ABSTRACT
Given the expanding number of complex therapeutic protein drugs and advanced therapy medicinal products that are being developed, improving our ability to assess the potential immunogenicity of biologics is critical to ensuring treatment efficacy and patient safety. In this context, the European Immunogenicity Platform annual meeting provides opportunities for experts from industry and academia, regulators and clinicians to convene and discuss immunogenicity assessment methods and tools. This report summarizes the key messages on immunogenicity testing, prediction, clinical relevance and advanced therapy medicinal products discussed at the 11th Open Scientific European Immunogenicity Platform Symposium on Immunogenicity of Biopharmaceuticals, Lisbon, Portugal, 17-19 February 2020.
Subject(s)
Biopharmaceutics/methods , Immunogenetics/methods , Europe , HumansABSTRACT
SSR149744C (SSR, 2-butyl-3-[4-[3-(dibutylamino)pro-pyl]benzoyl]-1-benzofuran-5-carboxylate isopropyl fumarate), is a new non-iodinated benzofuran derivative. The aim of this study was to evaluate in vivo its electrophysiological, hemodynamic, and anti-adrenergic properties and to determine its mechanism of action using in vitro studies. In chloralose-anesthetized dogs, SSR149744C (1-10 mg/kg i.v.) prolonged the sinus cycle length, A-H interval, Wenckebach cycle length, atrial effective refractory period (ERP), and atrio-ventricular node ERP in a dose-dependent manner without change of ventricular ERP and HV, QRS, or QTc intervals. Arterial blood pressure and ventricular inotropism were slightly decreased. SSR149744C, which has no or low affinity for alpha 1 and beta 1 adrenergic and angiotensin II AT1 receptors, reduced isoproterenol-induced tachycardia and phenylephrine- or angiotensin II-induced hypertension in anaesthetized dogs. In guinea pig papillary muscle, SSR149744C did not modify the resting potential, action potential amplitude and duration, but reduced the dV/dt max of the depolarization phase in a frequency-dependent manner. In isolated guinea pig cardiomyocytes and transfected CHO cells, SSR149744C (0.01-30 microM) inhibited several potassium currents: IKr (IC50 approximately 10 microM), IKs (IC50 approximately 30 microM), IK(ACh) (IC50 = 0.09 microM), and IKv1.5 (IC50 = 2.7 microM), the L-type calcium current: ICa(L) (IC50 approximately 5 microM) and also the amplitude of [Ca2+]i transient and cell shortening. Therefore, SSR149744C appears to have a multifactorial mechanism of action, which combines the blockade of several ion channels with the inhibition of responses of alpha 1 and beta 1 adrenergic as well as AT1 receptor stimulation. Like amiodarone, SSR149744C possesses the pharmacological effects of class I, II, III, and IV antiarrhythmic agents, which may confer upon this new drug a strong antiarrhythmic potential without ventricular proarrhythmia and iodine-related amiodarone-like side-effects.
Subject(s)
Anti-Arrhythmia Agents/chemistry , Anti-Arrhythmia Agents/pharmacokinetics , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Action Potentials/drug effects , Action Potentials/physiology , Adrenergic Antagonists/administration & dosage , Adrenergic Antagonists/chemistry , Adrenergic Antagonists/pharmacokinetics , Angiotensin II/administration & dosage , Angiotensin II/antagonists & inhibitors , Angiotensin II/pharmacokinetics , Animals , Anti-Arrhythmia Agents/administration & dosage , Benzofurans/administration & dosage , Blood Pressure/drug effects , CHO Cells , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/physiology , Cell Physiological Phenomena/drug effects , Cricetinae , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Female , Guinea Pigs , Heart Conduction System/drug effects , Heart Conduction System/physiology , Heart Rate/drug effects , Injections, Intravenous , Isoproterenol/administration & dosage , Isoproterenol/antagonists & inhibitors , Isoproterenol/pharmacokinetics , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Papillary Muscles/cytology , Papillary Muscles/drug effects , Papillary Muscles/physiology , Patch-Clamp Techniques/methods , Pharmaceutical Vehicles/administration & dosage , Pharmaceutical Vehicles/pharmacokinetics , Phenylephrine/administration & dosage , Phenylephrine/antagonists & inhibitors , Phenylephrine/pharmacokinetics , Potassium Channels/drug effects , Potassium Channels/genetics , Potassium Channels/metabolism , Signal Transduction/drug effects , TransfectionABSTRACT
The electrophysiological properties of dronedarone (SR33589), a noniodinated amiodarone-like agent, were studied on action potential (AP) and contraction of papillary muscle and on membrane ionic currents, Ca2+ transient, and shortening of ventricular cells of the guinea pig heart. In multicellular preparations, dronedarone (3, 10, and 30 microM) decreased maximum rate of rise of AP (dV/dt max) with a concentration- and frequency-dependent relationship; resting potential was not modified and AP amplitude was decreased only at 30 microM. The effects of dronedarone on AP durations (APDs) at different percentages of repolarization were not significantly changed, except for a slight decrease in APD30 and APD50 at the highest concentration. In isolated ventricular myocytes, dronedarone inhibited rapidly activating delayed-rectifier K+ current (I(Kr)) (median inhibitory concentration [IC50] /= 30 microM). Dronedarone blocked L-type Ca2+ current (I(Ca(L))) (IC50 = 0.18 +/- 0.018 microM at a stimulation frequency of 0.033 Hz) in a use- and frequency-dependent manner. Simultaneously to these electrophysiological effects, dronedarone reduced contraction amplitudes of papillary muscle and decreased Ca2+ transient and shortening of ventricular myocytes. The results show that dronedarone is a multichannel blocker because it decreases dV/dt max (I(Na)), I(Ca(L)), I(Kr), I(Ks), and I(K1). These effects are accompanied by a reduction in free intracellular calcium and contraction amplitudes. Dronedarone does not significantly change APD whatever the stimulation frequency. Our data demonstrate that the acute electrophysiological characteristics of dronedarone, despite absence of iodine in its molecular structure, are very similar to those of amiodarone in cardiac ventricle.
