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-10093710-B2
Publication Date
2018-10-09
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 compositions and methods for promoting the maturation and export of T cells from thymic tissue by contacting the thymic tissue, in vitro or in vivo, 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 to the patient.
The problem being solved is the lack of clinical experience and effective methods involving IL-15, which unlike IL-2 and IL-7, had not been utilized for immunotherapy despite its non-redundant cytokine role important for NK and CD8+ T-cell development, survival, and proliferation. The invention addresses inefficient IL-15 secretion and insufficient lymphocyte maturation and export from thymic tissues, which contribute to lymphocyte deficiencies such as lymphopenia.
The invention is based on the discovery that IL-15, particularly when complexed with IL-15 receptor alpha (IL-15Rα), functions as a heterodimeric cytokine that promotes terminal differentiation of immature thymocytes into mature single positive CD3high T cells, reduces thymocyte apoptosis, and induces migration or output of mature lymphocytes from central lymphoid tissues (thymus and bone marrow) to peripheral lymphoid and non-lymphoid tissues. Systemic or local administration of supraphysiological levels of IL-15 increases lymphocyte numbers in peripheral tissues, thereby providing a method to prevent or treat lymphopenia.
Claims Coverage
The patent contains 17 claims with multiple inventive features mainly centered on polynucleotides, expression vectors, stable cell lines, and methods for producing and using IL-15Rα-Fc fusion proteins and IL-15 for lymphocyte production and treatment.
Polynucleotide encoding IL-15 receptor alpha-Fc fusion protein
A polynucleotide encoding an IL-15 receptor alpha (IL-15Rα)-Fc fusion protein comprising amino acids 31 to 431 of SEQ ID NO:20.
Expression vectors comprising IL-15Rα-Fc polynucleotide
Expression vectors comprising the polynucleotide encoding IL-15Rα-Fc fusion protein, optionally further comprising a polynucleotide encoding IL-15.
IL-15 polypeptide and nucleotide sequence identity
IL-15 in the expression vector is at least 95% identical to amino acids 49 to 162 of SEQ ID NO:2, or comprises the amino acid or nucleotide sequences as set forth in SEQ ID NO:2, SEQ ID NO:1, or codon optimized sequences SEQ ID NO:3 or 4.
Stable cell lines expressing IL-15Rα-Fc and IL-15
Stable cell lines comprising the expression vector(s) encoding IL-15Rα-Fc fusion protein and IL-15, including 293 or CHO cell lines.
Method of producing IL-15/IL-15Rα-Fc heterodimer
Culturing the stable cell line containing expression vectors of IL-15Rα-Fc fusion protein and IL-15, optionally followed by purification of the heterodimeric complex.
The claims cover polynucleotides encoding IL-15Rα-Fc fusion proteins, corresponding expression vectors including those co-expressing IL-15, stable cell lines for expression, and methods of producing bioactive IL-15/IL-15Rα-Fc heterodimers, enabling therapeutic applications related to lymphocyte maturation and lymphopenia treatment.
Stated Advantages
IL-15 promotes maturation and export of mature T cells from thymic tissue.
Systemic administration of IL-15 prevents, reduces, or inhibits lymphocyte depletion and accelerates lymphocyte recovery in peripheral tissues.
IL-15 complexes with IL-15Rα to form bioactive heterodimers with increased stability and secretion.
IL-15 administration enhances lymphocyte proliferation, migration, and activation in both lymphoid and non-lymphoid tissues.
Documented Applications
Promoting T-cell maturation and export from thymus to peripheral lymphoid and non-lymphoid tissues.
Preventing, alleviating, reducing, and inhibiting lymphopenia or lymphocyte depletion in peripheral tissues.
Accelerating repopulation of lymphocytes after drug-induced lymphopenia, including chemotherapy and radiation therapy.
Treatment of immunodeficiency states including those secondary to HIV infection, genetic mutations affecting IL-15 or its receptor, or other conditions causing lymphopenia.
Providing compositions such as DNA vectors or purified protein heterodimers of IL-15/IL-15Rα for therapeutic use.
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