Thyroid-stimulating hormone receptor (TSHR) fusion proteins in Graves' disease
© 2020 Society for Endocrinology..
Graves' disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. We systematically investigated monomeric and dimeric fusion proteins of the A subunit of TSHR for efficacy to bind to the monoclonal patient antibody M22, to interact with Graves' patient serum samples, and to impact on anti-TSHR antibody titers, hyperthyroidism, tachycardia and other in vivo read-outs in a long-term mouse model of Graves' disease induced by immunization with a recombinant adenovirus encoding TSHR A. Binding assays and functional measurements of TSHR-dependent cAMP formation showed binding of monomeric TSHR-His and dimeric TSHR-Fc to the anti-TSHR antibody M22 at low-effective concentrations (EC50 of 5.7 nmol/L and 8.6 nmol/L) and inhibition of the effects of this antibody at high efficiencies (IC50 values of 16-20 nmol/L). Both proteins also block the effects of polyclonal anti-TSHR antibodies occurring in Graves' patient sera with somewhat lower average efficiencies (mean IC50 values of 29 nmol/L and 68 nmol/L). However, in vivo characterization of epicutaneous patch administrations of TSHR-Fc at doses of 0.3 and 0.6 mg/kg body weight in a murine Graves' disease model did not result in any improvement of disease parameters. In conclusion, high affinity binding of TSHR-Fc to pathological anti-TSHR antibodies was not matched by efficacy to improve Graves' disease parameter in a long-term mouse model.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:246 |
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| Enthalten in: |
The Journal of endocrinology - 246(2020), 2 vom: 01. Aug., Seite 135-147 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Holthoff, Hans-Peter [VerfasserIn] |
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| Links: |
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| Themen: |
Autoimmunity |
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| Anmerkungen: |
Date Completed 25.01.2021 Date Revised 25.01.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1530/JOE-20-0061 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM311517102 |
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| 520 | |a © 2020 Society for Endocrinology. | ||
| 520 | |a Graves' disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. We systematically investigated monomeric and dimeric fusion proteins of the A subunit of TSHR for efficacy to bind to the monoclonal patient antibody M22, to interact with Graves' patient serum samples, and to impact on anti-TSHR antibody titers, hyperthyroidism, tachycardia and other in vivo read-outs in a long-term mouse model of Graves' disease induced by immunization with a recombinant adenovirus encoding TSHR A. Binding assays and functional measurements of TSHR-dependent cAMP formation showed binding of monomeric TSHR-His and dimeric TSHR-Fc to the anti-TSHR antibody M22 at low-effective concentrations (EC50 of 5.7 nmol/L and 8.6 nmol/L) and inhibition of the effects of this antibody at high efficiencies (IC50 values of 16-20 nmol/L). Both proteins also block the effects of polyclonal anti-TSHR antibodies occurring in Graves' patient sera with somewhat lower average efficiencies (mean IC50 values of 29 nmol/L and 68 nmol/L). However, in vivo characterization of epicutaneous patch administrations of TSHR-Fc at doses of 0.3 and 0.6 mg/kg body weight in a murine Graves' disease model did not result in any improvement of disease parameters. In conclusion, high affinity binding of TSHR-Fc to pathological anti-TSHR antibodies was not matched by efficacy to improve Graves' disease parameter in a long-term mouse model | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Graves’ disease | |
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| 700 | 1 | |a Adler, Kristin |e verfasserin |4 aut | |
| 700 | 1 | |a Wenhart, Clara |e verfasserin |4 aut | |
| 700 | 1 | |a Ungerer, Martin |e verfasserin |4 aut | |
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