Abstract 2319: Dual inhibition of Ang-2 and VEGF via a novel human bispecific bivalent IgG1 CrossMAb shows potent anti-angiogenic, antitumoral, and antimetastatic efficacy and leads to a reduced side effect profile compared to single therapies
Authors: Thomas Markus , Kienast Yvonne , Scheuer Werner , Lorenzon Erica , Herting Frank , Odin Marielle , Schaefer Wolfgang , Regula Joerg Thomas , Stubenrauch Kay-Gunnar , Klein Christian 
Published: August 2012

Abstract
VEGF-A blockade has been extensively clinically validated as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of blood vessel remodeling, tumor angiogenesis, and metastasis. In tumors, Ang-2 is up-regulated and associated with poor prognosis. Recent data demonstrated that Ang-2 inhibitors, both as single agents or in combination with chemo- or anti-VEGF therapy, mediate anti-tumor effects. Additionally, it has been shown that the Ang-2/-1/Tie and the VEGF/VEGFR systems act in complementary ways suggesting that dual targeting may be more effective than targeting each pathway alone. Based on bevacizumab and the Ang-2 selective antibody LC06 we have generated a novel human bispecific bivalent IgG1 CrossMab antibody blocking VEGF-A and Ang-2 function simultaneously. Here we show in multiple subcutaneous and orthotopic in vivo models including models (semi-) resistant to anti-VEGF treatment that the systemic application of the Ang-2-VEGF CrossMAb effectively reduces angiogenesis, tumor growth and metastasis. Furthermore, we demonstrate that a highly selective anti-Ang-2 approach has safety related advantages in this model over an unselective treatment with an antibody targeting Ang-1 and Ang-2 simultaneously. Whereas anti-Ang-1/Ang-2 long-term treatment resulted in regression of healthy vessels in the mouse trachea, an anti-Ang-2 selective treatment did not affect the physiological vessels in the trachea of the mice at all. These results imply a clear differentiation between selective Ang-2 and unselective Ang-1/Ang-2 inhibition. Although anti-tumoral efficacy is retained selective Ang-2 inhibition did not lead to a further impairment of healthy vessels compared to anti-VEGF-A treatment only. Finally, we demonstrate a clear disadvantage of Ang-2 monotherapy compared to Ang-2-VEGF dual inhibition due to strong up-regulation of VEGF resulting not only in revascularization and tumor growth, but also in toxicity with macroscopic evidence of histopathological subcapsular peliosis-like changes in the liver. These pathological effects were inhibited by dual inhibition of Ang-2 and VEGF-A. Taken together, our data indicate that Ang-2 and VEGF-A exhibit angiogenic synergy in a mutually compensatory fashion and that their inhibition via the novel Ang-2-VEGF CrossMab mediates potent anti-tumoral, anti-metastatic and anti-angiogenic efficacy. Additionally the CrossMAb is expected to exhibtit a better side effect profile compared to the respective monotherapies and thereby represents a promising therapeutic agent for the therapy of cancer. These data support the investigation of the Ang-2-VEGF CrossMAb in PhI clinical trials scheduled for 2012.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2319. doi:1538-7445.AM2012-2319