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      Tumor- and Pregnancy-Derived Isoforms of Human Chorionic Gonadotropin: Biological and Diagnostic Relevance

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          Abstract

          Objectives: Human chorionic gonadotropin (hCG) and hCG variants are of high clinical importance for the diagnosis of pregnancy, monitoring of abnormal and ectopic pregnancies, testing for Down’s syndrome or monitoring therapy of hCG-secreting malignancies. In serum and urine, hCG appears in microheterogeneous isoforms with respect to protein backbone structure and the extent of glycosylation. The present study reports on the identification, immunological characterization, biological activity of glycosylation isoforms of pregnancy (preg) and tumor-derived (tu) hCG, and the impact of glycosylation on diagnostic immunoassays. Methods: Twenty-two urinary preg- and tu-hCG isoforms were separated by preparative isoelectrofocusing (hCG-pI variants) and characterized by Western blot. Number, topography and accessibility pattern of epitopes on their surface was evaluated by two-site radioimmunoassays using 14 different monoclonal antibodies (mabs). Binding of hCG isoforms to four different LH/CG receptors was investigated in radioreceptor assays, and their biological activity determined by measuring cAMP elevation. Results: All 22 hCG glycosylation variants appeared immunologically intact: each isoform, even when highly acidic, expressed all 14 surface epitopes which were arranged in a topographical manner indistinguishable from crude hCG. hCG isoforms were able to bind to four different receptor variants, with slightly varying affinities, but orientations indistinguishable from each other as shown by identical epitope accessibility patterns. Each of the hCG-pI variants was able to activate the LH/CG-Rs, but with varying reactivities. Conclusions: We conclude that in contrast to deglycosylated hCG, all hCG glycosylation isoforms investigated act as receptor agonists. Moreover, there is no overspecificity of mabs to certain hCG isoforms due to carbohydrate variability that exclude others from diagnostic measurement.

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          Most cited references 4

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          Crystal structure of human chorionic gonadotropin.

          The three-dimensional structure of human chorionic gonadotropin shows that each of its two different subunits has a similar topology, with three disulphide bonds forming a cystine knot. This same folding motif is found in some protein growth factors. The heterodimer is stabilized by a segment of the beta-subunit which wraps around the alpha-subunit and is covalently linked like a seat belt by the disulphide Cys 26-Cys 110. This extraordinary feature appears to be essential not only for the association of these heterodimers but also for receptor binding by the glycoprotein hormones.
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            Development and characterization of antibodies to a nicked and hyperglycosylated form of hCG from a choriocarcinoma patient: generation of antibodies that differentiate between pregnancy hCG and choriocarcinoma hCG.

            Human chorionic gonadotropin (hCG) exists in blood and urine as a variety of isoforms one of which contains peptide bond cleavages within its beta-subunit loop 2 and is referred to as nicked hCG (hCGn). This hCG isoform appears to be more prevalent in the urine of patients with certain malignancies and possibly in some disorders of pregnancy. Until now, only indirect immunoassays could be used to quantify hCGn. We report the development of two monoclonal antibodies (MAbs) to a form of hCGn isolated from a choriocarcinoma patient. This hCG isoform was not only 100% nicked, but also contained 100% tetrasaccharide-core O-linked carbohydrate moieties in its beta COOH-terminal region. Two-site immunometric assays have been developed using these new antibodies, B151 and B152. The former exhibits good specificity for hCGn independent of the source of the hCGn, the form excreted by choriocarcinoma patients or the form of hCGn from normal pregnancies. The latter antibody, B152, is sensitive to the carbohydrate moieties and possibly other differences in hCG isoforms, but is not for nicking of the beta-subunit. These two immunometric assays provide potential novel diagnostic tools for direct measurement of hCG isoforms which could not be accurately quantified earlier before development of the assays using these newly generated antibodies.
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              A change in the isoforms of human chorionic gonadotropin occurs around the 13th week of gestation

               L. WIDE,  L Wide,  JY Lee (1994)
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2003
                2003
                19 March 2003
                : 59
                : 3
                : 125-134
                Affiliations
                aInstitute for Pathophysiology, University of Innsbruck, Austria; bDivision of Endocrinology, Department of Medicine, University of Essen, Germany, and cInstitute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria
                Article
                69070 Horm Res 2003;59:125–134
                10.1159/000069070
                12637792
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 1, References: 32, Pages: 10
                Categories
                Original Paper

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