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Publication Number
US-12121755-B2
Publication Date
2024-10-22
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 proteins that use an IL-10 monomer as a tethering cytokine and link IL-10 to a second cytokine Z through a scFv VH/VL half-life–extending scaffold. The second cytokine is fused into the scFv hinge region between VH and VL, while IL-10 is provided at both ends of the fusion format, yielding a dual-ended IL-10 arrangement around the targeting scaffold.
In one aspect, the scaffold is based on an anti-Ebola monoclonal antibody-derived VH/VL region, with CDRs engrafted into the VH and VL. The engrafted CDRs include three light chain CDRs and three heavy chain CDRs from a second monoclonal antibody, enabling antigen targeting through corresponding CDR choices, including EGFR-, HER2-, PDGFR-, CD14-, MAdCAM-, and VEGFR1/VEGFR2-directed targeting.
The document also provides structural formulas for IL-10/IL-10 variants and for the fusion constructs, including IL-10 variant DV05/DV06/DV07. It further describes IL-10/IL-2 and IL-10/IL-4 fusions in this architecture, together with reported functional outcomes for suppression of pro-inflammatory effects, monocyte TNFα suppression, reduced IFNγ induction in CD8+ T cells, and protection against septic shock in an LPS context.
Claims Coverage
The provided material includes one independent claim defining a dual cytokine fusion protein of formula (I), with dependent claims refining framework sourcing, cross-engrafted CDR sourcing, and a pharmaceutical composition aspect. The independent claim contains at least five main inventive features: the dual-ended IL-10 formula, the anti-Ebola first monoclonal antibody scaffold, cross-engrafting of three light and three heavy CDRs from a second monoclonal antibody, the definition of Z as a cytokine other than IL-10, and specific IL-10, second antibody, and Z selections.
Dual cytokine fusion protein format with IL-10 at both ends
A dual cytokine fusion protein of formula (I) in which IL-10 is a monomer arranged on both sides of an scFv-derived VH/VL scaffold, with Z being a cytokine other than IL-10 and with n set to 1.
Anti-Ebola antibody-derived VH and VL regions
The first monoclonal antibody is an anti-Ebola antibody, and the VL and VH from the anti-Ebola antibody are used as X1 and X2 depending on which of X1 is VL or VH.
Cross-engrafted CDRs from first and second monoclonal antibodies
The VL and VH from the anti-Ebola antibody comprise three light chain CDRs and three heavy chain CDRs that are engrafted with three light chain CDRs and three heavy chain CDRs from a second monoclonal antibody.
Z is a cytokine other than IL-10
Z is defined as a cytokine other than IL-10, with formula (I) including a segment Z n between the indicated regions and with n equal to 1.
Specific IL-10, second antibody, and Z selection for formula (I)
The IL-10 is SEQ ID No: 16, the second antibody is an anti-PDGFR monoclonal antibody, and Z is IL-2.
Human anti-Ebola framework sourcing for VH/VL regions
The VH and VL regions include framework regions derived from a human anti-Ebola antibody.
Anti-HER2 CDR source for the cross-engrafting design
The framework region is grafted with three light chain CDRs and three heavy chain CDRs from an anti-HER2 monoclonal antibody.
Pharmaceutical composition including pharmaceutically acceptable components
A pharmaceutical composition is defined that includes the dual cytokine fusion protein together with pharmaceutically acceptable buffers and excipients.
The claim set centers on a dual cytokine fusion protein format with IL-10 on both ends, using an anti-Ebola antibody-derived VH/VL scaffold and cross-engrafted CDRs from a second monoclonal antibody. The independent claim further fixes IL-10 as SEQ ID No: 16, specifies Z as IL-2, sets n to 1, and specifies the second antibody as anti-PDGFR, while dependents refine framework sourcing, cross-grafted CDR sourcing, and the inclusion of pharmaceutical composition components.
Stated Advantages
Increased potency of IFNγ responses when IL-2 is tethered with an IL-10 variant (DV07) via the VH/VL linker/hinge.
Suppression of IL-2-mediated pro-inflammatory effects.
Reduced toxicity at therapeutic doses.
Improved anti-tumor activity in vivo compared to a reference construct.
Maintenance of mouse weight and survival while reducing overt IL-2 toxicity in vivo.
Superior monocyte TNFα suppression compared with either cytokine alone for IL-10 plus IL-4 and IL-10 variant DV06.
Reduced IFNγ induction in CD8+ T cells for IL-10/IL-4 fusions.
Protection against septic shock in an LPS sepsis model when dosed pre- or post-LPS.
Documented Applications
Antigen targeting via engrafted CDRs directed to EGFR, HER2, PDGFR, CD14, MAdCAM, and VEGFR1/VEGFR2.
Tumor treatment context using an in vivo CT26(hEGFR+) tumor study.
Sepsis model context using an LPS-induced sepsis model and assessing protection against septic shock with IL-10/IL-4 fusion constructs.
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