Successful treatment of pulmonary hypertension and right heart failure by antibody-based functional blocking of the extra-domain A of fibronectin in a preclinical animal model

Abstract

Abstract Background Pulmonary Hypertension (PH) as heterogeneous disease group is pathogenetically accompanied by pulmonary vascular and right ventricular tissue remodelling showing similarities between the clinical groups 1 (Pulmonary Arterial Hypertension), 2 (PH associated with left heart disease) and 3 (PH associated with lung disease). Since the remodelling process entails the abundant re-expression of extra-domain A containing fibronectin (ED-A+ Fn), which is virtually absent in healthy adult organs, a potential functional role in PH development and progression has been suggested and recently proven by our group. The human recombinant antibody F8 (IgG) specifically recognises ED-A+ Fn and is capable to block its function at least in vitro. Thus, F8 might serve as a novel therapeutic agent for the treatment or even prevention of PH. Purpose Against that background, the current study was aimed to test the therapeutic efficacy of F8 after systemic administration in a well-established preclinical model of PH in comparison to a non-specific control antibody and a dual endothelin receptor antagonist as standard of care. Methods Induction of PH was realized by subcutaneous injection of Monocrotaline (MCT) in mice. In total, 41 animals were included in the study approach and were divided into the following experimental groups: sham-treated controls (controls; n=7), PH mice without a specific treatment (PH_untreated; n=12), PH mice treated with the dual endothelin receptor antagonist Macitentan (PH_MAC; n=6), PH mice treated with the F8 antibody (PH_F8; n=8) and PH mice treated with an antibody of irrelevant antigen specificity in the murine system (PH_KSF; n=8). Treatment effects were evaluated on the haemodynamic, echocardiographic and microscopic level. Results In comparison to controls, untreated PH mice showed significantly higher right ventricular systolic pressure values (RVPsys, p<0.05) as well as impaired echocardiographic parameters of right ventricular morphology and function, i.e., enlarged basal right ventricular (RVbasal, p=0.016) diameters and reduced tricuspid annular plane systolic excursion values (TAPSE, p=0.008). In the PH_F8 group, haemodynamic and echocardiographic parameters were significantly improved compared to the PH_untreated or the PH_KSF group (p<0.05 for the majority of parameters). Histological evaluation revealed significant lung tissue damage after in the PH_untreated group compared to controls (p=0.008), which were significantly attenuated in the PH_F8 (p=0.04) but not the PH_KSF group (p=n.s.). Conclusion The therapeutic efficacy of the human recombinant F8 antibody specific to ED-A+ Fn has been proven for the first time in vivo in a well-established preclinical model of PH. F8 acts as a disease-modifier by attenuating PH associated lung tissue remodelling resulting in remarkable improvements of pulmonary hemodynamics and echocardiographic parameters of right ventricular load.