Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by Anti-beta(1)-Adrenoceptor Antibodies in a Human-Analogous Rat Model

作者：Boivin Valerie^*; Beyersdorf Niklas; Palm Dieter; Nikolaev Viacheslav O; Schlipp Angela; Mueller Justus; Schmidt Doris; Kocoski Vladimir; Kerkau Thomas; Huenig Thomas; Ertl Georg; Lohse Martin J; Jahns Roland

来源：PLos One, 2015, 10(2): e0117589.

DOI：10.1371/journal.pone.0117589

Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the beta(1) adrenergic receptor (beta(1)EC2). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human beta(1)EC2 (amino-acids 195-225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking beta(1)EC2 (beta(1)EC2-CP, 1.0 mg/kg every 4 weeks) or administration of the beta(1)-blocker bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received beta(1)EC2-CP/bisoprolol co-treatment. We found that beta(1)EC2-CP prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, beta(1)EC2-CP mono-therapy -or as an add-on to bisoprolol-almost fully reversed antibody-induced cardiac damage. The cyclo-peptide acted both by scavenging free anti-beta(1)EC2-antibodies and by targeting beta(1)EC2-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful anti-beta(1)EC2-antibodies and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to beta(1)-blockade represents a promising new therapeutic option in immune-mediated heart failure.

• 出版日期2015-2-20