MoAbs for the Management of Pancreatic Cancer

描述（由申请人提供）：胰腺癌是第九常见的 它是一种癌症，但它是癌症死亡的第四和第五大原因 在男性和女性中，分别。这种疾病最常见的症状是 非特异性的因此，在早期阶段诊断胰腺癌， 肿瘤生长是困难的，需要相当大的怀疑， 广泛的诊断检查，包括探查手术。 不幸的是，绝大多数患者都处于一个阶段， 肿瘤已经延伸到包膜外，侵入周围器官，和/或 已经广泛转移目前可用的治疗程序 胰腺癌还不能治愈， 提高生存时间。其后果是5年生存率低于3 百分之这项研究计划的长远目标是发展 用于胰腺癌管理的单克隆抗体（即， 检测、诊断、分期和治疗）。我们已经表征了PAM 4 单克隆抗体，提供证据，其使用的临床检测 胰腺癌在考虑使用放射性标记的 抗体作为临床应用治疗剂是肿瘤 与实验中获得的抗体相比， 模型在当前的研究项目中，我们将尝试克服这一点 通过研究旨在增加肿瘤对 放射性标记的抗体，同时维持高肿瘤-非肿瘤比率。我们将 具有附加的肽信号序列的工程化PAM 4抗体构建体， 内化和细胞内运输。这些将被审查， 确定几种细胞器贩运信号中哪一种提供最高的 肿瘤摄取和抗体靶向放射性同位素的保留。另外我们 将研究化合价对同功能和异功能的作用， 附加到抗体上的细胞器滞留信号。最后，PAM 4 IL 2融合 将检查蛋白质增强肿瘤对A 随后施用放射性标记的PAM 4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.