PUBLICATION
A novel engineered VEGF blocker with an excellent pharmacokinetic profile and robust anti-tumor activity
- Authors
- Liu, L., Yu, H., Huang, X., Tan, H., Li, S., Luo, Y., Zhang, L., Jiang, S., Jia, H., Xiong, Y., Zhang, R., Huang, Y., Chu, C.C., Tian, W.
- ID
- ZDB-PUB-150417-2
- Date
- 2015
- Source
- BMC cancer 15: 170 (Journal)
- Registered Authors
- Keywords
- none
- 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
- PubMed
- 25881012 Full text @ BMC Cancer
Citation
Liu, L., Yu, H., Huang, X., Tan, H., Li, S., Luo, Y., Zhang, L., Jiang, S., Jia, H., Xiong, Y., Zhang, R., Huang, Y., Chu, C.C., Tian, W. (2015) A novel engineered VEGF blocker with an excellent pharmacokinetic profile and robust anti-tumor activity. BMC cancer. 15:170.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping