Complexes of IL-15 and IL-15Ralpha and uses thereof
Inventors
Felber, Barbara K. • Finkielsztein, Sergio • Pavlakis, George N. • VOURNAKIS, John V.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10265382-B2
Publication Date
2019-04-23
Expiration Date
2028-06-27
Abstract
The present invention relates to agents that modulate interleυkin-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 provides agents, termed Therapeutic Agents, that modulate interleukin-15 (IL-15) signal transduction or function, targeting the interaction between IL-15 and its receptor. These Therapeutic Agents modulate IL-15-induced signal transduction and can be formulated with polymers such as poly-β-1→4-N-acetylglucosamine for administration to human subjects to modulate IL-15-mediated immune function.
The Therapeutic Agents are divided into Agonistic Therapeutic Agents that induce IL-15 signal transduction and enhance IL-15-mediated immune function, and Antagonistic Therapeutic Agents that reduce or inhibit IL-15 signal transduction and suppress IL-15-mediated immune function. The Agonistic Therapeutic Agents include complexes comprising 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 IL-15/IL-15Ra complexes. These are useful for prevention, treatment, and management of disorders benefitting from enhanced IL-15-mediated immune function such as cancer and infectious diseases. The Antagonistic Therapeutic Agents include antibodies that specifically bind IL-15/IL-15Ra complexes and prevent binding to the beta/gamma receptor complex, useful for disorders where suppression of IL-15-mediated immune function is beneficial, such as autoimmune disorders, graft versus host disease, transplantation rejection, and inflammatory disorders.
Significant aspects of the invention describe engineering IL-15Ra derivatives to inhibit cleavage by endogenous proteases or substituting cleavage sites, facilitating formation of stable complexes with IL-15. The IL-15/IL-15Ra complexes may include heterologous molecules, such as disease-associated antigens or antibodies, which can be conjugated to IL-15 or IL-15Ra without interfering with receptor binding. The use of polymers, specifically poly-β-1→4-N-acetylglucosamine, is emphasized to formulate these complexes or cells expressing IL-15/IL-15Ra for administration. Additionally, methods include generating irradiated cancer cells engineered to co-express IL-15 and IL-15Ra as Therapeutic Agents to enhance immune responses against cancer.
Claims Coverage
The patent discloses a method comprising seven main inventive features related to producing and purifying codon optimized human IL-15 and IL-15Ra complexes using engineered cells.
Recombinant production of codon optimized human IL-15 and IL-15Ra complex
A method of culturing cells expressing codon optimized human IL-15 encoded by nucleic acid sequences with at least 95% identity to specific regions of SEQ ID NOs: 9, 11, or 17, and human IL-15Ra encoded by nucleic acid sequences with at least 95% identity to specific regions of SEQ ID NOs: 13 or 15, followed by purification of the IL-15/IL-15Ra complex.
Specific nucleic acid combinations for IL-15 and IL-15Ra expression
Variants of the above method employing specific combinations of nucleic acid sequences from the named SEQ IDs to encode human IL-15 and IL-15Ra.
Selection of cell lines for production
Use of specific mammalian cell lines such as 293 or CHO cells for expressing the IL-15 and IL-15Ra nucleic acids to produce the complex.
High expression levels of IL-15
The method ensures cells express at least 0.15 pg (up to 2 pg) of human IL-15 per day in serum-free media as measured by ELISA, indicating high production yield.
The claims cover recombinant methods using codon optimized IL-15 and IL-15Ra nucleic acids expressed in mammalian cells to produce and purify IL-15/IL-15Ra complexes with defined nucleic acid sequences and high expression levels, focusing on specific nucleic acid sequence identities and cell line selection.
Stated Advantages
Therapeutic Agents enhance or suppress IL-15-mediated immune function depending on the therapeutic goal.
Formulation with polymers like poly-β-1→4-N-acetylglucosamine improves administration and stability of Therapeutic Agents.
Use of IL-15/IL-15Ra complexes or engineered cells enables stable expression and production of bioactive agents for therapy.
Methods enable targeting specific diseases by modulating IL-15 signaling, with applications in cancer, infectious, autoimmune, and inflammatory diseases.
Documented Applications
Treatment, prevention, and management of diseases involving modulation of IL-15-mediated signaling including cancer, infectious diseases, autoimmune diseases, inflammatory disorders, graft versus host disease, and transplantation rejection.
Use of agonistic Therapeutic Agents to enhance IL-15-mediated immune function for cancer and infectious disease therapy.
Use of antagonistic Therapeutic Agents to suppress IL-15-mediated immune function in autoimmune, inflammatory, graft versus host, and transplant rejection conditions.
Use of irradiated cancer cells engineered to express IL-15 and IL-15Ra as Therapeutic Agents to induce or enhance immune responses against tumors.
Formulation of therapeutic complexes or cells with polymers such as poly-β-1→4-N-acetylglucosamine for improved delivery.
Interested in licensing this patent?