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 ...