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PLoS One. 2018 Jan 25;13(1):e0187063. doi: 10.1371/journal.pone.0187063. eCollection 2018.

Evaluation of drug mechanism and efficacy of a novel anti-angiogenic agent, TTAC-0001, using multi-modality bioimaging in a mouse breast cancer orthotopic model.

Author information

1
Department of Radiology and the Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
2
Bioimaging Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
3
PharmAbcine; Inc., Daejeon Bioventure Town, Daejeon Korea.
4
Medical Research Institute, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangwon-do, Korea.

Abstract

PURPOSE:

Targeting 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 METHODS:

We 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).

RESULTS:

The 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.

CONCLUSION:

We 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.

PMID:
29370209
PMCID:
PMC5784895
DOI:
10.1371/journal.pone.0187063
[Indexed for MEDLINE]
Free PMC Article

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