The IL-7 pathway is critical for regulating the number of lymphocytes as has been shown in humans as well as in mice. We and our collaborators recently showed that the IL-7 receptor is mutated in pediatric lymphocytic leukemia, and the mutant receptors drive cell division. We developed a panel of monoclonal antibodies against mutant receptors, all of which also react with normal receptors. These mouse monoclonals have been chimerized with human IgG1 to optimize antibody-dependent cell-mediated cytotoxicity. These monoclonals are effective, as single agents, in treating human leukemia cells transplanted into mice.
We aim to pursue developing a clinical in leukemia patients. Using a different approach, we showed that drugs which block signaling from IL-7 receptor are able to kill leukemia cells in vitro. These are being tested against human leukemia cells transplanted into mice and evaluated for treating patients. The same monoclonal antibodies and drugs will also be evaluated in autoimmune diseases. It was previously found by others that a polymorphism in the coding region of IL-7 receptor predisposes to autoimmune diseases. We recently found that this polymorphism regulates the strength of signal by the receptor, offering promise for inhibiting these signals in autoimmunity. Our group has studied the IL-7 pathway for a number of years and have published a number of papers on the subject. Most recently we, together with a number of collaborators, found activating mutations in the IL-7 receptor that drive lymphocytic leukemias (Zenatti et al, Nature Genetics 2011). We are developing therapeutics to treat patients who fail conventional chemotherapy. We also found that a polymorphism in IL-7 receptor regulates the strength of signal, and that high signaling predisposes to autoimmunity (Mazzucchelli et al Semin Immunol 2012). Therefore, antagonists of the IL-7 pathway may be effective in autoimmunity, and we are exploring this possibility. Relevant cancer sites: Non-Hodgkins Lymphoma, Leukemia. Relevant Research Areas: Immunology, Autoimmune Disease, Hematology/Lymph, Clinical Research.
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