Department of Pharmacology and Toxicology, University of Würzburg, Comprehensive Heart Failure Centre (CHFC), University Hospital Würzburg, Würzburg, Germany.
Procorde, Martinsried, Germany.
PLoS One. 2018 Aug 20;13(8):e0201160. doi: 10.1371/journal.pone.0201160. eCollection 2018.
Despite advances in pharmacotherapy, heart failure still incurs significant morbidity and mortality. Stimulating antibodies directed against the secondextracellular loop of the human ß1-adrenergic receptor (anti-ß1EC2) cause myocyte damage and heart failure in rats. This receptor domain is 100% homologous between rats and humans.
ß1EC2-mimicking cyclopeptides (25-meric) markedly improved the development and/or course of anti-ß1EC2-mediated cardiomyopathy. Further developments should be investigated.
The shortened 18-meric cyclic peptide COR-1, in which one of the two disulphide bonds was removed to enable reproducible GMP production, can also be used to treat cardiomyopathic rats. Echocardiography, catheterization and histopathology of the rat hearts revealed that monthly intravenous administrations of COR-1 almost fully reversed the cardiomyopathic phenotype within 6 months at doses of 1 to 4 mg/kg body weight. Administration of COR-1 resulted in markedly reduced anti-ß1EC2-expressing memory B lymphocytes in the spleen despite continued antigenic boosts, but did not significantly decrease overall peripheral anti-ß1EC2 titers. COR-1 did not induce any anti-ß1EC2 or other immune response in naïve rats (corresponding to findings in healthy human volunteers). It did not cause any toxic side effects in GLP studies in dogs, rats or mice, and the "no observed adverse effect level" (NOAEL) exceeded the therapeutic doses by 100-fold.
The second generation immunomodulating epitope-mimicking cyclopeptide COR-1 (also termed JNJ-5442840) offers promise to treat immune-mediated cardiac diseases.
尽管在药物治疗方面取得了进展，但心力衰竭仍然导致了相当高的发病率和死亡率。针对人类β1-肾上腺素能受体第二细胞外环的刺激抗体（抗β1EC2）会在大鼠中引起心肌损伤和心力衰竭。该受体结构域在大鼠和人类之间是 100%同源的。
β1EC2 模拟环肽（25 聚体）显著改善了抗β1EC2 介导的心肌病的发展和/或病程。应进一步研究进一步的发展。
缩短的 18 聚体环状肽 COR-1 去除了其中一个二硫键，以实现可重复的 GMP 生产，也可用于治疗心肌病大鼠。大鼠心脏的超声心动图、心导管术和组织病理学检查显示，每月静脉注射 COR-1，在 1 至 4mg/kg 体重剂量下，在 6 个月内几乎完全逆转了心肌病表型。COR-1 的给药导致脾脏中表达抗β1EC2 的记忆 B 淋巴细胞显著减少，尽管持续存在抗原刺激，但并未显著降低外周总抗β1EC2 滴度。COR-1 未在未致敏大鼠中引起任何抗β1EC2 或其他免疫反应（与健康人类志愿者中的发现相对应）。它在狗、大鼠或小鼠的 GLP 研究中没有引起任何毒性副作用，“未观察到不良效应水平”（NOAEL）超过治疗剂量 100 倍。
第二代免疫调节表位模拟环肽 COR-1（也称为 JNJ-5442840）有望治疗免疫介导的心脏疾病。
