HCG Isoform Markers of Trophoblastic Malignancies

描述（由申请人提供）：HCG是妊娠期和非妊娠期滋养细胞疾病的主要肿瘤标志物。部分或完全葡萄胎妊娠后，一些患者发展为恶性妊娠滋养细胞疾病。患者可能在没有临床疾病证据的情况下出现循环hCG不明原因升高，仅因其hCG标志物而接受治疗。其他正在接受治疗的患者通过hCG标志物检测出对治疗产生耐药性或复发。我们建议评估几种新的hCG异构体免疫测定方法的效用，这些方法是我们实验室最近开发的，作为改进的hCG相关肿瘤标志物。新的标记可能有助于鉴别需要化疗的妇女亚群和那些在恶性磨牙妊娠后会自发缓解的妇女亚群。新的标记物也可以改善妊娠期和非妊娠期滋养细胞疾病患者的治疗护理，包括睾丸癌。这些标记基于四种不同的免疫测定系统：1.与碳水化合物相关的hCG变异。2. “缺口”形式的hCG。3. 同种异构体有“缺口化”和高糖基化。4. hCG和hLH核心片段。大多数hCG异构体已被证明在恶性肿瘤中发生结构改变，但以前没有测定测量系统来量化这些异构体。健康个体（垂体）产生的hCG同型异构体必须与恶性组织产生的hCG同型异构体明确区分。碳水化合物变异hCG异构体的检测是基于抗体B152（发展到绒毛膜癌分泌的hCG异构体），该抗体检测妊娠早期和各种恶性肿瘤中产生的不同o -糖基化形式的hCG。据报道，分泌hCG的癌症也会在β亚基内产生肽键断裂的“缺口”hCG同工型。这些将通过分析系统（B151）与快速色谱程序一起测量。绒毛膜癌和其他滋养细胞癌产生同种异构体，这些异构体既有“缺口”，也有高糖基化。这些是通过B151捕获B152检测试验检测的。还开发了专门测量尿hCG和尿hLH代谢物的系统，以便将hCG相关代谢物与绝经后妇女的正常hLH代谢物区分开来。将进行结构分析，以将异构体结构与测定测量相关联。

DESCRIPTION (provided by applicant): HCG is the main tumor marker for both gestational and non-gestational trophoblastic disease. After a pregnancy with partial or complete hydatidiform mole, some patients develop malignant gestational trophoblastic disease. Patients may display unexplained elevation of circulating hCG with no evidence of clinical disease and are treated solely because of their hCG marker. Other patients under treatment develop resistance to therapy or relapse as detected by the hCG marker. We propose to assess the utility of several new immunoassays for hCG isoforms, recently developed in our laboratory, as improved hCG-related tumor markers. New markers may help to identify the subpopulation of women who will require chemotherapy from those who will undergo spontaneous remission after a premalignant molar pregnancy. The new markers may also improve therapeutic care for both gestational and non-gestational trophoblastic disease patients, including testicular cancers. These markers are based on four differentiating immunoassay systems to: 1.carbohydrate-related variants of hCG. 2. "nicked" forms of hCG. 3. isoforms both "nicked" and hyperglycosylated. 4. hCG and hLH beta core fragments. Most of these hCG isoforms have been shown to be structurally altered in malignancies but no assay measurement systems existed previously to quantify these isoforms. The hCG isoforms produced by healthy individuals (from pituitary) must be clearly differentiated from those isoforms produced by malignant tissues. The detection of carbohydrate-variant hCG isoforms are based on the antibody B152 (developed to choriocarcinoma-secreted hCG isoforms) which detects a differentially O-glycosylated form of hCG produced very early in pregnancy as well as in various malignancies. HCG-secreting cancers have also been reported to produce "nicked" hCG isoforms with peptide bond cleavages within the beta subunit. These will be measured by assay system (B151) in conjunction with a rapid chromatographic procedure. Choriocarcinoma and other trophoblastic cancers produce isoforms, which are both "nicked", and hyperglycosylated. These are detected by a B151 capture B152 detection assay. Systems to specifically measure urinary hCG and urinary hLH metabolites have also been developed so that hCG-related metabolites can be distinguished from normal hLH metabolites in postmenopausal women. Structural analyses will be performed to correlate isoform structures with assay measurements.