Antibodies that activate the β1-AR (β1-adrenoreceptor) can induce heart failure in animal models. These antibodies are often found in patients with heart failure secondary to varying etiologies. Their binding to the β1 receptor leads to prolonged receptor activation with subsequent induction of cellular dysfunction, apoptosis, and arrhythmias. β-blocker therapy while highly effective for heart failure, may not be sufficient treatment for patients who have β1 receptor autoantibodies. Removal of these autoantibodies by immunoadsorption has been shown to improve heart failure in small studies. However, immunoadsorption is costly, time consuming, and carries potential risks. An alternative to immunoadsorption is neutralization of autoantibodies through the intravenous application of small soluble molecules, such as peptides or aptamers, which specifically target and neutralize β1-AR autoantibodies. Peptides may induce immunogenicity. Animal as well as early phase human studies with aptamers have not shown safety concerns to date and have demonstrated effectiveness in reducing autoantibody levels. Novel aptamers have the potential advantage of having a wide spectrum of action, neutralizing a variety of known circulating G-protein coupled receptor autoantibodies. These aptamers, therefore, have the potential to be novel therapeutic option for patients with heart failure who have positive for β1-AR autoantibodies. However, clinical outcomes trials are needed to assess the clinical utility of this novel approach to treat heart failure.

beta(1)-Adrenoreceptor Autoantibodies in Heart Failure Physiology and Therapeutic Implications

BC 007 is a substance with a novel and innovative mode of action for the first-time causal treatment of chronic heart failure, associated with the occurrence of autoantibodies against the β1-adrenoceptor, and other diseases of mostly the heart and vascular system, being accompanied by the occurrence of functionally active agonistic autoantibodies against G-protein-coupled receptors (fGPCR-AAb). The proposed mechanism of action of BC 007 is the neutralisation of these pathogenic autoantibodies which stimulate the respective receptor. To evaluate the safety, tolerability, pharmacokinetics and mode of action of BC 007, single intravenous infusions of increasing concentration were given to healthy young males and healthy elderly autoantibody-negative and autoantibody-positive participants of both sexes. This study was subdivided into three parts. Part A was a single-centre, randomised, double-blind, placebo-controlled safety and tolerability study including healthy young male autoantibody-negative Whites (N = 23) and Asians (N = 1), testing doses of 15, 50 and 150 mg BC 007 (Cohorts 1–3) and elderly male and female Whites (N = 8), testing a dose of 150 mg BC 007 (Cohort 4), randomly assigned in a 3:1 ratio to BC 007 or placebo. Open-label Part B included fGPCR-AAb-positive subjects (50 and 150 mg BC 007, Cohorts 1 and 2, respectively). Open-label Part C included fGPCR-AAb-positive subjects for testing doses of 300, 450, 750, 1350 mg and 1900 mg BC 007. Lower doses were either given as an infusion or divided into a bolus plus infusion up to a dose of 300 mg followed by a constant bolus of 150 mg up to a dose of 750 mg, while at doses of 1350 mg and 1900 mg it was a slow infusion with a constant infusion rate. Infusion times increased with increasing dose from 20 min (15, 50 or 150 mg) to 40 min (300, 450 or 750 mg), 75 min (1350 mg) and 105 min (1900 mg). The mean observed BC 007 area under the concentration–time curve (AUC0–24) increased with increasing dose in a dose proportional manner (slope estimate of 1.039). No serious adverse events were observed. Drug-related adverse events were predominantly the expected mild-to-moderate increase in bleeding time (aPTT), beginning with a dose of 50 mg, which paralleled the infusion and returned to normal shortly after infusion. fGPCR-AAb neutralisation efficiency increased with increasing dose and was achieved for all subjects in the last cohort. BC 007 is demonstrated to be safe and well tolerated. BC 007 neutralised fGPCR-AAb, showing a trend for a dose-response relationship in elderly healthy but fGPCR-AAb-positive subjects. NCT02955420.

/pdf/a-three-part-randomised-study-to-investigate-the-safety-243k9bmwzr.pdf

A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects.

Diastolic dysfunction is the alteration or the decline in the activity of of the ventricular function. It affects affects the organ’s capacity to fill with an adequate amount of blood during diastole. These alterations involve active or passive relaxation. Acute hypertension, ischemia, Infarction, Aortic Stenosis, Idiopathic Hypertrophic Cardiomyopathy, Diabetes and Obesity are the common causes of diastolic dysfunction. Alterations in the myocardial diastolic properties lead to left ventricular diastolic dysfunction which finally leads to diastolic heart failure. In this review, several therapeutic appraches including pharmacologic, nonpharmacologic, and surgical approaches for the treatment of diastolic dysfunction and heart failure will be discussed.

Diastolic dysfunction and the Risk of Heart Failure: Therapeutics Approaches

Graves´ disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. The disease can be modelled in mice using adenoviral immunizations with the extracellular A subunit of the TSHR, which induces a long-term stable disease state. TSHR binding cAMP-stimulatory antibodies, thyroid enlargement, elevated serum thyroxin levels, tachycardia, cardiac hypertrophy and orbitopathy are observed in these Ad-TSHR-immunized mice. T cell epitope-derived linear peptides have been identified using immunized HLA-DR3 transgenic mice, which may induce tolerance towards TSHR. A combination of such peptides are being investigated in a first clinical phase I trial in patients with Graves´ disease. Alternatively, intravenous administration of cyclic peptides derived from the interaction site of the TSHR A domain with stimulatory anti-TSHR antibodies can re-establish tolerance towards the antigen in immunized mice, improving symptoms of Graves´ disease within 3 - 4 months after starting these therapies. In immunologically naive mice, administration of the cyclic peptides did not induce any immune response.

Antigen-specific therapy of Graves´ disease and orbitopathy by induction of tolerance.

Various approaches have been used to model human Graves' disease in mice, including transfected fibroblasts, and plasmid or adenoviral immunisations with the extracellular A subunit of the human thyrotropin receptor (TSHR). Some of these models were only observed for a short time period or were self-limiting. A long-term model for human Graves' disease was established in mice using continuing immunisations (4-weekly injections) with recombinant adenovirus expressing TSHR. Generation of TSHR binding cAMP-stimulatory antibodies, thyroid enlargement and alterations, elevated serum thyroxin levels, tachycardia and cardiac hypertrophy were maintained for at least 9 months in all Ad-TSHR-immunised mice. Here, we show that these mice suffer from orbitopathy, which was detected by serial orbital sectioning and histomorphometry. Attempts to treat established Graves' disease in preclinical mouse model studies have included small molecule allosteric antagonists and specific antagonist antibodies which were isolated from hypothyroid patients. In addition, novel peptides have been conceived which mimic the cylindrical loops of the TSHR leucine-rich repeat domain, in order to re-establish tolerance toward the antigen. Here, we show preliminary results that one set of these peptides improves or even cures all signs and symptoms of Graves' disease in mice after six consecutive monthly injections. First beneficial effects were observed 3-4 months after starting these therapies. In immunologically naive mice, administration of the peptides did not induce any immune response.

/pdf/review-of-mouse-models-of-graves-disease-and-orbitopathy-198chopopp.pdf

Review of Mouse Models of Graves' Disease and Orbitopathy-Novel Treatment by Induction of Tolerance.

Aim: JNJ-54452840 (COR-1) is a novel investigational cyclopeptide with proposed mechanism of action that decreases circulating anti-β1-adrenergic receptor antibodies (anti-β1-Abs) in heart failure patients. In a phase-2, double-blind, placebo-controlled pilot study, effects of JNJ-54452840 were investigated on cardiac function at rest in patients with Dilated Cardiomyopathy (DCM) when administered in addition to guideline-recommended heart failure therapy versus 6-months of guideline-recommended therapy alone.
Methods: Patients with DCM and circulating anti-β1-Abs received treatment with placebo or JNJ-54452840 (6 doses of 20, 80 or 160 mg administered intravenously every 4 weeks) in addition to guideline-recommended heart failure therapy.
Results: Thirty-six patients (Caucasian, mean age 59.6 years, mean LVEF 32%) were enrolled. An increase (+5.4%) in centrally-assessed Left Ventricular Ejection Fraction (LVEF) was observed in 80 mg JNJ-54452840 group compared to a decrease (-1.6%) in the placebo group (primary efficacy endpoint). Among secondary efficacy endpoints, locally-assessed LVEF values were similar to primary results, suggesting lack of treatment effect from baseline to month 9. NT-proBNP values varied considerably between patients but were not significantly improved in JNJ-54452840-treated groups versus placebo. Compared to baseline, both JNJ-54452840 and placebo groups demonstrated a numerical increase in 6-minute walk test from baseline to month 6. The most common adverse events reported among JNJ-54452840-treated patients were cardiac failure and nasopharyngitis (n=4 each), and cough, sinusitis, increased heart rate (n=3 each).
Conclusion: Considering that this phase 2 trial, originally planned to recruit 160 patients was amended to a pilot study for strategic reasons, no definitive statements on the efficacy of JNJ-5445280 in DCM patients with circulating anti-β1-Abs can be made, although centrally-assessed LVEF appeared to improve in the 80 mg dose group. No compound-related safety or tolerability signals were observed.

/pdf/effects-of-jnj-54452840-an-anti-aa-1-receptor-antibody-kchzp72ivw.pdf

Effects of JNJ-54452840, an Anti-ÃÂ²1 Receptor Antibody Cyclopeptidein Heart Failure Patients: A Randomized, Double-blind, Parallel-group,Phase-2 Pilot Study

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Effects of JNJ-54452840, an Anti-ÃÂ²1 Receptor Antibody Cyclopeptidein Heart Failure Patients: A Randomized, Double-blind, Parallel-group,Phase-2 Pilot Study