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

Rationale 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. Objective ß1EC2-mimicking cyclopeptides (25-meric) markedly improved the development and/or course of anti-ß1EC2-mediated cardiomyopathy. Further developments should be investigated. Methods and results The shortened 18-meric cyclic peptide COR-1, in which one of the two disulphide bonds was removed to enable reproducibleGMPproduction, can also be used to treat cardiomyo- pathic rats. Echocardiography, catheterization and histopathology of the rat hearts revealed that monthly intravenous administrations of COR-1 almost fully reversed the cardiomyo- pathic 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 periph- eral 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. Conclusion The second generation immunomodulating epitope-mimicking cyclopeptide COR-1 (also termed JNJ-5442840) offers promise to treat immune-mediated cardiac diseases.