US-12624078-B2 - Modified interleukin-2 (IL-2) molecule and use thereof

US12624078B2US 12624078 B2US12624078 B2US 12624078B2US-12624078-B2

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.

Inventors

Yao Zhao
Yu Zhang
Huijie LIU
Jinhua Piao
Jianjun Zhang
Qiulei ZHANG
Wei Zhang
Guoyong WANG
Tianfu Zhang

Assignees

LETO LABORATORIES CO., LTD

Dates

Publication Date: 20260512
Application Date: 20211016
Priority Date: 20201018

Claims (2)

1 . 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 (ILI5R) comprising the amino acid sequence as shown in SEQ ID NO: 19, SEQ ID NO: 21, or SEQ ID NO: 22.
2 . A pharmaceutical composition comprising the protein heterodimer according to claim 1 .

Description

CROSS REFERENCE TO THE RELATED APPLICATIONS This application is the national phase entry of International Application No. PCT/CN2021/124246, filed on Oct. 16, 2021, which is based upon and claims priority to Chinese Patent Application No. 202011113975.7, filed on Oct. 18, 2020, and Chinese Patent Application No. 202111201233.4, filed on Oct. 15, 2021, the entire contents of which are incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy is named GBSHJL009_Sequence Listing.txt, created on 02/21/2023, and is 27,031 bytes in size. TECHNICAL FIELD The present application belongs to the field of biomedicine, and in particular, to a modified interleukin-2 (IL-2) molecule and a use thereof. BACKGROUND According to data released by the World Health Organization (WHO) in February 2017, there are more than 14 million new cancer cases worldwide every year, and this number is expected to increase to more than 21 million by 2030; and 8.8 million people die of cancer every year, and global cancer deaths account for nearly one-sixth of the total deaths. The prevention and treatment of cancer is a worldwide problem that needs to be solved urgently in the medical field. Currently, traditional methods for treating cancer include surgery, chemotherapy, hormone therapy, and radiotherapy (see, for example, Stockdale, 1998, Principles of Cancer Patient Management; and Scientific American: Medicine, Volume 3, edited by Rubenstein and Federman, Chapter 12, Section IV). However, surgery may be infeasible due to the patient's health or the disease being too advanced, and cancer cells often cannot be completely removed from the body of a patient after surgery. Radiotherapy is effective only when a tumor tissue is more susceptible to radiation than a normal tissue, and high-dose radiation often causes severe side effects. Hormone therapy is rarely used alone, and while the hormone therapy may be effective, it is often used to prevent or delay cancer recurrence after most of cancer cells are removed by other treatments. The biggest problem with chemotherapy is that a patient may quickly develop resistance to a chemotherapeutic agent. In addition, immunomodulatory factors (such as interleukins (ILs)) can also exert an antitumor effect in animal models and cancer patients, and the use of immunomodulatory factors can avoid the above-mentioned deficiencies in conventional therapies. However, systemic toxic side effects associated with immunomodulatory factors largely limit their use. Therefore, it is necessary to develop an effective therapy that can reduce the toxic side effects of immunomodulatory factors. SUMMARY In view of the above problems in the prior art, in a first aspect, the present application provides a modified IL-2 molecule. The modification includes 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. In some embodiments, the region in the IL-15 molecule that mediates the binding of the IL-15 molecule to the IL15Rα may be a contiguous amino acid sequence. In some embodiments, the region in the IL-15 molecule that mediates the binding of the IL-15 molecule to the IL15Rα may be a noncontiguous amino acid sequence. In some embodiments, the region in the IL-15 molecule that mediates the binding of the IL-15 molecule to the IL15Rα may include one or more noncontiguous amino acid sites. In some embodiments, the region in the IL-2 molecule that mediates the binding of the IL-2 molecule to the IL2Rα may be a contiguous amino acid sequence. In some embodiments, the region in the IL-2 molecule that mediates the binding of the IL-2 molecule to the IL2Rα may be a noncontiguous amino acid sequence. In some embodiments, the region in the IL-2 molecule that mediates the binding of the IL-2 molecule to the IL2Rα may include one or more noncontiguous amino acid sites. In some embodiments, the modification can reduce an affinity of the modified IL-2 molecule for the IL2Rα. In some embodiments, the modification can eliminate the affinity of the modified IL-2 molecule for the IL2Rα. In some embodiments, the affinity may be measured by a biolayer interferometry (BLI). In some embodiments, the region in the IL-2 molecule that mediates the binding of the IL-2 molecule to the IL2Rα may include a loop M or a variant thereof, and the loop M may include a sequence shown in SEQ ID NO: 1. In some embodiments, the region in the IL-2 molecule that mediates the binding of the IL-2 molecule to the IL2Rα may include a loop N or a variant