MONOCLONAL ANTIBODIES FOR THE MANAGEMENT OF CANCER

胰腺癌是第四和第五大癌症原因 分别是美国男性和女性的死亡率。 由于肿瘤的位置及其无声生长， 绝大多数患者出现在肿瘤晚期， 当疾病对传统治疗没有反应时， 方法论。 在过去几年的积极赠款， 我们证明了mAb-PAM 4，与胰腺癌粘蛋白反应， 能够将胰腺癌与正常胰腺癌和炎症胰腺癌区分开来， 胰腺组织;能够以特定的方式靶向，并且在高 实验性胰腺肿瘤的浓度;并且能够引起 生长抑制和/或实验性胰腺肿瘤消退。 这些数据为进一步开发和体内试验提供了依据。 mAb-PAM 4的临床应用将作为当前研究的一部分进行 提议 除了PAM 4，mAb-Mu 9，与粘蛋白反应，或其药学上可接受的盐， 粘蛋白样分子将用于放射免疫检测和治疗 结直肠癌的症状在这个项目中，我们打算研究 这两种抗体所针对的抗原。 我们将 检查免疫反应性表位的结构，并研究其 与粘蛋白内其他肽和碳水化合物结构的关系 型糖蛋白 此外，我们还打算研究 这些抗体的抗原和代谢命运在分子和 细胞水平。 这些结果将提供信息，以指导 进一步开发基于单克隆抗体的检测和治疗技术 抗原阳性的癌症患者。随着知识的发展， 分析抗原结构和抗原：抗体相互作用以及 作为临床前和临床靶向研究的反馈，我们将 开发第二代抗胰腺癌抗体。 最后，我们将研究基于PAM 4的酶免疫测定法的使用， 胰腺癌患者血液中抗原的检测和定量 癌症患者，希望提供早期检测， 可能更有效的治疗效果。 特异性， 灵敏度和诊断准确性将被确定。 在一个单独 研究中，我们将研究血液抗原 浓度与肿瘤负荷，作为其用于监测的前奏 治疗病人。

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.