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低免疫原性的人源化蛋白的双重优势，并且在转染细胞系增强后可高产制备。他们将在人类肿瘤异种移植小鼠中进行靶向，以确定最佳的时间和剂量，以最大限度地提高肿瘤的吸收和最大限度地减少正常组织的保留。肿瘤定位双特异性抗体的第二部分将针对由铼-188放射标记肽组成的放射免疫治疗，如果不与肿瘤附加的双特异性抗体结合，则可迅速清除生命系统。在动物预先被双特异性抗体靶向后，放射免疫治疗的剂量和注射时间将被优化。在所有参数优化后，将进行临床前放射免疫治疗研究和剂量测定。利用从临床前动物实验中获得的知识，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标记的识别肽作为铼-188版本的模型。有了I期临床试验的有希望的数据，如果结果如此有利，我们将在I/II期临床试验中进行放射免疫治疗。建议的商业应用：在预靶向方法中使用双特异性抗体的放射免疫治疗具有能够将高剂量辐射递送到肿瘤部位而不会在正常器官中明显保留的优势，最大限度地发挥了治疗方式的治疗潜力。患者将首先注射无毒双特异性抗体，在预定的定位和清除时间后，给予治疗性Re-188标记肽，以达到治疗效果。

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.