Autoantibodies Directed Against G-Protein-Coupled Receptors in Cardiovascular Diseases

Bornholz, Beatrice; Wallukat, Gerd; Roggenbuck, Dirk; Schimke, Ingolf

doi:10.1016/b978-0-12-803267-1.00003-x

Cited by 9 publications

(30 citation statements)

References 99 publications

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“…In our study cohort, DP with DoCM showed a prevalence of β1-AAB of about 70%, comparable as is in human DCM (6). Furthermore, non-surviving dogs were significantly more often positive for β1-AAB than survivors, which clearly agrees the findings with patients with human DCM studies (48–50).…”

Section: Discussionsupporting

confidence: 81%

“…(46). Today, it is increasingly accepted that autoimmunity is as an important pathogenic driver of human DCM (47) and functional autoantibodies such as β1-AAB and M2-AAB diseases came to the fore (6–9). Finding a comparable autoimmunity in DoCM, additionally to all the other similarities of DoCM with human DCM summarized (21–25), would Doberman pinchers predestinate as model to investigate the autoimmune background of human DCM in general and specifically treatment strategies directed to the functional autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…Through the use of specific blockers of the β1-adrenergic (bisoprolol) and muscarinic receptor 2 (atropine), the cells’ chronotropic response can be attributed to β1-AAB or M2-AAB. For comprehensive information about sample (IgG) preparation, bioassay test setup and measurement procedure of GPCR-AAB, see (6,33).…”

Section: Methodsmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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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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“…In contrast to patients with BPH/LUTS, where ETA-AAB were the only GPCR-AAB, nearly all patients with prostate cancer additionally carried α1-AAB which targeted the first extracellular loop, and specifically an epitope localized near the loop's N-terminus. α1-AABs were also frequently found in patients with idiopathic pulmonary hypertension, diabetes mellitus, drug-induced cancer [16,17], psoriasis [25] and dementia [19], where the α1-AAB targeted the second extracellular receptor loop.…”

Section: Discussionmentioning

confidence: 99%

“…This leads to the long-time perpetuation of downstream effects, making the GPCR-AAB a potent pathogenic driver or supporter [16,17]. Among the diseases which are thought to be related to GPCR-AAB-associated effects, cardiovascular diseases [18] are predominant but not exclusive, as exemplarily demonstrated for patients with dementia [19].…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Wallukat

Jandrig

Becker

et al. 2020

Preprint

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Background: For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called "functional autoantibodies" bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods: Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56-78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48-82 years, median 64) with urinary stone disorders (controls). Results: Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007. Conclusions: We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.

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The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman Pinschers of efficacy and outcomes

et al. 2020

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Aims Aptamer BC 007, a 15-mer single-strand DNA oligonucleotide (5'-GGTTGGTGTGGTTGG-3'), was developed to neutralize functional autoantibodies that bind to the extracellular domains of G protein-coupled receptors (GPCR-AAB), leading to the modulation of receptor-mediated signalling cascades that induce pathophysiological states. Among the GPCR-AAB, there are those directed against the β1-adrenergic receptor (β1-AAB) that are highly present in patients with dilated cardiomyopathy (DCM) and are increasingly accepted as disease drivers. Using Doberman Pinschers (DP) with DCM, which possess similarities with human DCM among these β1-AAB positivity for that the disease-driving role in DP DCM was demonstrated, the safety of BC 007, efficacy for neutralizing β1-AAB, and the DP's outcome were investigated. Methods and results Fourteen client-owned β1-AAB-positive DP with electrocardiographically and echocardiographically indicated DCM were treated with BC 007. For controlling, two groups were created: 14 β1-AAB-positive DP with DCM not treated with BC 007 (Control 1) and 14 DP with DCM closely matched to the BC 007-treated DP (Control 2), retrospectively selected from the institutional database of DP. After treatment, DP were monitored both echocardiographically, and for β1-AAB, and survival curves were calculated. Based on clinical and laboratory examination, no adverse effects associated with BC 007 treatment were observed during the study. Forty-eight hours after treatment, the DP's blood was free of β1-AAB, which led to a reduction or stabilization of left ventricular end-systolic volume (ESVI) during β1-AAB free time in 10 of the treated DP. In one DP, where β1-AAB returned after 3 months and ESVI worsened again, a second BC 007 treatment after 9 months again cleared the blood from β1-AAB and improved the ESVI. Compared with the controls, DP treated with BC 007 showed a significantly longer survival time [572 days, interquartile range (IQR) 442-840 days] vs. Control group 1 (266 days, IQR 97-438 days; logrank: P = 0.009) and Control group 2 (229 days, IQR 174-319 days; logrank: P = 0.012). Conclusions Treatment with BC 007 for β1-AAB neutralization was safe, resulted in a long-lasting reduction of β1-AAB combined with improved cardiac function and prolonged the survival of DP with DCM. Using a natural large animal model of DCM considered superior to small animal models of immunization-induced cardiomyopathy, combined with a study design comparable with clinical trials, we believe that our results provide the basis for optimism that treatment with BC 007 might also be effective in human patients with DCM.

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Autoantibodies Directed Against G-Protein-Coupled Receptors in Cardiovascular Diseases

Cited by 9 publications

References 99 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

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman Pinschers of efficacy and outcomes

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