EP-4736875-A1 - USE OF RAGE RECEPTOR INHIBITOR IN PREPARATION OF DRUG FOR INHIBITING LYMPHOCYTE REDUCTION OR DEATH

Abstract

Disclosed is use of a Rage receptor inhibitor in the preparation of a drug for inhibiting lymphocyte reduction or death. Using Rage as a target for in vitro screening of the drug for inhibiting lymphocyte reduction or death provides a new research direction for preparing more efficient tumor drugs.

Inventors

• LV, Ben
• LI, YI
• TANG, Yiting

Assignees

• The Third Xiangya Hospital of Central South University

Dates

Publication Date

20260506

Application Date

20240802

Claims (10)

1. Use of RAGE as a target for in vitro screening of products for inhibiting lymphocyte reduction or death.
2. The use according to claim 1, wherein the lymphocytes comprise T lymphocytes and B lymphocytes.
3. Use of a RAGE inhibitor in preparation of a product for inhibiting lymphocyte reduction or death.
4. The use according to claim 3, wherein the RAGE inhibitor is a molecule capable of inhibiting transcription or translation of a RAGE gene, or a molecule capable of specifically inhibiting expression or activation of a RAGE protein; preferably, the RAGE inhibitor is a nucleic acid molecule, an antibody, or a small-molecule compound; more preferably, the nucleic acid molecule is siRNA, shRNA, or sgRNA; more preferably, the small-molecule compound is one or two selected from the group consisting of FPS-ZM1 and Azeliragon.
5. The use according to claim 3, wherein the product for inhibiting lymphocyte reduction or death has a function of any one of the following (1)-(3): (1) increasing the number of CD3 + T cells; (2) increasing the number of CD19 + B cells; and (3) inhibiting programmed cell death; preferably, the programmed cell death is pyroptosis, apoptosis, or necroptosis.
6. The use according to claim 3, wherein the product for inhibiting lymphocyte reduction or death comprises the RAGE inhibitor alone or a composition of the RAGE inhibitor and other therapeutic agents.
7. The use according to claim 3, wherein the RAGE inhibitor is formulated into a pharmaceutical composition with a pharmaceutically acceptable excipient; preferably, the pharmaceutically acceptable excipient is one or more selected from the group consisting of a carrier, a diluent, a binder, a lubricant, and a wetting agent.
8. The use according to claim 7, wherein the pharmaceutical composition is in one or more forms selected from the group consisting of a solution, an injection, a spray, a nasal drop, an aerosol, a dry powder inhaler, a tablet, a capsule, and granules.
9. A method for screening a medicament that inhibits lymphocyte reduction or death, comprising: identifying substances capable of inhibiting or blocking the expression and/or function of RAGE as candidate medicaments by using RAGE as a medicament target.
10. The method according to claim 9, comprising: treating cells with a candidate medicament in vitro and incubating, or administering a candidate medicament to an animal model in vivo ; and subsequently assessing the reduction or death of lymphocytes in the cells or the animal model.

Description

TECHNICAL FIELD The present disclosure belongs to the field of biotechnology, and specifically relates to use of a receptor for advanced glycation endproducts (RAGE) inhibitor in preparation of a medicament for inhibiting lymphocyte reduction or death. BACKGROUND The incidence and mortality of malignant tumors and severe infections are on the rise, making them the second and third leading causes of death worldwide, respectively. A common feature of malignant tumors and severe infections is lymphocyte depletion, which leads to persistent immunosuppression or tumor immune escape in the body. Reducing lymphocyte depletion, enhancing lymphocyte viability and promoting immune response of the body can improve the overall survival rate. Since immunotherapy can enhance immunocompetence of the body and has potentially high specificity and low side effects, it demonstrates a broad development prospect. Immune checkpoint inhibitors (ICls) exert their effects by blocking the immunosuppressive ligand-receptor interaction involving CTLA-4 and PD-1. Tumor immunotherapy centered on immune checkpoint blockade (ICB) has revolutionized the landscape of tumor treatment. Although ICB therapy attenuates the primary inhibitory signals for T lymphocytes and enhances potential T cell-mediated antitumor activity, it is accompanied by progressive exhaustion and depletion-induced death of tumor-reactive T cells, leading to widespread drug resistance and failure to exert durable efficacy, thereby influencing treatment outcomes. To achieve optimal clinical outcomes, it is necessary to enhance response rate and duration of the body's immune function. Accordingly, specific small molecule inhibitors hold promise not only for suppressing key oncogenic signaling pathways, but also for sustaining lymphocyte viability while enhancing their response to exert more long-lasting effect, thereby serving as adjuvant agents to existing ICIs. Current ICB therapy benefits only a minority of cancer patients, and many fail to derive long-term benefits from treatment. Consequently, there is an urgent need in the scientific community to identify a mechanism capable of enhancing immune cell viability and preventing immune cell depletion to alleviate immunosuppression. This will facilitate the development of ICIs against novel targets, the combination of ICIs targeting different pathways, and the integration of ICIs with other treatment modalities, ultimately improving immune cell viability and reducing immune cell exhaustion. SUMMARY The present disclosure aims to at least resolve one of the technical problems mentioned above existing in the prior art. To this end, the present disclosure proposes use of RAGE as a target for in vitro screening of products for inhibiting lymphocyte reduction or death. The present disclosure further proposes use of a RAGE inhibitor in preparation of a product for inhibiting lymphocyte reduction or death. The present disclosure further proposes a method for screening a medicament that inhibits lymphocyte reduction or death. According to a first aspect of the present disclosure, use of RAGE as a target for in vitro screening of products for inhibiting lymphocyte reduction or death is provided. In some embodiments of the present disclosure, the lymphocytes comprise at least one of T lymphocytes and B lymphocytes. According to a second aspect of the present disclosure, use of a RAGE inhibitor in preparation of a product for inhibiting lymphocyte reduction or death is provided. In some embodiments of the present disclosure, the RAGE inhibitor is a molecule capable of inhibiting transcription or translation of a RAGE gene, or a molecule capable of specifically inhibiting expression or activation of a RAGE protein. In some embodiments of the present disclosure, the RAGE inhibitor is a nucleic acid molecule, an antibody, or a small-molecule compound. In some embodiments of the present disclosure, the nucleic acid molecule is siRNA, shRNA, or sgRNA. In some embodiments of the present disclosure, the small-molecule compound is one or two selected from the group consisting of FPS-ZM1 and Azeliragon. In some embodiments of the present disclosure, the product for inhibiting lymphocyte reduction or death has a function of any one of the following (1)-(3): (1) increasing the number of CD3+ T cells;(2) increasing the number of CD19+ B cells; and(3) inhibiting programmed cell death. In some embodiments of the present disclosure, the programmed cell death is pyroptosis, apoptosis, or necroptosis. In some embodiments of the present disclosure, the RAGE inhibitor can be used alone or can be used in combination with other therapeutic agents. In some embodiments of the present disclosure, the product for inhibiting lymphocyte reduction or death includes the RAGE inhibitor alone or a composition of the RAGE inhibitor and other therapeutic agents. In some embodiments of the present disclosure, the RAGE inhibitor is formulated into a pharmaceutical co