Aptamer BC 007 – A broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors

Haberland, Annekathrin; Holtzhauer, Martin; Schlichtiger, Alice; Bartel, Sabine; Schimke, Ingolf; Müller, Johannes; Dandel, Michael; Luppa, Peter B.; Wallukat, Gerd

doi:10.1016/j.ejphar.2016.06.061

Cited by 34 publications

(31 citation statements)

References 28 publications

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“…The specific epitope is located closer to the N-terminus, between amino acids 169 and 177; the same region was also demonstrated for M2-AAB of patients with DCM (unpublished data) or Chagas’ cardiomyopathy (54). Related to their specificity for β1-AAB inhibition, the second loop peptide (D1) and aptamer 110 (D2) did not inhibit M2-AAB, but the aptamer BC 007 (D3), the so-called “broad-band neutralizer” of GPCR-AAB, inhibited the Doberman pinscher M2-AAB as seen for M2-AAB from DCM patients (39,55).…”

Section: Discussionmentioning

confidence: 99%

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

Schimke

Wess

Wallukat

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

Schimke

Wess

Wallukat

et al. 2019

Preprint

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“…Thus, cyclopeptides based on the criteria outlined in the present study may complement therapeutic strategies that exclusively aim at (non-specific) autoantibody scavenging, such as extracorporeal IgG absorption 37 or the systemic application of aptamers. 38 Furthermore, the very same peptide core conveying to cyclopeptides the potency to prevent allosteric β 1 -AR activation by anti-β 1 EC II -aabs is obviously also a crucial prerequisite of the allosteric stimulation mechanism itself, which implies that the cyclopeptide actually mimics the 3D structure of the auto-epitope that provides the allosteric trigger. The proposed antibody-binding region as outlined in Figure 2 comprises the essential motif NDPK 211-214 framed by the equally essential disulfide bridge between cysteines C 209 ↔C 215 .…”

Section: Discussionmentioning

confidence: 99%

Unmasking features of the auto‐epitope essential for β₁‐adrenoceptor activation by autoantibodies in chronic heart failure

et al. 2020

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Aims Chronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β 1-adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine-map the conformational epitope within the second extracellular loop of the human β 1adrenoceptor (β 1 EC II) that is targeted by stimulating β 1-receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto-epitope. Methods and results Non-conserved amino acids within the β 1 EC II loop (compared with the amino acids constituting the EC II loop of the β 2-adrenoceptor) were one by one replaced with alanine; potential intra-loop disulfide bridges were probed by cysteine-serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β 1 EC II ± the above replacements, and (ii) by (auto)antibody stimulation of human β 1-adrenoceptors bearing corresponding point mutations. With the use of stimulating β 1-receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β 1 EC II loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK 211-214 motif and (ii) the intra-loop disulfide bond C 209 ↔C 215. Of note, aberrant intra-loop disulfide bond C 209 ↔C 216 almost fully disrupted the functional auto-epitope in cyclopeptides. Conclusions The conformational auto-epitope targeted by cardio-pathogenic β 1-receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β 1 EC II loop bearing the NDPK 211-214 motif and the C 209 ↔C 215 bridge while lacking cysteine C 216. Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β 1-autoantibodypositive CHF.

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“…Neutralisation of f GPCR-AAbs, including β1-AR-AAb, is a novel therapeutic principle, acknowledging the impact of autoantibodies on the pathogenesis of diseases of the heart and vascular system. BC 007 has shown its f GPCR-AAbneutralising effect in vitro [12], in spontaneously hypertensive rats in vivo [16] and recently with outcome benefit in f β1-AR-AAb positive Doberman pinschers with dilated cardiomyopathy [24]. Currently, it is under development for the causal treatment of diseases which are associated with the occurrence of f GPCR-AAbs (for review see [25]), such as HF here the β 1 -AR-AAb [4,26].…”

Section: Discussionmentioning

confidence: 99%

“…With BC 007, a substance has now been identified capable of neutralising functionally active autoantibodies in vivo, which are directed to the G-protein coupled receptors ( f GPCR-AAbs) including the f β 1 -AR-AAbs [12]. This includes f β 1 -AR-AAbs which target the first and also those which target the second extracellular loop of the β 1 -AR.…”

Section: Key Pointsmentioning

confidence: 99%

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

et al. 2020

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Background and Objective 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 (f GPCR-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. Methods 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 f GPCR-AAbpositive subjects (50 and 150 mg BC 007, Cohorts 1 and 2, respectively). Open-label Part C included f GPCR-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). Results The mean observed BC 007 area under the concentration-time curve (AUC 0-24) 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. f GPCR-AAb neutralisation efficiency increased with increasing dose and was achieved for all subjects in the last cohort. Conclusion BC 007 is demonstrated to be safe and well tolerated. BC 007 neutralised f GPCR-AAb, showing a trend for a dose-response relationship in elderly healthy but f GPCR-AAb-positive subjects. ClinicalTrials.gov Registration Number NCT02955420.

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Aptamer BC 007 – A broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors

Cited by 34 publications

References 28 publications

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

Unmasking features of the auto‐epitope essential for β₁‐adrenoceptor activation by autoantibodies in chronic heart failure

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

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Aptamer BC 007 – A broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors

Cited by 34 publications

References 28 publications

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

Unmasking features of the auto‐epitope essential for β1‐adrenoceptor activation by autoantibodies in chronic heart failure

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

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Unmasking features of the auto‐epitope essential for β₁‐adrenoceptor activation by autoantibodies in chronic heart failure