MONOCLONAL ANTIBODIES FOR TREATMENT OF CARCINOMAS

该项目旨在测试关于以下三个假设 人源化单抗(HUAB)治疗红斑狼疮的研究进展 上皮性肿瘤：(1)单抗能对抗限制分化 抗原用于选择性地输送治疗量的 是放射性同位素还是有毒物质？(Ii)含生物效应剂的单抗 功能(包括免疫肿瘤细胞溶解)集中在破坏性作用上。 肿瘤部位的炎症反应？(三)可限制肿瘤 基质抗原，如成纤维细胞激活蛋白(FAP)和 内毒素是上皮性癌症的治疗靶点吗？过去时 用小鼠单抗进行的研究已经确定了几个抗原系统 有望实现免疫治疗的结肠癌、肾癌和乳腺癌 方法，因为一些在肿瘤组织中高表达，但显示 只有有限的正常组织表达；一些是有效的靶点 补体介导的细胞毒性；一些已经显示出选择性肿瘤 I期患者的靶向生物分布/剂量学研究。 然而，小鼠单抗在治疗上皮性癌中的临床应用 肿瘤受到人类抗鼠抗体(HAMA)诱导的限制 防止延长和/或重复治疗的反应。对.的使用 可用单抗的嵌合(CHAB)和人性化(HUAB)版本提供了 克服这些缺点的有效方法和探索 单抗与放射性同位素或药物偶联的治疗潜力 具有固有的细胞毒性或致炎特性的单抗。目标I 重点介绍了两种单抗Huab A33和Chab G250对High 结肠癌和肾癌限制性抗原作为病毒载体的研究 放射性同位素和药物。此外，A33也是塔吉特的原型。 具有显著内化特性的抗原，允许使用 具有俄歇电子发射同位素的单抗结合物和具有 细胞内的作用部位。AIM II探索了免疫的使用 细胞毒性抗Le/y单抗Huab S193在结肠癌和乳腺病中的应用 肿瘤和免疫细胞毒IgM单抗F31的初步评价 肾癌患者。(免疫细胞毒性和免疫功能的评估 这些患者的致炎作用将与 (作者：Scheinberg和Houghton博士的项目。)AIM III代表着一个 上皮癌成像和治疗的新概念 利用中心抗体对抗反应性肿瘤间质限制性抗原 成纤维细胞(Huab F19，抗FAP)与肿瘤毛细血管内皮细胞 (Huab FB5，抗内毒素)。这些目标特别有吸引力。 因为间质间隔对上皮细胞的生长至关重要 癌症和间质靶点可能很容易进入循环 单抗。拟议的第一阶段和第二阶段试验将遵循一般研究。 以前为鼠标单抗开发的设计，重点是 生物分布研究(外部成像、基于活检的剂量测定、 放射自显影)和剂量学开发(与 核医学核心)。这些研究可能导致安全和有效的 上皮癌患者的免疫疗法。

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.