Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival
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Author
Kloepper, Jonas
Riedemann, Lars
Amoozgar, Zohreh
Seano, Giorgio
Susek, Katharina
Yu, Veronica
Dalvie, Nisha
Amelung, Robin
Datta, Meenal
Song, Jonathan
Askoxylakis, Vasileios
Taylor, Jennie
Lu-Emerson, Christine
Batista, Ana
Kirkpatrick, Nathaniel
Jung, Keehoon
Snuderl, Matija
Muzikansky, Alona
Stubenrauch, Kay
Krieter, Oliver
Wakimoto, Hiroaki
Xu, Lei
Munn, Lance
Duda, Dan
Fukumura, Dai
Batchelor, Tracy
Jain, Rakesh
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https://doi.org/10.1073/pnas.1525360113Metadata
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Kloepper, Jonas, Lars Riedemann, Zohreh Amoozgar, Giorgio Seano, Katharina Susek, Veronica Yu, Nisha Dalvie, et al. 2016. “Ang-2/VEGF Bispecific Antibody Reprograms Macrophages and Resident Microglia to Anti-Tumor Phenotype and Prolongs Glioblastoma Survival.” Proceedings of the National Academy of Sciences 113 (16): 4476–81. https://doi.org/10.1073/pnas.1525360113.Abstract
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.Terms of Use
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