Breast Cancer Therapy Using Antibody-Endostatin Fusion Proteins; Final rept. 25 Mar 2005-24 Mar 2008

摘要

The anti-angiogenic protein endostatin demonstrated considerable anti-tumor activity in animal models. However, limited anti-tumor activity has been observed in human Phase I/II trials. Trastuzumab has activity in HER2+ breast cancer used alone or in combination with chemotherapy. Prior studies using an anti-HER2 antibodymurine endostatin fusion demonstrated enhanced anti- tumor activity compared to anti-HER2 antibody or endostatin given alone or in combination. We generated two anti-HER2 human endostatin fusion proteins by fusing human wild type or a mutant form of human endostatin (huEndo- P125A) to the 3' end of a humanized anti-HER2 lgG3 antibody. HuEndo-P125A antibody fusion protein (alphaHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and capillary formation in vitro, to a greater degree than wild type endostatin fusion protein (alphaHER2-huEndo), endostatin alone, or anti-HER2 antibody (alphaHER2 lgG3). Treatment of SKBR-3 breast cancer xenografts with anti-HER2 lgG3-huEndo-P125A fusion resulted in complete regression, and improved survival, compared to either alphaHER2 lgG3, human endostatin, or anti-HER2 lgG3-huEndo treated mice. alphaHER2-huEndo fusion proteins specifically targeted tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor cell line EMT6 and EMT6 engineered to express HER2 antigen (EMT6-HER2). alphaHER2 huEndo-P125A fusion antibody showed enhanced anti-angiogenic and anti-tumor activity and inhibited EMT6- HER2 growth more effectively than huEndo (p = 0.003), or alphaHER2-huEndo (p = 0.004). Targeting anti-angiogenic proteins using antibody fusion proteins could improve clinical activity of anti-HER2 antibody and endostatin alike, and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities or using other antiangiogenic domains.