Abstract 3284: Preclinical and clinical evaluation of pharmacodynamic biomarkers of a novel anti-angiogenesis agent, anti-EGFL7

Abstract

Abstract In this study we report the use of pharmacodynamic (PD) biomarkers to guide the clinical development of a novel antibody targeting epidermal growth factor-like domain 7 (EGFL7). EGFL7 is a secreted protein produced by endothelial cells of nascent blood vessels in tumors and other proliferating tissues, but is expressed at low levels in healthy quiescent vessels and many non-vascular cell types (Campagnolo et al. 2005; Fitch et al. 2004; Parker et al. 2004; Soncin et al. 2003). Upon secretion, EGFL7 becomes tightly associated with the perivascular extracellular matrix (ECM), and supports endothelial cell adhesion and migration (Parker et al. 2004; Schmidt et al. 2007). EGFL7 protein also protects endothelial cells from stress-induced apoptosis (Xu et al. 2008). Anti-EGFL7 is a humanized monoclonal antibody that binds to EGFL7. In preclinical models, anti-EGFL7 when combined with anti-VEGF augments the survival benefit observed from anti-VEGF alone. Anti-EGFL7 is currently being investigated in Phase I trials (in solid tumors) in combination with bevacizumab. In addition to endothelial cells, circulating CD34Hi/CD31dim progenitor cells (CPCs) express high levels of EGFL7 transcript. This population of cells can differentiate into endothelial cells in vitro, and we found that the EGFL7 protein promotes proliferation and possibly survival of the undifferentiated CPCs in vitro. In preclinical xenograft models, administration of anti-EGFL7 resulted in delayed (day 15) reduction in CPCs, which based on the time course, is unlikely to be mediated simply by clearance of antibody-bound CPCs. Hence, evaluation of CPCs was incorporated into the dose escalation phase of anti-EGFL7 clinical development as a pharmacodynamic biomarker (PD) of drug activity. Biomarker analysis of CPCs in humans correlated with preclinical findings. For example, reduction in CPCs in response to anti-EGFL7 therapy was observed at a time point similar to that in mice. The treatment dependent decrease in CPCs may serve as a pharmacodynamic biomarker that may help guide dose selection as well as represent another potential mechanism for the anti-angiogenic properties of anti-EGFL7 Campagnolo L, Leahy A, Chitnis S, Koschnick S et al. (2005) Am J Pathol 167(1):275-84 Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H. (2004) Dev Dyn. 230(2):316-24 Parker LH, Schmidt M, Jin SW et al (2004) Nature 428(6984):754-8. Schmidt M, Paes K, De Mazière A, (2007) Development 134(16):2913-23. Soncin F, Mattot V, Lionneton F (2003) EMBO J. 22(21):5700-11 Xu D, Perez RE, Ekekezie II (2008) Am J Physiol Lung Cell Mol Physiol. 294(1):L17-23 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3284. doi:10.1158/1538-7445.AM2011-3284