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ID# UME-42

ANTIBODY NKG2D LIGAND FUSION PROTEIN FOR CANCER THERAPY

Drs. Joseph D. Rosenblatt , Seung-Uon Shin, and Khaled A. Tolba

Problem

Cytotoxic T lymphocytes and natural killer cells are essential effectors of anti-tumor immune responses in vivo. However, often the tumor is not seen by the immune system. This is especially true when the patient’s immune function is impaired or target antigens are not well expressed on the cancer cells. If anti-tumor antibodies could be linked to proteins expressed by cells during stress or disease the anti-tumor response would be dramatically increased.

Solution

One novel approach is to take advantage of a protein; NKG2D-L that is ubiquitously expressed during times of infection, disease and stress. By linking anti-tumor antibodies to NKG2D-L proteins in the form of antibody fusion proteins, we can target NKG2D-L to the surface of tumor cells, and therefore increase the ability of immune effector cells to recognize and eliminate tumor cells. Local delivery of NKG2DL is designed to re-target natural killer cells to tumor cells. This approach is designed to enhance anti-tumor response.

Competitive Advantage

Targeting molecules for cancer therapy allow much lower concentration of the toxic chemotherapeutic agent to be used. The advantage of this approach over non targeted molecules is its stability and the ability to use lower concentration.

Applications

The inventors have developed an approach to create a fusion protein using an NKG2D-L protein and modeled this approach using an antibody to the breast tumor antigen HER2/neu. This fusion protein acts by attaching to the HER2/neu receptor on the surface of cancer cells resulting in display of NKG2D-L on the cell surface, thereby targeting the cells for elimination. This approach to constructing ligand-antibody combinations may be applied to a variety of infections and tumors depending upon antibody specificity. Various fusion proteins could be created, including ones directed against a variety of known tumor antigens such as EGFR and PSMA in solid tumors and/or CD20 in lymphoma.

Patent Status

International Patent Appln No. PCT/US06/25658 entitled “ANTIBODY–NKG2D LIGAND FUSION PROTEIN FOR CANCER THERAPY” was filed on June 29, 2006. United States counterpart Patent Appln No. 11/427,628 entitled “ANTIBODY–IMMUNE LIGAND FUSION PROTEIN FOR CANCER THERAPY was filed on June 29, 2006.

Licensing Opportunity

We are seeking collaborative research and commercial options to further develop this fusion protein for cancer therapy.

About the Inventors

Joseph D. Rosenblatt, M.D.,
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.
Dr. Seung-Uon Shin, M.D. is currently 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. Sherrie 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. Khaled A. Tolba, M.D.
Khaled A. Tolba, M.D. is currently an Assistant Professor of Medicine within the Division of Hematology/Oncology at the University of Miami/Miller School of Medicine. Dr. Tolba trained in the laboratory of Dr. Joseph Rosenblatt and also completed a research fellowship at the Basel Institute of Immunology. Dr. Tolba was a faculty member at the University of Rochester until 2002, when he joined the faculty at the University of Miami Miller School of Medicine. Dr. Tolba is a recognized authority in the area of innate immunity as applied to tumor immunology, as well as in the use of gene therapy, antibody fusion and other modalities to augment immunogenicity of human tumors.

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.

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