P185 AND EGFR--RECOMBINANT ANTIBODIES AND ANIMAL MODELS

P185和EGFR——重组抗体和动物模型

• 批准号: 2393166
• 负责人: NORMAN C PETERSON
• 金额: $ 8.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2393166
• 关键词: antibody receptor; antineoplastics; athymic mouse; carcinogenesis inhibitor; cell transformation; disease /disorder model; epidermal growth factor; growth factor receptors; histopathology; immunocytochemistry; immunogenetics; molecular cloning; neoplasm /cancer immunology; pharmacokinetics; receptor expression; recombinant proteins

Over-expression of tyrosine kinase cell surface receptors p185neu/c-erbB2 is associated with a variety of human tumor cell-types. Several monoclonal antibodies which specifically recognize these receptors and result in disruption of tumor cell growth have been characterized. However, the clinical use of these antibodies has been hindered by the human anti-mouse antibody (HAMA) response to these foreign proteins. Additionally, animal models which over-express these tyrosine kinase receptors have not been developed or well characterized. During the first three years of this proposal, Dr. Peterson will receive training in recombinant DNA techniques, computer modeling, and biochemical and immunological methods to develop small bioactive polypeptides which are specific to p185neu/c-erbB2 and EGFR. These compounds will then be compared to their parental antibodies for their ability to mediate alterations in tumor cell physiology and growth inhibition and to further elucidate mechanisms of receptor mediated cell transformation. Additionally, because of their smaller size, these bioactive polypeptides are likely to be less immunogenic and may potentially serve as diagnostic and therapeutical agents in the treatment of cancer. The second objective of this project will address the development of animal models which are needed for comparative studies of p185new/c-erB2 and EGFR mediated cell transformation and to evaluate the in vivo effectiveness of those compounds which were developed during the first three years of this project. In order to meet this objective, Dr. Peterson will learn and develop immunohistochemical staining techniques in order to analyze paraffin embedded and frozen animal tumor specimens for over-expression of p185neu/c-erbB2 and/or EGFR. During years four and five, a variety of tumor specimens from different species obtained from the Veterinary Hospital of the University of Pennsylvania (VHUP), University Laboratory Animal Resources(ULAR), and various pharmaceutical companies in the vicinity will be analyzed for over-expression of p185neu/cerbB2 and EGFR. Once a particular species which develops tumors of the specified type are identified, normal tissues of that species will be analyzed for receptor over-expression. Additionally, tumor localization, tissue distribution, and plasma clearance of the compounds will be analyzed initially in xenografted athymic mice, and later in animal models and VHUP cancer patients whose tumor cells are positive for over-express p185neu/c-erbB2 and/or EGFR. Ultimately, the results of this work will provide useful insights in the study of comparative oncology and may lead to the development of effective compounds for the diagnosis and treatment of cancer.

酪氨酸激酶细胞表面受体的过表达P185NEU/C-ERBB2 与各种人类肿瘤细胞类型有关。 一些 单克隆抗体，专门识别这些受体和 导致肿瘤细胞生长的破坏。 但是，这些抗体的临床用途已受到 人类抗小鼠抗体（HAMA）对这些异物蛋白的反应。 此外，过表达这些酪氨酸激酶的动物模型 受体尚未开发或表征良好。 在 该提案的前三年，彼得森博士将接受培训 在重组DNA技术，计算机建模和生化和生化和 免疫学方法开发小型生物活性多肽 特定于P185NEU/C-ERBB2和EGFR。 这些化合物将是 与他们的父母抗体相比 肿瘤细胞生理和生长抑制的改变，并进一步 阐明受体介导的细胞转化的机制。 此外，由于它们的尺寸较小，这些生物活性多肽 免疫原性可能较少，并且有可能用作诊断 和治疗癌症治疗剂。 该项目的第二个目标将解决 P185NEW/C-ERB2比较研究所需的动物模型 EGFR介导的细胞转化并评估体内 那些在第一次开发的化合物的有效性 这个项目的三年。 为了实现这一目标，博士 彼得森将学习和发展免疫组织化学染色技术 为了分析石蜡嵌入和冷冻动物肿瘤标本 为了过表达P185NEU/C-ERBB2和/或EGFR。 在四年和五年中，来自不同的肿瘤标本 从大学兽医医院获得的物种 宾夕法尼亚州（VHUP），大学实验室动物资源（ULAR）和 将分析附近的各种制药公司 P185NEU/CERBB2和EGFR的过表达。 曾经是特定物种 确定了指定类型的肿瘤，正常 该物种的组织将被分析以过表达受体。 另外，肿瘤定位，组织分布和血浆 最初将在异种移植中分析化合物的清除 无胸腺小鼠，后来在动物模型和VHUP癌症患者中 肿瘤细胞对过表达的P185NEU/C-ERBB2和/或EGFR阳性。 最终，这项工作的结果将为您提供有用的见解 比较肿瘤学的研究，可能导致 有效的诊断和治疗的化合物。