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Publication Number
US-12116389-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 invention relates to dual cytokine fusion protein therapeutics based on a monomeric IL-10 scaffold. A monomeric IL-10 is fused in an architecture of (IL-10)-(X1)–(Z n)–(X2)-(IL-10), where X1 is a VL or VH region from an anti-Ebola monoclonal antibody and X2 is a VH or VL region from the first monoclonal antibody. The scaffold incorporates a cytokine Z other than IL-10 as a second cytokine connected through an integer n of 1.
The antibody component is a VL and VH system that includes 3 light chain CDRs and 3 heavy chain CDRs. These CDRs are engrafted such that 3 light chain CDRs and 3 heavy chain CDRs from a second monoclonal antibody are used in the engrafted regions of the anti-Ebola antibody variable regions. In the specific example described, the second antibody is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody and Z is IL-2, with IL-10 being SEQ ID No: 1.
The described embodiments further include IL-10 variant therapeutics using an EBV IL-10 substitution scheme (DV05/DV06/DV07) and insertion or fusion of a second cytokine in the scFv hinge/linker region between VH and VL. The documented molecules include DK2_10 (DV07+IL-2) and DK4_10 (IL-10 variant DV06/DV07 with IL-4 variants), where DK2_10 is stated to show enhanced IFN-γ potentiation and reduced IL-2 toxicity compared to alternative IL-2 placement, and DK4_10 is stated to show superior monocyte/macrophage TNFα suppression and reduced CD8+ IFN-γ induction. A sepsis model is described to indicate efficacy for survival and prevention of septic shock for DK4_10mCD14DV06.
Claims Coverage
The partial content provides coverage anchored by one independent claim (clm-00001) that defines a dual cytokine fusion protein architecture using a monomeric IL-10 scaffold and an antibody variable-region system from an anti-Ebola antibody, linked through a second cytokine Z; the dependent claims (clm-00002, clm-00003, clm-00004) refine the framework/CDR engraftment specifics and add pharmaceutical composition coverage. The main inventive features emphasized in the independent claim include the specific IL-10 dual-cytokine fusion formula architecture, the anti-Ebola variable-region integration, and the specification of Z as IL-2 with an anti-EGFR second monoclonal antibody for CDR grafting, together with the n constraint of 1.
Dual cytokine fusion protein architecture with monomeric IL-10
A dual cytokine fusion protein of formula (I) in which “IL-10” is a monomer and is arranged as (IL-10)-(X1)–(Z n)–(X2)-(IL-10) with n being an integer of 1, where “Z” is a cytokine other than IL-10.
Anti-Ebola variable regions fused into the IL-10 architecture
The fusion protein uses X1 as a VL or VH region from an anti-Ebola monoclonal antibody and X2 as the corresponding VH or VL region from the first monoclonal antibody, arranged such that when X1 is a VL, X2 is a VH, and when X1 is a VH, X2 is a VL.
CDR engraftment between anti-Ebola and anti-EGFR antibodies with Z as IL-2
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, wherein the IL-10 is SEQ ID No: 1, the second antibody is an anti-EGFR monoclonal antibody, and Z is IL-2.
Framework regions from a human anti-Ebola antibody
The VH and VL regions include framework regions obtained from a human anti-Ebola antibody.
Three-by-three CDR grafting pattern using defined CDR counts
The framework region from an anti-Ebola antibody is engineered with three VH CDRs and three VL CDRs taken from an anti-EGFR monoclonal antibody.
Pharmaceutical composition with pharmaceutically acceptable buffers and excipients
A pharmaceutical composition includes the dual cytokine fusion protein together with pharmaceutically acceptable buffers and excipients.
Across the provided independent claim and refinements, the core coverage centers on a dual cytokine fusion protein that uses a monomeric IL-10 scaffold linked through a second cytokine Z with n=1, integrates anti-Ebola antibody variable regions (VL/VH), and defines CDR engraftment to a second monoclonal antibody (anti-EGFR) with Z specified as IL-2; dependent claims further narrow framework source (human anti-Ebola), specify the three-by-three VH/VL CDR grafting pattern, and cover pharmaceutical compositions with buffers and excipients.
Stated Advantages
Enhanced IFN-γ potentiation with reduced IL-2 toxicity for DK2_10 compared to alternative IL-2 placement.
Superior monocyte/macrophage TNFα suppression and reduced CD8+ IFN-γ induction for DK4_10 compared to related embodiments.
Efficacy in a sepsis model for survival/prevention of septic shock associated with DK4_10mCD14DV06.
Documented Applications
A sepsis/septic shock model is described, including efficacy for survival/prevention of septic shock for DK4_10mCD14DV06.
Immunological readouts are documented, including enhanced IFN-γ potentiation, reduced IL-2 toxicity, monocyte/macrophage TNFα suppression, and reduced CD8+ IFN-γ induction for specified dual cytokine fusion proteins.
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