Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12116393-B2
Publication Date
2024-10-15
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 disclosure relates to a dual cytokine fusion protein of formula (I) in which IL-10 is provided as a monomer and is fused on both sides of an additional cytokine Z. The protein includes VL and VH regions that are derived from a first monoclonal antibody, where Z is a cytokine other than IL-10 and n is an integer of 1. In the disclosed embodiment, IL-10 is specified by SEQ ID No: 14 and Z is specified as IL-4.
The VL and VH regions are built using a scFv antigen binding format in which 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 disclosed linkage of the second cytokine Z into the VH/VL-based fusion architecture is framed by structural formulae such as IL10-(X1)-(Z)n-(X2)-IL10 and IL10-(L)-(X1)-(L)-(Zn)-(L)-(X2)-(L)-IL10, with the CDR engraftment strategy supporting targeted dual cytokine behavior.
The disclosure further specifies second-antibody targeting through an anti-VEGFR2 monoclonal antibody component and specifies Z as IL-4. In refinements described, an IL-4 non-glycosylated form is used, including the non-glycosylated IL-4 sequence identified as SEQ ID No. 44, and a pharmaceutical composition is provided comprising the fusion protein with pharmaceutically acceptable buffers and excipients.
Claims Coverage
The independent claim defines a dual cytokine fusion protein of formula (I) with a defined IL-10 monomer architecture, a second cytokine Z specified as IL-4, and an scFv-based VH/VL targeting derived from an anti-Ebola monoclonal antibody with CDR engraftment from an anti-VEGFR2 monoclonal antibody. Dependent claims further restrict the framework/CDR engineering, constrain IL-4 to a non-glycosylated form with a specified sequence, and add a pharmaceutical composition formulation.
Dual cytokine fusion protein of formula (I) with IL-10 on both ends and cytokine Z
A dual cytokine fusion protein of formula (I) where IL-10 is a monomer, Z is a cytokine other than IL-10, n is an integer of 1, and the protein is represented as NH2-(IL-10)-(X1)-(Zn)-(X2)-(IL-10)-COOH, with X1 and X2 being VL or VH regions from the first monoclonal antibody.
Anti-Ebola scFv VH/VL with 3 light chain CDRs and 3 heavy chain CDRs engrafted to a second 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.
Anti-VEGFR2 targeting with IL-4 as Z and IL-10 as SEQ ID No: 14
IL-10 is SEQ ID No: 14, the second antibody is an anti-VEGFR2 monoclonal antibody, and Z is IL-4.
Non-glycosylated IL-4 form as the cytokine Z component
The IL-4 component is a non-glycosylated form of IL-4 in the fusion protein.
Specified sequence for non-glycosylated IL-4 (SEQ ID No. 44)
The non-glycosylated form of IL-4 includes a sequence identified as SEQ ID No. 44.
Pharmaceutical composition including the dual cytokine fusion protein
A pharmaceutical composition comprising the dual cytokine fusion protein together with pharmaceutically acceptable buffers and excipients.
Overall, the claim set centers on a dual cytokine fusion protein using IL-10 monomers fused around IL-4, combined with an anti-Ebola-derived VH/VL architecture that uses 3 light and 3 heavy CDRs engrafted with CDRs from an anti-VEGFR2 monoclonal antibody, with dependent claims constraining IL-4 to a non-glycosylated form defined by SEQ ID No. 44 and covering a pharmaceutical composition containing the fusion protein.
Stated Advantages
Modulates monocyte TNFα suppression while avoiding IL-2-mediated toxicity.
Improves anti-tumor activity versus Degfr:DV07 in CT26 (hEGFR+) mice.
Suppresses LPS-induced TNFα secretion from monocytes.
Inhibits IFNγ induction from CD8+ T cells.
Provides a sepsis survival benefit shown for an IL-4-containing regimen.
Documented Applications
CT26 (hEGFR+) tumor mouse model, described in connection with improved anti-tumor activity versus Degfr:DV07.
Assays involving LPS-induced TNFα secretion from monocytes and IFNγ induction from CD8+ T cells, described in connection with cytokine-containing regimens.
Sepsis/septic shock mouse model described through a sepsis survival benefit for an IL-4-containing regimen.
Interested in licensing this patent?