HCG Isoform Markers of Trophoblastic Malignancies

描述(申请人提供)：人绒毛膜促性腺激素是妊娠和非妊娠滋养细胞疾病的主要肿瘤标志物。部分性或完全性葡萄胎妊娠后，部分患者发展为恶性妊娠滋养细胞疾病。患者可能会表现出循环中hCG原因不明的升高，没有临床疾病的证据，仅仅因为他们的hCG标志物而接受治疗。根据hCG标记物的检测，其他接受治疗的患者对治疗产生抵抗力或复发。我们建议评估我们实验室最近开发的几种新的hCG亚型免疫分析方法作为改进的hCG相关肿瘤标记物的实用性。新的标记物可能有助于将需要化疗的妇女亚群与那些在癌前磨牙妊娠后自然缓解的妇女区分开来。新的标记物还可以改善对妊娠和非妊娠滋养细胞疾病患者的治疗，包括睾丸癌。这些标记物基于四种不同的免疫分析系统：1.人绒毛膜促性腺激素的糖相关变体。2.人绒毛膜促性腺激素的“割裂”形式。3.同工酶既有“缺陷型”，也有高糖化。4.人绒毛膜促性腺激素和促黄体生成素β核心片段。这些hCG亚型中的大多数已被证明在恶性肿瘤中发生了结构上的改变，但以前没有检测系统来定量这些亚型。健康个体产生的hCG亚型(来自脑下垂体)必须与恶性组织产生的亚型明显区别。检测碳水化合物变异的hCG亚型是基于抗体B152(发展为绒毛膜癌分泌的hCG亚型)，它检测到怀孕早期以及各种恶性肿瘤中产生的不同O-糖基化形式的hCG。据报道，分泌人绒毛膜促性腺激素的癌症也会产生“缺口”的hCG异构体，并在β亚基内发生肽键断裂。这些将由分析系统(B151)结合快速层析程序进行测量。绒毛膜癌和其他滋养细胞癌产生的亚型都是“刻痕”的，并且是高糖化的。这些都是通过B151捕获B152检测试验来检测的。还开发了专门测量尿液hCG和尿液HLH代谢物的系统，以便hCG相关代谢物可以与绝经后妇女正常的HLH代谢物区分开来。将进行结构分析，以将异构体结构与化验测量相关联。

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.