title: Double anti-angiogenic and anti-inflammatory protein Valpha targeting VEGF-A and TNF-alpha in retinopathy and psoriasis.
abstract: Pathological angiogenesis usually involves disrupted vascular integrity, vascular leakage, and infiltration of inflammatory cells, which are governed mainly by VEGF-A and TNF-α. Although many inhibitors targeting either VEGF-A or TNF-α have been developed, there is no single inhibitor molecule that simultaneously targets both molecules. Here, we designed and generated a novel chimeric decoy receptor (Valpha) that can simultaneously bind to VEGF-A and TNF-α and block their actions. In this experimental design, we have shown that Valpha, which is an effective synchronous blocker of VEGF-A and TNF-α, can drastically increase treatment effectiveness through its dual-blocking characteristics. Valpha contains the VEGF-A-binding domain of VEGFR1, the TNF-α-binding domain of TNFR2, and the Fc domain of IgG1. Valpha exhibited strong binding characteristics for its original counterparts, VEGF-A and TNF-α, but not for the extracellular matrix, resulting in a highly favorable pharmacokinetic profile in vivo. Compared with VEGF-Trap or Enbrel, both of which block either VEGF-A or TNF-α, singularly, Valpha is a highly effective molecule for reducing abnormal vascular tufts and the number of F4/80(+) macrophages in a retinopathy model. In addition, Valpha showed superior relief effects in a psoriasis model with regard to epidermal thickness and the area of blood and lymphatic vessels. Thus, the simultaneous blocking of VEGF-A and TNF-α using Valpha is an effective therapeutic strategy and cost-efficient for treatment of retinopathy and psoriasis.
authors.affiliation: National Research Laboratory for Vascular Biology and Stem Cells, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Keehoon
authors.initials: K
authors.lastname: Jung
authors.forename: Donghun
authors.initials: D
authors.lastname: Lee
authors.forename: Hye Song
authors.initials: HS
authors.lastname: Lim
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Lee
authors.forename: Yeon Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Gyun Min
authors.initials: GM
authors.lastname: Lee
authors.forename: Sun Chang
authors.initials: SC
authors.lastname: Kim
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001168:Arthritis / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008264:Macrophages / Q000166:cytology; D017434:Protein Structure, Tertiary; D011565:Psoriasis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D012164:Retinal Diseases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A