Interleukin-15 (IL-15) fusion proteins and uses thereof
Inventors
Li, Yue-Sheng • Rui, Lingyun • Xu, Jing
Assignees
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Publication Number
US-12319722-B2
Publication Date
2025-06-03
Expiration Date
Abstract
The present disclosure provides novel and improved IL-15 fusion proteins for use in the treatment of cancer and other disorders. In various embodiments, the fusion proteins of the invention have two functional domains: an IL-15/IL-15RαSushi domain (also referred to herein as an “IL-15/IL-15RαSushi complex”) and an Fc domain, each of which can take different forms, and configured such that the IL-15 is fused to the C-terminal of the Fc domain and co-expressed and non-covalently complexed with IL-15RαSushi. Importantly, the fusions proteins of the present invention address several of the limitations observed with the IL-15 therapeutics evaluated to date; specifically, the fusion proteins demonstrate extended the half-life of IL-15 in vivo, and demonstrate superior preclinical activity compared to rIL-15 or related cytokine therapeutics.
Core Innovation
The invention relates to isolated Interleukin-15 (IL-15) fusion protein complexes comprising an IL-15 polypeptide, or variant thereof, linked to an Fc domain and an IL-15 Receptor alpha (IL-15Rα) domain noncovalently linked to the IL-15 polypeptide to form an IL-15/IL-15Rα-Fc fusion protein complex. The IL-15 polypeptide is an IL-15 variant polypeptide comprising a substitution of S to D at position 58 of SEQ ID NO: 2. The fusion protein complex is selected from configurations in which the IL-15 polypeptide is linked to either the C-terminus or the N-terminus of the Fc domain.
The described formats further include an IL-15Rα Sushi+ domain or IL-15Rα Sushi/ECD sequences noncovalently associated with an IL-15-Fc construct. The noncovalent IL-15Rα association is presented as maintaining native complex formation during purification and as supporting reduced aggregation, improved developability, and functional properties including enhanced IL-15Rβ binding. Fusion formats compared in the provided content include monovalent versus dimeric Fc fusion and N-terminal versus C-terminal Fc fusion orientation.
The described dimeric IL-15/IL-15Rα-Fc fusion protein complexes comprise two IL-15 polypeptides, or variants thereof, linked to two Fc domains and two IL-15Rα domains noncovalently linked to each IL-15 polypeptide, with at least one IL-15 polypeptide comprising the S to D substitution at position 58 of SEQ ID NO: 2. The invention states that IL-15 fusion formats incorporating an IL-15/IL-15Rα Sushi complex with an Fc domain extend in vivo half-life and improve preclinical activity versus rIL-15.
Claims Coverage
The consolidated claim set includes four independent claims. Across these claims, the core inventive coverage comprises noncovalent IL-15/IL-15Rα association in IL-15/IL-15Rα-Fc complexes using an IL-15 S58D variant, with IL-15 or IL-15Rα positioned relative to the Fc domain as either C-terminus-linked or N-terminus-linked, and with dimeric forms covered for both IL-15-linked and IL-15Rα-linked Fc configurations.
Noncovalently linked IL-15/IL-15Rα-Fc complex with IL-15 S58D variant
An isolated IL-15 fusion protein complex comprising an IL-15 polypeptide, or variant thereof, linked to an Fc domain and an IL-15Rα domain noncovalently linked to the IL-15 polypeptide to form an IL-15/IL-15Rα-Fc fusion protein complex, wherein the IL-15 polypeptide comprises a substitution of S to D at position 58 of SEQ ID NO: 2.
Fc-linked IL-15 orientation selected between C-terminus and N-terminus
The isolated IL-15 fusion protein complex wherein the IL-15 polypeptide is linked to the C-terminus of the Fc domain or to the N-terminus of the Fc domain.
Noncovalently linked IL-15/IL-15Rα-Fc complex with IL-15Rα linked to Fc
An isolated IL-15 fusion protein complex comprising an IL-15Rα domain linked to an Fc domain and an IL-15 polypeptide, or variant thereof, noncovalently linked to the IL-15Rα domain to form an IL-15/IL-15Rα-Fc fusion protein complex, wherein the IL-15 polypeptide comprises a substitution of S to D at position 58 of SEQ ID NO: 2.
Fc-linked IL-15Rα orientation selected between C-terminus and N-terminus
The isolated IL-15 fusion protein complex wherein the IL-15Rα domain is linked to the C-terminus of the Fc domain or to the N-terminus of the Fc domain.
Dimeric IL-15/IL-15Rα-Fc fusion with two IL-15 polypeptides and two IL-15Rα domains
An isolated IL-15 fusion protein complex comprising two IL-15 polypeptides, or variants thereof, linked to two Fc domains and two IL-15Rα domains noncovalently linked to each IL-15 polypeptide to form a dimeric IL-15/IL-15Rα-Fc fusion protein complex, wherein the IL-15 polypeptide comprises a substitution of S to D at position 58 of SEQ ID NO: 2.
Dimeric Fc orientation selected between IL-15 C-terminus-linked and N-terminus-linked configurations
The dimeric IL-15/IL-15Rα-Fc fusion protein complex wherein the two IL-15 polypeptides are linked to the C-terminus of the two Fc domains or to the N-terminus of the two Fc domains.
Dimeric IL-15/IL-15Rα-Fc fusion with IL-15Rα linked to Fc and at least one IL-15 S58D variant polypeptide
An isolated IL-15 fusion protein complex comprising two IL-15Rα domains linked to two Fc domains and two IL-15 polypeptides, or variants thereof, noncovalently linked to the IL-15Rα domains to form a dimeric IL-15/IL-15Rα-Fc fusion protein complex, wherein at least one of the IL-15 polypeptides comprises an amino acid substitution of S to D at position 58 of SEQ ID NO: 2.
Dimeric Fc orientation selected between IL-15Rα C-terminus-linked and N-terminus-linked configurations
The dimeric fusion protein complex wherein the two IL-15Rα domains are linked to the C-terminus of the two Fc domains or to the N-terminus of the two Fc domains.
Collectively, the independent claims define IL-15/IL-15Rα-Fc fusion protein complexes using an IL-15 S to D substitution at position 58 of SEQ ID NO: 2 and noncovalent IL-15/IL-15Rα association with Fc-domain linkage orientation at either the N-terminus or C-terminus. The claims also extend to dimeric forms including two IL-15 polypeptides and two IL-15Rα domains linked to Fc domains, and some dependent claims further cover pharmaceutical compositions with pharmaceutically acceptable carriers.
Stated Advantages
Reduced aggregation, as characterized by aggregation propensity and purity measures.
Improved purity of the fusion protein formats compared across tested formats.
Enhanced super-agonist activity, including increased IL-15Rβ binding and increased pSTAT5/Ki67 potency.
Higher serum exposure and longer-lasting Ki67 induction in vivo.
Improved NK/CD8 expansion in vivo.
Reduced lung metastasis and solid tumor growth in vivo.
Good tolerability, including body weight and reduced liver enzyme effects (ALT/AST).
Extends in vivo half-life.
Improves preclinical activity versus rIL-15.
Provides improved developability and functional properties, including enhanced IL-15Rβ binding.
Documented Applications
Biological activity evaluation in human PBMC/NK/T cells, including IL-15Rβ binding, CD69 induction, pSTAT5 signaling, and Ki67 proliferation.
In vivo mouse studies evaluating repeated dosing PK/PD and single dosing PK/PD in mouse models, including NK/CD8 expansion, Ki67 induction, and tumor outcomes such as reduced lung metastasis and solid tumor growth.
Therapeutic uses including cancer.
Therapeutic uses including viral infection.
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