title: 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.
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Holthoff
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Faßbender
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimann
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Adler
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
authors.affiliation: Procorde-advanceCOR, D 82152 Martinsried, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ungerer
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D049970:Graves Ophthalmopathy / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use*; D011989:Receptors, Thyrotropin / Q000737:chemistry*
chemical_list: D018828:Immunoglobulins, Thyroid-Stimulating; D010456:Peptides, Cyclic; D011989:Receptors, Thyrotropin; C094372:thyrotropin-binding inhibitory immunoglobulin