Long-Term Effect of a Vaccine Targeting Endothelin-1 Receptor Type A in Pulmonary Arterial Hypertension

Abstract

Background: Previously, we invented a therapeutic vaccine targeting the endothelin-A receptor (termed ETRQβ-002). ETRQβ-002 successfully prevented the remodeling of pulmonary arterioles (PAs) and right ventricle (RV) without significant immune-mediated damage in experimental pulmonary arterial hypertension (PAH) mice models.Objective: Here, we aim to further evaluate the long-term effects of ETRQβ-002.Methods: PAH mice model was induced by a combination of subcutaneous injection with Sugen5416 and chronic hypoxic conditions (10% O2). PAH mice were immunized with ETRQβ-002 at different time points, and the experiment lasted for 21 weeks. Hemodynamic, histological, and biochemical analyses were conducted to evaluate the long-term effects of ETRQβ-002.Results: We demonstrated that the titer of the specific antibody against ETR-002 could be maintained chronically after periodic booster immunization in PAH mice. Long-term reduction of right ventricular systolic pressure and amelioration of PA remodeling by ETRQβ-002 were confirmed. Moreover, we found that ETRQβ-002 also exerted antiproliferation, anti-inflammation, and antifibrosis effects in PA remodeling. Besides, ETRQβ-002 durably limited pathological RV hypertrophy and fibrosis. Finally, no immune-mediated damage was observed in hepatic or renal function or by pathology in liver and kidney during the long-term administration of ETRQβ-002.Conclusion: Our findings indicate that ETRQβ-002 provides long-term therapeutic effects in Sugen/hypoxia-induced PAH animals and offers a promising clinical prospect for PAH treatment.

B-cells in pulmonary arterial hypertension: friend, foe or bystander?

“…Vaccine immunisation against the second extracellular loop of ETAR leads to the generation of inhibitory antibodies in MCT rats (conversely to naturally occurring anti-ETAR antibodies, which are agonistic) [ 162 ]. Anti-ETAR vaccination is associated with improved clinical (haemodynamics, right ventricle hypertrophy) and pathophysiological (pulmonary artery thickening, proliferation, inflammation and fibrosis) outcomes with no obvious side-effects [ 162 , 163 ].…”

Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs

“…The PAH vaccine ETRQβ-002 against endothelin receptor A could effectively reduce right ventricular systolic pressure and reverse right ventricular hypertrophy and pulmonary vascular remodeling in PAH animal models with a three-month observation period after vaccine injection [ 118 ]. It exhibited long-term therapeutic effects in lowering right ventricular systolic pressure and ameliorating pulmonary vascular remodeling, without immune-mediated damage to hepatic or renal function within 21 weeks [ 119 ]; further exploration into its efficacy and safety among PAH patients is required.…”

Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going

“…Currently, getagozumab is in phase 1b clinical trials [268]. In addition, a monoclonal antibody against ET A receptors (ETRQβ-002 vaccine/mAb) has been developed to effectively ameliorate pulmonary arterial hypertension (PAH) in MCT-treated and SUGEN-hypoxia-induced animal models, with satisfactory safety properties [269,270]. Similar to ET A receptors, antibodies targeting ET B receptors, such as Rendomab-B1 and Rendomab-B4, are also available for cancer treatment, particularly for melanoma [46].…”