title: Novel glycosylated VEGF decoy receptor fusion protein, VEGF-Grab, efficiently suppresses tumor angiogenesis and progression.
abstract: Antiangiogenic therapies targeting VEGFA have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has been limited, with drawbacks including acquisition of resistance and activation of compensatory pathways resulting from elevated circulating VEGFB and 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, and PlGF. VEGF-Grab has the second and third immunoglobulin (Ig)-like domains of VEGF receptor 1 (VEGFR1) fused to IgG1 Fc, with three potential glycosylation sites introduced into the third Ig-like domain of VEGF-Grab by mutagenesis. Compared with VEGF-Trap, VEGF-Grab showed more potent decoy activity against VEGF and PlGF, mainly attributed to the VEGFR1 backbone. Most importantly, the negatively charged O-glycans attached to the third Ig-like domain of VEGFR1 counterbalanced the originally positively charged VEGFR1 backbone, minimizing nonspecific binding of VEGF-Grab to the extracellular matrix, and resulting in greatly improved pharmacokinetic profile. These advancements led to stronger and more durable antiangiogenic, antitumor, and antimetastatic efficacy in both implanted and spontaneous tumor models as compared with VEGF-Trap, while toxicity profiles were comparable with VEGF-Trap. Collectively, our results highlight VEGF-Grab as a promising therapeutic candidate for further clinical drug development.
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea. Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. hm_kim@kaist.ac.kr gykoh@kaist.ac.kr.
authors.forename: Chan
authors.initials: C
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Hannah
authors.initials: H
authors.lastname: Yang
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Intae
authors.initials: I
authors.lastname: Park
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Nuri
authors.initials: N
authors.lastname: Oh
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Serenus
authors.initials: S
authors.lastname: Hua
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Haneul
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: An
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Sun Chang
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Gyun Min
authors.initials: GM
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea. hm_kim@kaist.ac.kr gykoh@kaist.ac.kr.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Ho Min
authors.initials: HM
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D061307:Human Umbilical Vein Endothelial Cells; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; C098069:PIGF protein, human; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A