NEW DIAGNOSTIC/MONITORING ASSAYS FOR OVARIAN CANCER

COGS诊断公司计划开发三种新的检测试剂盒，以确定它们对监测和/或诊断卵巢癌患者的有用性。卵巢癌中过表达的三种新的丝氨酸蛋白酶已被克隆和测序，并已申请了组合物、诊断和治疗用途的专利。蛋白酶已显示; 1）在早期疾病中过表达，2）代表卵巢癌的所有亚型，包括粘液性肿瘤; 3）具有分泌信号序列或跨膜结构域，使得蛋白质被置于细胞外空间; 4）通过免疫组织化学定位发现存在于肿瘤细胞中和5）所有3种基因的转录物也大量存在于卵巢癌提取物中，但在正常卵巢中不存在，在正常成人组织中完全不存在或含量非常低。因此，我们计划开发代表每种蛋白酶的新的ELISA测定法，以确定这些测试相对于CA 125用于检测和监测卵巢癌的价值。 建议在E.大肠杆菌或酵母菌中，以提供用于单克隆和多克隆抗体生产的抗原。从这些试剂中，将配置ELISA测定，并通过检测正常女性、良性疾病女性和卵巢癌女性血清中的抗原水平进行评价。对于更好地监测所有卵巢肿瘤、更早地检测卵巢癌或肿瘤存在与血清抗原水平之间更特异性的关系，将进一步开发比CA 125检测更有效的检测方法，用于β位点检测和FDA批准。建议的商业应用：目前存在估计为100，000，000美元的CA 125监测肿瘤负荷和肿瘤复发的市场。CA 125提供了有限的早期诊断能力（相当于I期和II期的约50%），并且在粘液性卵巢肿瘤中表达较差（卵巢癌的10-15%）。超越CA 125局限性的新检测为进入更大的卵巢癌监测和早期诊断市场提供了机会。本文所述的新型丝氨酸蛋白酶的测定提供了研究和临床护理中的其他应用，例如测定蛋白酶在肿瘤生长和进展中的作用，以及评估预后因素，这些预后因素可以鉴定用于疫苗或抑制药物治疗的患者。

COGS Diagnostics plans to develop three new test kits to determine their usefulness for monitoring and/or diagnosis of ovarian cancer patients. Three novel serine proteases overexpressed in ovarian carcinoma have been cloned and sequenced and patents have been filed for composition, diagnostic and therapeutic use. The proteases have been shown; 1) to be overexpressed in early stage disease, 2) to represent all subtypes of ovarian carcinoma including mucinous tumors; 3) to possess either secretion signal sequences or transmembrane domains such that the proteins are placed in the extracellular space; 4) by immunohistochemical localization found to be present in tumor cells and 5) transcripts of all 3 genes were also present in abundance in ovarian carcinoma extracts, but not in normal ovary and either not at all or at very low levels in normal adult tissues. We plan therefore, to develop new ELISA assays representing each protease to determine the value of these tests relative to CAl25 for the detection and monitoring of ovarian carcinoma. It is proposed to produce recombinant proteases in either E. coli or yeast to provide antigen for both monoclonal and polyclonal antibody production. From these reagents, ELISA assays will be configured and evaluated by testing antigen levels in the sera of normal women, women with benign disease and women with ovarian carcinoma. Assays which prove more efficacious than the CA125 assay for either better monitoring of all ovarian tumors, earlier detection of ovarian carcinoma or more specific relationship between tumor presence and serum antigen levels will be further developed for beta site testing and FDA approval. PROPOSED COMMERCIAL APPLICATIONS: There presently exists an estimated $100,000,000 market for CA125 to monitor tumor burden and tumor recurrence. CA125 has provided limited capacity for early diagnosis (equals approximately 50% of stages I & II) and is poorly expressed in mucinous ovarian tumors (10-15% of ovarian cancers). New tests which surpass the limitations of CA125 offer the opportunity to enter an even larger market for monitoring and early diagnosis of ovarian cancer. Assays for novel serine proteases described here offer other applications in research and clinical care e.g. assaying the role of proteases in tumor growth and progression, and evaluating prognostic factors which may identify patients for vaccines or inhibition drug therapy.