Cell expressing complexes of IL-15 and IL-15Ralpha
Inventors
Pavlakis, George N. • Vournakis, John N. • Felber, Barbara K. • Finkielsztein, Sergio
Assignees
Novartis AG • US Department of Health and Human Services
Publication Number
US-9931377-B2
Publication Date
2018-04-03
Expiration Date
2028-06-27
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Abstract
The present invention relates to agents that modulate interleukin-15 (“IL-15”) signal transduction or function (“Therapeutic Agents”) and the use ol″ those agents to modulate immune function. The Therapeutic Agents target the interaction between IL-15 and its receptor and modulate IL-15-induced signal transduction. The Therapeutic Agents may be formulated with polymers, such as poly-β-1-♦4-N-acetylglucosamine. for administration to a human subject to modulate IL-15-mediated immune function.
Core Innovation
The invention relates to agents that modulate interleukin-15 (IL-15) signal transduction or function and their use to modulate immune function. These Therapeutic Agents target the interaction between IL-15 and its receptor, modulating IL-15-induced signal transduction, and can be formulated with polymers such as poly-β-1→4-N-acetylglucosamine for administration to human subjects.
The Therapeutic Agents include Agonistic Therapeutic Agents that induce IL-15 signal transduction and enhance IL-15-mediated immune function, useful for preventing, treating, and managing diseases that benefit from enhanced IL-15 function, such as cancer and infectious diseases. The Agonistic Therapeutic Agents comprise complexes of IL-15 covalently or noncovalently bound to interleukin-15 receptor alpha (IL-15Ra), nucleic acids encoding IL-15 and IL-15Ra, or cells expressing such complexes.
The invention also provides Antagonistic Therapeutic Agents that reduce or inhibit IL-15 signal transduction and suppress IL-15-mediated immune function. These include antibodies that specifically bind to IL-15/IL-15Ra complexes and prevent binding to the βγ subunits of the IL-15 receptor, and cells engineered to express such antibodies. The Antagonistic Therapeutic Agents are useful for preventing, treating, or managing disorders where suppression of IL-15 immune function is beneficial, such as autoimmune disorders, graft versus host disease, transplantation rejection, and inflammatory disorders.
The invention further relates to methods for producing IL-15/IL-15Ra complexes and cells expressing these complexes in high amounts, including irradiated cancer cells engineered to co-express IL-15 and IL-15Ra for therapeutic administration. The Therapeutic Agents may be administered alone or in combination therapy with other treatments to modulate immune responses.
Claims Coverage
The claims encompass 23 inventive features focused on isolated cells expressing IL-15 and soluble IL-15Ra complexes, with specific amino acid sequence identities, expression levels, and cell types, including irradiated cancer cells and recombinant mammalian cell lines.
Isolated cell expressing human IL-15 and soluble human IL-15Ra complex with specified sequence identity and expression level in serum-free media
An isolated cell recombinantly expresses human IL-15 and a soluble form of human IL-15Ra at least 95% identical to amino acid residues 31-267 of SEQ ID NO:3, expressing at least 0.15 pg of human IL-15 per day when cultured in serum-free media.
Specific amino acid sequence identities of human IL-15 and human IL-15Ra
The human IL-15 is at least 95% identical to amino acid residues 49-162 of SEQ ID NO:1; the human IL-15Ra comprises the amino acid sequence of residues 31-267 of SEQ ID NO:3, or a soluble form of human IL-15Ra is at least 95% identical to residues 31-205 of SEQ ID NO:4, alone or in combination.
Isolated cell expressing complex of codon-optimized human IL-15 and IL-15Ra sequences with expression in serum-free media
An isolated cell recombinant expresses a complex comprising human IL-15 and human IL-15Ra from codon-optimized nucleic acid sequences encoding human IL-15 and IL-15Ra (95% identical to residues 31-267 or 31-205 of SEQ ID NOs:14 or 16), expressing at least 0.15 pg of human IL-15 per day in serum-free media.
Isolated cell is a mammalian cell line including 293H, 293, or CHO cell lines
The isolated cell expressing IL-15 and IL-15Ra complex may be a mammalian cell line derived from 293H, 293, or CHO cell lines.
Isolated cell can be an irradiated cancer cell
The isolated cell expressing human IL-15 and soluble human IL-15Ra complex may be an irradiated cancer cell.
Isolated cell expresses defined amounts of human IL-15
The cell expresses at least 0.6 pg, at least 1 pg, or up to 2 pg of human IL-15 per day when cultured in serum-free media.
The claims define isolated cells that recombinantly express human IL-15 and soluble forms of human IL-15Ra with high amino acid sequence identity, specified expression levels in serum-free media, including irradiated cancer cells and recombinant mammalian cell lines such as 293H, 293, or CHO cells, using both native and codon-optimized nucleic acid sequences.
Stated Advantages
Enhancement of IL-15-mediated immune functions, including antibody production, T cell proliferation, and natural killer (NK) cell proliferation.
Suppression of IL-15-mediated immune functions, useful for managing autoimmune, inflammatory, and transplant rejection disorders.
Increased stability and bioactivity of IL-15 when produced from cells co-expressing IL-15 and IL-15Ra.
Improved therapeutic potential of IL-15/IL-15Ra complexes via formulation with natural polymers like poly-β-1→4-N-acetylglucosamine.
Documented Applications
Prevention, treatment, and management of diseases involving modulation of IL-15-mediated function, including cancer, infectious diseases, autoimmune diseases, inflammatory disorders, graft versus host disease, and transplantation rejection.
Use of irradiated cancer cells expressing IL-15 and IL-15Ra complexes as therapeutic agents for cancer immunotherapy.
Gene therapy protocols administering nucleic acids encoding IL-15 and IL-15Ra complexes to modulate immune function.
Formulation of Therapeutic Agents with polymers for administration to enhance or suppress IL-15-mediated immune responses in human or veterinary applications.
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