Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension

Abstract

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.

Serum Liberation of Fetal Fibronectin Variants in Patients with Pulmonary Hypertension: ED-A+ Fn as Promising Novel Biomarker of Pulmonary Vascular and Right Ventricular Myocardial Remodeling

“…This goes in line with recent findings of our group showing a strong re-expression of the molecule in human tissue and serum samples from patients suffering from, e.g., coronary artery disease, aortic stenosis, heart failure of different aetiology or rejection after heart transplantation [26][27][28]30,33,36]. Moreover, we could report similar findings in several preclinical models of cardiac allograft vasculopathy or PH, respectively [29,31,32,37]. In a very recent study, including elderly patients suffering from severe symptomatic aortic stenosis, our group investigated a panel of biomarkers with respect to their association to the novel staging classification of extra-valvular cardiac damage [38].…”

“…From our current data, we cannot state this interesting point concludingly. However, in recent studies of our group, we could show in preclinical animal models of PH that ED-A + Fn is re-expressed both in the pulmonary vasculature as well as in the remodelled right ventricle [31,32].…”

“…For both, a re-occurrence in processes of pathological tissue remodelling, e.g., neoplastic diseases, chronic inflammation or cardiovascular disorders, has been described mainly in human tissue samples or preclinical disease models [23][24][25][26][27][28][29][30]. In rat and mouse models of PH, a relevant re-expression of ED-A + Fn associated with both pulmonary vascular as well as right ventricular myocardial remodelling could be recently demonstrated by our group [31,32]. With respect to the potential value of ED-A + or ED-B + Fn as circulating biomarkers to improve diagnosis, prognosis estimation or therapy surveillance in cardiovascular diseases, there are only very limited data [33] and, up to now, there are no studies focusing on their potential role in human PH.…”

Cellular and Molecular Mechanism of Traditional Chinese Medicine on Ventricular Remodeling

“…In recent years, a large number of studies have confirmed that the immune response triggered by a myocardial injury, myocardial ischemia, and other factors can produce a variety of cytokines ( 15 ), and most of them, especially the inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β, and IL-10 are involved in the occurrence and development of VR ( 13 , 16 ). The major inflammatory cytokines that promote VR are TNF-α, IL-1β, and IL-6.…”

Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension

“…Pulmonary arterial hypertension (PAH) is a rare vascular disease with an annual incidence of two cases per million (Peacock et al, 2007). PAH is defined by a mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3.0 Wood units (Gouyou et al, 2021). As an obliterative vasculopathy, PAH is characterized by high pulmonary arterial pressure, resulting in right ventricular failure and even death (Boucly et al, 2017;Tang et al, 2018).…”