Heterodimers of IL-15 and IL-15R alpha to increase thymic output and to treat lymphopenia
Inventors
Bergamaschi, Cristina • Felber, Barbara K. • Pavlakis, George N. • Valentin, Antonio
Assignees
US Department of Health and Human Services
Publication Number
US-11041008-B2
Publication Date
2021-06-22
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, either in vivo or in vitro, 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 in need thereof by administering IL-15 to the patient.
The background section identifies a problem in that immunodeficient conditions and lymphopenia, including those induced by diseases such as HIV infection or therapies such as anticancer or antiviral drugs, result in the depletion of lymphocytes in peripheral tissues. Common therapies using gamma-chain cytokines like IL-2 and IL-7 have limitations, and there is no clinical experience with IL-15 despite its critical role in lymphocyte development and proliferation. IL-15's unique biology includes its function as a heterodimer with the IL-15 receptor alpha (IL-15Rα), which is necessary for efficient secretion and bioactivity. The invention addresses the need for methods to promote T cell maturation and lymphocyte repopulation to treat lymphopenia.
The invention is based on the discovery that supraphysiological levels of IL-15 promote the maturation of double positive CD4+CD8+ thymocytes into mature single positive CD3high T cells while also decreasing thymocyte apoptosis. This maturation promotes migration or output of the mature T cells from the thymus to peripheral lymphoid and non-lymphoid tissues. Systemic administration of IL-15 similarly promotes maturation and migration of other lymphocytes, including B and NK cells, from the bone marrow to peripheral tissues, resulting in increased lymphocyte populations in various organs and blood, which provides a means to prevent or treat lymphopenia.
Claims Coverage
The patent includes 12 claims, with claims 1-3 being independent claims covering IL-15/IL-15Rα-Fc heterodimers and their compositions, and the remaining claims dependent, describing formulations and administration methods. The main inventive features cover the specific composition of the heterodimer, the sequence identities of the components, and administration details.
IL-15/IL-15Rα-Fc heterodimer composition
An IL-15/IL-15Rα-Fc heterodimer comprising IL-15Rα-Fc bound to IL-15, where the IL-15Rα-Fc comprises amino acids 31 to 431 of SEQ ID NO:20.
Specific IL-15 sequence identity
The IL-15 polypeptide in the heterodimer comprises an amino acid sequence that is at least 95% identical to amino acids 49 to 162 of SEQ ID NO:2.
Composition comprising IL-15/IL-15Rα-Fc heterodimer
A composition comprising the IL-15/IL-15Rα-Fc heterodimer, optionally further comprising a chemotherapeutic agent such as an anticancer chemical agent including vinblastine, fludarabine, aclarubicin, doxorubicin, exemestane, alefacept, alemtuzumab, pamidronate, idarubicin, or cyclophosphamide.
Administration methods
Formulations of the composition for intravenous, intramuscular, subcutaneous, intradermal, intranasal, or inhalational delivery, administered daily, weekly, bi-weekly, monthly, or as needed.
Overall, the claims cover a biologically active IL-15/IL-15Rα-Fc heterodimer comprising specific sequence ranges of the receptor and cytokine components, pharmaceutical compositions including this heterodimer, optionally combined with chemotherapeutic or glucocorticoid agents, and methods of administration to achieve therapeutic effects.
Stated Advantages
Systemic administration of supraphysiological IL-15 promotes maturation and export of mature T cells from the thymus to peripheral tissues.
IL-15 administration prevents, alleviates, reduces, and/or inhibits lymphopenia or depletion of lymphocytes in peripheral tissues.
IL-15 accelerates recovery and repopulation of lymphocytes in peripheral tissues after lymphocyte depletion due to drug therapy or disease.
Documented Applications
Promoting the maturation of T cells in thymic tissue in vivo or in vitro.
Promoting lymphocyte migration from central lymphoid tissues (thymus, bone marrow) to peripheral lymphoid and non-lymphoid tissues.
Preventing or treating lymphopenia or lymphocyte depletion in subjects, including drug-induced lymphopenia caused by anticancer or antiviral agents or radiation therapy.
Accelerating recovery and repopulation of depleted lymphocytes in peripheral tissues after lymphodepletion conditions.
Co-administration with chemotherapeutic agents or glucocorticoids for lymphopenia management.
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