IMPROVED RADIOIODINATION METHODS FOR RADIOIMMUNOTHERAPY

改进的放射免疫治疗的放射碘定位方法

• 批准号: 6015548
• 负责人: SERENGULAM V GOVINDAN
• 金额: $ 47.45万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6015548
• 关键词: breast neoplasms; cell line; enzyme linked immunosorbent assay; immunological substance; immunotherapy; iodination; laboratory mouse; method development; monoclonal antibody; radiation therapy; radiotracer; tumor antigens

The ultimate goal of this work is to produce clinically useful, commercially viable, therapy agent for breast cancer. Radioimmunotherapy has shown clinical efficacy against radiosensitive lymphomas in recent years, and is considered a potentially attractive modality for treating metastatic breast cancer. The therapy agent will be based on a humanized monoclonal antibody (hMAb) hRS7, which targets a breast cancer antigen and which would minimize patient immune response to MAb in eventual clinical application. Phase II work will involve humanization of RS7, process optimizations for clinical-scale radioiodinations, and extensive experimentations to demonstrate preclinical utility of the proposed agent in subcutaneous and systemic animal models of breast cancer. The internalizing hRS7 will be radiolabeled with a residualizing form of I-131 radionuclide, developed in Phase I, so as to increase the retention of the nuclide in the tumor and thereby enhance therapeutic efficacy. The goals are to achieve clinical- scale radiolabelings of hRS7 with >90% efficiency and about 10 mCi/mg of specific activity, and establish significant therapeutic advantage of the optimized product compared to conventionally radioiodinated hRS7, irrelevant hMAb and untreated control. Promising radiochemistry and preclinical results will form the basis for clinical studies in Phase III. PROPOSED COMMERCIAL APPLICATIONS: Radioimmunotherapy (RAIT) is a promising treatment modality, worthy of exploration as adjuvant systemic therapy of metastatic breast cancer in patients with poor prognosis. To realize the full potential of RAIT in this regard, commercially viable optimum delivery agents, such as improved radioiodinated humanized antibodies, must be used. The proposed Phase II research addresses these important issues.

这项工作的最终目的是为乳腺癌生产临床上有用的，商业上可行的治疗剂。近年来，放射免疫疗法已显示出针对放射敏感性淋巴瘤的临床功效，被认为是治疗转移性乳腺癌的潜在吸引力。该治疗剂将基于人性化的单克隆抗体（HMAB）HRS7，该抗体靶向乳腺癌抗原，并最终在最终临床应用中最大程度地减少患者对MAB的免疫反应。第二阶段的工作将涉及RS7的人性化，用于临床尺度放射分解的过程优化以及广泛的实验，以证明在皮下和全身性乳腺癌模型中所提出的药物的临床前实用性。内部化的HRS7将以I-131放射性核素的残差形式进行放射性标记，该核素在I期中开发，以增加核素在肿瘤中的保留，从而提高治疗功效。目标是实现效率> 90％和约10 mCI/mg特定活性的HRS7的临床标准标记，并与常规放射性二十片HRS7，无关紧要的HMAB和未经处理的对照相比，建立了优化产品的显着治疗优势。有希望的放射化学和临床前结果将构成第三阶段临床研究的基础。拟议的商业应用：放射免疫疗法（RAIT）是一种有前途的治疗方式，值得探索，作为预后不良患者的转移性乳腺癌的辅助系统治疗。为了在这方面实现Rait的全部潜力，必须使用商业上可行的最佳递送剂，例如改进的放射性人性化抗体。拟议的第二阶段研究解决了这些重要问题。