Clinical evaluation of an anti-mesothelin immunotoxin

描述（由申请人提供）：尽管在治疗方面取得了进步 卵巢癌，晚期卵巢癌患者的预后 还是很穷。 规避与化疗相关的耐药性的方法 卵巢癌是需要的。 自从担任肿瘤学研究员以来 在国家癌症研究所 Ira Pastan 博士的实验室，我一直在 参与开发针对间皮素的免疫毒素。 间皮素是一种 细胞表面糖蛋白在某些卵巢癌患者中过度表达 癌症、恶性间皮瘤和某些鳞状细胞癌。 间皮素是靶向治疗的一个有吸引力的候选者，因为它不是 由间皮细胞以外的正常组织表达，并且不脱落 大量进入血液。 SS 1 (dsFv)-PE38 是重组体 通过融合二硫键稳定的轻链和重链开发的免疫毒素 具有突变体的鼠抗间皮素可变区（Fv）的链 假单胞菌外毒素。 它在体外表现出显着的活性 导致裸鼠中表达间皮素的肿瘤消退。 相比于 与现有的免疫毒素相比，SS 1 (dsFv)-PE38 具有多种优点，包括体积小 大小应增加肿瘤渗透并降低免疫原性。 的 该研究项目的目标是评估 SS 1 的安全性和有效性 (dsFv)-PE38 表达卵巢癌间皮素的患者，以及 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体验全方位药物的机会 从我的抗间皮素免疫毒素的临床前工作到它们的发展 对患者进行临床评估。 这个奖项也将使我能够追求 结构化的研究培训计划，成为成为一名 多产的临床研究员。 培训将包括研究生课程 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的演讲。 我的导师和共同导师 成熟的临床和基础研究人员将提供监督和 科学指导。 拟议的研究和培训将使我能够 成为一名独立调查员，参与开发和评估新的 癌症患者的生物制剂。

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.