Procorde-advanceCOR, Martinsried, Germany.
Thyroid. 2019 Feb;29(2):258-267. doi: 10.1089/thy.2018.0326.
Cyclic peptides derived from some cylindrical loops of the leucine-rich repeat domain (LRD) of the thyrotropin receptor (TSHR) have been shown to treat disease manifestations in a mouse model of Graves' disease during a long-term protocol of four-weekly immunizations with adenovirus coding for the TSHR A-subunit (Ad-TSHR289).
In a follow-up study, two additional cyclic peptides were tested, which were shortened in order to obtain additional information on the minimally involved epitopes and to enable easier production conditions. In addition, a linear peptide was tested, which mimics parts of three loops of the native TSHR LRD structure, and is potentially able to block the discontinuous epitopes of anti-TSHR antibodies.
The novel peptides markedly reduced thyroid size, serum thyroxine levels, retro-orbital fibrosis, and tachycardia in Ad-TSHR289-immunized mice. In immunologically naïve mice, administration of the peptides did not induce any immune response.
In summary, novel cyclic peptides mitigate many clinical findings in a mouse model of established Graves' disease and orbitopathy, and may therefore provide an additional therapeutic option compared to existing drugs or interventions.
来源于促甲状腺激素受体 (TSHR) 富含亮氨酸重复结构域 (LRD) 一些圆柱状环的环肽，已被证明在以腺病毒编码 TSHR A 亚基（Ad-TSHR289）为基础的长达四周免疫方案的 Graves 病小鼠模型中可治疗疾病表现。
在后续研究中，测试了另外两种缩短的环肽，以便获得关于最小涉及的表位的额外信息，并能实现更容易的生产条件。此外，还测试了一种线性肽，它模拟了天然 TSHR LRD 结构的三个环的部分，并且可能能够阻断抗 TSHR 抗体的不连续表位。
新型肽可显著减少 Ad-TSHR289 免疫小鼠的甲状腺大小、血清甲状腺素水平、眼眶后纤维化和心动过速。在免疫原性未成熟的小鼠中，给予这些肽不会引起任何免疫反应。
总之，新型环肽可减轻已建立的 Graves 病和眼眶病小鼠模型中的许多临床发现，因此可能提供比现有药物或干预措施更多的治疗选择。
