Thyroid-stimulating hormone receptor (TSHR) fusion proteins in Graves’ disease

in Journal of Endocrinology
Authors:
Hans-Peter Holthoff Procorde – advancecor, Martinsried, Germany

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Kerstin Uhland Procorde – advancecor, Martinsried, Germany

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Gabor Laszlo Kovacs 1st Department of Internal Medicine, Flor Ferenc Hospital, Kistarcsa, Hungary

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Andreas Reimann Procorde – advancecor, Martinsried, Germany

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Kristin Adler Procorde – advancecor, Martinsried, Germany

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Clara Wenhart Procorde – advancecor, Martinsried, Germany

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Martin Ungerer Procorde – advancecor, Martinsried, Germany

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Correspondence should be addressed to M Ungerer: ungerer@procorde.com

*(H-P Holthoff and K Uhland contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-20-0061
Volume/Issue:
Volume 246: Issue 2
Article Type:
Research Article
Page Range:
135–147
Online Publication Date:
Aug 2020
Copyright:
© 2020 Society for Endocrinology 2020
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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.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
13
Article Type:
Research Article
Received Date:
02 Apr 2020
Accepted Date:
21 May 2020
Print Publication Date:
01 Aug 2020
Online Publication Date:
Aug 2020
Keywords:
thyroid; Graves’ disease; autoimmunity; peptides

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