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The DNA-Based Drug BC 007 neutralizes agonistically acting autoantibodies directed against G protein–coupled receptors – Successful mode of action demonstrated in clinical phase 1 trial

corresponding

JOHANNES MÜLLER*1, ANNEKATHRIN HABERLAND1, GERD WALLUKAT1, NIELS-PETER BECKER1, KATRIN WENZEL1, PETER GÖTTEL1, SARAH SCHULZE-ROTHE1, INGOLF SCHIMKE1, TUBA YILMAZ1, AYŞE ABAY1, GEORG GOLOR2, MATTHIAS GROSSMANN2, ANGELA SINN2, ANNE WALLUKAT1, ANNE-SOPHIE HÖNICKE1, HANNA DAVIDEIT1, SUSANNE BECKER1
*Corresponding author
1. Berlin Cures, Zug, Switzerland
2. PAREXEL International GmbH, Berlin, Germany

Abstract

Autoimmunity has been shown to be the pathogenic driver in a variety of diseases whose causes were previously unknown. When agonistic autoantibodies which activate G protein–coupled receptors (GPCR-AAb) are present, they damage primarily the heart and the vascular system. For example, autoantibodies that activate β1-adrenoceptors can cause dilated cardiomyopathy, leading to heart failure. Removal of GPCR-AAbs by immunoadsorption has already demonstrated a very beneficial effect. However, despite its therapeutic success, immunoadsorption has not become a widely accepted therapeutic option. BC 007, a nonmodified DNA aptamer that can neutralize GPCR-AAbs after infusion, is the first applicable alternative for treating the cause of GPCR-AAb–induced diseases. Here we report the successful neutralization of various GPCR-AAbs in autoantibody-positive, healthy elderly volunteers in the framework of phase 1 safety and tolerability testing.


INTRODUCTION

Autoimmunity has increasingly been shown to be involved in the pathogenesis of various diseases whose causes were previously unknown (1,2). When autoantibodies which activate G protein–coupled receptors (GPCR-AAb) are present, they damage primarily the heart and the vascular system. For example, autoantibodies that activate β1-adrenoceptors can cause dilated cardiomyopathy, Chagas cardiomyopathy, or peripartum cardiomyopathy, all of which lead to heart failure (2). Other such autoantibodies target the β2- or α1-adrenoceptors (β2-AAb, α1-AAb), the endothelin (ETA-AAb) or angiotensin (AT1-AAb) receptors, and protease-activated receptors (PAR-AAb) or muscarinic (M-AAb) receptors, which are essential factors in the pathogenesis of asthma, glaucoma, pulmonary arterial hypertension, transplant allograft rejection, and other diseases (3). The removal of GPCR-AAbs by immunoadsorption has already demonstrated a very beneficial effect on e.g. cardiac function: mortality rates have been reduced significantly when β1-AAb is targeted in patients with dilated cardiomyopathy (4); or ...



 

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