PCSK9 inhibitor-based microsatellite stable colorectal cancer combination therapy

Abstract

The invention discloses a microsatellite stable colorectal cancer combination therapy based on a PCSK9 inhibitor, and belongs to the technical field of cancer treatment. The medicine for treating the microsatellite stable colorectal cancer comprises a PCSK9 inhibitor and a composition, and the composition comprises a PD-1 antibody and / or 5-fluorouracil. The invention provides a combination therapy of a PCSK9 blocking antibody combined with chemotherapy and immunotherapy. The combination therapy comprises a combination of a PCSK9 inhibitor, a PD-1 antibody and 5-FU for treatment of microsatellite stable colorectal cancer. The combination therapy can significantly enhance the sensitivity of the microsatellite stable colorectal cancer to 5-FU chemotherapy.

Description

Technical Field

[0001] The present invention relates to the technical field of cancer treatment, and particularly to a combination therapy for microsatellite stable colorectal cancer based on PCSK9 inhibitors. Background Art

[0002] With the changes in lifestyle, the acceleration of the aging process, and the changes in dietary structure, the incidence of colorectal cancer shows an upward trend. For early-stage patients, surgery remains the main means of treating colorectal cancer. However, for advanced patients who cannot surgically remove the tumor, a comprehensive treatment method is mostly adopted, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, etc. Chemotherapy is widely used in the treatment of colorectal cancer and can effectively control the progression of the tumor and prolong the survival period of patients. However, the effects of chemotherapy vary among individuals, the sensitivity of patients to chemotherapy drugs is different, and drug resistance may occur during the treatment process. Targeted therapy is only recommended for patients with corresponding targets (such as vascular endothelial growth factor and epidermal growth factor receptor). Immunotherapy is a new and promising cancer treatment method, but it is only recommended as the first-line treatment drug for highly microsatellite unstable (MSI-H) colorectal cancer, which accounts for about 5% of advanced colorectal cancer. Patients with microsatellite stable (MSS) colorectal cancer, which accounts for about 95%, do not benefit. Therefore, it is urgent to develop new treatment strategies to improve the efficacy of advanced colorectal cancer, especially MSS colorectal cancer. Summary of the Invention

[0003] In view of the deficiencies of the prior art, the present invention proposes a combination therapy for microsatellite stable colorectal cancer based on PCSK9 inhibitors.

[0004] The object of the present invention can be achieved by the following technical solutions:

[0005] In the first aspect of the present invention, there is provided a drug for treating microsatellite stable colorectal cancer, comprising a PCSK9 inhibitor and a composition,

[0006] The composition comprises a PD-1 antibody, or a combination of a PD-1 antibody and one or more of 5-fluorouracil, oxaliplatin, and calcium folinate.

[0007] Optionally, the PCSK9 inhibitor comprises one or more of a PCSK9 monoclonal antibody, siRNA, shRNA, polypeptide, and small molecule compound.

[0008] Optionally, the PCSK9 inhibitor includes one or more of Alirocumab, Evolocumab, Tafoleximab, Frovocimab, Recaticimab, Lodelcizumab, Ralpancizumab, Ongericimab, Bococizumab, Ebronucimab, Inclisiran, PCSK9 degrader 1, PCSK9 modulator-2, PCSK9 modulator-3, PCSK9 modulator-4, AZD0780, PCSK9-IN-1, PCSK9-IN-2, PCSK9-IN-3, PCSK9-IN-9, PCSK9-IN-10, PCSK9-IN-11, PCSK9-IN-12, PCSK9-IN-13, PCSK9-IN-14, PCSK9-IN-15, PCSK9-IN-16, PCSK9-IN-17, PCSK9-IN-18, PCSK9-IN-19, PCSK9-IN-20, PCSK9-IN-22, PCSK9-IN-23, PCSK9-IN-24, PCSK9-IN-26, PCSK9-IN-27, PCSK9-IN-28, PCSK9-IN-29, PCSK9-IN-30, PCSK9-IN-31, PCSK9-IN-32, E28362, Bezeparsen, Dim16, DC371739, MeIm, SPC4061, SBC-115076, R-IMPP, PF-06446846, AZD8233, PF-06815345, Lerodalcibep, 5-O-Methylembelin, Pinostrobin, BRD8518, SBC-115337, CVI-LM001, SPC5001, Pep2-8, SBC-110736, Cepadacursen sodium, Nicodicosapent, 7030B-C5, and Enlicitide chloride.

[0009] Optionally, the PD-1 antibody includes one or more of Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Serplulimab, Penpulimab, Zimberelimab, Pucotenlimab, Cadonilimab, Ivonescimab.

[0010] The second aspect of the present invention relates to an application, including any one of the following applications:

[0011] Use of a PCSK9 inhibitor and a composition in the preparation of a drug for treating microsatellite stable colorectal cancer;

[0012] Use of a PCSK9 inhibitor and a PD-1 antibody in the preparation of a drug for improving the reduced number of CD8+ T cell infiltration in patients with microsatellite stable colorectal cancer;

[0013] Use of a PCSK9 inhibitor and a composition in the preparation of a drug for inhibiting the tumor growth of microsatellite stable colorectal cancer;

[0014] Wherein, the composition includes a PD-1 antibody, and the PD-1 antibody is combined with one or more of 5-fluorouracil, oxaliplatin, and calcium folinate.

[0015] Optionally, the PCSK9 inhibitor includes one or more of a PCSK9 monoclonal antibody, siRNA, shRNA, polypeptide, and small molecule compound.

[0016] Optionally, the PCSK9 inhibitor includes one or more of Alirocumab, Evolocumab, Tafoleximab, Frovocimab, Recaticimab, Lodelcizumab, Ralpancizumab, Ongericimab, Bococizumab, Ebronucimab, Inclisiran, PCSK9 degrader 1, PCSK9 modulator-2, PCSK9 modulator-3, PCSK9 modulator-4, AZD0780, PCSK9-IN-1, PCSK9-IN-2, PCSK9-IN-3, PCSK9-IN-9, PCSK9-IN-10, PCSK9-IN-11, PCSK9-IN-12, PCSK9-IN-13, PCSK9-IN-14, PCSK9-IN-15, PCSK9-IN-16, PCSK9-IN-17, PCSK9-IN-18, PCSK9-IN-19, PCSK9-IN-20, PCSK9-IN-22, PCSK9-IN-23, PCSK9-IN-24, PCSK9-IN-26, PCSK9-IN-27, PCSK9-IN-28, PCSK9-IN-29, PCSK9-IN-30, PCSK9-IN-31, PCSK9-IN-32, E28362, Bezeparsen, Dim16, DC371739, MeIm, SPC4061, SBC-115076, R-IMPP, PF-06446846, AZD8233, PF-06815345, Lerodalcibep, 5-O-Methylembelin, Pinostrobin, BRD8518, SBC-115337, CVI-LM001, SPC5001, Pep2-8, SBC-110736, Cepadacursen sodium, Nicodicosapent, 7030B-C5, and Enlicitide chloride.

[0017] Optionally, the PD-1 antibody includes one or more of Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Serplulimab, Penpulimab, Zimberelimab, Pucotenlimab, Cadonilimab, Ivonescimab.

[0018] Optionally, the drug includes an injection and an oral preparation.

[0019] Optionally, the drug further includes pharmaceutically acceptable excipients.

[0020] Advantages of the present invention:

[0021] ① The present invention provides a combination therapy of PCSK9 blocking antibody combined with immunotherapy, and the combination therapy includes a PCSK9 inhibitor and a PD-1 antibody combined for the treatment of microsatellite stable colorectal cancer. The PCSK9 inhibitor can significantly enhance the sensitivity of microsatellite stable colorectal cancer to PD-1 blocking therapy.

[0022] ② The present invention provides a combination therapy of PCSK9 blocking antibody combined with chemotherapy, and the combination therapy includes a PCSK9 inhibitor and 5-FU combined for the treatment of microsatellite stable colorectal cancer. The PCSK9 inhibitor can significantly enhance the sensitivity of microsatellite stable colorectal cancer to 5-FU chemotherapy.

[0023] ③ The present invention provides a combination therapy of PCSK9 blocking antibody combined with chemotherapy and immunotherapy, and the combination therapy includes a PCSK9 inhibitor, a PD-1 antibody and 5-FU combined for the treatment of microsatellite stable colorectal cancer. The combination therapy can significantly enhance the sensitivity of microsatellite stable colorectal cancer to 5-FU chemotherapy. Description of the Drawings

[0024] The present invention will be further described below with reference to the drawings.

[0025] Figure 1 It shows the effect of detecting the combination therapy of PCSK9 monoclonal antibody and PD-1 antibody on the growth of subcutaneous xenografts of microsatellite stable (MSS) colorectal cancer (CRC) in mice in Example 1 of the present application, where:

[0026] Figure 1 A in it is the specific administration time of the combination therapy of PCSK9 monoclonal antibody and PD-1 antibody.

[0027] Figure 1 B in it is the tumor growth curve of subcutaneous xenografts of microsatellite stable (MSS) colorectal cancer (CRC) model in mice under the condition of single or combined administration of PCSK9 monoclonal antibody and PD-1 antibody.

[0028] Figure 1C shows the infiltration of CD8+ T cells in subcutaneous xenografts of the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of immunohistochemical detection of PCSK9 monoclonal antibody and PD-1 antibody alone or in combination.

[0029] Figure 1 D is a statistical chart of the number of CD8+ T cell infiltrations per unit area in subcutaneous xenografts of the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of immunohistochemical detection of PCSK9 monoclonal antibody and PD-1 antibody alone or in combination.

[0030] Figure 2 It shows the effect of the combination of PCSK9 monoclonal antibody and 5-fluorouracil alone or in combination on the tumor growth of subcutaneous xenografts in the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model in Example 2 of this application, where:

[0031] Figure 2 A in it is the specific administration time of the combination therapy of PCSK9 monoclonal antibody and 5-fluorouracil.

[0032] Figure 2 B is a tumor growth curve of subcutaneous xenografts in the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of PCSK9 monoclonal antibody and 5-fluorouracil alone or in combination.

[0033] Figure 2 C is a photo of the tumor body of subcutaneous xenografts in the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of PCSK9 monoclonal antibody and 5-fluorouracil alone or in combination.

[0034] Figure 2 D is a statistical chart of the weights of subcutaneous xenografts in the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of PCSK9 monoclonal antibody and 5-fluorouracil alone or in combination.

[0035] Figure 3 It shows the effect of the combination of PCSK9 monoclonal antibody, PD-1 antibody and 5-fluorouracil on the tumor growth of subcutaneous xenografts in the mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model in Example 3 of this application, where:

[0036] Figure 3 A in it is the specific administration time of the combination therapy of PCSK9 monoclonal antibody and PD-1 monoclonal antibody combined with 5-fluorouracil.

[0037] Figure 3 In B, it is a tumor growth curve graph of subcutaneous transplanted tumors in a mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of the combination of PCSK9 monoclonal antibody and PD-1 monoclonal antibody and the administration of 5-fluorouracil alone or in combination.

[0038] Figure 3 In C, it is a photo of the tumor body of subcutaneous transplanted tumors in a mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of the combination of PCSK9 monoclonal antibody and PD-1 monoclonal antibody and the administration of 5-fluorouracil alone or in combination.

[0039] Figure 3 In D, it is a statistical graph of the weights of subcutaneous transplanted tumors in a mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC) model under the conditions of the combination of PCSK9 monoclonal antibody and PD-1 monoclonal antibody and the administration of 5-fluorouracil alone or in combination. Detailed implementation manners

[0040] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0041] Example 1: Detect the effect of the combination therapy of PCSK9 monoclonal antibody and PD-1 antibody on the growth of subcutaneous transplanted tumors in a mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC).

[0042] 1. Research object

[0043] BALB / c mice at 6-8 weeks old were purchased from Guangdong Zhiyuan Biomedical Technology Co., Ltd.; mouse colon26 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0044] 2. Experimental method

[0045] 1×10 6 colon26 cells were inoculated subcutaneously into the lower back of BALB / c mice to establish a subcutaneous transplanted tumor model of mouse colon26 microsatellite stable (MSS) colorectal cancer (CRC). After inoculating the tumor cells, the mice were randomly assigned to the following four groups for treatment:

[0046] ① Saline group (saline) control group: The mice were given saline by intraperitoneal injection on the 6th day after tumor inoculation, with an injection volume of 100 μl, an injection frequency of once every 2 days, and a total of 6 injections.

[0047] ② α-PD-1 group: Mice were intraperitoneally injected with PD-1 antibody on the 6th day after tumor inoculation. The injection dose was 100 μg per mouse (1 μg / μl), the injection frequency was once every 2 days, and the total number of injections was 6 times.

[0048] ③ Alirocumab group: Mice were intraperitoneally injected with PCSK9 monoclonal antibody on the 6th day after tumor inoculation. The injection dose was 500 μg per mouse (5 μg / μl), the injection frequency was once every 2 days, and the total number of injections was 6 times.

[0049] ④ α-PD-1 + Alirocumab group: Mice were intraperitoneally injected with both PD-1 antibody at a dose of 100 μg per mouse and PCSK9 monoclonal antibody at a dose of 500 μg per mouse on the 6th day after tumor inoculation. The total volume was 100

[0050] μl. The injection frequency was once every 2 days, and the total number of injections was 6 times.

[0051] The subcutaneous tumor volume of mice was measured every 2 days. Using vernier calipers, the longest diameter (L) of the subcutaneous tumor in mice and the longest transverse diameter (W) perpendicular to the longest diameter were determined. The subcutaneous tumor volume calculation formula was V = 0.52 × L × W 2 . Two-way ANOVA was used to evaluate the differences between the two groups. When *P < 0.05, **P < 0.01, ***P < 0.001, the differences were considered statistically significant.

[0052] When the subcutaneous tumor volume reached the ethical endpoint, all mice were euthanized, and immunohistochemistry was performed to detect the effect of PCSK9 antibody and PD-1 antibody alone or in combination therapy on the infiltration of CD8 + T cells in subcutaneous transplanted tumors of microsatellite-stable colorectal cancer in mice. The specific steps were as follows: The subcutaneous tumors were removed and soaked in 4% paraformaldehyde tissue fixative and fixed at 4°C for 24 hours. The fixed tissue was paraffin-embedded and cut into 2.5 μm sections. The sections were placed in 10 mM sodium citrate and heated in a pressure cooker for 30 minutes for antigen retrieval. The repaired tissue sections were pre-dropped with goat serum blocking solution, and then incubated overnight at 4°C in a wet box with the primary antibody against CD8 (Cell Signaling Technology). The secondary antibody used was HRP-labeled rabbit anti-mouse IgG. The slices were scanned with a scanner (Hamamatsu) and the data were analyzed and statistically processed.

[0053] 3. Experimental conclusions

[0054] AsFigure 1 As shown, compared with the control group of mice, the combined use of PCSK9 monoclonal antibody and PD-1 antibody can significantly slow down the growth rate of subcutaneous colorectal cancer xenografts in mice and exert a better therapeutic effect. Under the condition of the combined use of PCSK9 monoclonal antibody and PD-1 antibody, the infiltrated CD8 + T cells in the tumor significantly increase, indicating that the combined use of PCSK9 monoclonal antibody and PD-1 antibody can effectively improve the current situation of low infiltration of CD8 + T cells in the subcutaneous xenografts of the microsatellite stable (MSS) colorectal cancer (CRC) model, thereby enhancing the anti-tumor immune ability of the body.

[0055] Example 2: Effects of the individual or combined use of PCSK9 monoclonal antibody and 5-fluorouracil on the tumor growth of subcutaneous xenografts in the colon26 microsatellite stable (MSS) colorectal cancer (CRC) model in mice.

[0056] 1. Research subjects

[0057] Same as Example 1.

[0058] 2. Experimental methods

[0059] 1×10 6 colon26 cells were inoculated subcutaneously on the lower back of BALB / c mice to establish a subcutaneous xenograft model of colon26 microsatellite stable (MSS) colorectal cancer (CRC) in mice. After inoculating the tumor cells, the mice were randomly assigned to the following four groups for treatment:

[0060] ① Saline control group: Mice were given saline by intraperitoneal injection on the 6th day after tumor inoculation, with an injection volume of 100 μl, an injection frequency of once every 2 days, and a total of 6 injections.

[0061] ② Chemotherapy group (5-FU): Mice were given 5-FU by intraperitoneal injection on the 6th day after tumor inoculation, with an injection dose of 25 mg / kg (100 μl) per mouse, an injection frequency of once every 2 days, and a total of 6 injections.

[0062] ③ PCSK9 monoclonal antibody group (Alirocumab): Mice were given PCSK9 monoclonal antibody by intraperitoneal injection on the 6th day after tumor inoculation, with an injection dose of 500 μg (5 μg / μl) per mouse, an injection frequency of once every 2 days, and a total of 6 injections.

[0063] ④Chemotherapy group (5-FU) + PCSK9 monoclonal antibody group (Alirocumab): Mice were intraperitoneally injected with 5-FU at a dose of 25 mg / kg (100 μl) per mouse and PCSK9 monoclonal antibody at a dose of 500 μg per mouse on the 6th day after tumor inoculation. The total volume was 100 μl, and the injection frequency was once every 2 days for a total of 6 times.

[0064] The subcutaneous tumor volume of mice was measured every 2 days. Using vernier calipers, the longest diameter (L) of the subcutaneous tumor in mice and the longest transverse diameter (W) perpendicular to the longest diameter were determined. The formula for subcutaneous tumor volume was V = 0.52 × L × W. 2 . When the subcutaneous tumor volume reached the ethical endpoint, all mice were euthanized, and the subcutaneous tumors were dissected and weighed. Two-way ANOVA and t-test were used to evaluate the differences between the two groups. When *P < 0.05, **P < 0.01, ***P < 0.001, the differences were considered statistically significant.

[0065] 3. Experimental conclusions

[0066] As Figure 2 shown, compared with the control group of mice, 5-FU chemotherapy could slow down the growth rate of subcutaneous transplanted tumors in the colon26 microsatellite stable colorectal cancer model of mice to a certain extent. The combination of PCSK9 monoclonal antibody and 5-FU chemotherapy could further alleviate the tumor growth rate. The same conclusion was also obtained by detecting the tumor size and weight by the endpoint method, indicating that the combination of PCSK9 monoclonal antibody and 5-FU chemotherapy could promote the efficacy of chemotherapy on subcutaneous transplanted tumors in the colon26 microsatellite stable (MSS) colorectal cancer (CRC) model of mice, and this combination of drugs could play a better therapeutic role.

[0067] Example 3: Effect of PCSK9 monoclonal antibody combined with PD-1 antibody and 5-fluorouracil on the tumor growth of subcutaneous transplanted tumors in the colon26 microsatellite stable (MSS) colorectal cancer (CRC) model of mice.

[0068] 1. Research subjects

[0069] Same as Example 1.

[0070] 2. Experimental methods

[0071] 1*10 6 colon26 cells were inoculated subcutaneously into the lower dorsal side of BALB / c mice to establish a subcutaneous transplanted tumor model of colon26 microsatellite stable (MSS) colorectal cancer (CRC) in mice. After inoculating the tumor cells, the mice were randomly assigned to the following four groups for treatment:

[0072] ① Saline control group: Mice were given saline by intraperitoneal injection on the 8th day after tumor inoculation. The injection volume was 100 μl, the injection frequency was once every 2 days, and the total number of injections was 6 times.

[0073] ② 5-FU chemotherapy group: Mice were given 5-FU by intraperitoneal injection on the 8th day after tumor inoculation. The injection dose was 25 mg / kg (100 μl) per mouse, the injection frequency was once every 2 days, and the total number of injections was 6 times.

[0074] ③ α-PD-1 + Alirocumab group: Mice were given PD-1 antibody by intraperitoneal injection at a dose of 100 μg per mouse and PCSK9 monoclonal antibody at a dose of 500 μg per mouse simultaneously on the 8th day after tumor inoculation. The total volume was 100

[0075] μl. The injection frequency was once every 2 days, and the total number of injections was 6 times.

[0076] ④ 5-FU + Alirocumab + α-PD-1 group: Mice were given 5-FU by intraperitoneal injection at a dose of 25 mg / kg (100 μl) per mouse, PCSK9 monoclonal antibody at a dose of 500 μg per mouse, and PD-1 antibody at a dose of 100 μg per mouse simultaneously on the 8th day after tumor inoculation. The total volume was 100 μl. The injection frequency was once every 2 days, and the total number of injections was 6 times.

[0077] The subcutaneous tumor volume of mice was measured every 2 days. Using vernier calipers, the longest diameter (L) and the longest transverse diameter (W) perpendicular to the longest diameter of the subcutaneous tumor in mice were determined. The subcutaneous tumor volume calculation formula was V = 0.52×L×W 2 . When the subcutaneous tumor volume reached the ethical endpoint, all mice were euthanized, and the subcutaneous tumors were dissected and weighed. Two-way ANOVA and t-test were used to evaluate the differences between the two groups. When *P < 0.05, **P < 0.01, ***P < 0.001, the differences were considered statistically significant.

[0078] 3. Experimental conclusions

[0079] As Figure 3As shown, consistent with the results of Example 1, the combined use of the PCSK9 monoclonal antibody and the PD-1 antibody can significantly slow down the growth rate of subcutaneous transplanted tumors in the colon26 microsatellite stable colorectal cancer model in mice. Consistent with the results of Example 2, 5-FU chemotherapy can slow down the growth rate of subcutaneous transplanted tumors in the colon26 microsatellite stable colorectal cancer model in mice. The combination of the PCSK9 monoclonal antibody, the PD-1 antibody, and 5-fluorouracil can further inhibit the growth of subcutaneous transplanted tumors in the colon26 microsatellite stable (MSS) colorectal cancer (CRC) model in mice. The same conclusion was also obtained by detecting the tumor size and weight using the endpoint method, indicating that the combined use of the PCSK9 monoclonal antibody, the PD-1 antibody, and 5-FU chemotherapy can play a better therapeutic role in the treatment of subcutaneous transplanted tumors in the colon26 microsatellite stable (MSS) colorectal cancer (CRC) model in mice.

[0080] It should be noted that the embodiments of the present application disclose that the PCSK9 monoclonal antibody can be used in combination with the PD-1 antibody and / or 5-FU to achieve better therapeutic effects. The PCSK9 monoclonal antibody in this embodiment can be replaced by other components that can inhibit the expression or production of PCSK9, such as reagents that interfere with or block the expression of PCSK9. More specifically, reference can be made to the prior art, which will not be elaborated in this application. In some other embodiments of the present application, in addition to the combinations given in Embodiments 1 to 3 of the present application, the drugs of the present application may also include other pharmaceutically acceptable excipients to assist the above drugs in exerting their effects.

[0081] In the description of this specification, the descriptions referring to terms such as "one embodiment", "example", "specific example", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples.

[0082] The above shows and describes the basic principles, main features, and advantages of the present invention. Those skilled in the art of this industry should understand that the present invention is not limited by the above embodiments. The above embodiments and the descriptions in the specification only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed.

Claims

1. A drug for treating microsatellite stable colorectal cancer, characterized in that: Including PCSK9 inhibitors and compositions, The composition includes PD-1 antibody, or PD-1 antibody combined with one or more of 5-fluorouracil, oxaliplatin, and folinate.

2. The drug for treating microsatellite stable colorectal cancer according to claim 1, characterized in that: The PCSK9 inhibitor includes one or more of PCSK9 monoclonal antibodies, siRNA, shRNA, polypeptides, and small molecule compounds.

3. The drug for treating microsatellite stable colorectal cancer according to claim 2, characterized in that: The PCSK9 inhibitors include Alirocumab, Evolocumab, Tafoleximab, Frovocimab, Recaticimab, Lodelcizumab, Ralpancizumab, Ongericimab, Bococizumab, Ebronucimab, Inclisiran, PCSK9 degrader 1, PCSK9 modulator-2, PCSK9 modulator-3, PCSK9 modulator-4, AZD0780, PCSK9-IN-1, PCSK9-IN-2, PCSK9-IN-3, PCSK9-IN-9, PCSK9-IN-10, PCSK9-IN-11, PCSK9-IN-12, PCSK9-IN-13, PCSK9-IN-14, PCSK9- IN-15, PCSK9-IN-16, PCSK9-IN-17, PCSK9-IN-18, PCSK9-IN-19, PCSK9-IN-20, PCSK9-IN-22, PCSK9-IN-23, PCSK9-IN-24, PCSK9-IN-26, PCSK9-IN-27, PCSK9 -IN-28, PCSK9-IN-29, PCSK9-IN-30, PCSK9-IN-31, PCSK9-IN-32, E28362, Bezeparsen, Dim16, DC371739, MeIm, SPC4061, SBC-115076, R-IMPP, PF-06446846, AZD8233, PF-06815345, Lerodalcibep, 5-O-Methylembelin, Pinostrobin, BRD8518, SBC-115337, CVI-LM001, SPC5001, Pep2-8, SBC-110736, Cepadacursen sodium, Nicodicosapent, 7030B-C5 and Enlicitide chloride.

4. The drug for treating microsatellite stable colorectal cancer according to claim 1, characterized in that: The PD-1 antibody includes one or more of Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Serplulimab, Penpulimab, Zimberelimab, Pucotenlimab, Cadonilimab, and Ivonescimab.

5. An application, characterized in that: Includes any of the following applications: Use of PCSK9 inhibitors and compositions in the preparation of drugs for treating microsatellite stable colorectal cancer; The use of PCSK9 inhibitors and PD-1 antibodies in the preparation of drugs for improving the reduction of CD8+T cell infiltration in patients with microsatellite stable colorectal cancer; Use of PCSK9 inhibitors and compositions in the preparation of drugs for inhibiting the growth of microsatellite-stable colorectal cancer tumors; The composition comprises PD-1 antibody, PD-1 antibody combined with one or more of 5-fluorouracil, oxaliplatin, and folinate.

6. The use according to claim 5, characterized in that: The PCSK9 inhibitor includes one or more of PCSK9 monoclonal antibodies, siRNA, shRNA, polypeptides, and small molecule compounds.

7. The use according to claim 6, characterized in that: The PCSK9 inhibitors include Alirocumab, Evolocumab, Tafoleximab, Frovocimab, Recaticimab, Lodelcizumab, Ralpancizumab, Ongericimab, Bococizumab, Ebronucimab, Inclisiran, PCSK9 degrader 1, PCSK9 modulator-2, PCSK9 modulator-3, PCSK9 modulator-4, AZD0780, PCSK9-IN-1, PCSK9-IN-2, PCSK9-IN-3, PCSK9-IN-9, PCSK9-IN-10, PCSK9-IN-11, PCSK9-IN-12, PCSK9-IN-13, PCSK9-IN-14, PCSK9- IN-15, PCSK9-IN-16, PCSK9-IN-17, PCSK9-IN-18, PCSK9-IN-19, PCSK9-IN-20, PCSK9-IN-22, PCSK9-IN-23, PCSK9-IN-24, PCSK9-IN-26, PCSK9-IN-27, PCSK9 -IN-28, PCSK9-IN-29, PCSK9-IN-30, PCSK9-IN-31, PCSK9-IN-32, E28362, Bezeparsen, Dim16, DC371739, MeIm, SPC4061, SBC-115076, R-IMPP, PF-06446846, AZD8233, PF-06815345, Lerodalcibep, 5-O-Methylembelin, Pinostrobin, BRD8518, SBC-115337, CVI-LM001, SPC5001, Pep2-8, SBC-110736, Cepadacursen sodium, Nicodicosapent, 7030B-C5 and Enlicitide chloride.

8. The use according to claim 5, characterized in that: The PD-1 antibody includes one or more of Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Serplulimab, Penpulimab, Zimberelimab, Pucotenlimab, Cadonilimab, and Ivonescimab.

9. The use according to claim 5, characterized in that: The medicine includes injection and oral preparation.

10. The use according to claim 5, characterized in that: The drug also includes pharmaceutically acceptable excipients.

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