Cyclic Peptides for Effective Treatment in a Long-Term Model of Graves Disease and Orbitopathy in Female Mice

Abstract

A model for human Graves disease in mice was used to compare several treatment approaches. The mice received regular adenovirus (Ad) thyroid-stimulating hormone receptor (TSHR) A subunit immunizations (injections every 4 weeks). The generation of anti-TSHR antibodies, enlarged thyroid sizes (goiter), elevated serum thyroxine levels, retro-orbital fibrosis, and cardiac involvement (tachycardia and hypertrophy) were consistently observed over 9 months. Treatment of established disease in these mice using cyclic peptides that mimic one of the cylindrical loops of the TSHR leucine-rich repeat domain improved or cured all investigated parameters after six consecutive monthly injections. The first significant beneficial effects were observed 3 to 4 months after starting these therapies. In immunologically naïve mice, administration of any of the cyclic peptides did not induce any immune response. In contrast, monthly injections of the full antigenic TSHR A domain as fusion protein with immunoglobulin G crystallizable fragment induced clinical signs of allergy in Ad-TSHR-immunized mice and anti-TSHR antibodies in naïve control mice. In conclusion, cyclic peptides resolved many clinical findings in a mouse model of established Graves disease and orbitopathy. In contrast to blocking TSHR by allosteric modulation, the approach does not incur a direct receptor antagonism, which might offer a favorable side effect profile.

Comprehensive research on thyroid diseases associated with autoimmunity: autoimmune thyroid diseases, thyroid diseases during immune-checkpoint inhibitors therapy, and immunoglobulin-G4-associated thyroid diseases

“…Both B-and T-cells responses to TSHR peptide 78-94 were significantly suppressed by peptide 37m. Other studies using mutant TSHR peptides as treatment for GD have been recently reported [25,26]. Epitope specific treatment of GD targeted to TSHR antigen may therefore be hopeful.…”

Current Understanding of the Progression and Management of Thyroid Associated Orbitopathy: A Systematic Review

“…Cyclic peptides were created that replicated the tertiary structure of the TSHR leucine-rich repeat domain. The cyclic peptides were able to stabilize TSH receptor-binding antibodies, reducing thyroid hyperplasia and improving retro-orbital fibrosis [71]. This is an encouraging result in an animal model, and future confirmatory animal studies may lead to translation to clinical therapy for TAO.…”

“…Cyclic peptides may be another promising avenue for future therapy. Holthoff et al established a mouse model that was immunized with a recombinant adenovirus expressing the human TSH receptor (TSHR) [71]. Cyclic peptides were created that replicated the tertiary structure of the TSHR leucine-rich repeat domain.…”

Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?

“…Among the early studies thus far performed are those examining the impact of cyclic peptides from the TSHR in the leucine-rich domain. These were found to lessen the disease phenotype of mice immunized with adenovirus encoding TSHR289 (96,97). Studies performed in HLA-DR3 transgenic mice utilized a mixture of two immunodominant regions of the TSHR in technology termed antigen-processing-independent epitopes (Apitopes) demonstrated suppression of both T cell and antibody responses to the receptor (98).…”