Acute tumour response to a bispecific Ang-2-VEGF-A antibody: insights from multiparametric MRI and gene expression profiling.

Abstract

BACKGROUND:

To assess antivascular effects, and evaluate clinically translatable magnetic resonance imaging (MRI) biomarkers of tumour response in vivo, following treatment with vanucizumab, a bispecific human antibody against angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A).

METHODS:

Colo205 colon cancer xenografts were imaged before and 5 days after treatment with a single 10 mg kg(-1) dose of either vanucizumab, bevacizumab (anti-human VEGF-A), LC06 (anti-murine/human Ang-2) or omalizumab (anti-human IgE control). Volumetric response was assessed using T2-weighted MRI, and diffusion-weighted, dynamic contrast-enhanced (DCE) and susceptibility contrast MRI used to quantify tumour water diffusivity (apparent diffusion coefficient (ADC), × 10(6) mm(2) s(-1)), vascular perfusion/permeability (K(trans), min(-1)) and fractional blood volume (fBV, %) respectively. Pathological correlates were sought, and preliminary gene expression profiling performed.

RESULTS:

Treatment with vanucizumab, bevacizumab or LC06 induced a significant (P<0.01) cytolentic response compared with control. There was no significant change in tumour ADC in any treatment group. Uptake of Gd-DTPA was restricted to the tumour periphery in all post-treatment groups. A significant reduction in tumour K(trans) (P<0.05) and fBV (P<0.01) was determined 5 days after treatment with vanucizumab only. This was associated with a significant (P<0.05) reduction in Hoechst 33342 uptake compared with control. Gene expression profiling identified 20 human genes exclusively regulated by vanucizumab, 6 of which are known to be involved in vasculogenesis and angiogenesis.

CONCLUSIONS:

Vanucizumab is a promising antitumour and antiangiogenic treatment, whose antivascular activity can be monitored using DCE and susceptibility contrast MRI. Differential gene expression in vanucizumab-treated tumours is regulated by the combined effect of Ang-2 and VEGF-A inhibition.

• Authors: Lauren C J Baker, Jessica K R Boult, Markus Thomas, Astrid Koehler, Tapan Nayak, Jean Tessier, Chia-Huey Ooi, Fabian Birzele, Anton Belousov, Magdalena Zajac, Carsten Horn, Clare LeFave, Simon P Robinson
• Journal: British journal of cancer (Br J Cancer) Vol. 115 Issue 6 Pg. 691-702 (09 06 2016) ISSN: 1532-1827 [Electronic] England
• PMID: 27529514 (Publication Type: Journal Article)

Chemical References

• ANGPT2 protein, human
• Angiogenesis Inhibitors
• Angiopoietin-2
• Antibodies, Bispecific
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Omalizumab
• Bevacizumab
• Immunoglobulin E
• vanucizumab

Topics

• Adenocarcinoma (blood supply, diagnostic imaging, drug therapy, pathology)
• Angiogenesis Inhibitors (immunology, therapeutic use)
• Angiopoietin-2 (antagonists & inhibitors, immunology)
• Animals
• Antibodies, Bispecific (therapeutic use)
• Antibodies, Monoclonal (immunology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Bevacizumab (therapeutic use)
• Cell Line, Tumor
• Colonic Neoplasms (blood supply, diagnostic imaging, drug therapy, pathology)
• DNA Replication (drug effects)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoglobulin E (immunology)
• Magnetic Resonance Imaging (methods)
• Mice
• Molecular Targeted Therapy
• Neovascularization, Pathologic (diagnostic imaging, drug therapy, pathology)
• Omalizumab (therapeutic use)
• Tumor Burden
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, immunology)
• Xenograft Model Antitumor Assays