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Publication Number
US-12268903-B2
Publication Date
2025-04-08
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 a dual cytokine fusion protein that includes IL-10 as a monomer and a second cytokine Z other than IL-10. The protein is defined by a formula (I) with an NH2-(IL-10)-(X1)-(Z^n)-(X2)-(IL-10)-COOH structure, in which IL-10 is positioned at both termini of the construct and Z^n is linked between the antibody-derived regions X1 and X2.
X1 and X2 are VL or VH regions from an anti-Ebola monoclonal antibody, with the condition that when X1 is a VL then X2 is a VH, and when X1 is a VH then X2 is a VL. 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.
The document further describes dual cytokine fusion proteins that fuse IL-10 monomers, including EBV IL-10 variants such as DV05, DV06, and DV07, to a VH/VL scFv scaffold, with a second cytokine Z including IL-2, IL-4, and IL-15 linked in a hinge/linker region between the VH and VL. The background problem being solved is to achieve therapeutic modulation of immune and inflammatory responses using dual cytokine fusion proteins involving IL-10 and a second cytokine other than IL-10.
Claims Coverage
The patent documents one independent claim defining the dual cytokine fusion protein of formula (I) with an anti-Ebola antibody scaffold that includes CDR engrafting from a second monoclonal antibody, and it includes dependent claims adding formulation and framework/CDR engrafting details. The independent claim contains 3 principal inventive feature groups: the structural formula with terminal IL-10 monomers and a Z^n cytokine other than IL-10; the antibody-derived VL/VH domain arrangement and anti-Ebola origin; and the specified CDR engrafting pattern plus a particular anti-EGFR/IL-15/SEQ ID embodiment.
Terminal IL-10 monomers with Z^n dual cytokine structure
A dual cytokine fusion protein of formula (I) with NH2-(IL-10)-(X1)-(Z^n)-(X2)-(IL-10)-COOH, wherein IL-10 is a monomer and Z is a cytokine other than IL-10 with n being an integer of 1.
Anti-Ebola VL/VH scaffold defining X1 and X2 orientation
X1 is a VL or VH region from a first monoclonal antibody and X2 is a VH or VL region from the first monoclonal antibody, with the first monoclonal antibody being an anti-Ebola antibody and with X1/X2 orientation such that a VL pairs with a VH.
CDR engrafting from a second monoclonal antibody and specified anti-EGFR/IL-15 embodiment
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, with an embodiment wherein IL-10 is SEQ ID No: 16, the second antibody is an anti-EGFR monoclonal antibody, Z is IL-15, and n is 1.
Pharmaceutical composition with pharmaceutically acceptable buffers and excipients
A pharmaceutical composition including the dual cytokine fusion protein together with pharmaceutically acceptable buffers and pharmaceutically acceptable excipients.
Human anti-Ebola framework-derived VH/VL regions
VH and VL regions in the fusion protein that include framework regions derived from a human anti-Ebola antibody.
Detailed three-and-three VH/VL CDR engrafting between anti-Ebola and anti-EGFR
Engrafting the frame region from an anti-Ebola antibody with three VH CDRs and three VL CDRs from an anti-EGFR monoclonal antibody.
Overall claim coverage centers on a dual cytokine fusion protein defined by terminal IL-10 monomers and a Z^n cytokine other than IL-10, attached to an anti-Ebola VL/VH scaffold with 3 light and 3 heavy CDRs engrafted from a second monoclonal antibody, plus an explicit anti-EGFR/IL-15/SEQ ID No: 16 embodiment (n = 1). Dependent claims further cover pharmaceutical composition components, human anti-Ebola framework sourcing, and a specified three VH/three VL CDR engrafting pattern.
Stated Advantages
Increases IFN-γ potentiation potency while suppressing IL-2-associated pro-inflammatory/IFN-γ responses for IL-2 tethered to the IL-10 fusion construct.
Synergistically enhance monocyte/macrophage TNFα suppression and reduce CD8+ T cell IFN-γ for IL-10 + IL-4 fusion constructs.
Improved anti-tumor performance in vivo in the tumor model described.
Survival benefit in sepsis in vivo.
Documented Applications
Therapeutic methods and related use cases for cancer.
Therapeutic methods and related use cases for inflammatory and immune diseases, including Crohn’s disease, psoriasis, and rheumatoid arthritis.
Therapeutic methods and related use cases for sepsis and septic shock.
In vivo tumor model use described for anti-tumor performance, including a tumor model referenced as CT26 (hEGFR+).
In vivo sepsis model use described for survival benefit with specific constructs.
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