PRETARGETING WITH ANTI-CEA MABS FOR THERAPY

项目2项目负责人：Yazaki，Paul首席研究员：RaubitSChek，Andrew 产品说明： 为了增强放射免疫疗法的治疗功效，已经研究了预靶向策略。 开发用于将抗体的缓慢肿瘤靶向和清除特性与药物递送分离， 放射性物质。这两个步骤的分离允许治疗剂量的快速递送 减少对正常组织，尤其是骨髓的暴露。尽管之前的预定位 虽然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实用性。 有问题的问题包括肿瘤靶向剂的免疫原性、健康的正常组织暴露于肿瘤靶向剂的免疫原性、肿瘤靶向剂的免疫原性和肿瘤靶向剂的免疫原性。 放射性试剂，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输送系统提供了巨大的机会。的 癌胚抗原（CEA）系统仍然是我们工作的主要重点。在这个项目中，建议 工作包括处理这些问题的三种办法。第一个具体的目标是一个合乎逻辑的延伸， 临床测试的三步生物素为基础的方法，纳入抗生物素抗体作为桥接剂 生物素化的抗CEA抗体和生物素-γ-DOTA之间的差异。二是发展双特异性 靶向CEA阳性肿瘤和9 CY-DOTA放射性配体的抗体方法。井 将特征化的抗CEA T84.66和抗DOTA 2D12.5单克隆抗体设计成 基于双特异性双抗体、串联双抗体和双-双抗体-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，通过发现一种令人兴奋的单一方法， 基于可变结构域抗体的支架技术，其将允许产生新的抗CEA和抗CEA抗体。 CEA/CEA复合物靶向剂。这些目标将同时进行，但在其各自的领域中并不排斥。 途径。从项目各方面获得的知识将被纳入开发 用于临床应用的单个预靶向系统。

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.