Modified interleukin-2 (IL-2) molecule and use thereof
Inventors
Zhao, Yao • Zhang, Yu • LIU, Huijie • Piao, Jinhua • Zhang, Jianjun • ZHANG, Qiulei • Zhang, Wei • WANG, Guoyong • Zhang, Tianfu
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Assignees
Member
Glycos Biomedical LtdWe are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
We are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
Publication Number
US-12624078-B2
Publication Date
2026-05-12
Expiration Date
Abstract
A modified interleukin-2 (IL-2) molecule is obtained by being subjected to a modification as follows: substituting a region in an IL-2 molecule that mediates the binding of the IL-2 molecule to interleukin-2 receptor alpha (IL2Rα) with a region in an interleukin-15 (IL-15) molecule that mediates the binding of the IL-15 molecule to interleukin-15 receptor alpha (IL15Rα). The region in the IL-15 molecule that mediates the binding of the IL-15 molecule to the IL15Rα includes 9 or more amino acid residues. Furthermore, a protein heterodimer including the modified IL-2 molecule and IL15Rα (a Sushi domain) or a variant thereof is provided. The modified IL-2 molecule and/or the protein heterodimer including the modified IL-2 significantly reduce(s) an affinity of IL2Rα to greatly reduce its side effects in clinical treatment and is promising drug candidate.
Core Innovation
The invention relates to modified interleukin-2 (IL-2) and modified IL-2/IL-15R a (Sushi domain) heterodimers. The modified IL-2 is produced by substituting the IL-2 IL2R a-binding region with the corresponding IL-15 IL15R a-binding region, wherein the IL-15 IL15R a-binding region comprises 9 residues.
The described heterodimers include a sushi domain of the IL-15 receptor (IL15R a), and are configured to substantially reduce IL2R a binding. At the same time, the invention aims to retain and/or optimize IL2/15R signaling for antitumor activity.
The document further describes functional outcomes associated with this design, including reduced IL-2 receptor alpha (IL2R a) binding and reduced regulatory T cell (Treg) proliferation, while supporting antitumor efficacy in tumor/cancer models. The core embodiments are described with loop and helix region substitutions corresponding to specific SEQ IDs, including optional Fc fusion configurations.
Claims Coverage
The partial claim set provided includes one independent claim. The inventive feature centers on a protein heterodimer defined by a modified IL-2 amino acid sequence together with a specified IL-15 receptor sushi domain sequence.
Protein heterodimer with modified IL-2 and IL-15 receptor sushi domain
A protein heterodimer comprising a modified IL-2 comprising the amino acid sequence as shown in SEQ ID NO: 14 and a sushi domain of IL15 receptor comprising the amino acid sequence as shown in SEQ ID NO: 19, SEQ ID NO: 21, or SEQ ID NO: 22.
Across the provided independent claim, the inventive coverage is directed to a specific protein heterodimer architecture combining a defined modified IL-2 (SEQ ID NO: 14) with one of several defined IL-15 receptor sushi domain sequences (SEQ ID NO: 19, 21, or 22).
Stated Advantages
Substantially reduces IL2R a binding.
Aims to reduce IL-2 toxic side effects while retaining and/or optimizing IL2/15R signaling for antitumor activity.
Reduced Treg proliferation.
Documented Applications
Antitumor activity in B16F10 melanoma xenograft models.
Pre-toxicity outcomes in cynomolgus monkeys.
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