Heterodimers of IL-15 and IL-15R alpha to increase thymic output and to treat lymphopenia
Inventors
Pavlakis, George N. • Felber, Barbara K. • Valentin, Antonio • Bergamaschi, Cristina
Assignees
US Department of Health and Human Services
Publication Number
US-9975937-B2
Publication Date
2018-05-22
Expiration Date
2030-08-13
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Abstract
The present invention provides method for promoting the maturation and export of T cells from thymic tissue by contacting the thymic tissue with supraphysiological levels of interleukin (IL)-15. The present invention also provides methods for preventing, alleviating, reducing, and/or inhibiting lymphopenia or peripheral depletion of lymphocytes in a patient in need thereof by administering to the patient IL-15.
Core Innovation
The present invention provides compositions and methods for promoting the maturation and export of T cells from thymic tissue by contacting the thymic tissue with supraphysiological levels of interleukin (IL)-15. It also provides methods for preventing, alleviating, reducing, and/or inhibiting lymphopenia or peripheral depletion of lymphocytes in a patient by administering IL-15.
The invention is based on the discovery that IL-15 promotes the migration of T cells out of the thymus to peripheral lymphoid and non-lymphoid tissues and concurrently promotes the maturation of lymphocytes in the bone marrow, including B cells and natural killer (NK) cells, and their migration to peripheral tissues.
The problem being solved is that although IL-2 and IL-7 cytokines are used in immunotherapy, there is no clinical experience with IL-15, which has unique biological effects important for development, survival, and proliferation of NK and CD8+ T-cells. IL-15 is difficult to produce and secrete efficiently, and its physiological form is a heterodimer with IL-15Rα that has not been previously exploited therapeutically to promote T cell maturation and output from thymic tissue and to treat lymphopenia.
Claims Coverage
The patent includes two independent claims covering compositions comprising specific forms of IL-15/IL-15Rα heterodimers and their combinations with chemotherapeutic agents. These claims define inventive features protecting the composition comprising novel forms of IL-15 complexes and their therapeutic combinations.
Composition comprising IL-15 bound to soluble IL-15Rα and IL-15 bound to IL-15Rα-Fc fusion heterodimers
A composition comprising a first IL-15/IL-15Rα heterodimer where IL-15 is bound to a soluble form of IL-15Rα (amino acids 31 to 200 of SEQ ID NO:20) not in Fc fusion form, and a second IL-15/IL-15Rα-Fc heterodimer comprising IL-15 bound to an IL-15Rα-Fc fusion protein.
Composition comprising IL-15 bound to soluble IL-15Rα and a chemotherapeutic agent
A composition comprising an IL-15/IL-15Rα heterodimer where IL-15 is bound to a soluble form of IL-15Rα (amino acids 31 to 200 of SEQ ID NO:20) not in Fc fusion form, combined with a chemotherapeutic agent.
Composition comprising IL-15 bound to soluble IL-15Rα and an anticancer agent
The chemotherapeutic agent specifically being an anticancer agent, including vinblastine, fludarabine, aclarubicin, doxorubicin, exemestane, alefacept, alemtuzumab, pamidronate, idarubicin, or cyclophosphamide.
The claims cover novel compositions comprising heterodimers of IL-15 with soluble IL-15Rα and IL-15Rα-Fc fusion forms, as well as their therapeutic combinations with chemotherapeutic and anticancer agents for treatment of diseases associated with lymphopenia.
Stated Advantages
Administration of IL-15 promotes the maturation and migration of T cells from the thymus and lymphocytes from bone marrow to peripheral lymphoid and non-lymphoid tissues.
IL-15 administration prevents, reduces, and inhibits lymphopenia by accelerating lymphocyte recovery after depletion due to drugs or radiation.
Different IL-15/IL-15Rα heterodimer forms have distinct stability, localization, and biological effects, allowing tailored therapeutic use.
Delivery of IL-15 as a heterodimer with IL-15Rα induces higher production and bioactivity compared to IL-15 alone.
Documented Applications
Promoting T-cell maturation in thymic tissue by contacting thymic tissue with IL-15 in vivo or in vitro.
Promoting migration or export of mature lymphocytes from central lymphoid tissues (thymus, bone marrow) to peripheral lymphoid and non-lymphoid tissues.
Preventing, reducing, or inhibiting lymphopenia or depletion of lymphocytes in peripheral tissues by systemic administration of IL-15.
Accelerating recovery and repopulation of lymphocytes after lymphodepletion caused by chemotherapy, antiviral therapy, or radiation therapy.
Co-administration of IL-15 with chemotherapeutic or antiviral agents to prevent lymphopenia induced by these treatments.
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