Use of IL-15 preparations 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-8871191-B2
Publication Date
2014-10-28
Expiration Date
2030-08-13
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 invention provides 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 inhibiting lymphopenia or peripheral depletion of lymphocytes in a patient by administering IL-15.
IL-15 promotes the maturation of double positive CD4+CD8+ thymocytes to single positive CD3high T cells and increases their migration from the thymus to peripheral tissues including lymphoid and non-lymphoid tissues. IL-15 systemic administration also promotes the maturation and export of lymphocytes including T cells, B cells, and NK cells from central lymphoid tissues such as thymus and bone marrow to peripheral tissues.
The problem being solved is the deficiency of mature lymphocytes in peripheral tissues, including lymphopenia caused by various factors such as drug-induced immunodeficiency, diseases like HIV infection, radiation therapy, or genetic mutations resulting in non-functional IL-15 or IL-15 receptor subunits. Prior treatments with common gamma-chain cytokines like IL-2 and IL-7 do not address the lack of therapeutic use of IL-15 for such purposes.
Claims Coverage
The claims include independent claims directed to methods of treating lymphopenia by administering IL-15 and IL-15Rα-Fc fusion protein either as heterodimers or encoded by nucleic acids, covering both polypeptide and nucleic acid modalities.
Use of IL-15/IL-15Rα-Fc heterodimer for treating lymphopenia
A method of treating lymphopenia comprising systemically administering a heterodimer comprising interleukin-15 (IL-15) with at least 95% amino acid identity to mature IL-15 and an IL-15Rα-Fc fusion protein comprising soluble IL-15Rα fused to an Fc region having at least 95% identity to SEQ ID NO:17 or SEQ ID NO:20, at a dose maintaining supraphysiological IL-15 plasma levels for two or more days.
Treatment of drug-induced lymphopenia with IL-15/IL-15Rα-Fc heterodimer
Method wherein the lymphopenia is drug-induced, e.g., caused by anticancer agents, and wherein the heterodimer is administered subcutaneously at IL-15 plasma levels of 1 to 1000 ng/ml, in amounts around 0.01 mg/kg.
Nucleic acid-mediated expression of IL-15 and IL-15Rα-Fc fusion for lymphopenia treatment
A method comprising administering nucleic acid sequences encoding IL-15 and IL-15Rα-Fc fusion protein with specified sequence identities, administered at a dose that maintains supraphysiological plasma IL-15 levels for two or more days, optionally encoded on the same or separate vectors.
The patent claims cover both protein and nucleic acid-based methods of treating lymphopenia using IL-15 in complex with an IL-15Rα-Fc fusion protein at supraphysiological levels, addressing various types of lymphopenia including drug-induced conditions, with specified sequences and dosages.
Stated Advantages
IL-15 promotes rapid maturation and export of T cells from thymus to peripheral tissues.
Systemic administration of IL-15 accelerates recovery from lymphopenia and lymphocyte depletion in peripheral tissues.
IL-15 administration increases numbers of NK cells, CD8+ T cells, and overall lymphocytes in lymphoid and non-lymphoid tissues.
Improved lymphocyte reconstitution after chemotherapy or radiation, shortening lymphopenia duration.
Different IL-15/IL-15Rα complexes have variable stability and effects, allowing tailored therapeutic use.
Documented Applications
Promoting maturation and migration of T cells from thymus to peripheral lymphoid and non-lymphoid tissues.
Promoting maturation and output of B cells and natural killer (NK) cells from bone marrow to peripheral tissues.
Preventing, reducing, or inhibiting lymphopenia or lymphocyte depletion in patients, including drug-induced lymphopenia caused by anticancer drugs, antiviral drugs, or radiation therapy.
Accelerating repopulation of lymphocytes in peripheral tissues after depletion.
Interested in licensing this patent?