A novel angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to Pan-Angiopoietin-1/-2 inhibitors

PLoS One. 2013;8(2):e54923. doi: 10.1371/journal.pone.0054923. Epub 2013 Feb 6.

Abstract

There is increasing experimental evidence for an important role of Angiopoietin-2 (Ang-2) in tumor angiogenesis and progression. In addition, Ang-2 is up-regulated in many cancer types and correlated with poor prognosis. To investigate the functional role of Ang-2 inhibition in tumor development and progression, we generated novel fully human antibodies that neutralize specifically the binding of Ang-2 to its receptor Tie2. The selected antibodies LC06 and LC08 recognize both rodent and human Ang-2 with high affinity, but LC06 shows a higher selectivity for Ang-2 over Ang-1 compared to LC08 which can be considered an Ang-2/Ang-1 cross-reactive antibody. Our data demonstrate that Ang-2 blockade results in potent tumor growth inhibition and pronounced tumor necrosis in subcutaneous and orthotopic tumor models. These effects are attended with a reduction of intratumoral microvessel density and tumor vessels characterized by fewer branches and increased pericyte coverage. Furthermore, anti-Ang-2 treatment strongly inhibits the dissemination of tumor cells to the lungs. Interestingly, in contrast to the Ang-2/Ang-1 cross-reactive antibody LC08 that leads to a regression of physiological vessels in the mouse trachea, the inhibition with the selective anti-Ang-2 antibody LC06 appears to be largely restricted to tumor vasculature without obvious effects on normal vasculature. Taken together, these data provide strong evidence for the selective Ang-2 antibody LC06 as promising new therapeutic agent for the treatment of various cancers.

MeSH terms

  • Angiopoietin-1 / antagonists & inhibitors*
  • Angiopoietin-1 / immunology
  • Angiopoietin-2 / antagonists & inhibitors*
  • Angiopoietin-2 / immunology*
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology*
  • Antibody Specificity
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / immunology
  • Cornea / drug effects
  • Cornea / immunology
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Microvessels / drug effects
  • Microvessels / immunology
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / immunology
  • Phosphorylation
  • Random Allocation
  • Receptor, TIE-2 / antagonists & inhibitors
  • Receptor, TIE-2 / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Angiopoietin-1
  • Angiopoietin-2
  • Antibodies, Neutralizing
  • Antineoplastic Agents
  • Receptor, TIE-2

Grant support

The authors have no support or funding to report.