PRETARGETING WITH ANTI-CEA MABS FOR THERAPY

项目2项目负责人：Yazaki，Paul首席调查员：RaubitSChek，Andrew 说明： 为了提高放射免疫治疗的疗效，已经采取了预靶向策略 开发的目的是将抗体的缓慢肿瘤靶向和清除特性与递送的 放射治疗剂。这两个步骤的分离允许快速输送治疗剂 减少接触正常组织，尤其是骨髓。尽管之前的预定位 这些策略已经显示出临床反应，但主要挑战阻碍了它们的临床应用。 问题包括肿瘤靶向剂的免疫原性，健康的正常组织暴露于 放射治疗剂、试剂的纯度和生产。尽管如此，这些挑战提供了 为改进高效的多步骤交付系统带来的巨大机遇。这个 癌胚抗原(CEA)系统仍然是我们工作的主要焦点。在这个项目中，建议的 工作包括解决这些问题的三种方法。第一个具体目标是 临床测试三步生物素为基础的方法，加入抗生物素抗体作为桥接剂 生物素标记的抗CEA抗体与生物素-γ-DOTA之间的相互作用。第二个是发展双专门化 针对CEA阳性肿瘤和9CY-DOTA放射性配基的抗体方法。这口井 特化的抗CEA T84.66和抗DOTA 2D12.5单抗将设计成 基于双特异性Diabody、串联Diabody和Diabody-Fc形式的重组双特异性抗体。 第三个目标是探索一种全新的方法，这使得发现一首令人兴奋的单曲成为可能。 基于可变区抗体的支架技术将允许生产新型抗CEA和抗-CEA CEA/CEA复合靶向制剂。这些目标将并行进行，但不是排他性的 小路。从项目的各个方面获得的知识将被纳入到 一种用于临床应用的单一预靶向系统。

Project 2 Project Leader: Yazaki, Paul Principal Investigator: RaubitSChek,Andrew DESCRIPTION: To enhance the therapeutic efficacy of radioimmunotherapy, pretargeting strategies have been developed to uncouple the antibody's slow tumor targeting and clearance properties from the delivery of a radiotherapeutic agent. Separation of these two steps allows for the rapid delivery of a therapeutic dose reducing the exposure to normal tissues, especially the bone marrow. Although previous pretargeting strategies have demonstrated clinical responses, major challenges have blocked their clinical utility. Problematic issues include immunogenicity of tumor targeting agents, healthy normal tissue exposure to the radiotherapeutic agent, and purity and production of reagents. Nonetheless, these challenges offer tremendous opportunities for the improvement of an efficient multi-step delivery system. The carcinoembryonic antigen (CEA) system remains the primary focus of our work. In this project, the proposed work includes three approaches to address these issues. The first specific aim is a logical extension of the clinically tested three-step biotin-based approach, incorporating an anti-biotin antibody as the bridging agent between biotinylated anti-CEA antibody and biotin-^Y-DOTA. The second is the development of a bispecific antibody approach that targets both CEA-positive tumors and the 9CY-DOTA radioligand. The well characterized anti-CEA T84.66 and anti-DOTA 2D12.5 monoclonal antibodies will be designed into recombinant bispecific antibodies based on a bispecific diabody, tandem diabody and di-diabody-Fc format. The third aim explores a completely new approach made possible by the discovery of an exciting single variable domain antibody-based scaffold technology that will allow the production of novel anti-CEA and anti- CEA/CEA complex targeting agents. These aims will be conducted in parallel but are not exclusive in their pathways. Knowledge gained from all aspects of the Project will be incorporated toward the development of a single pretargeting system for clinical application.