EP-4736877-A1 - PHARMACEUTICAL COMPOSITION AND USE THEREOF

Abstract

Provided are a pharmaceutical composition and use thereof. The pharmaceutical composition comprises a PD-1 monoclonal antibody or a CTLA-4 monoclonal antibody, and further comprises a Rage inhibitor. The prepared composition, by means of blocking Rage in combination with the PD-1 or CTLA-4 monoclonal antibody, can significantly inhibit tumor growth or even lead to the disappearance of tumors, thereby providing 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. A pharmaceutical composition, comprising a PD-1 monoclonal antibody or a CTLA-4 monoclonal antibody, and a RAGE inhibitor.
2. The pharmaceutical composition according to claim 1, wherein the RAGE inhibitor comprises a molecule capable of blocking transcription or translation of a RAGE gene, or a molecule capable of specifically inhibiting expression or activation of a RAGE protein.
3. The pharmaceutical composition according to claim 2, wherein the RAGE inhibitor is a nucleic acid molecule, an antibody, or a small-molecule compound.
4. The pharmaceutical composition according to claim 3, wherein the nucleic acid molecule is selected from the group consisting of siRNA, shRNA, and sgRNA; and/or, the small-molecule compound is one or two selected from the group consisting of FPS-ZM1 and Azeliragon.
5. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable excipient; preferably, the pharmaceutically acceptable excipient comprises at least one of a diluent, a vehicle, a filler, a binder, a disintegrant, an absorption promoter, a surfactant, an adsorbent carrier, a lubricant, a sweetener, and a flavoring agent.
6. The pharmaceutical composition according to claim 1, 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.
7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition can be administered into a body such as muscle, intradermal, subcutaneous, venous or mucosal tissues by means of injection, spraying, nasal drops, eye drops, permeation, absorption, or physically or chemically-mediated methods, or is administered into a body after being mixed with or encapsulated by another substance.
8. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating tumors.
9. The use according to claim 8, wherein the tumor comprises at least one of solid tumors and non-solid tumors; preferably, the tumor comprises at least one of intestinal cancer, gastric cancer, esophageal cancer, hypopharyngeal cancer, laryngeal cancer, oral cancer, nasal cavity cancer, pancreatic cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, fallopian tube cancer, kidney cancer, melanoma, brain tumor, thyroid cancer, parathyroid cancer, leukemia, lymphoma, myeloma, sarcoma, prostate cancer, bladder cancer, bile duct cancer, gallbladder cancer, and head and neck squamous cell carcinoma; more preferably, the intestinal cancer comprises at least one of rectal cancer, colorectal cancer, small intestinal cancer and large intestinal cancer.
10. The use according to claim 8, wherein a method of use of the medicament comprises: inhibiting or blocking expression of a RAGE target in a subject, and administering a PD-1 monoclonal antibody or a CTLA-4 monoclonal antibody for treatment.

Description

TECHNICAL FIELD The present disclosure belongs to the field of biotechnology, and specifically relates to a pharmaceutical composition and use thereof. BACKGROUND Immune checkpoint inhibitors (ICIs) represent a form of immunotherapy with potentially high specificity and low side effects. They function by modulating immune cell activity and facilitating tumor cell elimination through pathways involving co-inhibitory or co-stimulatory signals. The most well-established ICIs, PD-1/PD-L1 and CTLA-4 monoclonal antibodies, act by releasing inhibitory signals in T lymphocytes. Since the successful introduction of immune checkpoint blockade (ICB) therapy in 2011 for treating unresectable or metastatic melanoma, ICB therapy has provided long-term clinical benefits to patients suffering from various tumor types, including curing a subset of patients. Consequently, the clinical success of ICB therapy has revolutionized the field of cancer immunotherapy. In September 2014, the Food and Drug Administration (FDA) granted accelerated approval to the first PD-1 immune checkpoint inhibitor for second-line treatment of melanoma. To date, numerous ICIs have been approved worldwide for second-/third-line or even first-line treatment of various solid tumors (such as non-small cell lung cancer, urothelial carcinoma, etc.) and for all microsatellite instability-high (MSI-H) solid tumors. As a result, ICB therapy has become a cornerstone of cancer treatment along with conventional treatment methods such as surgery, chemotherapy and radiotherapy. Although ICB therapy demonstrates significant potential of the human immune system in combating cancer, its efficacy against some "cold" tumors remains limited, and many cancer patients fail to respond to ICB therapy. When used as monotherapy, ICIs achieve response rates ranging from 10% to 35%, with approximately 70% of patients without clinical benefit. Furthermore, resistance to ICB therapy is highly prevalent. Mechanistically, CTLA-4 regulates APC-induced T-cell response by blocking CD28-B7 interaction, whereas PD-1 modulates T cell responses during the effector phase by attenuating TCR signaling. The primary mechanism of PD-1 and CTLA-4 monoclonal antibodies involves releasing the signals that inhibit T cell function to exert antitumor effects. However, they cannot prevent the concurrent progressive exhaustion and exhaustion-induced death of tumor-reactive T cells. Consequently, ICB therapy fails to elicit a lasting antitumor effect, thereby compromising the overall therapeutic outcome. 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 immune cell 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. 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 enhancing immune cell viability and preventing 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 provides a pharmaceutical composition. The present disclosure further provides a preparation method of the pharmaceutical composition. The present disclosure further provides use of the pharmaceutical composition. According to a first aspect of the present disclosure, a pharmaceutical composition is provided, including a PD-1 monoclonal antibody or a CTLA-4 monoclonal antibody, and a receptor for advanced glycation endproducts (RAGE) inhibitor. In some embodiments of the present disclosure, the RAGE inhibitor includes a molecule capable of blocking 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 selected from the group consisting of siRNA, shRNA, and 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 pharmaceutical composition further includes a pharmaceutically acceptable excipient. In some embodiments of the present disclosure,