Long-Acting VEGF Binding Proteins for Treating Cancer

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) has been identified as a key mediator of tumor angiogenesis and has emerged as the single most commonly upregulated angiogenic factor in both grafted and naturally occurring tumors. VEGF exerts its biological activity by binding to its tyrosine kinase receptors, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1/KDR). Preclinical studies have examined the biological activities of different types of VEGF antagonists, including anti-VEGF neutralizing antibodies, soluble versions of the receptor molecules, and inhibitors of VEGF-R2 tyrosine kinase. In each case, significant inhibition of tumor growth and reduced vasculature was observed. We propose to prepare and evaluate long acting versions of one of these antagonists, specifically VEG-R1 receptor (Fit-l). During Phase I we will identify sites in the soluble portion of Flt-1 (sFlt-1) that can be modified with an inert polymer without significantly affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified sFlt-1 proteins for testing in animal models of cancer. Based on our previous work, these modified sFlt-1 proteins should be superior to the present preparations of recombinant soluble Flt-1. In particular we expect to see improved stability, higher potency, greater solubility, longer circulating half-lives, less frequent dosing and reduced antigenicity. These improved biological and physical characteristics should expedite pre-clinical and clinical evaluation of sFlt-1 as an anti-angiogenesis agent.