BMC cancer, 2015-03, Vol.15 (1), p.170-170, Article 170
2015
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- Autor(en) / Beteiligte
- Titel
- A novel engineered VEGF blocker with an excellent pharmacokinetic profile and robust anti-tumor activity
- Ist Teil von
- BMC cancer, 2015-03, Vol.15 (1), p.170-170, Article 170
- Ort / Verlag
- England: BioMed Central Ltd
- Erscheinungsjahr
- 2015
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. 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. 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). 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1471-2407eISSN: 1471-2407DOI: 10.1186/s12885-015-1140-1Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4466810
- Format
- –
- Schlagworte
- Adenocarcinoma - drug therapy, Adenocarcinoma - pathology, Analysis, Angiogenesis Inhibitors - pharmacology, Animal genetic engineering, Animals, Biological products, Cell Line, Tumor, Cell Proliferation - drug effects, Colorectal Neoplasms - drug therapy, Colorectal Neoplasms - pathology, Drug Design, Female, Health aspects, Human Umbilical Vein Endothelial Cells - physiology, Immunoglobulin Fc Fragments - chemistry, Immunoglobulin Fc Fragments - pharmacology, Immunoglobulin Fc Fragments - therapeutic use, Immunoglobulin G, Immunoglobulin G - chemistry, Lung Neoplasms - drug therapy, Lung Neoplasms - pathology, Macular degeneration, 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, Recombinant proteins, 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