定了化合物MIP-1145具有更大的化学稳定性，并且在动物中具有更理想的分布特性。 131i-MIP-1145是一种射线固化的苯甲酰胺分子，具有极高的选择性结合与黑色素表达黑色素瘤，其保留率延长和低靶器官的积累。 131i-MIP-1145的分子靶标特异性和高肿瘤积累是有效治疗黑色素瘤转移的理想特性。初步的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用131i-MIP-1145治疗两次治疗后完全缓解了肿瘤。该提案的前六个月阶段将着重于为高剂量（150 MCI）的高特异性活动131i-MIP-1145开发稳定的配方。在进行广泛的临床前安全性和功效研究之前，必须牢固确定配方组成。该提案的第二阶段将着重于开发一个连续的流量生产过程，该过程将在自动实验室合成系统上进行验证，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。为了生产人类测试的材料，必须启动针对关键组件前体和参考标准的GMP生产活动。放射性131I-MIP-1145验证前生产的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是FDA应用的骨干。请求快速考虑考虑的理由是，在人类黑色素瘤患者中进行成像 /剂量测定研究后，就可以使治疗量表生产批次准备治疗患者。该提案的创新是对转移性黑色素瘤进行潜在治疗治疗的令人兴奋的希望。成功完成SBIR计划后，Molecular Insight将为行业赞助的IND应用程序制定临床方案。公共卫生相关性：转移性黑色素瘤的系统性放疗：一种新型放射性药物的创新，仅针对恶性黑色素细胞中的黑色素。恶性黑色素瘤的发病率比美国任何其他类型的癌症都快。一种放射性药物，能够用细胞破坏放射性同位素标记并仅针对黑色素瘤组织，将为转移性疾病的治疗提供一种药物。 I-131标记为恶性黑色素瘤标记的分子靶向放射治疗剂的成功开发将向现在无法治愈的疾病引入这种治疗技术，并引起对治疗放射学领域的极大关注。分子见解潜在的新药：131i-MIP-1145将使全身放射疗法靶向黑色素阳性转移性黑色素瘤，并结合个性化剂量给药和治疗随访。恶性黑色素瘤的发生率上升，转移的早期和广泛发生，以及当前疗法的反应率较差，这代表了为转移性黑色素瘤患者提供有效治疗的生命挽救和宝贵的商业机会。