Double Anti-angiogenic and Anti-inflammatory Protein Valpha Targeting VEGF-A and TNF-alpha in Retinopathy and Psoriasis

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Pathological angiogenesis usually involves disrupted vascular integrity, vascular leakage, and infiltration of inflammatory cells, which are governed mainly by VEGF-A and TNF-alpha. Although many inhibitors targeting either VEGF-A or TNF-alpha 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-alpha and block their actions. In this experimental design, we have shown that Valpha, which is an effective synchronous blocker of VEGF-A and TNF-alpha, can drastically increase treatment effectiveness through its dual-blocking characteristics. Valpha contains the VEGF-A-binding domain of VEGFR1, the TNF-alpha-binding domain of TNFR2, and the Fc domain of IgG1. Valpha exhibited strong binding characteristics for its original counterparts, VEGF-A and TNF-alpha, 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-alpha, 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-alpha using Valpha is an effective therapeutic strategy and cost-efficient for treatment of retinopathy and psoriasis.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2011-04
Language
English
Article Type
Article
Keywords

ENDOTHELIAL GROWTH-FACTOR; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; SKIN INFLAMMATION; RHEUMATOID-ARTHRITIS; CANCER MODEL; IN-VIVO; RECEPTOR; MOUSE; NEOVASCULARIZATION

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.286, no.16, pp.14410 - 14418

ISSN
0021-9258
URI
http://hdl.handle.net/10203/100968
Appears in Collection
BS-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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