A novel engineered VEGF blocker with an excellent pharmacokinetic profile and robust anti-tumor activity

BMC Cancer. 2015 Mar 25:15:170. doi: 10.1186/s12885-015-1140-1.


Background: Relatively poor penetration and retention in tumor tissue has been documented for large molecule drugs including therapeutic antibodies and recombinant immunoglobulin constant region (Fc)-fusion proteins due to their large size, positive charge, and strong target binding affinity. Therefore, when designing a large molecular drug candidate, smaller size, neutral charge, and optimal affinity should be considered.

Methods: We engineered a recombinant protein by molecular engineering the second domain of VEGFR1 and a few flanking residues fused with the Fc fragment of human IgG1, which we named HB-002.1. This recombinant protein was extensively characterized both in vitro and in vivo for its target-binding and target-blocking activities, pharmacokinetic profile, angiogenesis inhibition activity, and anti-tumor therapeutic efficacy.

Results: HB-002.1 has a molecular weight of ~80 kDa, isoelectric point of ~6.7, and an optimal target binding affinity of <1 nM. The pharmacokinetic profile was excellent with a half-life of 5 days, maximal concentration of 20.27 μg/ml, and area under the curve of 81.46 μg·days/ml. When tested in a transgenic zebrafish embryonic angiogenesis model, dramatic inhibition in angiogenesis was exhibited by a markedly reduced number of subintestinal vessels. When tested for anti-tumor efficacy, HB-002.1 was confirmed in two xenograft tumor models (A549 and Colo-205) to have a robust tumor killing activity, showing a percentage of inhibition over 90% at the dose of 20 mg/kg. Most promisingly, HB-002.1 showed a superior therapeutic efficacy compared to bevacizumab in the A549 xenograft model (tumor inhibition: 84.7% for HB-002.1 versus 67.6% for bevacizumab, P<0.0001).

Conclusions: HB-002.1 is a strong angiogenesis inhibitor that has the potential to be a novel promising drug for angiogenesis-related diseases such as tumor neoplasms and age-related macular degeneration.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Drug Design
  • Female
  • Human Umbilical Vein Endothelial Cells / physiology
  • Immunoglobulin Fc Fragments / chemistry
  • Immunoglobulin Fc Fragments / pharmacology*
  • Immunoglobulin Fc Fragments / therapeutic use
  • Immunoglobulin G / chemistry
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Physiologic / drug effects*
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / pharmacology*
  • Recombinant Fusion Proteins / therapeutic use
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / chemistry
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-1 / chemistry
  • Vascular Endothelial Growth Factor Receptor-1 / pharmacokinetics
  • Vascular Endothelial Growth Factor Receptor-1 / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-1 / therapeutic use
  • Zebrafish / embryology


  • Angiogenesis Inhibitors
  • HB-002.1 fusion protein
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1