Method of Treating Multiple Myeloma by Targeting CD28
Kelvin Lee and Lawrence Boise
Problem
Multiple Myeloma is the second most common hematological malignancy behind Non-Hodgkins' lymphoma, with 15,000 new cases diagnosed each year. There is an increasing incidence and earlier age of onset in this incurable but treatable disease. Patients characteristically respond initially to chemotherapy, but then relapse with increasingly more chemoresistant disease. Thus novel therapies that can bypass the underlying resistance mechanisms are clearly needed.
Solution
The current invention relates to novel methods that use therapeutic monoclonal antibodies to CD28 found on myeloma cells. Monoclonal antibodies against CD28 may:
(1) be directly lethal to myeloma cells (via antibody-mediated complement targeting),
(2) prevent myeloma proliferation (by blocking CD28 function on myeloma cells), and/or
(3)be toxic to myeloma cells after conjugation to radioisotopes or cellular toxins.
Competitive Advantage
Targeting CD-28 on myeloma cells could be a single agent treatment as opposed to the existing highly toxic treatments available.
Applications
Targeting CD28 on myeloma cells can be used as a single agent for the treatment of multiple myeloma, or in combination with other chemotherapy for a variety of diseases. As examples:
(1) Toxin-conjugated anti-CD28 monoclonal antibodies have been made;
(2) Efficacy of these antibodies has been demonstrated in vitro;
(3) Animal models involving human myeloma implantation are being developed to allow for in vivo testing of these antibodies.
Patent Status
International Patent Application
WO2008008455
entitled "METHOD OF TARGETING MULTIPLE MYELOMA," was published on January 17, 2008.
Licensing Opportunity
Seeking collaborative research and licensing options.
About the Inventors
Lawrence Boise, Ph.D., is a Full Professor in the Microbiology and Immunology Dept at the University of Miami and a member of the Sylvester Comprehensive Cancer Center. Dr. Boise has studied mechanisms of apoptosis in multiple myeloma, a cancer of antibody-producing plasma cells in the bone marrow. Together with Dr. Kelvin Lee, he has shown that arsenic in concert with ascorbic acid may have substantial therapeutic potential. Dr. Boise's research has also included several projects on the regulation of apoptosis. He is an NIH funded investigator and holds 5 U.S. patents and has published over 60 papers in the areas of apoptosis, CD28 regulation of cell survival, and myeloma.
Kelvin Lee, M.D., received his M.D. degree from the University of Michigan in 1984. He did his residency in Internal Medicine at the University of Colorado, and a fellowship in Oncology at the University of Michigan. In 1992, he joined the Uniformed Services University of the Health Science and the Naval Medical Research Institute as an Assistant Professor of Medicine, with work focusing on hemapoietic stem cell biology and DNA vaccines. In 1996, he was awarded the Federal Laboratory Consortium Excellence in Technology Transfer Award for work developing self contained hematopoietic bioreactor systems. In 1999, Dr. Lee joined the Departments of Microbiology/Immunology and Internal Medicine (Hematology/Oncology) at the University of Miami as a tenured Associate Professor, and was promoted to full Professor in 2005. He is an NIH funded investigator with over 50 publications in the areas of immunology and multiple myeloma. Currently, Dr. Lee is at the Roswell Park Cancer Center.
Selected References
Lee K, Taylor C, Petryniak B, Turka L, June CH, and Thompson CB. The genomic organization of the CD28 gene: Implications for CD28 mRNA expression and heterogeneity. J Immunol. 1990;145:344-352.
Shahinian A, Pfeffer K, Lee KP,* Kundig TM, Kishihara K, Wakeham A, Kawai K, Ohashi PS, Thompson CB, and Mak TW. CD28 deficient mice fail to respond to lectins and are defective in some but not all lymphocyte functions. Science. 1993;261:609-612.
*(co-first authors).
Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, Neil J, Reis I, Kharfan-Dabaja M, Eckman J, Goodman M, Fernandez HF, Boise LH, and Lee KP. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intra- cellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clinical Cancer Res. 2002;8:3658-3668.
Bahlis N.J., King, A.M., Kolonias, D., Carlson, L.M., Hong, Y. L., Hussein, M.A., Terebolo, H.R., Byrne Jr., G.E., Levine, B.L., Boise, L.H., Lee, K.P. CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood, 109, 5002-5010, 2007.
Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, and Thompson CB. Bcl-x, a Bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993;74:597-608.
Boise LH, Minn AJ, June CH, Noel PJ, Accavitti MA, Lindsten T, and Thompson CB. CD28 stimulation can promote T cell survival by enhancing the expression of Bcl-xL. Immunity. 1995;3:87-98.
Boise LH, Noel PJ, and Thompson CB. CD28 and Apoptosis. Curr Opin Immunol., 1995;7:620-625.
Bahlis NJ, King AM, Kolonias D, Carlson LM, Hussein M, Terebolo H, Byrne GE, Levine BL, Boise LH, and Lee KP. CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood, 109, 5002-5010, 2007.
Obeng, E.A., Carlson, L.M., Gutman, D., Harrington, Jr., W.J., Lee, K.P., Boise, L.H. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood, 107, 4907-4916, 2006.
Grad, J.M,. Bahlis, N.J., Reis, I., Ochiro, M.M., Dalton, W.S., Boise, L.H. Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in Multiple Myeloma cells. Blood. 98, 805-813, 2001
