Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants

Nnane, Ivo P.; Plotnikov, Alexei H.; Peters, Gary; Johnson, Maureen; Kojak, Clare; Vutikullird, Apinya; Ariyawansa, Jay; Vries, Ronald de; Davies, Brian E.

doi:10.1007/s40262-015-0309-8

Cited by 6 publications

(5 citation statements)

References 17 publications

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“…These studies also reconfirmed renal and liver safety. A phase Ib study investigated shorter dosing intervals[ 32 ]–using this unusually short dosing interval regime, two participants with predisposing risk factors (including a factor V Leiden mutation) had thromboembolic adverse events; further detailed analysis including functional tests revealed neither pro-coagulatory nor anti-coagulatory substance-related effects of COR-1 per se . Other experimental antibody-directed strategies consist in their removal from the circulation by specific or non-specific immunoadsorption using either matrix-coupled peptides derived from ß 1 EC2–[ 33 ]or protein A columns[ 34 ].…”

Section: Discussionmentioning

confidence: 99%

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

Boivin‐Jahns

Uhland²,

Holthoff³

et al. 2018

PLoS ONE

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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.

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Section: Discussionmentioning

confidence: 99%

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

Boivin‐Jahns

Uhland²,

Holthoff³

et al. 2018

PLoS ONE

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“…Immunization of animals with ECL2 of b1AR resulted in deleterious cardiac remodeling reflecting its causative role in DCM. Consistently, an early phase, dose-ranging clinical study using COR-1 indicated tolerability 140 resulting in randomized double-blinded phase II studies 141 (ClinicalTrials.gov.NCT01391507, JNJ-54452840, an anti-b1AR antibody cyclopeptides containing ECL2 shown to reverse anti-b1AR autoantibody-induced myocardial damage in rat 142 ). The randomized study was terminated due to adverse events, but its relationship to autoantibodies could not be determined.…”

Section: Conclusion Challenges and Clinical Implicationsmentioning

confidence: 99%

“…The randomized study was terminated due to adverse events, but its relationship to autoantibodies could not be determined. 141 However, there is increasing appreciation that b1AR autoantibodies may bind to the ECL2 of b1AR regulating receptor function through allosteric modulation without binding to the orthosteric agonist/antagonist site. 10,52,115,122,133 This would allow b1AR autoantibodies to noncanonically modulate agonist and/or antagonist signaling and subsequent cardiac outcomes.…”

Section: Conclusion Challenges and Clinical Implicationsmentioning

confidence: 99%

Autoantibodies and Cardiomyopathy: Focus on Beta-1 Adrenergic Receptor Autoantibodies

Tang

Prasad

2022

Journal of Cardiovascular Pharmacology

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Antibody response to self-antigens leads to autoimmune response that plays a determinant role in cardiovascular disease outcomes including dilated cardiomyopathy (DCM). Although the origins of the self-reactive endogenous autoantibodies are not wellcharacterized, it is believed to be triggered by tissue injury or dysregulated humoral response. Autoantibodies that recognize G protein-coupled receptors are considered consequential because they act as modulators of downstream receptor signaling displaying a wide range of unique pharmacological properties. These wide range of pharmacological properties exhibited by autoantibodies has cellular consequences that is associated with progression of disease including DCM. Increase in autoantibodies recognizing beta-1 adrenergic receptor (b1AR), a G protein-coupled receptor critical for cardiac function, is observed in patients with DCM. Cellular and animal model studies have indicated pathological roles for the b1AR autoantibodies but less is understood about the molecular basis of their modulatory effects. Despite the recognition that b1AR autoantibodies could mediate deleterious outcomes, emerging evidence suggests that not all b1AR autoantibodies are deleterious. Recent clinical studies show that b1AR autoantibodies belonging to the IgG3 subclass is associated with beneficial cardiac outcomes in patients. This suggests that our understanding on the roles the b1AR autoantibodies play in mediating outcomes is not well-understood. Technological advances including structural determinants of antibody binding could provide insights on the modulatory capabilities of b1AR autoantibodies in turn, reflecting their diversity in mediating b1AR signaling response. In this study, we discuss the significance of the diversity in signaling and its implications in pathology.

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“…58 One peptide, cyclic peptide (JNJ-54452840), has been investigated in a phase I study in healthy humans and in patients with DCM. 60,61 In a phase II double-blind, parallel-group, controlled trial, patients were randomly assigned to 20, 80, and 160 mg of cyclic peptide, or placebo, given for 6 months.…”

Section: Peptides For Autoantibody Neutralizationmentioning

confidence: 99%

β ₁ -Adrenoreceptor Autoantibodies in Heart Failure

Düngen

Đorđević

Felix

et al. 2020

Circ: Heart Failure

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Antibodies that activate the β 1 -AR (β 1 -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 β 1 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 β 1 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 β 1 -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 β 1 -AR autoantibodies. However, clinical outcomes trials are needed to assess the clinical utility of this novel approach to treat heart failure.

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Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants

Abstract: JNJ-54452840 demonstrated similar pharmacokinetics in both groups. JNJ-54452840 was possibly immunogenic, and two participants reported thromboembolic serious adverse events. The relationship between these events and antibody formation is not known.

Cited by 6 publications

References 17 publications

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

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

Autoantibodies and Cardiomyopathy: Focus on Beta-1 Adrenergic Receptor Autoantibodies

β ₁ -Adrenoreceptor Autoantibodies in Heart Failure

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Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants

Abstract: JNJ-54452840 demonstrated similar pharmacokinetics in both groups. JNJ-54452840 was possibly immunogenic, and two participants reported thromboembolic serious adverse events. The relationship between these events and antibody formation is not known.

Cited by 6 publications

References 17 publications

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

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

Autoantibodies and Cardiomyopathy: Focus on Beta-1 Adrenergic Receptor Autoantibodies

β 1 -Adrenoreceptor Autoantibodies in Heart Failure

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Product

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β ₁ -Adrenoreceptor Autoantibodies in Heart Failure