Angiopoietin-2 specific CVX-060 inhibits tumor growth cooperatively with chemotherapy

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Huang H, Do J, Li L, Lai J, Liu D, Pirie-Shepherd S, Levin N, Bradshaw C, Woodnutt G, Lappe R, Bhat A

Angiopoietin-2 specific CVX-060 inhibits tumor growth cooperatively with chemotherapy

Cancer Res. 2008 May 1;68(9_Supplement):2493.

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Abstract

Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are ligands of the endothelial cell receptor Tie2. Ang-1 is essential for maintaining stable vasculature. In remodeling endothelial cells, Ang-2 serves as an endogenous Ang-1 antagonist. Ang-2 promotes the dissociation of pericytes from existing blood vessels, and results in unstable blood vessels, which can proliferate and migrate to form new blood vessels in the presence of VEGF. Ang-2 over-expression in many cancers correlates with more invasive disease and poorer prognosis. CVX-060, a specific Ang-2 binding CovX-BodyTM, was produced by fusing a chemically modified pharmacophore to the Fab binding site of a specially designed antibody. CVX-060 blocked Ang-2-Tie2 interaction with an IC50 of 1nM. The anti-tumor activity of CVX-060 was evaluated in staged Colo-205. Significant reduction in tumor growth (P < 0.01) was observed [T/C (Treatment/Control) = 53%] with monotherapy. CVX-060 in combination with Irinotecan or Docetaxel produced even greater inhibition of tumor growth (T/C from ~50% to 36% and 31%, respectively) and delayed the time to reach a pre-determined tumor volume (2000 mm3) when compared to Vehicle control and monotherapy groups. In fact, the combination groups never reached 2000 mm3 during the study. Ang2 protein levels examined by immunostaining were significantly reduced in CVX-060 treated tumors. Tumor microvessel density assessed by CD31 staining was also significantly reduced by ~33% (P < 0.01). Histological analysis revealed that CVX-060 increased tumor necrosis by 63% (P < 0.01). Tie2 expressing monocytes can be recruited into tumors and differentiate into pro-angiogenic macrophages. Tie2+ CD14+ or CD11b+ cell number examined by immunohistochemistry were reduced by 76% in CVX-060 treated tumors compared to the Vehicle group (P < 0.01). These data demonstrate that the Ang-2 CovX-BodyTM CVX-060 can effectively reduce Ang-2 protein level and Tie2+ macrophages inside the tumor mass, and inhibit tumor angiogenesis and growth. Significant combination benefit was also observed with other standard of care agents.

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