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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 β 1  adrenergic receptor (β 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 β 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 β 1 EC2 (β 1 EC2-CP, 1.0 mg/kg every 4 weeks) or administration of the β 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 β 1 EC2-CP/bisoprolol co-treatment. We found that β 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, β 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-β 1 EC2-antibodies and by targeting β 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-β 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 β 1 -blockade represents a promising new therapeutic option in immune-mediated heart failure.

Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by Anti-β1-Adrenoceptor Antibodies in a Human-Analogous Rat Model