Abstract B86: Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficiency

Abstract

Abstract Purpose: VEGF-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis. Experimental Design: We have recently described a novel generic method for the production of bivalent bispecific human IgG1 antibodies. Subsequently, we have applied the CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on Bevacizumab, and the other arm recognizing Ang-2 based on LC06, a highly Ang-2 selective human IgG1 antibody. Ang-2-VEGF CrossMab was evaluated in vitro and in vivo using molecular, biochemical, cellular and histological analyses to determine its pharmacologic properties, along with its mechanism of action. Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and patient and cell line-derived human tumor xenografts at both early and late stages of tumor development. Furthermore, a strong inhibition of angiogenesis and an enhanced vessel normalization phenotype were observed. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiological vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting. Conclusion: Our data indicate that Ang-2-VEGF-A CrossMab mediates potent anti-tumor, anti-angiogenic, and anti-metastatic efficacy and represents a promising therapeutic agent for the therapy of cancer. Citation Format: Erica Lorenzon, Yvonne Kienast, Romi Raemsch, Werner Scheuer, Frank Herting, Dirk Bernicke, Wolfgang Schaefer, Joerg Regula, Kay Stubenrauch, Sidney Yu, Huynh Hung The, Laurent Martarello, Christian Klein, Markus Thomas. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficiency. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B86.