IP Library › Granted Patent US 12,343,379
Granted Patent B2
US 12,343,379 · App. 18/055,581 · Granted Jul 1, 2025

Interleukin-18 variants and methods of use

Inventors: Aaron Ring (New Haven, CT); Ting Zhou (New Haven, CT); Suzanne Fischer (New Haven, CT)
Assignee: YALE UNIVERSITY
A61K38/20C07K14/54A61K35/17A61K35/768A61K38/1774A61K47/642A61K2300/00A61P35/00C07K14/70596C07K2319/02C07K2319/21C07K2319/35C07K2319/50C12N15/85
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Quick Facts
Patent No.
US 12,343,379
App. No.
18/055,581
Granted
Jul 1, 2025
Kind
B2
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).

Claims (24)

1. A method of promoting interleukin-18 (IL-18) signaling activity in a subject in need thereof, comprising administering to the subject a composition comprising a nucleic acid encoding a modified IL-18 polypeptide that specifically binds to the IL-18 receptor (IL-18R) and exhibits reduced binding to the IL-18 binding protein (IL-18BP) as compared to wild type (WT) IL-18 as set forth in SEQ ID NO: 30, wherein the modified IL-18 polypeptide comprises 90% or more sequence identity with WT IL-18 as set forth in SEQ ID NO:30 and at least four amino acid substitutions, relative to WT IL-18 as set forth in SEQ ID NO:30, at positions selected from: Methionine-51, Glutamine-56, Proline-57, Methionine-60, Glutamine-103, Serine-105, Aspartic acid-110, Asparagine-111, and Methionine-113.

2. The method of claim 1 , wherein the modified IL-18 polypeptide comprises substitutions relative to SEQ ID NO: 30 at five or more of the following positions: 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.

3. The method of claim 1 , wherein the at least four amino acid substitutions, relative to SEQ ID NO: 30, are selected from the group consisting of:

(1) Methionine-51 to threonine, Methionine-51 to lysine, Methionine-51 to aspartic acid, Methionine-51 to asparagine, Methionine-51 to glutamic acid, or Methionine-51 to arginine,

(2) Glutamine-56 to glutamic acid, Glutamine-56 to alanine, Glutamine-56 to arginine, Glutamine-56 to valine, Glutamine-56 to glycine, Glutamine-56 to lysine, or Glutamine-56 to leucine,

(3) Proline-57 to leucine, Proline-57 to glycine, Proline-P57 to alanine, or Proline-57 to lysine,

(4) Methionine-60 to lysine, Methionine-60 to glutamine, Methionine-60 to arginine, or Methionine-60 to leucine,

(5) Glutamine-103 to glutamic acid, Glutamine-103 to lysine, Glutamine-103 to proline, Glutamine-103 to alanine, or Glutamine-103 to arginine,

(6) Serine-105 to arginine, Serine-105 to aspartic acid, Serine-105 to lysine, Serine-105 to asparagine, or Serine-105 to alanine,

(7) Aspartic acid-110 to histidine, Aspartic acid-110 to lysine, Aspartic acid-110 to asparagine, Aspartic acid-110 to glutamine, Aspartic acid-110 to glutamic acid, Aspartic acid-110 to serine, or Aspartic acid-110 to glycine,

(8) Asparagine-111 to histidine, Asparagine-111 to tyrosine, Asparagine-111 to aspartic acid, Asparagine-111 to arginine, Asparagine-111 to serine, or Asparagine-111 to glycine, and

(9) Methionine-113 to valine, Methionine-113 to arginine, Methionine-113 to threonine, or Methionine-113 to lysine.

4. The method of claim 3 , wherein the modified IL-18 polypeptide comprises five or more substitutions, relative to SEQ ID NO: 30, selected from the group consisting of:

(1) Methionine-51 to threonine, Methionine-51 to lysine, Methionine-51 to aspartic acid, Methionine-51 to asparagine, Methionine-51 to glutamic acid, or Methionine-51 to arginine,

(2) Lysine-53 to arginine, Lysine-53 to glycine, Lysine-53 to serine, or Lysine-53 to threonine,

(3) Glutamine-56 to glutamic acid, Glutamine-56 to alanine, Glutamine-56 to arginine, Glutamine-56 to valine, Glutamine-56 to glycine, Glutamine-56 to lysine, or Glutamine-56 to leucine,

(4) Proline-57 to leucine, Proline-57 to glycine, Proline-P57 to alanine, or Proline-57 to lysine,

(5) Methionine-60 to lysine, Methionine-60 to glutamine, Methionine-60 to arginine, or Methionine-60 to leucine,

(6) Glutamine-103 to glutamic acid, Glutamine-103 to lysine, Glutamine-103 to proline, Glutamine-103 to alanine, or Glutamine-103 to arginine,

(7) Serine-105 to arginine, Serine-105 to aspartic acid, Serine-105 to lysine, Serine-105 to asparagine, or Serine-105 to alanine,

(8) Aspartic acid-110 to histidine, Aspartic acid-110 to lysine, Aspartic acid-110 to asparagine, Aspartic acid-110 to glutamine, Aspartic acid-110 to glutamic acid, Aspartic acid-110 to serine, or Aspartic acid-110 to glycine,

(9) Asparagine-111 to histidine, Asparagine-111 to tyrosine, Asparagine-111 to aspartic acid, Asparagine-111 to arginine, Asparagine-111 to serine, or Asparagine-111 to glycine, and

(10) Methionine-113 to valine, Methionine-113 to arginine, Methionine-113 to threonine, or Methionine-113 to lysine.

5. The method of claim 1 , wherein the modified IL-18 polypeptide comprises 95% or more sequence identity with any one of the amino acid sequences as set forth in SEQ ID NOs: 34-59, 73-91, and 191-193.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2022
From: RING, AARON; ZHOU, TING; FISCHER, SUZANNE
To: YALE UNIVERSITY
Reel/Frame 061774/0643 →
Continuity (4)
Division 16123063 · Sep 6, 2018
Provisional Application 62554605 · Sep 6, 2017
Provisional Application 62652279 · Apr 3, 2018
Related Publication 20230241172A1 · Aug 3, 2023
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