CN-122011127-A - Double-target antagonistic polypeptide targeting PD-1 and CTLA-4 or pharmaceutically acceptable salt thereof and application thereof

Abstract

The application provides a polypeptide or pharmaceutically acceptable salt thereof, wherein the polypeptide has an amino acid sequence shown as SEQ ID NO. 1 or SEQ ID NO. 2. The polypeptides of the application, or pharmaceutically acceptable salts thereof, can bind to PD-1 and CTLA-4 for effective inhibition of PD-1 and CTLA-4. Thus, the polypeptide or the pharmaceutically acceptable salt thereof can be used for detecting PD-1 and/or CTLA-4, and can also be used for treating or preventing diseases mediated by PD-1 and/or CTLA-4 (such as tumors or cancers, such as non-small cell lung cancer, melanoma, lymphoma, leukemia and the like).

Inventors

• HE BING
• Lv Tianxu
• YAO JIANHUA

Assignees

• 腾讯科技（深圳）有限公司

Dates

Publication Date

20260512

Application Date

20260414

Claims (12)

1. 1. A polypeptide or a pharmaceutically acceptable salt thereof, wherein the polypeptide has an amino acid sequence as shown in SEQ ID No. 1 or SEQ ID No. 2.
2. 2. A polypeptide derivative or a pharmaceutically acceptable salt thereof, comprising: the polypeptide of claim 1, or a pharmaceutically acceptable salt thereof, and A modifying group, the polypeptide or a pharmaceutically acceptable salt thereof being linked to the modifying group.
3. 3. The polypeptide derivative or pharmaceutically acceptable salt thereof according to claim 2, wherein the polypeptide derivative or pharmaceutically acceptable salt thereof satisfies one of the following conditions: 1) The modification group is connected with an active group at the side chain or the tail end of the amino acid in the polypeptide, wherein the active group is at least one selected from-NH 2 , -SH, -OH and-COOH; 2) The modification group is connected with-NH 2 of an amino acid side chain in the polypeptide; The modifying group has at least one of the following structures: ; ; ; 。
4. 4. a nucleic acid molecule, expression vector, recombinant cell, wherein the nucleic acid molecule encodes the polypeptide of claim 1; the expression vector carries the nucleic acid molecule; the recombinant cells carrying the above-mentioned nucleic acid molecules or the above-mentioned expression vectors, or The recombinant cell expresses the polypeptide of claim 1.
5. 5. Use of the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, or the polypeptide derivative of any one of claims 2-3 or a pharmaceutically acceptable salt thereof, in the preparation of an inhibitor of dual targets PD-1 and CTLA-4.
6. 6. A fusion protein comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, or the polypeptide derivative of any one of claims 2-3 or a pharmaceutically acceptable salt thereof.
7. 7. A reagent or kit comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2 to 3 or a pharmaceutically acceptable salt thereof, or the fusion protein of claim 6.
8. 8. A pharmaceutical composition comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2 to 3 or a pharmaceutically acceptable salt thereof, or the fusion protein of claim 6.
9. 9. Use of the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof, the polypeptide derivative of any one of claims 2-3 or a pharmaceutically acceptable salt thereof, the fusion protein of claim 6 or the pharmaceutical composition of claim 8 in the manufacture of a medicament for the treatment or prevention of a PD-1 and/or CTLA-4 mediated disease.
10. 10. The use according to claim 9, wherein the PD-1 and/or CTLA-4 mediated disease comprises a tumor or cancer.
11. 11. The use according to claim 10, wherein the tumor or cancer comprises a solid tumor or a hematological malignancy.
12. 12. A method of detecting PD-1 and/or CTLA-4, comprising: Contacting a sample to be tested with the polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, the polypeptide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 3, the fusion protein according to claim 6, or the reagent or kit according to claim 7; Determining whether the sample to be detected contains PD-1 and/or CTLA-4 based on the signal generated by the contact product.

Description

Double-target antagonistic polypeptide targeting PD-1 and CTLA-4 or pharmaceutically acceptable salt thereof and application thereof Technical Field The invention belongs to the technical field of biopharmaceuticals, and in particular relates to a targeting PD-1 and CTLA-4 double-target antagonistic polypeptide or pharmaceutically acceptable salt thereof and application thereof. Background Programmed death receptor-1 (PD-1) is a key immune checkpoint receptor expressed primarily on the surface of activated T cells, B cells and bone marrow cells. In the physiological state, PD-1 transmits inhibitory signals by binding to ligands expressed by tumor cells (PD-L1 or PD-L2), inhibiting T cell overactivation, thereby maintaining immune tolerance and preventing autoimmune disease. However, in tumor microenvironments, tumor cells often "hijack" by a mechanism that highly expresses PD-L1, leading to the depletion of T cell function and mediating immune escape of the tumor. Thus, blocking the PD-1 pathway has become a core strategy for tumor immunotherapy, aimed at reactivating T-cell recognition and killing capacity of tumor cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is another transmembrane receptor that is predominantly expressed on the surface of activated T cells, belonging to the immunoglobulin superfamily, and is another key immunonegative regulatory molecule. CTLA-4 functions primarily in the early stages of the immune response (e.g., in the lymph nodes), limiting the initial activation and proliferation of T cells by competing with CD28 for binding to B7 ligand (CD 80/CD 86). CTLA-4 has important significance in regulating and controlling the intensity and breadth of anti-tumor immune response, and the inhibition aiming at the target spot can obviously enhance the immune response of organisms to tumors. In the prior art, the main clinical protocol for such targets is monoclonal antibodies (Monoclonal Antibodies, mAbs). By binding to PD-1 or CTLA-4 with high affinity, its interaction with the corresponding ligand is blocked, thereby releasing the inhibition of T cells. In addition, there are some studies on polypeptide inhibitors against single targets of PD-1 or CTLA-4, but still at an immature stage in terms of tissue permeability and therapeutic efficacy. However, these single-target inhibitors still have significant limitations in clinical applications. The tumor immune escape mechanism has high complexity and compensation, and single blocking of the PD-1 pathway often leads to compensatory escape of tumors through activation of CTLA-4 and other immune checkpoints, thereby leading to insufficient therapeutic resistance or immune stimulation intensity. At present, though monoclonal antibodies have combined drug administration schemes, in the field of polypeptide drugs, double-target polypeptide research capable of accurately combining and blocking two targets of PD-1 and CTLA-4 at the same time is extremely deficient. The design of such molecules requires extremely high spatial configuration accuracy, and the prior art has difficulty in combining the binding affinity of two targets with the stability of the molecules. Therefore, a novel PD-1 and CTLA-4 double-target inhibition polypeptide is developed, the synergistic blocking mechanism of the polypeptide is utilized to enhance the killing effect of an immune system on tumors, and the polypeptide has important clinical value and application potential in the field of tumor immunotherapy. Disclosure of Invention The present application aims to solve at least one of the technical problems existing in the prior art to at least some extent. To this end, the application provides a PD-1 and CTLA-4 dual-target inhibition polypeptide. The present application has been completed based on the following findings by the inventors: Current PD-1 or CTLA-4 single-target antagonistic peptides/inhibitors, while exhibiting a certain efficacy in anti-tumor immunotherapy, have some significant limitations: (1) Stability and pharmacokinetic problems-natural or existing polypeptide sequences generally have a short half-life in vivo, are very susceptible to degradation by proteases in vivo and are rapidly cleared by the kidneys, which limits the effective accumulation of the drug in tumor tissue and the duration of therapeutic effect, increasing the frequency of administration and complexity of clinical application. (2) The efficacy of single-target inhibition is limited and the existing research and development is focused on single-target antagonism of PD-1 or CTLA-4. However, tumor immune escape mechanisms are highly complex and compensatory, and single blockade of the PD-1 pathway often results in compensatory escape of tumors by activating CTLA-4, etc. other immune checkpoints. The existing single-target polypeptide is difficult to generate enough immunity excitation strength due to single action mechanism, and cannot reach the expected anti-tumor depth. Aimin