Double Antiangiogenic Protein, DAAP, Targeting VEGF-A and Angiopoietins in Tumor Angiogenesis, Metastasis, and Vascular Leakage

Abstract

Two vascular growth factor families, VEGF and the angiopoietins, play critical and coordinate roles in tumor progression and metastasis. A single inhibitor targeting both VEGF and angiopoietins is not available. Here, we developed a chimeric decoy receptor, namely double anti-angiogenic protein (DAAP), which can simultaneously bind VEGF-A and angiopoietins, blocking their actions. Compared to VEGF-Trap or Tie2-Fc, which block either VEGF-A or angiopoietins alone, we believe DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumors; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage.

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…Preclinical studies have used a number of approaches including (1) specific VEGF blockade with agents that interfere with VEGF binding to its receptors (including antihuman VEGF antibodies such as A4.6.1 and bevacizumab), antimurine VEGF antibodies, and the "VEGF-Trap" aflibercept; (2) inhibition of VEGFR2 function (using anti-VEGFR2 antibodies such as DC101 or receptor tyrosine kinase inhibitors [TKIs] which inhibit the kinase domain of VEGFRs). In addition, elegant preclinical work examining the role of Yuan et al 1996;Tong et al 2004;Dickson et al 2007b;Taguchi et al 2008;Falcon et al 2009;Juan et al 2009;Kamoun et al 2009;Chae et al 2010;Koh et al 2010;Primo et al 2010. b Jain et al 1998;Izumi et al 2002;Delmas et al 2003;Qayum et al 2009. d Inai et al 2004;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Dings et al 2007;Fischer et al 2007;Zhou et al 2008;Falcon et al 2009;Juan et al 2009;Kamoun et al 2009;Ohta et al 2009;Zhou and Gallo 2009;Chae et al 2010;Primo et al 2010.…”

“…Recently, a dual pharmacological inhibitor of VEGF and the angiopoietins (named the "double antiangiogenic protein," DAAP) (Koh et al 2010) was shown to inhibit the growth of several murine tumors and, in the case of implanted ovarian carcinoma, resulted in a normalization of vessels. This is likely to be the first of many studies examining the strategy of inhibiting multiple proangiogenic factors to attain a greater degree of vessel normalization.…”

Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity

“…To produce recombinant proteins (sVEGFR3-Fc and dimeric-Fc), stable CHO cell lines that secrete these recombinant proteins were used as previously described (59). Recombinant proteins in supernatant were purified by column chromatography with protein A-agarose gel (Oncogene) using acid elution.…”

The spatiotemporal development of adipose tissue

“…To inhibit VEGF/VEGFR signaling, postnatal mice were subcutaneously administered with 25 mg/kg VEGF-Trap (Holash et al, 2002;Koh et al, 2010) every other day from P1 to P9, and then sacrificed. For control mice, 25 mg/kg of Fc (a control protein of VEGF-Trap) was injected in the same manner.…”