Use of IL-15 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-10894816-B2
Publication Date
2021-01-19
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 invention provides methods and compositions for promoting the maturation and export of T cells from thymic tissue by contacting the tissue with supraphysiological levels of interleukin (IL)-15. The methods include administering IL-15 in vivo or in vitro to promote T cell maturation from double positive CD4+CD8+ thymocytes to single positive CD3high T cells, reduce apoptosis of thymocytes, and increase migration of mature T cells to peripheral lymphoid and non-lymphoid tissues.
Additionally, the invention addresses the prevention, alleviation, reduction, and inhibition of lymphopenia or depletion of lymphocytes in peripheral tissues by systemically administering IL-15. The systemic administration of IL-15 promotes the maturation and migration of lymphocytes such as T cells, B cells, and natural killer (NK) cells from central lymphoid tissues (thymus and bone marrow) to peripheral tissues, enhancing repopulation and accelerating recovery from lymphocyte depletion. The invention supports the use of IL-15 alone or in combination with IL-15 receptor alpha (IL-15Rα), including heterodimeric complexes or nucleic acids encoding these proteins, administered at doses sufficient to achieve supraphysiologic levels.
The problem solved by this invention stems from the need to enhance immune reconstitution in patients suffering from lymphopenia or immunodeficiency, including drug-induced lymphocyte depletion from chemotherapy or radiation therapy, or due to disease such as HIV infection. Prior therapies involving gamma-chain cytokines IL-2 and IL-7 did not include clinical experience with IL-15. The invention overcomes challenges related to inefficient IL-15 secretion, complex regulation, and biological differences compared with IL-2, providing methods to deliver bioactive IL-15, alone or as a heterodimer with IL-15Rα, for targeted promotion of lymphocyte maturation, migration, and recovery in immune-depleted individuals.
Claims Coverage
The patent includes one independent claim focusing on methods of treating depletion of lymphocytes by administering a purified IL-15/IL-15Rα heterodimer comprising a specific soluble IL-15Rα fragment.
Use of purified IL-15/IL-15Rα heterodimer comprising soluble IL-15Rα fragment
A method of reducing or inhibiting depletion of lymphocytes and/or promoting repopulation of depleted lymphocytes in peripheral tissue in a human subject by administering a composition comprising a purified IL-15/IL-15Rα heterodimer consisting of IL-15 bound to a soluble form of IL-15Rα comprising amino acids 31 to 200 of SEQ ID NO:20.
Treatment of lymphopenia or cancer by IL-15/IL-15Rα heterodimer administration
Application of the purified IL-15/IL-15Rα heterodimer method to subjects suffering from cancer or lymphopenia.
Incorporation of IL-15 with defined amino acid identity
The IL-15 component comprises an amino acid sequence at least 95% identical to amino acids 49 to 162 of SEQ ID NO:2, including embodiments with the exact amino acid sequence of amino acids 49 to 162 of SEQ ID NO:2.
Treatment in context of chemotherapy
The method applies to subjects who have undergone, are undergoing, or will undergo chemotherapy, particularly with chemical agents.
Administration modalities and frequencies
The composition can be administered via intravenous, intramuscular, subcutaneous, intradermal, intranasal, or inhalational routes. Administration can be daily, weekly, bi-weekly, monthly, or as needed.
Co-administration with glucocorticoids
The method optionally includes co-administration of glucocorticoids with the IL-15/IL-15Rα heterodimer.
The independent claim claims a method of treating lymphocyte depletion by administering a purified IL-15/IL-15Rα heterodimer with a defined soluble IL-15Rα fragment, encompassing treatment of lymphopenia and cancer, including use in chemotherapy contexts, with specified amino acid sequences and administration routes and schedules, optionally combined with glucocorticoids.
Stated Advantages
Systemic administration of IL-15 promotes maturation and export of lymphocytes from central lymphoid tissues to peripheral tissues.
IL-15 administration accelerates recovery from lymphocyte depletion and lymphopenia.
IL-15 enhances the repopulation of peripheral tissues with mature T cells, B cells, and NK cells.
Co-expression or co-administration of IL-15 with IL-15Rα substantially increases bioactive IL-15 levels and stability.
Documented Applications
Promoting maturation and migration of T cells from thymic tissue to peripheral lymphoid and non-lymphoid tissues.
Preventing, reducing, or inhibiting lymphopenia or lymphocyte depletion in a patient, including drug-induced lymphopenia from anticancer or antiviral drugs and radiation therapy.
Promoting or accelerating repopulation of lymphocytes in peripheral tissues in subjects with lymphodepletion due to disease, chemotherapy, or genetic mutations affecting IL-15 or its receptor.
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