title: Novel receptor-derived cyclopeptides to treat heart failure caused by anti-β1-adrenoceptor antibodies in a human-analogous rat model.
abstract: 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 β1 adrenergic receptor (β1EC2). 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 β1EC2 (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 β1EC2 (β1EC2-CP, 1.0 mg/kg every 4 weeks) or administration of the β1-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 β1EC2-CP/bisoprolol co-treatment. We found that β1EC2-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, β1EC2-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-β1EC2-antibodies and by targeting β1EC2-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-β1EC2-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 β1-blockade represents a promising new therapeutic option in immune-mediated heart failure.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; Rudolf-Virchow-Center/DFG-Research-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany; Comprehensive Heart Failure Centre (CHFC), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Boivin
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Beyersdorf
authors.affiliation: Rudolf-Virchow-Center/DFG-Research-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Palm
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; Rudolf-Virchow-Center/DFG-Research-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany; Lehrstuhl Anatomie I, University of München (LMU), München, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schlipp
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kocoski
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kerkau
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.affiliation: Comprehensive Heart Failure Centre (CHFC), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; Rudolf-Virchow-Center/DFG-Research-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany; Comprehensive Heart Failure Centre (CHFC), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; Rudolf-Virchow-Center/DFG-Research-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany; Comprehensive Heart Failure Centre (CHFC), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Jahns
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017298:Bisoprolol / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D006333:Heart Failure / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology*
chemical_list: D000906:Antibodies; D010456:Peptides, Cyclic; D018342:Receptors, Adrenergic, beta-1; D017298:Bisoprolol