Improved pharmacokinetics and efficacy of endostatin by fusion with IgG Fc domain

4598 Endostatin, a 187 amino acid fragment from the C-terminus of collagen 18 has been shown to be a potent angiogenic inhibitor. Recently, it was demonstrated that p53 upregulates prolyl-4-hydoxylase, the enzyme responsible for cleaving endostatin from collagen 18. Because, endostatin has a very short half-life, we have expressed this protein fused to Fc. The half-life of endostatin is approximately 4 hours whereas it is approximately two weeks for Fc-endostatin, following injection in mice. This difference in half-life makes it possible to employ significantly smaller doses of Fc-endostatin. Previously, our laboratory established that the efficacy of endostatin in mice follows a U-shaped curve when examined as a function of the protein concentration. Anti-tumor activities of endostatin and Fc-endostatin were investigated. We now report that the amount required for inhibition of tumors by Fc-endostatin is at least 150-fold less than that of endostatin. This finding will likely have an impact on future trials of this inhibitor. Endostatin has been administered to patients in a Phase I and II clinical trials. Employing Fc-endostatin should enable us to generate sufficient protein for a more meaningful clinical trial of endostatin. Both Avastin (anti-VEGF monoclonal antibody produced by Genentech) and VEGF-trap ( Regeneron Pharmaceuticals ) employ similar Fc constructs for increasing the half-lives of their anti-angiogenic proteins.