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Immunotherapy of ET-1 Receptor Type A for PAH
Study Questions:
Would a monoclonal antibody vaccine (mAb) against endothelin-1 (ET-1) receptor type A (ETAR) have a role in treatment of pulmonary arterial hypertension (PAH)?
Methods:
In vivo, ETRQβ-002 vaccine was used to vaccinate monocrotaline (MCT)- and Sugen/hypoxia–induced pulmonary hypertension animals. The mAb against ETR-002 was also injected into the PAH animals. The effect of ETRQβ-002 vaccine on pulmonary hypertension and remodeling of pulmonary arterioles and right ventricle (RV) was evaluated. Further, the possible immune-mediated damage was detected in normal vaccinated animals.
Results:
ETRQβ-002 vaccine induced strong antibody production. In vitro, the anti–ETR-002 antibody bound to ETAR and inhibited Ca2+-dependent signal transduction events, including extracellular signal-regulated kinase phosphorylation and elevation of intracellular Ca2+ concentration induced by ET-1. In vivo, both ETRQβ-002 vaccine and the mAb significantly decreased the RV systolic pressure up to 20 mm Hg and 10 mm Hg in MCT-exposed rats and Sugen/hypoxia–exposed mice, respectively. Also, ETRQβ-002 vaccine/mAb ameliorated pathological remodeling of pulmonary arterioles and hypertrophy of the RV in PAH animals. Additionally, no significant immune-mediated damage was detected in vaccinated animals.
Conclusions:
ETRQβ-002 vaccine/mAb attenuated remodeling of pulmonary arterioles and RV in MCT- and Sugen/hypoxia–induced PAH animals. It decreased RV systolic pressure effectively by inhibiting signal transduction initiated by ET-1. The vaccine/mAb may provide a novel method for PAH treatment.
Perspective:
Survival and quality of life in PAH has improved markedly in the modern era during which drugs targeting the pathobiology have been effective. But the overall 5-year survival is still only 59% compared to historic 50% mortality at 2 years in the 1990s. The vaccine targeting type A ET-1 receptor reduces and prevents arteriole remodeling and the increasing RV pressure and RV hypertrophy in the monocrotaline rat model and the rat model of vascular endothelial growth factor inhibitor (SUGEN) plus chronic hypoxemia. Precapillary or PAH has many different pathogeneses within group I, which is typified by hereditary/idiopathic, drug-induced, connective tissue diseases, and congenital heart disease. Taking the vaccine from the rat model to clinical utility in the era when placebo-controlled trials are no longer ethical, the diseases are relatively rare, and patients with New York Heart Association functional class I-III do quite well will be no small task; particularly finding out whether long-term vaccine therapy creates a blocking antibody.
Keywords: Antibodies, Blocking, Antibody Formation, Arterioles, Blood Pressure, Connective Tissue Diseases, Endothelin-1, Extracellular Signal-Regulated MAP Kinases, Hypertension, Pulmonary, Heart Failure, Hypertrophy, Right Ventricular, Immunotherapy, Immunotherapy, Active, Monocrotaline, Phosphorylation, Quality of Life, Receptor, Endothelin A, Secondary Prevention, Signal Transduction, Vaccines
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