Cyclopeptide COR-1 to treat beta1-adrenergic receptor antibody-induced heart failure

Abstract

RationaleDespite 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.Objectiveß1EC2-mimicking cyclopeptides (25-meric) markedly improved the development and/or course of anti-ß1EC2-mediated cardiomyopathy. Further developments should be investigated.Methods and resultsThe 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.ConclusionThe second generation immunomodulating epitope-mimicking cyclopeptide COR-1 (also termed JNJ-5442840) offers promise to treat immune-mediated cardiac diseases.

Targeted Degradation of Antigen-Specific Pathogenic Autoantibodies That Cause Heart Failure

“…For the development of β-MoDE-A we utilized an existing, high affinity cyclic peptide ligand of anti-β1AR antibodies called COR1. 18 COR1 constitutes a molecular mimic of the second extracellular loop of the β1AR, and contains the entirety of the recognition epitope of agonistic anti-β1AR antibodies. Thus, β-MoDE-A 1 was synthesized from an azide-labeled COR1 peptide and a tri-GalNAc ASGPR ligand bearing a strained dibenzylcyclooctyne via strain-promoted azide-alkyne cycloaddition (see Supporting Information for synthetic details and characterization data).…”

“…6 These antibodies are believed to drive disease by chronically stimulating β1AR, 9-11 and the presence of antibody worsens mortality rates by up to threefold in certain patient subsets. [12][13][14][15][16] Recent animal studies have demonstrated that these anti-β1AR antibodies are sufficient to induce HF, 17,18 and neutralization of anti-β1AR antibodies using peptide mimics of β1AR can reverse HF in rats. 18 Furthermore, removal of these autoantibodies from HF patients through IA improves heart function and survival rate.…”

“…[12][13][14][15][16] Recent animal studies have demonstrated that these anti-β1AR antibodies are sufficient to induce HF, 17,18 and neutralization of anti-β1AR antibodies using peptide mimics of β1AR can reverse HF in rats. 18 Furthermore, removal of these autoantibodies from HF patients through IA improves heart function and survival rate. 6,19,20 Therefore, the strategy we report herein has the potential to have a profound benefit for a large number of patients.…”

Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non‐ischaemic heart failure

“…5 Consequently, B cells and autoantibodies are emerging targets in CHF therapy. [6][7][8][9][10] Among various heart-reactive autoantibodies discussed in the above context, autoantibodies against cardiac G-protein-coupled receptors (GPCRs) are candidates that have been studied earlier. 2,11,12 CHF-associated GPCR autoantibodies are intriguing candidates because they impact receptor-mediated autonomous heart regulation and thereby damage the heart.…”

“…Heart‐reactive autoantibodies potentially contribute to cardio‐pathogenesis because CHF‐like symptoms can be transferred from patients to mice via B lymphocytes 5 . Consequently, B cells and autoantibodies are emerging targets in CHF therapy 6–10 …”