Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression

• DOI: 10.1158/1535-7163.mct-14-0968-t
• Publication Date: 2014-12-23T03:49:15Z
• Authors: Jung-Eun Lee; Chan Kim; Hannah Yang; Intae Park; Nuri Oh; Serenus Hua; Haneul Jeong; Hyun Joo An; Sun Chang Kim; Gyun Min Lee; Gou Young Koh; Ho Min Kim
• Keywords: Decoy; Tumor progression

Antiangiogenic therapies targeting VEGFA have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has limited, with drawbacks including acquisition of resistance and activation compensatory pathways resulting from elevated circulating VEGFB placental growth factor (PlGF). To bypass these disadvantages, we developed a novel glycosylated soluble decoy receptor fusion protein, VEGF-Grab, that can neutralize VEGFA, VEGFB, PlGF. VEGF-Grab second third immunoglobulin (Ig)-like domains VEGF 1 (VEGFR1) fused IgG1 Fc, three potential glycosylation sites introduced into Ig-like domain by mutagenesis. Compared VEGF-Trap, showed more potent activity against PlGF, mainly attributed VEGFR1 backbone. Most importantly, negatively charged O-glycans attached counterbalanced originally positively backbone, minimizing nonspecific binding extracellular matrix, greatly improved pharmacokinetic profile. These advancements led stronger durable antiangiogenic, antitumor, antimetastatic both implanted spontaneous tumor models as compared while toxicity profiles were comparable VEGF-Trap. Collectively, our results highlight promising therapeutic candidate for further drug development.