Clinical evaluation of an anti-mesothelin immunotoxin

抗间皮素免疫毒素的临床评价

• 批准号: 6436662
• 负责人: RAFFIT HASSAN
• 金额: $ 2.36万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2002-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436662
• 关键词: antineoplastics; biomarker; clinical research; clinical trial phase I; drug design /synthesis /production; drug screening /evaluation; female; human subject; human therapy evaluation; human tissue; immunoconjugates; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplasm /cancer immunotherapy; ovary neoplasms; patient oriented research; prognosis; tumor antigens

DESCRIPTION (provided by applicant): Despite advances in the treatment of ovarian cancer, the prognosis of patients with advanced ovarian cancer is still poor. Approaches which circumvent chemo-resistance associated with ovarian cancer are needed. Since working as an oncology fellow in the laboratory of Dr. Ira Pastan at the National Cancer Institute, I have been involved in developing immunotoxins targeting mesothelin. Mesothelin is a cell surface glycoprotein that is overexpressed in some patients with ovarian cancer, malignant mesotheliomas and certain squamous cell carcinomas. Mesothelin is an attractive candidate for targeted therapy since it is not expressed by normal tissues except mesothelial cells and is not shed in significant amounts into the bloodstream. SS 1 (dsFv)-PE38 is a recombinant immunotoxin developed by fusing the disulfide stabilized light and heavy chains of a murine anti-mesothelin variable region (Fv) with a mutant Pseudomonas exotoxin. It exhibits significant activity in vitro as well as causes regression of mesothelin expressing tumors in nude mice. Compared to prior immunotoxins, SS 1 (dsFv)-PE38 has several advantages including small size which should increase tumor penetration and decrease immunogenicity. The goal of this research project is to evaluate the safety and efficacy of SS 1 (dsFv)-PE38 in patients with mesothelin expressing ovarian cancer, and also to understand the prognostic significance of mesothelin expression in cancer of the ovary. This award provides me the opportunity to experience the full spectrum of drug development from my pre-clinical work on anti-mesothelin immunotoxins to their clinical evaluation in patients. This award will also allow me to pursue a structured research training program, an essential first step to become a productive clinical researcher. Training will include graduate courses in clinical research, tumor immunology, participation in clinical and laboratory meetings and presentation at scientific meetings. My mentor and co-mentors who are established clinical and basic researchers will provide oversight and scientific guidance. The proposed research and training will allow me to become an independent investigator involved in developing and evaluating new biologic agents in patients with cancer.

描述（由申请人提供）：尽管在治疗方面取得了进展， 卵巢癌晚期患者的预后如何？ 仍然贫穷。 避免与以下疾病相关的化学耐药性的方法 卵巢癌是必需的。 作为一名肿瘤学研究员， 在国家癌症研究所伊拉帕斯坦博士的实验室里，我一直在 参与开发针对间皮素的免疫毒素。 间皮素是一种 在某些卵巢癌患者中过度表达的细胞表面糖蛋白 癌症、恶性间皮瘤和某些鳞状细胞癌。 间皮素是靶向治疗的有吸引力的候选物，因为它不是靶向治疗的靶向药物。 由正常组织表达，但间皮细胞除外， 进入血液中 SS 1（dsFv）-PE 38是一种重组的 通过融合二硫键稳定的轻链和重链 具有突变体的鼠抗间皮素可变区（Fv）的链 假单胞菌外毒素 它在体外表现出显著的活性， 导致裸鼠中表达间皮素的肿瘤消退。 相比 在现有的免疫毒素中，SS 1（dsFv）-PE 38具有几个优点， 其大小应增加肿瘤穿透并降低免疫原性。 的 本研究项目的目的是评估SS 1的安全性和有效性 （dsFv）-PE 38在表达间皮素的卵巢癌患者中的应用，以及对 了解间皮素表达在癌症中的预后意义， 卵巢 这个奖项为我提供了一个机会，体验全方位的药物 从我的抗间皮素免疫毒素的临床前工作发展到它们的 患者的临床评价。 这个奖项也将允许我追求一个 结构化的研究培训计划，成为一个重要的第一步， 多产的临床研究员 培训将包括以下方面的研究生课程： 临床研究，肿瘤免疫学，参与临床和实验室 会议和在科学会议上发言。 我的导师和同事 谁是建立临床和基础研究人员将提供监督， 科学指导。 拟议的研究和培训将使我能够 成为一名独立的调查员，参与开发和评估新的 癌症患者的生物制剂。