Complexes of IL-15 and IL-15Ralpha and uses thereof
Inventors
Felber, Barbara K. • Finkielsztein, Sergio • Pavlakis, George N. • VOURNAKIS, John V.
Assignees
Novartis AG • US Department of Health and Human Services
Publication Number
US-11110150-B2
Publication Date
2021-09-07
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 Therapeutic Agents that modulate interleukin-15 (IL-15) signal transduction or function, targeting the interaction between IL-15 and its receptor to regulate IL-15-mediated immune function. These agents can be formulated with polymers, especially poly-β-1→4-N-acetylglucosamine, and are intended for administration to human subjects to alter IL-15-mediated immune responses.
The Therapeutic Agents include Agonistic Therapeutic Agents that induce IL-15 signal transduction and enhance IL-15-mediated immune function. These agents encompass complexes of IL-15 covalently or noncovalently bound to interleukin-15 receptor alpha (IL-15Ra), nucleic acids encoding IL-15 and IL-15Ra, and cells engineered to express such complexes. Various forms of IL-15Ra derivatives, including soluble forms and mutants inhibiting cleavage by endogenous proteases, are described. The complexes may be conjugated to heterologous molecules such as disease-associated antigens or antibodies, which do not interfere with binding functionality. Additionally, the Antagonistic Therapeutic Agents suppress IL-15 signaling, including antibodies that specifically bind IL-15/IL-15Ra complexes and inhibit their interaction with the βγ receptor subunits, useful for disorders benefiting from immune suppression.
The invention addresses the problem that despite understanding IL-15's role in immune modulation, the therapeutic use of various forms of IL-15Ra alone or in complex with IL-15 to modulate IL-15 functions was unclear. IL-15 is known to exist mainly as a membrane-bound form rather than soluble serum protein, and soluble IL-15Ra had contradictory functional roles reported, with recent reports suggesting that IL-15 complexed with soluble IL-15Ra maintains immune enhancing activity. The invention provides compositions and methods to exploit these complexes as therapeutic agents to modulate immune functions for diseases including cancer, infectious diseases, autoimmune diseases, and transplant rejection.
Claims Coverage
The patent discloses one independent method claim concerning the recombinant production of human IL-15 and IL-15Ra complexes.
Method of producing human IL-15 and IL-15Ra complexes
A method involving culturing a cell expressing human IL-15 encoded by a nucleic acid sequence with at least 95% identity to nucleic acid residues 1 to 489 of SEQ ID NO:2 and human IL-15Ra encoded by either (i) a nucleic acid sequence with at least 95% identity to nucleic acid residues 1 to 804 of SEQ ID NO:5; or (ii) a nucleic acid sequence with at least 95% identity to nucleic acid residues 1 to 615 of SEQ ID NO:6, followed by purification of the human IL-15 and IL-15Ra complex.
Use of specific nucleic acid sequences for IL-15 and IL-15Ra
Specifying the use of nucleic acid sequences comprising nucleic acid residues 1 to 489 of SEQ ID NO:2 for human IL-15 and nucleic acid residues either 1 to 804 of SEQ ID NO:5 or 1 to 615 of SEQ ID NO:6 for human IL-15Ra encoding in the production process.
Cell lines suitable for recombinant production
Culturing the IL-15 and IL-15Ra-expressing cells in specific cell lines selected from a broad group including 293, COS, CHO, HeLa, NIH3T3, and others as enumerated in the claim for recombinant IL-15/IL-15Ra complex production.
The claims cover a method of recombinant production of IL-15/IL-15Ra complexes utilizing specific nucleic acid sequences and cell lines, focusing on producing and purifying biologically active human IL-15 and IL-15Ra complexes using defined recombinant techniques.
Stated Advantages
Therapeutic Agents target and modulate IL-15-induced signal transduction to enhance or suppress IL-15-mediated immune functions beneficial for disease treatment.
Formulation with polymers such as poly-β-1→4-N-acetylglucosamine improves delivery and administration to human subjects.
Engineered cells expressing IL-15 and IL-15Ra in high amounts increase yield and bioactivity of IL-15, facilitating therapeutic use.
Combination therapy with other biological or chemical agents enhances therapeutic efficacy against diseases involving IL-15 signaling.
Documented Applications
Prevention, treatment, and management of diseases involving IL-15-mediated signaling, including cancer, infectious disease, autoimmune disease, and transplantation rejection.
Enhancement of IL-15-mediated immune function to treat cancer and infectious diseases.
Suppression of IL-15-mediated immune function for autoimmune disorders, graft versus host disease, transplantation rejection, and inflammatory disorders.
Use of irradiated cells engineered to express IL-15 and IL-15Ra as immunotherapeutic agents for cancer and infectious diseases.
Formulation with polymers for administration to human subjects or veterinary uses.
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