Philochem AG, CH-8112 Otelfingen, Switzerland.
Department of Internal Medicine I, Univerisity Hospital Jena, 07747 Jena, Germany.
Int J Mol Sci. 2021 Mar 27;22(7):3460. doi: 10.3390/ijms22073460.
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.
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.
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.
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.
肺动脉高压（PH）是一种预后不良的异质性疾病。对于大多数患者来说，仅有有限的治疗选择。因此，人们非常关注开发新的治疗策略，重点关注肺血管和右心室重构。白细胞介素 9（IL9）是一种具有促炎和抗炎功能的多效细胞因子。本研究旨在评估由 IL9 与针对纤维连接蛋白 EDA 结构域的交替剪接的 F8 抗体融合而成的 F8IL9F8 的治疗活性，该抗体在 PH 中的肺血管和右心室心肌中大量表达。
通过右心导管检查、超声心动图以及组织学和免疫组织化学分析，评估 F8IL9F8 在比较内皮素受体拮抗剂（ERA）或具有无关抗体特异性的 IL9 免疫细胞因子（KSFIL9KSF）时对单克隆抗体诱导的 PH 模型中抑制 PH 进展的疗效。
与对照组相比，除 F8IL9F8 组外，所有 MCT 诱导的 PH 组的收缩期右心室压力（RVPsys）均显著升高，多种右心室超声心动图参数均显著受损。与 MCT 组相比，F8IL9F8 和 ERA 治疗均导致 RVPsys 显著降低，超声心动图参数得到改善，而 KSFIL9KSF 组则观察不到。只有 F8IL9F8 可显著减轻肺组织损伤，并显著减少肺和右心室中的白细胞和巨噬细胞积聚。
本研究首次提供了 F8IL9F8 作为 PH 新治疗药物的临床前证据，该药物采用了针对心血管重构的疾病修饰概念。
