There is an unmet need for effective treatment strategies targeting both vascular remodeling and right heart failure to reduce morbidity and mortality in patients with pulmonary arterial hypertension (PAH). The resistin-like molecule (RELM) family proteins are pleiotropic cytokines and growth factors implicated in obesity, type II diabetes and cardiovascular diseases. Our previous rodent work suggested that human resistin (hResistin) is mechanistically critical to PAH etiology and constitutes a therapeutic target for this disease.
We aimed to develop human antibodies (Abs) against hResistin and investigate their therapeutic effects in PAH development.
Methods & Results:
The anti-hResistin monoclonal Abs were developed through phage screening of human library, validated for their in vitro anti-proliferative function against hResistin in human pulmonary artery smooth muscle cell (SMC)s, and further screened for immunogenicity, manufacturability and toxic actions. The lead human Abs also exhibited cross-reactive capability of blocking rodent RELM actions in human SMC assays, which formed the basis for in vivo determination of therapeutic efficacy, a critical step in moving these Abs toward human use. In the chronic hypoxia-induced rodent PAH model, prevention studies revealed that anti-hResistin Ab treatment effectively reduced vascular wall thickness of the remodeling pulmonary small arteries, decreased RV pressure and ameliorated cardiac hypertrophy. The cardio-protective activities were further proved by echocardiography assessment showing attenuated RV thickness and improved PAT/PET ratios in the Ab-treated hypoxic rats. Notably, reversal of the established pulmonary vascular remodeling, RV dysfunction and hypertrophy were also achieved by two-week Ab administration in the experimental PAH animals.
hResistin blockade with human therapeutic Abs efficaciously prevented and reversed the proliferative pulmonary vascular remodeling, maladaptive RV remodeling and impaired RV function in experimental PAH. We thus successfully established the anti-hResistin neutralizing Abs as a novel therapy for PAH and the associated RV failure in an animal model.