Interleukin-18 variants and methods of use
Inventors
Ring, Aaron • Zhou, Ting • Fischer, Suzanne
Assignees
Publication Number
US-12343379-B2
Publication Date
2025-07-01
Expiration Date
2038-09-06
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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 5 such as IL-18 binding protein (IL-18BP).
Core Innovation
The invention provides compositions and methods comprising activators of interleukin-18 (IL-18) activity, particularly IL-18 variant polypeptides that promote IL-18 signaling even in the presence of an inhibitory molecule such as IL-18 binding protein (IL-18BP). These IL-18 variants exhibit substantially reduced binding to IL-18BP while maintaining or enhancing binding to the IL-18 receptor (IL-18R). This overcomes the limitation in the clinical efficacy of wild-type IL-18, whose activity is inhibited by endogenous IL-18BP in various disease contexts.
The problem being addressed is the limited clinical efficacy of IL-18 as an immunotherapeutic agent for cancer due to upregulation of IL-18BP, which acts as a soluble immune checkpoint by neutralizing IL-18 signaling. There is a need for IL-18 variants that can signal through IL-18R without being neutralized by IL-18BP to effectively treat and prevent diseases such as cancer, infectious diseases, metabolic disorders, and macular degeneration.
The invention includes IL-18 variant polypeptides comprising specific mutations relative to wild-type human or murine IL-18, as well as nucleic acids encoding these variants. Methods include administering the variant IL-18 polypeptides or nucleic acids to subjects in need, alone or in combination with other agents such as immune checkpoint inhibitors, cancer cell opsonizing agents, altered immune cells, or oncolytic viruses to treat or prevent diseases or disorders that benefit from enhanced IL-18 signaling.
Claims Coverage
The claims include independent claims directed to methods of promoting IL-18 signaling by administering nucleic acids encoding modified IL-18 polypeptides with reduced IL-18BP binding and compositions thereof.
Modified IL-18 polypeptide sequence identity and mutations
Administering to a subject a nucleic acid encoding a modified IL-18 polypeptide that specifically binds IL-18 receptor and exhibits reduced IL-18BP binding compared to wild type, where the modified polypeptide has 90% or more sequence identity to wild-type human IL-18 (SEQ ID NO: 30) and contains at least four amino acid substitutions at specified positions including Methionine-51, Glutamine-56, Proline-57, Methionine-60, Glutamine-103, Serine-105, Aspartic acid-110, Asparagine-111, and Methionine-113.
Expanded mutations in modified IL-18 polypeptides
The modified IL-18 polypeptide may comprise substitutions at five or more specified positions including Tyrosine-1, Leucine-5, Lysine-8, Methionine-51, Lysine-53, Serine-55, Glutamine-56, Proline-57, Glycine-59, Methionine-60, Glutamic acid-77, Glutamine-103, Serine-105, Aspartic acid-110, Asparagine-111, Methionine-113, Valine-153, and Asparagine-155.
Specific amino acid substitutions providing decoy resistance
Combinations of specific amino acid substitutions at positions Methionine-51, Glutamine-56, Proline-57, Methionine-60, Glutamine-103, Serine-105, Aspartic acid-110, Asparagine-111, and Methionine-113 selected from detailed residue changes permitting IL-18 BP resistance while retaining IL-18 receptor binding and signaling capability.
The claims cover nucleic acids encoding IL-18 variants with defined mutations that confer reduced binding to IL-18BP and retained or enhanced binding to IL-18 receptor, compositions comprising these variants, and methods of treating diseases including cancer by administering such nucleic acids or compositions to promote IL-18 signaling.
Stated Advantages
IL-18 variants provide IL-18 signaling activity uninhibited by IL-18 binding protein, overcoming the natural negative regulation of IL-18.
The variants demonstrate potent anti-tumor activity in preclinical cancer models as monotherapies and synergizing with immune checkpoint inhibitors.
Administration of variants reduces body fat composition, indicating potential metabolic disease applications.
Variants show improved thermal stability and reduced tachyphylaxis compared to wild-type IL-18.
IL-18BP antagonists can enhance endogenous IL-18 activity, offering an alternative therapeutic approach.
Documented Applications
Immunotherapeutic agent for the treatment and prevention of cancer, including tumors resistant to immune checkpoint inhibitors and tumors with loss of MHC class I expression.
Treatment of metabolic diseases and disorders such as obesity, diabetes, and metabolic syndrome by reducing body fat composition.
Treatment of infectious diseases, including viral infections such as systemic vaccinia virus infection.
Anti-angiogenic therapy for macular degeneration, including wet age-related macular degeneration.
Use as an immune stimulant to increase activity or number of immune cells like T cells, NK cells, and myeloid cells.
Combination therapies with immune checkpoint inhibitors, cancer cell opsonizing agents, altered immune cells, and oncolytic viruses.
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