Breast Cancer Therapy Using Antibody-Endostatin Fusion Proteins
Annual rept. 25 Mar 2006-24 Mar 2007
MIAMI UNIV FL
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To produce a more effective form of trastuzumab and improve efficacy of endostatin we constructed several anti- HER2 IgG3-endostatin fusion proteins by fusing human endostatin to the 3 end of a humanized anti-HER2 IgG3 antibody. Antibody targeting is designed to enhance local delivery of endostatin to tumor as well as increase endostatin half-life. We constructed two endostatin fusion proteins based on native human endostatin andor a mutant endostatin with a P125A substitution to confer increased antiangiogenic activity. Native and P125A mutant fusion proteins inhibited tube formation and proliferation of HUVEC in vitro although P125A fusion protein showed greater inhibition than either native endostatin or endostatin fusion protein. Treatment of established SKBR-3 with the mutant P125A fusion resulted in complete regression of xenografts in SCID mice 55 tumor free compared to untreated anti-HER2 lgG3 human endostatin or the native endostatin fusion protein treated mice. Combination of huEndo fusion protein and Avastin synergistically enhanced anti-tumor activity. Linking endostatin to an antibody may significantly enhance anti-tumor activity of trastuzumab. Mutant P125A fusion antibody showed better anti-tumor activity. Targeting antiangiogenic proteins using antibody is a versatile approach that could be applied to other targets e.g. EGFR PSMA or using other antiangiogenic protein domains.
- Medicine and Medical Research