UMF-101

Immunomodulating Tumor Necrosis Factor Receptor 25 (TNFR25) Agonists, Antagonists and Immunotoxins

Vadim Deyev, Robert B. Levy and Eckhard R. Podack

Problem

This invention addresses several problems two of which are: inflammatory bowel disease (IBD: Crohn's disease, ulcerative colitis) and anti tumor vaccines. IBD is a chronic disease and current treatment options such as TNF or TNFR blockers are only partially successful and not curative. On the other hand, anti tumor vaccines are gaining increased recognition as potential anti tumor agents. However, the cytotoxic T lymphocytes (CTL) generated by tumor vaccines are often suppressed in the tumor environment thus lowering the vaccines' efficacy. To address these issues, molecules that would act as potent costimulators for the generation of tumor specific CTL could interfere with suppressor cells and thus make the vaccines more effective.

Solution

Immunomodulating agents can be used either to stimulate or indirectly augment the immune system or in other cases have an immunosuppressive effect. The recently discovered TNFR25 agonists and antagonists have an anti-inflammatory action which can be used, among other things, to treat disease caused by chronic inflammation. Furthermore, these agents costimulate CTLs and interfere with suppressor cells.

Competitive Advantage

Tumor vaccines that are currently available are often suppressed in the tumor environment. This approach increases the vaccine's ability to act on the tumor due to increased stability. The myriad of biological effects that this immunomodulating agent can achieve is far superior to anything currently in use.

Applications

TNFR25 antagonists are capable of inhibiting CD8 T cell-mediated cellular immune responses and can for example, mitigate organ or tissue rejection following tissue transplantation.

TNFR25 agonists represent biological response modifiers that alter the interaction between the body's cellular immune defenses and cancer cells to boost, direct, or restore the body's ability to fight the cancer when given in combination with tumor vaccines. Combination of tumor vaccines with TNFRSF25 agonists holds great promise for anti tumor vaccine therapy.

TNFR25 specific immunotoxins are also capable of increasing the effectiveness of a chemotherapeutic regimen by depleting a cancer patient of naturally occurring immunosuppressive cells.

Patent Status

International Patent Appln No. WO2007027751 entitled "IMMUNOMODULATING TUMOR NECROSIS FACTOR RECEPTOR 25 (TNFR25) AGONISTS, ANTAGONISTS AND IMMUNOTOXINS" was published on March 8, 2007. A U.S. Patent application US20070128184A1 was published on June 7, 2007.

Licensing Opportunity

We are seeking collaboration on further pre-clinical and clinical development. We will entertain all commercial options to further develop these molecules.

About the Inventors

Vadim Deyev, M.D., Ph.D., is an Assistant Scientist at the Department of Microbiology and Immunology. Dr. Deyev is currently working along with Dr. Podack to develop and utilize an antibody that effectively halts inflammation in mouse models of asthma. Dr. Deyev's project, one of the first of five research projects chosen from a number of applicants, will be conducted in the newly opened labs at the Wallace H. Coulter Center for Translational Research at the University of Miami.

Robert B. Levy, Ph.D., is the Director of Graduate Studies in the Department of Microbiology and Immunology at the University of Miami/Miller School of Medicine. Dr. Levy had postdoctoral training at the National Institutes of Health and is currently examining the role of donor T cells and their effector function in the development of Graft vs. Host Disease (GVHD). Bone Marrow Transplant (BMT) has been employed for the reconstitution and treatment of patients with a variety of both hematopoietic disorders as well as solid tissue tumors. GVHD remains the major obstacle to more widespread application of BMT.

Eckhard Podack, M.D., is the University of Miami/Miller School of Medicine chair of the Department of Microbiology and Immunology. From 1996-2006, he was also the Associate Director for Basic Science at the University of Miami/Sylvester Comprehensive Cancer Center. Dr. Podack received his M.D. in 1968 from Johann Wolfgang Goethe University, Frankfurt, Germany; Medical Board. Some of his research interests include: induction of immunity by heat shock protein gp96-Ig, immunotherapy for advanced non-small-cell lung carcinoma (NSCLC), and CD30, the governor of T-cells.

Selected References

Blazar BR, Levy RB, Mak TW, Panoskaltsis-Mortari A, Muta H, Jones M, Roskos M, Serody JS, Yagita H, Podack ER, and Taylor PA. CD30/CD30 ligand (CD153) interaction regulates CD4+ T cell-mediated graft-versus-host disease. J Immunol. 2004;173:2933-2941.

Raez LE, Cassileth PA, Schlesselman JJ, Sridhar K, Padmanabhan S, Fisher EZ, Baldie PA, and Podack ER. Allogeneic vaccination with a B7.1 HLA-A gene-modified adeno-carcinoma cell line in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2004;22:2800-2807.

Marks L, Altman NH, Podack ER, and Levy RB. Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients. Transplantation. 2004;77:804-812.

Raez LE, Cassileth PA, Schlesselman JJ, Padmanabhan S, Fisher EZ, Baldie PA, Sridhar K, and Podack ER. Induction of CD8 T-cell-Ifn-gamma response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma. Cancer Gene Ther. 2003;10:850-858.