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Publication Number
US-12263358-B2
Publication Date
2025-04-01
Expiration Date
Abstract
The application relates to a dual cytokine fusion protein composition, pharmaceutical composition, and/or formulation thereof comprising IL-10 or IL-10 variant molecules fused to a single chain variable fragment scaffolding system and a second cytokine, where the second cytokine is linked in the hinge region of the scFv. The application also relates to methods of using the dual cytokine fusion protein composition for treating cancer, inflammatory diseases or disorders, and immune and immune mediated diseases or disorders.
Core Innovation
The invention relates to dual cytokine fusion protein compositions of formula (I), in which a monomeric IL-10 is fused into a structured scaffolding that includes antibody regions, and a second cytokine Z other than IL-10 is linked into the fusion. The formula specifies that IL-10 is present at both ends of the fusion format and that Z is separated between antibody-derived regions, with n being an integer of 1.
The fusion format uses a VL or VH region from a first monoclonal antibody (X1) and a complementary VH or VL region (X2) derived from the first monoclonal antibody. The first monoclonal antibody is an anti-ebola antibody, and the VL and VH from the anti-ebola antibody include 3 light chain CDRs and 3 heavy chain CDRs that are engrafted with 3 light chain CDRs and 3 heavy chain CDRs from a second monoclonal antibody, specified as an anti-EGFR monoclonal antibody.
The described subject matter provides dual cytokine fusion designs together with nucleic acids encoding the fusion proteins and pharmaceutical formulations. The partial content also reports in vitro and in vivo evidence for tethering IL-2/IL-10 via an scFv linker to enhance antigen-specific T-cell IFNγ potency while suppressing IL-2-mediated pro-inflammatory/toxicity signals, and for IL-10/IL-4 dual fusions to more potently suppress LPS-induced monocyte TNFα and reduce IFNγ induction.
Claims Coverage
The document includes one independent claim defining the overall dual cytokine fusion protein architecture, its antibody scaffold and CDR engrafting, and specific cytokine assignments. The dependent claims refine formulation aspects and narrow the antibody framework origin and the CDR engrafting pattern and source.
Dual cytokine fusion protein of formula (I)
A dual cytokine fusion protein of formula (I) in which IL-10 is a monomer fused in a format having a VL/VH-derived scaffold (X1 and X2), and a cytokine Z other than IL-10 linked between the IL-10 segments, wherein n is an integer of 1.
Anti-ebola scaffold with CDR engrafting from a second monoclonal antibody
The fusion protein wherein the first monoclonal antibody is an anti-ebola antibody and the VL and VH from the anti-ebola antibody include 3 light chain CDRs and 3 heavy chain CDRs that are engrafted with 3 light chain CDRs and 3 heavy chain CDRs from a second monoclonal antibody.
Specific cytokine and second antibody combination (IL-7 with anti-EGFR; IL-10 SEQ ID No: 1)
Wherein the IL-10 is SEQ ID No: 1, the second antibody is an anti-EGFR monoclonal antibody, and Z is IL-7, with n being 1.
Pharmaceutical composition with pharmaceutically acceptable buffers and excipients
A pharmaceutical composition that includes the dual cytokine fusion protein together with pharmaceutically acceptable buffers and pharmaceutically acceptable excipients.
VH and VL framework regions derived from human anti-Ebola antibody
The fusion protein wherein the VH and VL regions include framework regions derived from a human anti-Ebola antibody.
CDR engrafting count constrained to three VH and three VL CDRs from the anti-EGFR antibody
The fusion protein wherein the frame region from the anti-Ebola antibody is engrafted with three VH CDRs and three VL CDRs from an anti-EGFR monoclonal antibody.
Overall, the claim set centers on a dual cytokine fusion protein defined by formula (I), using an anti-ebola antibody-derived VL/VH scaffold with 3+3 CDR engrafting from an anti-EGFR antibody, and specifying IL-10 as SEQ ID No: 1 with Z as IL-7 (n=1). Dependent claims further add pharmaceutical composition components and narrow the antibody framework origin and the exact CDR engrafting counts and source.
Stated Advantages
Enhances antigen-specific T-cell IFNγ potency while suppressing IL-2-mediated pro-inflammatory/toxicity signals.
More potently suppresses LPS-induced monocyte TNFα and reduces IFNγ induction.
Documented Applications
Therapeutic applications in cancer.
Inflammatory/immune diseases including Crohn’s disease, psoriasis, and rheumatoid arthritis.
Sepsis/septic shock.
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