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.
Highlights
Anti-angiogenesis has emerged in the last few years as an effective therapy to target the tumor stromal compartment [1] and is thought to act in a broader fashion compared to cytotoxic therapies.Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are functional ligands of the Tie2 receptor tyrosine kinase that is expressed on endothelial cells [2,3,4]
We have recently described two species cross-reactive Ang-2 antibodies LC06 and LC08 that were obtained from human antibody libraries by panning with Ang-2 and competitive elution with Tie2-Fc protein [22]
To further elucidate the mechanism of action behind the observed tumor growth inhibition previously described for LC06 and LC08, we examined if this effect was related to alterations of the vessel architecture and the function of the intratumoral microvessels
Summary
Anti-angiogenesis has emerged in the last few years as an effective therapy to target the tumor stromal compartment [1] and is thought to act in a broader fashion compared to cytotoxic therapies.Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are functional ligands of the Tie receptor tyrosine kinase that is expressed on endothelial cells [2,3,4]. Ang-2 is expressed by endothelial cells and stored in Weibel-Palade-bodies. It acts as an antagonist of Tie by blocking Ang-1 dependent Tie activation. Ang-2 is further described to act as a functional destabilization factor, rendering vasculature in a more plastic state amenable to sprouting (under the influence of other angiogenic cytokines such as VEGF) and is found to be increased in highly vascularized tumors and in pro-angiogenic diseases (e.g. macula degeneration, rheumatoid arthritis, osteoarthritis, psoriasis) [10]. In contrast to its broad expression in the vasculature of human tumors, Ang-2 shows limited postnatal expression in normal tissue (e.g. at sites of vascular remodeling like ovary, placenta, uterus) making it a tumor specific target for anti-angiogenic therapies
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