MONOCLONAL ANTIBODIES FOR THE MANAGEMENT OF CANCER

胰腺癌是导致癌症的第四和第五大原因。 今天，在美国，男性和女性的死亡人数分别为。 由于肿瘤的位置及其沉默的生长， 绝大多数患者处于肿瘤晚期 当疾病对传统治疗无效时生长 方法论。在目前正在进行的赠款的过去几年中， 我们证明了mAb-PAM4与胰腺癌粘液反应， 能够将胰腺癌与正常和炎症区分开来 胰腺组织；能够以特定方式和高度靶向 对实验性胰腺肿瘤的浓度；并能够引起 对实验性胰腺肿瘤的生长抑制和/或消退。 这些数据为进一步的开发和体内研究提供了理论基础 单抗-PAM4在临床上的应用 求婚。除了PAM4，单抗-Mu9，与粘蛋白反应，或 粘蛋白类分子将用于放射免疫检测和治疗 结直肠癌。在这个项目中，我们打算研究自然界 这两种抗体所针对的抗原。我们会 检测免疫反应表位的结构并研究其 粘蛋白与其他多肽和碳水化合物结构的关系 类型糖蛋白。此外，我们打算检查交互作用 与这些抗体的抗原和代谢命运在分子和 细胞水平。这些结果将为指导 基于单抗的检测和治疗技术的进一步发展 抗原阳性的癌症患者。随着知识的发展， 抗原结构和抗原分析：抗体相互作用 作为临床前和临床目标研究的反馈，我们将 开发用于治疗胰腺癌的第二代抗体。 最后，我们将研究基于PAM4的酶免疫分析在 胰腺血中抗原的检测与定量 癌症患者希望能提供更早的检测 潜在更有效的治疗结果。它的特殊性， 敏感度和诊断准确度将被确定。在一个单独的 研究我们将检查血液抗原之间的关系 浓度与肿瘤负担，作为其在监测中使用的前奏 对病人的治疗。

Cancer of the pancreas is the fourth and fifth leading cause of cancer deaths among men and women, respectively, in the United States today. Because of the location of the tumor and its silent growth, the overwhelming majority of patients present at a late stage of tumor growth when the disease is not responsive to traditional treatment methodologies. During the past few years of the currently active grant, we demonstrated that mAb-PAM4, reactive with a pancreatic cancer mucin, was able to distinguish pancreatic cancer from normal and inflamed pancreatic tissue; was able to target in a specific manner, and at high concentrations to experimental pancreatic tumors; and was able to cause growth inhibition and/or regression of experimental pancreatic tumors. These data provided rationale for the further development and in vivo clinical application of mAb-PAM4 to be performed as part of the current proposal. In addition to PAM4, mAb-Mu9, reactive with mucin, or a mucin-like molecule will be used for radioimmunodetection and therapy of colorectal cancer. In this Project we intend to examine the nature of the antigens to which these 2 antibodies are directed. We will examine the structure of the immunoreactive epitopes and study their relationship to other peptide and carbohydrate structures within mucin type glycoproteins. In addition, we intend to examine the interaction with antigen and metabolic fate of these antibodies at the molecular and cellular levels. These results will provide information to guide the further development of mAb-based technologies for detection and therapy of antigen positive cancer patients. With the knowledge developed from analyses of antigen structure and antigen:antibody interactions as well as feedback from preclinical and clinical targeting studies we will develop second generation antibodies for use against pancreatic cancer. Finally, we will examine the use of a PAM4-based enzyme immunoassay for the detection and quantitation of antigen in the blood of pancreatic cancer patients in the hope of providing earlier detection with potentially more effective therapeutic outcome. The specificity, sensitivity, and diagnostic accuracy will be determined. In a separate study we will examine the relationship of the blood antigen concentration with tumor burden, as a prelude to its use in monitoring treatment of patients.