The DNA-BASED THERAPEUTIC AGENT BC 007 COMPLETELY NEUTRALIZES AGONISTIC AUTOANTIBODIES DIRECTED AGAINST Β1-Adrenoceptors: RESULTS OF a PHASE 1 TRIAL

Mueller, Johannes; Haberland, Annekathrin; Becker, Niels-Peter; Wenzel, Katrin; Wallukat, Gerd; Goettel, Peter; Schulze-Rothe, Sarah; Schimke, Ingolf; Golor, Georg; Großmann, Matthias; Sinn, Angela; Steiper, Martina; Yilmaz, Tuba; Wallukat, Anne; Davideit, Hanna

doi:10.1016/s0735-1097(18)31186-0

Cited by 10 publications

(17 citation statements)

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“…This peptide acts comparable to the second loop mimics COR-1 which was already studied to counteract β1-AAB in patients with DCM (14). The other two substances are aptamers (15,35): the first (aptamer 110; D2) is able to neutralize only β1-AAB due to specific β1-AAB binding, which was demonstrated in vitro and in an animal study (36,37), while the second (BC 007; D3), as demonstrated in animal and human studies, is able to inhibit several GPCR-AAB, including β1-AAB and M2-AAB (38,39). After drug pre-incubation of β1-AAB or M2AAB containing IgG from DP with the drugs (test concentration 1 μmol/l), the mixture was added to the bioassay for measurement of the chronotropic activity of IgG.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…It would be interesting to know in this context, if beta1autoantibody activated T cells would be able to act as stimulator of the beta1-autoantibody production, similar to the function of other T cell co-stimulatory factors which again include, e.g., TLR9 ligands [7], sustaining the vicious circle. If so, this would finally offer an explanation for the already observed long-lasting persistence of autoantibody absence after even a one-time removal only, as seen after immunoadsorption [8] and also already at the single application of the autoantibody neutralizer BC 007 (here, observation period of one month) [9]. One treatment would practically be enough to interrupt this cycle.…”

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confidence: 87%

“…One treatment would practically be enough to interrupt this cycle. BC 007 is the broadband aptamer for the neutralization of heart failure relevant agonistic acting autoantibodies which attack essential heart and circulatory system-regulating receptors including the beta1-receptor [9,10]. Independent from an answer to this question, with the antibody neutralizer BC 007, the TLR9 pathway will additionally be counteracted [11].…”

mentioning

confidence: 99%

“…BC 007, currently under preparation for phase II of the heart failure efficacy testing, has already shown its autoantibody-neutralizing efficacy in humans besides its favorable side effect profile [9]. Derived from the good experiences made with the removal of these autoantibodies via immuoadsorption [2,13], it is hoped that a huge number of heart failure patients will benefit from this novel causal treatment.…”

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Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling—Additional Information About TLR9 Involvement

Haberland

Müller

Wenzel

2019

Cardiovasc Drugs Ther

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“…At lower doses, the share of successfully f GPCR-AAb neutralised patients in the total number of treated patients was lower, as shown in Table 4. A more detailed breakdown according to the single f AAb subtypes can be taken from Müller et al [22].…”

Section: F Gpcr-aab Status After Dosing (Mode Of Action)mentioning

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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The DNA-BASED THERAPEUTIC AGENT BC 007 COMPLETELY NEUTRALIZES AGONISTIC AUTOANTIBODIES DIRECTED AGAINST Β1-Adrenoceptors: RESULTS OF a PHASE 1 TRIAL

Cited by 10 publications

References 0 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

Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling—Additional Information About TLR9 Involvement

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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