Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4476-81. doi: 10.1073/pnas.1525360113. Epub 2016 Apr 4.


Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

Keywords: anti-angiogenic therapy; anti-tumor immunity; macrophage polarization; microglia reprogramming; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Bispecific / pharmacology*
  • Antibodies, Neoplasm / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Ribonuclease, Pancreatic / antagonists & inhibitors*
  • Ribonuclease, Pancreatic / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vesicular Transport Proteins / antagonists & inhibitors*
  • Vesicular Transport Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Bispecific
  • Antibodies, Neoplasm
  • Antineoplastic Agents
  • Neoplasm Proteins
  • VEGFA protein, human
  • VPS51 protein, human
  • Vascular Endothelial Growth Factor A
  • Vesicular Transport Proteins
  • vascular endothelial growth factor A, mouse
  • Ang2 protein, mouse
  • Ribonuclease, Pancreatic