MoAbs for the Management of Pancreatic Cancer

简介(申请人提供)：胰腺癌在最常见的癌症中排名第九 癌症是一种癌症，但它是导致癌症死亡的第四和第五大原因 分别在男性和女性身上。这种疾病最常见的症状是 性质上不特定的。从而在早期诊断胰腺癌。 肿瘤的生长充其量是困难的，需要相当大的怀疑和 广泛的诊断性检查，包括探查手术。 不幸的是，绝大多数患者所处的阶段 肿瘤已扩展到包膜外，侵犯周围器官，和/或 已经广泛转移。治疗程序目前适用于 胰腺癌既没有治愈的方法，也没有实质性的效果。 延长生存时间。其后果是5年存活率不到3 百分比。这项研究计划的长期目标是发展 用于治疗胰腺癌的单抗(即， 检测、诊断、分期和治疗)。我们已经对PAM4进行了描述 为其在临床检测中的应用提供证据 胰腺癌。考虑使用放射性标记的一个一般性问题 抗体作为临床应用的治疗剂是肿瘤 与实验中所达到的相比，抗体的增值很低。 模特们。在目前的研究项目中，我们将尝试克服这一点 通过研究旨在增加肿瘤摄取的方法来解决问题 放射性标记抗体，同时保持较高的肿瘤-非肿瘤比率。我们会 具有附加的肽信号序列的工程PAM4抗体构建体 内化和细胞内贩运。将对这些进行审查，以 确定几个细胞器贩运信号中哪一个提供的最高 肿瘤对抗体靶向放射性同位素的摄取和滞留。此外，我们 我将检验价对同官能团和异官能团的作用 附加在抗体上的细胞器保留信号。最后，PAM4IL2融合 将检测蛋白质是否具有增强肿瘤摄取 随后给予放射性标记的PAM4抗体。

DESCRIPTION (provided by applicant): Pancreatic cancer is the ninth most common form of cancer, yet it is the fourth and fifth leading cause of cancer deaths in men and women, respectively. The most common symptoms of the disease are nonspecific in nature. Thus diagnosing pancreatic cancer at an early stage of tumor growth is difficult at best, requiring considerable suspicion and extensive diagnostic workup, up to and including exploratory surgery. Unfortunately then, the vast majority of patients present at a stage when the tumor has extended outside of the capsule to invade surrounding organs, and/or has metastasized extensively. Treatment procedures currently available for pancreatic cancer have not been able to bring about a cure nor substantially improve survival time. The consequence is a 5-year survival rate of less than 3 percent. The long-term objective of this research proposal is the development of monoclonal antibodies for the management of pancreatic cancer (i.e., detection, diagnosis, staging and therapy). We have characterized the PAM4 monoclonal antibody, providing evidence as to its use clinical detection of pancreatic cancer. A general issue in considering the use of radiolabeled antibody as a therapeutic agent for clinical application is that tumor accretion of antibody has been low compared to that achieved in experimental models. In the current research project, we will attempt to overcome this problem by investigating methodologies designed to increase tumor uptake of radiolabeled antibody while maintaining high tumor-nontumor ratios. We will engineer PAM4 antibody constructs having appended peptide signal sequences for internalization and intracellular trafficking. These will be examined to determine which of several organelle trafficking signals provides the highest tumor uptake and retention of antibody targeted radioisotope. In addition, we will examine the role of valence for homofunctional and heterofunctional organelle retention signals appended to the antibody. Finally, a PAM4IL2 fusion protein will be examined for its ability to enhance tumor uptake of a subsequently administered radiolabeled PAM4 antibody.