MONOCLONAL ANTIBODIES FOR TREATMENT OF CARCINOMAS

该项目旨在测试三个假设， 开发基于人源化单克隆抗体（huAb）的治疗， 上皮癌：（1）抗限制性分化的mAb 抗原可用于选择性递送治疗量的 放射性同位素或毒剂？(ii)具有生物效应物的单克隆抗体 功能（包括免疫肿瘤细胞溶解）集中在破坏性作用 肿瘤部位有炎症反应吗(iii)局限性肿瘤 基质抗原如成纤维细胞活化蛋白（FAP）， 内唾液酸蛋白作为上皮癌的治疗靶点？ 过去 用小鼠单克隆抗体进行的研究已经鉴定了几种抗原系统， 结肠癌、肾癌和乳腺癌有望获得免疫抑制 方法，因为有些在肿瘤组织中高度表达，但显示 只有有限的正常组织表达;有些是有效的目标， 补体介导的细胞毒性;有些已经显示出选择性肿瘤 患者I期生物分布/剂量测定研究中的靶向。 然而，小鼠单克隆抗体在治疗上皮性肿瘤中的临床效用还有待进一步研究。 人类抗鼠抗体（HAMA）的诱导限制了肿瘤的发生 防止延长和/或重复治疗的反应。 使用 可用mAb的嵌合（chAb）和人源化（huAb）形式提供了一种 克服这些缺点和探索 mAb与放射性同位素或药物缀合物的治疗潜力， 具有内在细胞毒性或致炎特性的mAb。 AIM I 重点是使用两种单克隆抗体，huAb A33和chAb G250， 结肠癌和肾癌的限制性抗原作为 放射性同位素和药物。 此外，A33作为目标的原型， 具有突出内化特征的抗原，允许使用 具有俄歇电子发射同位素的mAb缀合物和具有 细胞内的作用位点。 目的二探讨使用免疫 结肠和乳腺癌患者中的细胞毒性抗Le/y mAb，huAb S193 癌症，并初步评估免疫细胞毒性IgM，mAb F31， 肾癌患者。 (The免疫细胞毒性和 这些患者的致炎作用将与 Scheinberg和霍顿博士的项目。） 目标三是 用于上皮癌的成像和治疗的新概念， 使用针对反应性肿瘤间质的限制性抗原的huAb 成纤维细胞（huAb F19，抗FAP）和肿瘤毛细血管内皮细胞 (huAb FB 5，抗内唾液酸蛋白）。 这些目标特别吸引人 因为基质区室对于上皮细胞的生长至关重要， 癌症和基质靶点可以容易地被循环的 单克隆抗体 拟议的I期和II期试验将遵循一般性研究 先前为小鼠mAb开发的设计，重点是 生物分布研究（外部成像，基于活组织检查的剂量测定， 放射自显影）和剂量测定发展（与 核医学核心）。 这些研究可能会导致安全有效的 免疫疗法用于上皮癌患者。

This project is designed to test three hypotheses with regard to the development of humanized monoclonal antibody (huAb)-based therapies of epithelial cancers: (1) Can mAbs against restricted differentiation antigens be used for selective delivery of therapeutic amounts of radioisotopes or toxic agents? (ii) Can mAbs with biological effector functions (including immune tumor cell lysis) focus the destructive effect of an inflammatory reaction at the tumor site? (iii) Can restricted tumor stromal antigens such as fibroblast activation protein (FAP) and endosialin serve as therapeutic targets in epithelial cancers? Past studies with mouse mAbs have identified several antigenic systems of colon, kidney, and breast cancers that hold promise for immunotherapeutic approaches because some are highly expressed in tumor tissues but show only limited normal tissue expression; some are efficient targets for complement-mediated cytotoxicity; and some have shown selective tumor targeting in phase I biodistribution/dosimetry studies in patients. However, the clinical utility of mouse mAbs in the therapy of epithelial cancers is limited by the induction of human antimouse antibody (HAMA) responses that prevent prolong and/or repeat treatment. The use of chimeric (chAb) and humanized (huAb) versions of available mAbs offers a powerful method for overcoming these shortcomings and for exploring the therapeutic potential of mAb conjugates with radioisotopes or drugs and mAbs with intrinsic cytotoxic or inflammatogenic properties. Aim I focuses on the use of two mAbs, huAb A33 and chAb G250, against highly restricted antigens of colon and kidney cancers as carriers for radioisotopes and drugs. Moreover, A33 serves as a prototype for target antigens with prominent internalization characteristics, allowing the use of mAb-conjugates with Auger electron-emitting isotopes and drugs with intracellular sites of action. Aim II explores the use of an immune cytotoxic anti-Le/y mAb, huAb S193, in patients with colon and breast cancer, and initial evaluation of an immune cytotoxic IgM, mAb F31, in patients with kidney cancer. (The assessment of immune cytotoxic and inflammatogenic effects in these patients will be conducted in conjunction with Projects by Drs. Scheinberg and Houghton.) Aim III represents a novel concept for the imaging and therapy of epithelial cancers that employs huAbs against restricted antigens of reactive tumor stromal fibroblasts (huAb F19, anti-FAP) and tumor capillary endothelial cells (huAb FB5, anti-endosialin). These targets are particularly attractive because the stromal compartment is critical for the growth of epithelial cancers, and stromal targets may be readily accessible to circulating mAbs. The proposed phase I and II trials will follow a general study design previously developed for mouse mAbs, with emphasis on biodistribution studies (external imaging, biopsy-based dosimetry, autoradiography) and dosimetry development (in conjunction with the Nuclear Medicine Core). These studies may lead to safe and effective immunotherapies for patients with epithelial cancers.