Abstract 1370: RO5323441, a humanized monoclonal antibody against the placenta growth factor, blocks PlGF-induced VEGFR-1 phosphorylation in vitro and tumor growth in vivo
Authors: Rizzo Christine , Yin Xuefeng Yin , Packman Kathryn , Higgins Brian , Schnueriger Alfred , Thomas Markus , Weidner Michael , Heimbrook Dave , Simcox Mary Ellen C. 
Published: February 2011

Solid tumor growth requires new blood vessel formation or angiogenesis. Inhibition of angiogenesis as a therapeutic strategy in oncology has been validated by treatments that block vascular endothelial growth factor (VEGF) or its receptors, such as bevacizumab (Avastin®), which is an anti-VEGF antibody that prolongs survival in colorectal, lung and other cancer patients in combination with chemotherapy. However, since not all tumors are sensitive to VEGF blockade and resistance mechanisms to VEGF therapies can develop, inhibition of additional targets may be necessary in order to control tumor growth and achieve better clinical effects. PlGF is a member of the VEGF family that is found only in very low levels under normal physiological conditions, but is up-regulated in almost all major malignant diseases. PlGF expression has shown to correlate with tumor stages and patient survival in breast cancer, CRC and gastric cancer [1-3]. Pre-clinical data support a role for PlGF in tumor angiogenesis, and demonstrate that blocking PlGF can inhibit tumor growth [4]. RO5323441, a humanized IgG1 monoclonal antibody directed against PlGF, has demonstrated anti-tumor activity in human tumor xenograft models in mice, has a benign preclinical toxicology profile and is being developed for the treatment of multiple advanced cancer indications. RO5323441 binds to both PlGF-1 and PlGF-2 in a dose dependent manner, and is not cross-reactive with murine PlGF or human VEGF. RO5323441 inhibits the binding of human PlGF-1 or PlGF-2 to VEGFR −1 with IC50 values of 0.1 and 0.2 nM, respectively. RO5323441 blocks PlGF-induced VEGFR-1 phosphorylation in Flt-1-transfected HEK293 cells. Antitumor activity has been demonstrated in mutliple tumor models including ACHN and Caki-1 renal cell carcinoma and Huh-7, hepatocellular carcinoma xenografts. Inhibition of established tumors ranged from 43-97% with twice weekly dosing. A refractory model of non-small cell lung cancer has also been identified. Studies to understand the mechanism of action and to identify pharmacodynamic markers and have been carried out in ACHN-tumor bearing mice.

References

1. Wei SC, Tsao PN, Yu SC, et al. Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut. 2005 May; 54(5):666-72.

2. Parr C, Watkins G, Boulton M et al. Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer. 2005 Dec;41(18):2819-27.

3. Chen CN, Hsieh FJ, Cheng YM, et al. The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett. 2004 Sep 15;213(1):73-82.

4. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007. 131 : 463-75.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1370.