title: Acute tumour response to a bispecific Ang-2-VEGF-A antibody: insights from multiparametric MRI and gene expression profiling.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Lauren C J
authors.initials: LCJ
authors.lastname: Baker
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Jessica K R
authors.initials: JKR
authors.lastname: Boult
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Penzberg DE-82377, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Penzberg DE-82377, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Koehler
authors.affiliation: Roche pRED, Roche Innovation Center, Basel CH-4070, Switzerland.
authors.forename: Tapan
authors.initials: T
authors.lastname: Nayak
authors.affiliation: Roche pRED, Roche Innovation Center, Basel CH-4070, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Tessier
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Penzberg DE-82377, Germany.
authors.forename: Chia-Huey
authors.initials: CH
authors.lastname: Ooi
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Penzberg DE-82377, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Birzele
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Penzberg DE-82377, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Belousov
authors.affiliation: Roche pRED, Roche Innovation Center, Welwyn AL7 1TW, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zajac
authors.affiliation: Roche pRED, Roche Innovation Center, Basel CH-4070, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Horn
authors.affiliation: Roche pRED, Roche Innovation Center, New York, NY 10016, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: LeFave
authors.affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000627:therapeutic use*; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D000069444:Omalizumab / Q000627:therapeutic use; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: C586513:ANGPT2 protein, human; D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069444:Omalizumab; D000068258:Bevacizumab; D007073:Immunoglobulin E; C000619444:vanucizumab