Abstract
PurposeTargeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic effects because VEGFR-2 is the major signaling regulator of VEGF/VEGFR pathways. We aimed to elucidate the drug mechanism and anti-tumor efficacy of TTAC-0001, a novel, fully human anti-VEGFR-2/KDR monoclonal antibody, in mouse orthotopic breast cancer model using multi-modal bioimaging.Materials and methodsWe used orthotopic xenograft tumor model in which human breast cancer cells (MDA-MB-231) were injected into the right mammary fat pad of Balb/c nude mice. We investigated its biodistribution using serial fluorescence imaging after injecting fluorescent-labelled-drug and mode of action using Matrigel plug angiogenesis assays. The anti-tumor efficacy of drug was assessed using ultrasonography and bioluminescence imaging. Histopathologic analyses, including hematoxylin and eosin staining and immunohistochemistry with anti-CD31 and anti-Ki-67 antibodies, were performed. Each experiment had four groups: control, bevacizumab 10 mg/kg (BVZ-10 group), TTAC-0001 2 mg/kg (TTAC-2 group), and TTAC-0001 10 mg/kg (TTAC-10 group).ResultsThe TTAC-10 group showed good tumor targeting that lasted for at least 6 days and had a good anti-angiogenic effect with decreased hemoglobin content and fewer CD31-positive cells in the Matrigel plug. Compared with BVZ-10 and TTAC-2 groups, the TTAC-10 group showed the strongest anti-tumor efficacy, inhibiting tumor growth as detected by ultrasonography and bioluminescence imaging. The TTAC-10 group also showed the lowest viable tumor and micro-vessel areas and the lowest Ki-67 index in histopathologic analyses.ConclusionWe firstly demonstrated that TTAC-0001 effectively inhibited tumor growth and neovascularization in mouse orthotopic breast cancer model. It may provide a future treatment option for breast cancer.
Highlights
Tumor angiogenesis is a potential target for anti-cancer therapy, as it plays an essential role in oxygen and nutrient supply [1, 2]
After injecting Alexa Fluor1 647-labeled TTAC-0001, a focal signal appeared in the right flank area after 24 h and was detected in both TTAC-2 and TTAC-10 groups, but not in the control group
These results are suggestive of tumor targeting of TTAC-0001 to the right mammary fat pad of the mouse
Summary
Tumor angiogenesis is a potential target for anti-cancer therapy, as it plays an essential role in oxygen and nutrient supply [1, 2]. Inhibition of the VEGFR-2/kinase insert domain receptor (KDR) has potential anti-angiogenic effects because VEGFR-2 is the major signaling regulator of VEGF/ VEGFR pathways [5]. From this perspective, TTAC-0001, a human anti-VEGFR-2/KDR monoclonal antibody, was developed. Preclinical research revealed potential anti-tumor activity of TTAC-0001 in colorectal, non-small-cell lung cancer and glioblastoma tumor models [6,7,8,9,10]. There have been no previous studies of TTAC-0001 for breast cancer
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