RADIOIMMUNOTHERAPY USING BISPECIFIC ANTIBODIES

这项SBIR第二阶段的工作将寻求开发和优化使用双特异性抗体预靶向治疗癌症的放射免疫治疗试剂。我们将制备的双特异性抗体具有低免疫原性人源化蛋白的双重优势，并将在增强转基因细胞系后高产率地制备。它们将针对携带人类肿瘤异种移植瘤的小鼠，以确定最佳的时间和剂量，以最大限度地增加肿瘤摄取，并最大限度地减少正常组织滞留。肿瘤定位双特异性抗体的第二个臂将针对由Re-188放射性标记多肽组成的放射免疫治疗，如果没有与肿瘤附加的双特异性抗体结合，这种多肽可以迅速清除生命系统。在动物被双特异性抗体预先靶向后，放射免疫疗法的注射剂量和时间将得到优化。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。利用从临床前动物工作中获得的知识，开发的试剂将在I期临床试验中进行测试，使用相应的氚-99m标记识别肽作为Re-188版本的模型。有了来自I期临床试验的有希望的数据，如果结果合理，我们将在I/II期临床试验中继续进行放射免疫治疗。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治疗的优点是能够将高剂量的辐射传递到肿瘤部位，而不会在正常器官中显著滞留，从而最大限度地发挥治疗方法的治疗潜力。患者将首先注射无毒的双特异性抗体，在预定的时间进行定位和清除后，再注射治疗性Re-188标记多肽以达到治疗效果。

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.