The therapeutic effects of the VEGF decoy receptor fusion protein VEGF-Grab in chronic inflammatory diseases

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BACKGROUND: Placental growth factor (PlGF) plays a crucial role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS), by enhancing angiogenesis, disease-aggravating features of fibroblast-like synoviocytes (FLSs), and pathogenic T helper type 17 (Th17) cells. The therapeutic potential of a VEGF decoy receptor fusion protein, VEGF-Grab, which potently binds and neutralises VEGF and PlGF, has not been studied in autoimmune diseases. Therefore, we investigated the therapeutic effects of VEGF-Grab in RA and MS by using in vitro and in vivo models. METHODS: Two forms of VEGF-Grab (PB101 and PB102) were engineered to enhance their binding affinity for VEGF and PlGF. In vitro assays-including Transwell migration and wound-healing assays of endothelial cells and FLSs, as well as Th17 cell differentiation-were employed to evaluate the effects of VEGF-Grab on angiogenesis and immune-cell function. To assess therapeutic efficacy in vivo, mouse models of inflammatory and autoimmune arthritis, as well as experimental autoimmune encephalomyelitis (EAE), were utilised. FINDINGS: Our results indicate that VEGF-Grab exerted significant inhibitory effects across various animal models of autoimmune diseases, targeting abnormal angiogenesis, cartilage invasion, and pathogenic Th17 cells. Furthermore, combined treatment with IFN-β in the EAE model suggested enhanced efficacy of therapeutic effects. INTERPRETATION: Our findings highlight the multifaceted therapeutic potential of VEGF-Grab in RA and MS, targeting angiogenesis, the aggressiveness of FLSs, and the pathogenicity of Th17 cells, all driven by the 'angio-lymphokine', PlGF. Thus, VEGF-Grab has the potential to be a therapeutic candidate for the treatment of RA and MS, warranting further clinical exploration. FUNDING: This study was supported by grants funded by the National Research Foundation of Korea (RS-2024-00442793 to W.U.K.), and Biomlogic/GenoFocus and Panolos Biosciences (to S.H.L.).

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