IMPROVED RADIOIODINATION METHODS FOR RADIOIMMUNOTHERAPY

这项工作的最终目标是生产临床上有用的、商业上可行的乳腺癌治疗剂。近年来，放射免疫治疗已显示出对放射敏感性淋巴瘤的临床疗效，被认为是治疗转移性乳腺癌的一种潜在的有吸引力的方式。该治疗剂将基于人源化单克隆抗体（hMAb） hRS7，其靶向乳腺癌抗原，并将在最终临床应用中最大限度地减少患者对MAb的免疫反应。二期工作将包括RS7的人源化、临床规模放射的工艺优化，以及广泛的实验，以证明该药物在乳腺癌皮下和全身动物模型中的临床前效用。内化的hRS7将用I-131放射性核素的残留形式进行放射性标记，这是在I期开发的，以增加核素在肿瘤中的保留，从而提高治疗效果。目标是实现hRS7的临床规模放射性标记，效率约为90%，比活性约为10 mCi/mg，并与常规放射性hRS7，无关hMAb和未经处理的对照相比，确定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成为III期临床研究的基础。建议的商业应用：放射免疫治疗（RAIT）是一种很有前景的治疗方式，值得探索作为转移性乳腺癌预后不良患者的辅助全身治疗。为了充分发挥RAIT在这方面的潜力，必须使用商业上可行的最佳递送剂，例如改进的放射性人源化抗体。拟议的第二阶段研究将解决这些重要问题。

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.