MESOTHELIN ANTIGENS FOR DIAGNOSIS/THERAPY OF OVARIAN CA

用于诊断/治疗卵巢 CA 的间皮素抗原

• 批准号: 6377809
• 负责人: INGEGERD E HELLSTROM
• 金额: $ 31.5万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-02 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377809
• 关键词: active immunization; biomarker; carcinoma; cell mediated cytotoxicity; clinical research; cytotoxic T lymphocyte; diagnosis design /evaluation; diagnostic tests; early diagnosis; enzyme linked immunosorbent assay; gene expression; glycoproteins; helper T lymphocyte; human subject; laboratory mouse; membrane proteins; monoclonal antibody; neoplasm /cancer diagnosis; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; ovary neoplasms; tumor antigens; vaccine development; vector vaccine

DESCRIPTION: (Applicant's Abstract) More than 70% of women diagnosed with ovarian carcinomas are likely to die from progressive disease; although combination chemotherapy often causes a complete clinical remission, the remissions are commonly not sustained. The applicant's goal is to decrease mortality by finding ways to detect ovarian carcinomas earlier and by developing a therapeutic vaccine causing the immunological destruction of those cancer cells remaining after chemotherapy. A prerequisite for these goals is existence of antigens commonly expressed by ovarian carcinomas and rarely in normal tissues. These antigens can serve as diagnostic markers and therapeutic targets. This project focuses on molecules that belong to the mesothelin-megakaryocyte potentiating factor (MPF) family and that are overexpressed in more than 90% of ovarian carcinoma. She has made several mouse Mabs that bind to the C-terminal membrane associated domain but not to the N-terminal 30 kd or 33 kd parts normally cleaved during cellular processing. She recently discovered a new member of the mesothelin/MPF family, which has an 82bp insertion, lacks a stop codon, and is expected to have a soluble rather than membrane-bound C-terminal domain. To the extent tested, the 82 bp insertion has only been detected in ovarian carcinomas and subgroups of some other tumors. Soluble mesothelin-related (MR) molecules can be detected in sera from patients with ovarian carcinoma as a tumor marker, and she hypothesizes that the newly discovered molecule with the 82 bp insert is this marker. She now proposes, first, to further investigate the characteristics of that molecule with respect to its tumor specificity, to make Mabs to the 98AA new C-terminus encoded by the 82 bp insertion and the frameshift of 212 bp it causes, and to study whether they offer advantages for detecting antigen in serum. Second, she shall investigate whether a serum assay for MR molecules facilitates the early diagnosis and "monitoring" of patients with ovarian carcinoma, when used alone or in combination with an assay for CA125. Third, she shall study whether patients with ovarian carcinoma make antibodies to MR molecules, and, if so, whether detection of such antibodies facilitates early diagnosis. Finally, she shall investigate whether an immune response can be generated, in vitro, against (non-soluble) mesothelin and/or against the soluble MR molecule. This will be approached using gene based tumor vaccine(s), taking into account what has been learned about the role of costimulation, via CD80/CD86 and signaling, via 4-lBB. As part of this study, she shall investigate whether the soluble MR molecule (SMR) can act as an inhibitor of the immune response and, if so, whether the inhibition can be overcome.

描述：（申请人的摘要）超过70％的妇女被诊断出患有 卵巢癌可能死于进行性疾病。虽然 联合化疗通常会导致完整的临床缓解， 汇款通常无法持续。申请人的目标是减少 通过寻找较早检测卵巢癌的方法来死亡 开发一种治疗性疫苗，导致免疫学破坏者 化学疗法后仍保持癌细胞。这些目标的先决条件是 卵巢癌通常表达的抗原存在，很少在 正常组织。这些抗原可以用作诊断标记和治疗性 目标。该项目的重点是属于 间皮素 - 毛细生细胞增强因子（MPF）家族， 超过90％的卵巢癌过表达。她做了几只老鼠 与C末端膜相关结构域结合但不与之结合的mAb N末端30 kd或33 kD的部分通常在细胞加工过程中切割。 她最近发现了中皮/MPF家族的新成员，该家族有一个 82bp插入，缺少终止密码子，预计将具有可溶的副本 比膜结合的C末端结构域。在测试的范围内，82 bp 仅在某些卵巢癌和亚组中检测到插入 其他肿瘤。可以在血清中检测到可溶性间皮相关（MR）分子 从卵巢癌作为肿瘤标记的患者中，她假设 该标记是带有82 bp插入物的新发现的分子。她 现在，首先建议进一步研究该特征 关于其肿瘤特异性的分子，将mabs变为98AA新 由82 bp插入和212 bp IT的移架编码的C末端 原因，并研究它们是否提供了检测抗原的优势 血清。其次，她应研究MR分子的血清测定法 促进卵巢患者的早期诊断和“监测” 癌，当单独使用或与CA125的测定法结合使用时。第三， 她应研究卵巢癌患者是否对MR产生抗体 分子，如果是的，则检测这种抗体是否促进 诊断。最后，她应调查是否可以进行免疫反应 在体外产生的（非溶性）间皮素和/或针对 可溶性MR分子。这将使用基因基肿瘤疫苗进行处理 考虑到有关共同刺激作用的知识 CD80/CD86和信号传导，通过4磅。作为这项研究的一部分，她将 研究可溶性MR分子（SMR）是否可以充当 免疫反应，如果是这样，是否可以克服抑制作用。