RADIOIMMUNOTHERAPY USING BISPECIFIC ANTIBODIES

这项SBIR II期工作将寻求开发和优化使用双特异性抗体预靶向的癌症放射免疫治疗试剂。我们将制备的双特异性抗体将具有作为低免疫原性人源化蛋白质的双重优点，并且在转染细胞系增强后将以高产率扩增。它们将在携带人肿瘤异种移植物的小鼠中靶向，以确定最大化肿瘤摄取和最小化正常组织保留的优选时间和剂量。肿瘤定位的双特异性抗体的第二臂将对由β-188-放射性标记的肽组成的放射免疫素具有特异性，如果不被肿瘤附加的双特异性抗体结合，则其快速清除活系统。在用双特异性抗体预靶向动物后，将优化放射免疫球蛋白的注射剂量和时间。在优化所有参数后，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，使用相应的锝-99m标记的识别肽作为锝-188版本的模型。有了第一阶段临床试验的良好数据，如果结果值得的话，我们将在第一/第二阶段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具有能够将高剂量的放射递送至肿瘤部位而不会显著保留在正常器官中的优点，从而最大化治疗模式的治疗潜力。患者将首先注射无毒双特异性抗体，并且在预定的定位和清除时间之后，将施用治疗性Re-188标记的肽以实现治疗应答。

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.