Background: Placental growth factor (PlGF) is a pro-angiogenic factor belonging to the VEGF family, with approximately 53% homology to VEGF [1]. While both PlGF and VEGF bind to VEGFR1, VEGFR2 serves as a receptor for only VEGF, not for PlGF. In autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS), PlGF promotes pathogenic angiogenesis and inflammation by inducing Th17 cells and enhancing the aggressive behavior of fibroblast-like synoviocytes from RA patients (RA-FLSs) [2, 3]. VEGF-Grab (designated as PB101 and its improved version PB102), an Fc fusion protein containing VEGFR1’s second and third Ig-like domains, demonstrates enhanced anti-angiogenic effects through novel glycosylation sites that reduce nonspecific ECM binding [4]. While VEGF-Grab’s efficacy has been shown in tumor-related contexts, its therapeutic potential in autoimmune diseases remains unexplored.

Objectives: To investigate the therapeutic potential of VEGF-Grab, a dual inhibitor of VEGF and PlGF, in RA and MS by targeting pathological vessel formation, the invasive characteristics of RA-FLSs, and the pathogenic function of Th17 cells.

Methods: Cell migration was assessed using wounding migration and Transwell assays in EA.hy926 endothelial cells and RA-FLSs. Angiogenesis was evaluated through tube formation assay and in vivo Matrigel plug assay. A humanized synovitis severe-combined immunodeficient (SCID) mouse model was used to assess cartilage invasion by RA-FLSs. VEGF-Grab was characterized for its monomer purity by size exclusion HPLC (SE-HPLC), serum stability by ELISA, and binding kinetics by surface plasmon resonance. Pharmacokinetic analysis was performed in SD rats. T cell differentiation was examined through in vitro Th17 cell culture, and cytokine levels were measured by ELISA. Flow cytometry was used to analyze immune cell populations. The therapeutic effect was evaluated using adjuvant-induced arthritis (AIA), collagen-induced arthritis (CIA), and experimental autoimmune encephalomyelitis (EAE) mouse models.

Results: PB101 reduced PlGF-mediated endothelial cell migration and tube formation in vitro . PB101 effectively inhibited angiogenesis and macrophage infiltration in Matrigel plug assays in vivo. Treatment with PB101 suppressed RA-FLS migration and cartilage destruction in a humanized synovitis model. The improved version, PB102, showed enhanced molecular stability, extended half-life, and increased binding affinity to PlGF and VEGF. PB102 effectively inhibited both Th17 cell differentiation and maintenance, with notable reduction in the pathogenic subset co-expressing IL-17 and GM-CSF. In arthritis models, PB102 demonstrated superior therapeutic effects compared to PB101, significantly reducing inflammation, pannus formation, and joint destruction. Furthermore, in the EAE model of multiple sclerosis, PB102 showed enhanced efficacy compared to standard IFN-β treatment, and their combination exhibited the strongest therapeutic effects by modulating pathogenic Th17 cells and reducing inflammatory cytokine production.

Conclusion: VEGF-Grab effectively inhibits PlGF-induced angiogenesis and reduces the pathogenic activities of RA-FLSs and Th17 cells. Its therapeutic efficacy was validated in both RA and MS animal models, with its improved version PB102 showing enhanced pharmaceutical properties and superior efficacy. By simultaneously targeting angiogenesis and inflammatory cell activity, VEGF-Grab represents a promising dual-target therapeutic approach for autoimmune diseases.

REFERENCES: [1] Hans W C, et al., The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J Biol Chem . 2004;279(11):10382-8.

[2] Seung-Ah Y, et al., Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity. Nat Immunol . 2019;20(10):1348-1359.

[3] Seung-Ah Y, eat al., Placental Growth Factor-1 and -2 Induce Hyperplasia and Invasiveness of Primary Rheumatoid Synoviocytes. J Immunol . 2015;194(6):2513-2521.

[4] Jung-Eun L, et al., Novel glycosylated VEGF decoy receptor fusion protein, VEGF-Grab, efficiently suppresses tumor angiogenesis and progression. Mol Cancer Ther . 2015;14(2):470-9.

Acknowledgements: This study was supported by the the National Research Foundation (NRF) funded by the Ministry of Education, Science, and Technology, Republic of Korea (RS-2024-00442793 to W.U.K.), and the Biomlogic/GenoFocus and Panolos Biosciences (to S.H.L.).

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.