Hernández-Cedeño Mabel, Rodríguez-Ulloa Arielis, Ramos Yassel, González Luis J, Serrano-Díaz Anabel, Zettl Katharina, Wiśniewski Jacek R, Martinez-Donato Gillian, Guillen-Nieto Gerardo, Besada Vladimir, Domínguez-Horta María Del Carmen
Autoimmunity Project, Department of Pharmaceuticals, Biomedical Research Division, Center for Genetic Engineering & Biotechnology (CIGB), Havana 10600, Cuba.
Mass Spectrometry Laboratory, Proteomics Group, Department of System Biology, Biomedical Research Division, Center for Genetic Engineering & Biotechnology (CIGB), Havana 10600, Cuba.
Biomedicines. 2024 Nov 29;12(12):2740. doi: 10.3390/biomedicines12122740.
Jusvinza is an immunomodulatory drug composed of an altered peptide ligand (APL) designed from a novel CD4+ T cell epitope of human heat shock protein 60 (HSP60), an autoantigen involved in the pathogenesis of rheumatoid arthritis (RA). The peptide induces regulatory T cells and decreases levels of TNF-α and IL-17; pre-clinical and phase I clinical studies support its use for the treatment of RA. This peptide was repositioned for the treatment of COVID-19 patients with signs of hyperinflammation. Neutrophils play a pathogenic role in both RA and severe forms of COVID-19. To add novel evidence about the mechanism of action of Jusvinza, the proteomic profile regulated by this peptide of neutrophils isolated from four RA patients was investigated using LC-MS/MS and bioinformatics analysis. A total of 149 proteins were found to be differentially modulated in neutrophils treated with Jusvinza. The proteomic profile regulated by Jusvinza is characterized by the presence of proteins related to RNA splicing, phagocytosis, endocytosis, and immune functions. In response to Jusvinza treatment, several proteins that regulate the NF-κB signaling pathway were differentially modulated, supporting the peptide's anti-inflammatory effect. Proteins related to metabolic pathways that supply ATP for cellular functions or lipid metabolites with immunoregulatory properties were also identified. Additionally, several structural components of neutrophil extracellular traps (NETs) were decreased in Jusvinza-treated cells, supporting its impairment of this biological process. Of note, these findings were validated by in vitro experiments which confirmed that Jusvinza decreased NET formation. Such results provide evidence of the molecular mechanism of action and support the therapeutic potentialities of Jusvinza to treat other diseases characterized by hyperinflammation besides RA and COVID-19.
Jusvinza是一种免疫调节药物，由一种经过改变的肽配体（APL）组成，该肽配体是根据人类热休克蛋白60（HSP60）的新型CD4 + T细胞表位设计而成，HSP60是一种自身抗原，参与类风湿性关节炎（RA）的发病机制。该肽可诱导调节性T细胞并降低TNF-α和IL-17的水平；临床前和I期临床研究支持其用于治疗RA。该肽被重新定位用于治疗有过度炎症迹象的COVID-19患者。中性粒细胞在RA和严重形式的COVID-19中均起致病作用。为了补充有关Jusvinza作用机制的新证据，使用LC-MS/MS和生物信息学分析研究了从四名RA患者中分离出的中性粒细胞经该肽调节的蛋白质组图谱。发现共有149种蛋白质在接受Jusvinza治疗的中性粒细胞中受到差异调节。Jusvinza调节的蛋白质组图谱的特征是存在与RNA剪接、吞噬作用、胞吞作用和免疫功能相关的蛋白质。在Jusvinza治疗反应中，几种调节NF-κB信号通路的蛋白质受到差异调节，支持了该肽的抗炎作用。还鉴定了与为细胞功能提供ATP的代谢途径或具有免疫调节特性的脂质代谢物相关的蛋白质。此外，在接受Jusvinza治疗的细胞中，中性粒细胞胞外陷阱（NETs）的几种结构成分减少，这支持了其对这一生物学过程的损害。值得注意的是，这些发现通过体外实验得到了验证，这些实验证实Jusvinza减少了NET的形成。这些结果提供了作用分子机制的证据，并支持Jusvinza除了治疗RA和COVID-19之外，还具有治疗其他以过度炎症为特征的疾病的治疗潜力。
