Interleukin-18 variants and methods of use
Inventors
Ring, Aaron • Zhou, Ting • Fischer, Suzanne
Assignees
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Publication Number
US-12403180-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The present invention provides compositions and methods comprising an activator of interleukin-18 (IL-18) activity for use in therapeutic and non-therapeutic applications. The activator provides IL-18 signaling activity even in the presence of an inhibitory molecule such as IL-18 binding protein (IL-18BP).
Core Innovation
The invention relates to IL-18 variant polypeptides and polynucleic acids encoding the IL-18 variant polypeptides. The IL-18 variant polypeptides comprise 90% or more sequence identity with wild-type IL-18 set forth in SEQ ID NO:30 and five or more substitution mutations, specifically bind IL-18 receptor (IL-18R), and exhibit decreased binding affinity to IL-18 binding protein (IL-18BP) relative to wild-type IL-18.
The disclosure describes decoy-resistant (DR) IL-18 variants that resist IL-18BP inhibition while maintaining IL-18R binding and enabling separation between receptor binding and IL-18BP binding. It also describes decoy-to-the-decoy (D2D) IL-18 variants that bind IL-18BP while exhibiting reduced interaction with IL-18R to neutralize IL-18BP and enable endogenous IL-18 signaling.
The invention further includes a method comprising administering to a subject a polynucleic acid encoding the IL-18 variant polypeptide and a cell that is an immune cell or an engineered immune cell in which the IL-18 variant polypeptide comprises the specified substitution mutations. The immune-cell component includes engineered immune cell types such as CAR-T cells, CAR-NK cells, T cells transduced with an engineered T cell receptor, and NK cells transduced with an engineered T cell receptor.
Claims Coverage
The partial content identifies one independent method claim, supported by dependent claim refinements. Across the inventive concept, the claims require an IL-18 variant polypeptide meeting specified sequence identity and mutation-count criteria and binding to IL-18R coupled with decreased binding affinity to IL-18BP, in a method of administering a polynucleic acid and an immune cell component.
Decoy-resistant IL-18 receptor binding with decreased IL-18BP affinity
An IL-18 variant polypeptide that comprises 90% or more sequence identity with WT IL-18 set forth in SEQ ID NO:30, five or more substitution mutations selected from a specified group, specifically binds IL-18 receptor (IL-18R), and exhibits decreased binding affinity to IL-18 binding protein (IL-18BP) relative to wild-type IL-18.
Polynucleic acid encoding an IL-18 variant for administration with an immune-cell component
A method comprising administering to a subject a polynucleic acid encoding the IL-18 variant polypeptide and a cell that is an immune cell or an engineered immune cell in which the IL-18 variant polypeptide comprises substitution mutations relative to wild-type IL-18 set forth in SEQ ID NO:30 at specified alternative mutation-position sets.
The claims focus on IL-18 variant polypeptides defined by sequence identity and multiple specified substitution mutations that preserve IL-18R binding while reducing IL-18BP binding affinity. The method of administration combines a polynucleic acid encoding the variant with an immune cell or engineered immune cell component containing or expressing the IL-18 variant with one of the explicitly listed mutation sets.
Stated Advantages
Enables IL-18 signaling by providing IL-18 variants that specifically bind IL-18 receptor while exhibiting reduced IL-18BP binding/neutralization relative to wild-type IL-18.
Provides decoy-to-the-decoy (D2D) IL-18 variants that bind IL-18BP while exhibiting reduced interaction with IL-18R to neutralize IL-18BP and thereby enable endogenous IL-18 signaling.
Resists IL-18BP inhibition while maintaining IL-18R binding.
Enables separation between receptor binding and IL-18BP binding.
IL-18BP-independent in cell signaling while retaining IL-18R-associated signaling.
Documented Applications
Treating or preventing cancer, including checkpoint-inhibitor resistant and MHC class I-lost tumors.
Treating or preventing metabolic disease, including obesity and diabetes, with the stated aim of reducing body fat.
Treating or preventing infectious disease, including poxvirus and vaccinia virus with IL-18BP orthologs.
Treating or preventing macular degeneration, including wet AMD.
Use with optional co-therapies, including immune checkpoint inhibitors and opsonizing agents, as explicitly described in the document.
Yeast display-based directed evolution and selection of decoy-resistant IL-18 variants.
Binding characterization using yeast binding isotherms and surface plasmon resonance (SPR).
Human and mouse library design and engineered variant sequence sets.
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