Introduction: In the last decades, mounting evidence has pointed out the human ether-a-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 beta 1 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-beta 1). This antibody has been proven to target with high affinity the hERG1/beta 1 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 scDbhERG1-beta 1, 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 scDbhERG1-beta 1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDbhERG1-beta 1 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/beta 1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs.Results: The scDb-hERG1-beta 1 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-beta 1 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 scDbhERG1-beta 1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.

Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-β1 integrin macromolecular complex / Santini, Lorenzo; Duranti, Claudia; Palandri, Chiara; Giammarino, Lucrezia; Musumeci, Monica; Carlucci, Lucia; Capitani, Chiara; Colasurdo, Rossella; Recchia, Fabio; Cerbai, Elisabetta; Coppini, Raffaele; Arcangeli, Annarosa. - In: FRONTIERS IN PHARMACOLOGY. - ISSN 1663-9812. - ELETTRONICO. - 14:(2023), pp. 1237431-1237431. [10.3389/fphar.2023.1237431]

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

Duranti, Claudia
Supervision
;
Palandri, Chiara
Membro del Collaboration Group
;
Giammarino, Lucrezia
Membro del Collaboration Group
;
Musumeci, Monica
Membro del Collaboration Group
;
Colasurdo, Rossella
Membro del Collaboration Group
;
Cerbai, Elisabetta
Supervision
;
Coppini, Raffaele
Supervision
;
Arcangeli, Annarosa
Supervision
2023

Abstract

Introduction: In the last decades, mounting evidence has pointed out the human ether-a-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 beta 1 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-beta 1). This antibody has been proven to target with high affinity the hERG1/beta 1 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 scDbhERG1-beta 1, 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 scDbhERG1-beta 1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDbhERG1-beta 1 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/beta 1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs.Results: The scDb-hERG1-beta 1 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-beta 1 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 scDbhERG1-beta 1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.
2023
14
1237431
1237431
Santini, Lorenzo; Duranti, Claudia; Palandri, Chiara; Giammarino, Lucrezia; Musumeci, Monica; Carlucci, Lucia; Capitani, Chiara; Colasurdo, Rossella; Recchia, Fabio; Cerbai, Elisabetta; Coppini, Raffaele; Arcangeli, Annarosa
File in questo prodotto:
File Dimensione Formato  
fphar-14-1237431.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 2.74 MB
Formato Adobe PDF
2.74 MB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1345036
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 2
social impact