Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-β1 integrin macromolecular complex

Frontiers in Pharmacology

Pharmacology

Annarosa Arcangeli¹  Claudia Duranti¹  Rossella Colasurdo²  Chiara Capitani²  Elisabetta Cerbai³  Lorenzo Santini³  Lucrezia Giammarino³  Raffaele Coppini³  Chiara Palandri³  Monica Musumeci³  Fabio Recchia⁴  Lucia Carlucci⁴ 

[1] Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy;Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy;Department of Medical Biotechnology, University of Siena, Siena, Italy;Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy;Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy;

关键词: cancer therapy;    IKr;    APD;    QT prolongation;    bispecific antibodies;   

DOI  :  10.3389/fphar.2023.1237431

 received in 2023-06-09, accepted in 2023-08-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: In the last decades, mounting evidence has pointed out the human ether-á-go-go–related gene (hERG1) potassium channel as a novel biomarker in human cancers. However, hERG1 sustains the cardiac repolarizing current IKr and its blockade can induce a prolonged QT interval at the ECG, which increases the risk of life-threatening arrhythmias. This represents a major hindrance for targeting hERG1 for antineoplastic therapeutic purposes. Based on our discovery that hERG1 resides in a macromolecular complex with the β1 subunit of integrin adhesion receptors only in tumors, and not in the heart, we generated (and patented WO2019/015936) a novel engineered, single chain, bispecific antibody in the format of a diabody (scDb-hERG1-β1). This antibody has been proven to target with high affinity the hERG1/β1 integrin complex and to exert a good antineoplastic activity in preclinical mouse models.Methods: In the present study, we evaluated the cardiac safety of the scDb-hERG1-β1, determining the action potential duration (APD) of human cardiomyocytes, either atrial (from valve-disease patients) or ventricular (from aortic stenosis patients). Cardiac cells were incubated in vitro with i) the scDb-hERG1-β1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDb-hERG1-β1 was assembled. All the tests were performed before and after treatment with the specific hERG1 blocker E4031. In addition, we have performed preliminary experiments, analyzing the effects of the scDb-hERG1/β1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs.Results: The scDb-hERG1-β1 did not produce any lengthening of APD compared to control (vehicle) conditions, either in atrial or ventricular cardiomyocytes, whereas both the hERG1-mAb and the scFv-hERG1 produced a significant APD prolongation. The addition of E4031 further prolonged APD. The scDb-hERG1-β1 did not produce any alterations of the QT (and QTc) interval values, once injected intravenously in farm pigs.Discussion: Overall, the above evidences plead for the cardiac safety of the scDb-hERG1-β1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.

【 授权许可】

Unknown   
Copyright © 2023 Santini, Duranti, Palandri, Giammarino, Musumeci, Carlucci, Capitani, Colasurdo, Recchia, Cerbai, Coppini and Arcangeli.