Antibody-Endostatin Fusion Protein and its Variants
Sherrie Morrison (UCLA), Joseph D. Rosenblatt and Seung-Uon Shin
Problem
The ability to specifically target and modulate the activity of tumor cells is limited by the half-life of targeting molecules. Anti-angiogenic tumor therapies have recently attracted intense interest because of their broad-spectrum action, toxicity, and absence of drug resistance. However, if these molecules could have a tumor antigen targeting domain and an anti-tumor effector function domain, this would be an ideal addition to the armamentarium available for cancer.
Solution
Endostatin is a well characterized and effective anti-angiogenic agent. One major problem with endostatin is its short half-life. The invention provides methods and compositions for targeting a chimeric fusion protein containing both an anti-angiogenic agent such as endostatin and a carrier domain to a tumor making it more specific and longer lived.
Competitive Advantage
As effective as anti angiogenic molecules are, they have half-life and concentration problems that this technology addresses.
Applications
The inventors have developed a novel approach to create a human fusion protein and have used it to construct endostatin fused to targeting sequences derived from an anti HER-2 antibody. The possible applications are:
(1) To enhance the local delivery of endostatin to a tumor;
(2) To increase endostatin half-life;
(3) To target endostatin to the Her-2 tumor;
(4) To achieve higher local concentration of endostatin;
(5) To increase endostatin activity through presentation as a dimer.
Patent Status
PCT Application
WO2009003145
entitled "ANTIBODY-ENDOSTATIN FUSION PROTEIN AND ITS VARIANTS" was published on December 31, 2008.
Licensing Opportunity
We are seeking collaborative research and commercial options to further develop this technology.
About the Inventors
Joseph D. Rosenblatt, M.D., is the William Harrington Professor of Medicine, Microbiology and Immunology and Chief of the Division of Hematology/Oncology in the Department of Medicine at the University of Miami/Miller School of Medicine and also serves in the role of the Associate Director for Clinical and Translational Research of the University of Miami Sylvester Comprehensive Cancer Center.
Dr. Rosenblatt is well known in the area of cancer immunotherapy and gene therapy, and has been funded by the National Cancer Institute and the Department of Defense to pursue development of novel antibody fusion proteins, along with his co-inventor, Dr. Seung-Uon Shin. Dr. Rosenblatt is an authority on the use of co-stimulatory ligands, and other immune effector molecules delivered through gene transfer and/or antibody fusion proteins for purposes of augmenting immune responses to human and murine tumors.
Dr. Seung-Uon Shin, M.D., is a Research Associate Professor of Clinical Medicine in the Division of Hematology/Oncology at the University of Miami/Miller School of Medicine. He received his Ph.D. in Cell Biology in 1987 from the Albert Einstein College of Medicine and also holds an M.S. in Pharmacy from the Seoul National University. Dr. Shin is a recognized authority in the area of antibody fusion protein production, having performed his postdoctoral research in the laboratory of Dr. Sherie Morrison, one of the world's premier antibody engineering laboratories. Drs. Rosenblatt and Shin have co-authored numerous articles together on the use of antibody fusion proteins as agents directed against breast and other cancers.
Dr. Sherrie Morrison, Ph.D. is a Distinguished Professor in the Department of Microbiology, Immunology and Molecular Genetics at the University of California in Los Angeles. From 1992-2002 she served as department chair. Prior to coming to UCLA Dr. Morrison was a Professor in the Department of Microbiology at Columbia University, College of Physicians and Surgeons. She received her B.A. and Ph.D. from Stanford University and completed post-doctoral training at Columbia University, Albert Einstein College of Medicine and University of California at Berkeley. She has published over 230 articles and was a pioneer in the development of recombinant antibodies and antibody-fusion proteins.
Selected References
Recent Publications :
Lee, Y.J., Kim, D.H., Chung, Y., Shin, S-U. and Kang, C.Y. Comparison of the anti-tumor efficacies of Her-2/neu DNA vaccines inducing contrasting IgG immunity but comparable CTL activity in mice. Vaccine 21(5-6):521-31, 2003.
Lee, Y.J., Kim, D.H., Chung, Y., Shin, S.-U. and Kang, C.Y. Comparison of the antitumor efficacies of Her-2/neu DNA vaccines inducing contrasting IgG immunity but comparable CTL activity in mice. Vaccine 21(5-6):521-31, 2003.
Shah, S., Divekar, A. A., Hilchey, S. P., Cho, H.-M., Newman, C. L., Shin, S.-U., Nechustan, H., Challita-Eid, P. M., Segal, B. M., Yi, K. H. and Joseph D. Rosenblatt, D. J. Increased rejection of primary tumors in mice lacking B cells: Inhibition of anti-tumor CTL and T(H)1 cytokine responses by B cells. Int J Cancer. 117(4):574-586, 2005.
Cho, H.-M., Rosenblatt, J. D., Kang, Y. S., Iruela-Arispe, M. L., Morrison, S. L., Penichet, M. L., Kwon, Y. G., Kim, T. W., Webster, K. A., Nechustan, H., Shin, S.-U. Enhanced inhibition of murine tumor and human breast tumor xenografts using targeted delivery of an antibody-endostatin fusion protein. Mol Cancer Ther. 4(6):956-67, 2005.
Cho, H.-M., Kim, H.-J., Kwon, Y.-K., Kim, T.-W., Kim, J., Kang, Y.-S., Iruela-Arispe, Morrison, S. L., Rosenblatt, J. D. and Shin, S.-U. Pharmacokinetics, organ distribution, and efficacy of recombinant murine endostatin in mice; localization to kidney cortex. Preparation. 2007.
