RADIOIMMUNOTHERAPY USING BISPECIFIC ANTIBODIES

使用双特异性抗体的放射免疫治疗

• 批准号: 6377254
• 负责人: HANS J HANSEN
• 金额: $ 25.4万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2002-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377254
• 关键词: antibody specificity; antitumor antibody; biotherapeutic agent; carcinoembryonal antigen; cell line; clinical research; clinical trial phase I; colorectal neoplasms; dosage; drug design /synthesis /production; high performance liquid chromatography; human subject; immunological substance; laboratory mouse; neoplasm /cancer radioimmunotherapy; pharmacokinetics; radiotracer; technetium; transfection

This SBIR Phase II work will seek to develop and optimize reagents for the radioimmunotherapy of cancer using bispecific antibody pretargeting. The bispecific antibodies that we will make will have the dual advantages of being low-immunogenic humanized proteins, and will be preparable in high yield after enhancement of transfected cell lines. They will be targeted in human tumor xenograft-bearing mice, to determine preferred times and doses to maximize tumor uptake and minimize normal tissue retention. The second arm of the tumor-localized bispecific antibody will be specific for a radioimmunotherapeutic comprised of a rhenium-188- radiolabeled peptide, that clears living systems rapidly, if not bound by tumor-appended bispecific antibody. Doses and timings of injections of the radioimmunotherapeutic will be optimized, after animals have been pretargeted with the bispecific antibody. After optimization of all parameters, preclinical radioimmunotherapy studies and dosimetry determinations will be done. Using knowledge gained from the preclinical animal work, the developed agents will be tested in a Phase I clinical trial, using the corresponding technetium-99m-labeled recognition peptide as a model for the rhenium-188 version. With promising data from the Phase I clinical trials, we will proceed to radioimmunotherapy in a Phase I/II clinical trial if the results so merit. PROPOSED COMMERCIAL APPLICATIONS: Radioimmunotherapy using bispecific antibody in a pretargeting approach has the advantage of being capable of high dose delivery of radiation to tumor sites without significant retention in normal organs, maximizing the therapeutic potential of the treatment modality. Patients will be injected with the nontoxic bispecific antibody first, and after the predetermined time for localization and clearance, therapeutic Re-188 labeled peptide will be administered to achieve a therapeutic response.

这项 SBIR II 期工作将寻求使用双特异性抗体预靶向开发和优化用于癌症放射免疫治疗的试剂。我们将制备的双特异性抗体将具有低免疫原性人源化蛋白的双重优点，并且在转染细胞系增强后可高产制备。它们将针对携带人类肿瘤异种移植的小鼠，以确定最佳时间和剂量，以最大限度地提高肿瘤摄取并最大限度地减少正常组织保留。肿瘤定位双特异性抗体的第二臂将特异性针对由铼188放射性标记肽组成的放射免疫治疗剂，如果不与肿瘤附加的双特异性抗体结合，该治疗剂可以快速清除生命系统。在用双特异性抗体对动物进行预靶向后，将优化放射免疫治疗剂的注射剂量和时间。所有参数优化后，将进行临床前放射免疫治疗研究和剂量测定。利用从临床前动物工作中获得的知识，开发的药物将在 I 期临床试验中进行测试，使用相应的 technetium-99m 标记的识别肽作为铼-188 版本的模型。凭借 I 期临床试验的有希望的数据，如果结果值得的话，我们将在 I/II 期临床试验中进行放射免疫治疗。拟议的商业应用：在预靶向方法中使用双特异性抗体的放射免疫疗法的优点是能够将高剂量的放射线输送到肿瘤部位，而不会在正常器官中显着滞留，从而最大限度地发挥治疗方式的治疗潜力。首先向患者注射无毒双特异性抗体，在预定的定位和清除时间后，将施用治疗性Re-188标记肽以实现治疗反应。