Medicine composition for treating bile duct cancer and application thereof
By combining immune checkpoint inhibitors and PCAF inhibitors in the treatment of cholangiocarcinoma, the immune function of CD8+ T cells was significantly enhanced, the problems of poor immunotherapy and immune escape of cholangiocarcinoma were solved, and the treatment effect and prognosis were improved.
Patent Information
- Application Number
- CN202510562501.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2025-03-10
- Filing Date
- 2025-04-30
- Publication Date
- 2025-06-13
AI Technical Summary
The immune environment of cholangiocarcinoma is complex, and the tumor microenvironment inhibits the immune response, resulting in poor immunotherapy effects, lack of clear biomarkers and difficult to predict the therapeutic effect, and immune-related side effects and safety issues need to be further solved.
By combining treatment with a therapeutically effective amount of immune checkpoint inhibitor (such as PD-1 inhibitor) with PCAF inhibitors, the immune function of CD8+ T cells is significantly enhanced, the immune escape problem of tumors is overcome, and the therapeutic effect and prognosis are improved.
It significantly enhances the anti-tumor effect of CD8+ T cells, improves the therapeutic effect and prognosis, overcomes the immune escape problem of cholangiocarcinoma, and reduces the production of drug resistance.
Smart Images
Figure CN120131940A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of biopharmaceutical technology, and particularly to a drug combination for treating cholangiocarcinoma and its applications. Background Art
[0002] Cholangiocarcinoma (CCA) is a malignant tumor originating from cholangiocytes, usually with a poor prognosis and no obvious early symptoms, resulting in most patients being in the advanced stage at the time of diagnosis. Immunotherapy, as an emerging method for cancer treatment, has received extensive attention in the treatment of cholangiocarcinoma in recent years. Immune checkpoint inhibitors, such as PD-1 / PD-L1 inhibitors and CTLA-4 inhibitors, have achieved success in other cancers and have been applied to the treatment of cholangiocarcinoma. Some patients have shown good efficacy after using these immunotherapies, especially in advanced and recurrent cases. However, the overall effect of immunotherapy is still limited, and many patients develop drug resistance to immunotherapy.
[0003] Currently, the difficulties in the treatment of cholangiocarcinoma are as follows: First, the immune environment of cholangiocarcinoma is relatively complex, and the tumor microenvironment inhibits the immune response, resulting in poor immunotherapy effects; second, there are no clear biomarkers, making it difficult to predict which patients can benefit from immunotherapy; third, immune-related side effects and safety issues still need to be further resolved. Therefore, the application of immunotherapy in cholangiocarcinoma still requires further research and optimization. Summary of the Invention
[0004] (I) Technical Problems to be Solved
[0005] In view of this, one of the main objects of the present invention is to provide a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of an immune checkpoint inhibitor and a PCAF inhibitor; (2) a pharmaceutically or immunologically acceptable carrier or excipient.
[0006] By using a PCAF inhibitor in combination with a PD-1 immune checkpoint inhibitor to treat cholangiocarcinoma, the immune function of CD8 + T cells is significantly enhanced. The PCAF inhibitor promotes the effectiveness of the immune response by improving the activity and proliferation of T cells. On this basis, the PD-1 immune checkpoint inhibitor further relieves the immunosuppressive effect of tumor cells on T cells and restores the anti-tumor ability of T cells. The combination therapy not only effectively enhances the anti-tumor effect of CD8 + T cells, but also overcomes the immune escape problem of cholangiocarcinoma to a certain extent, thereby improving the treatment effect and prognosis.
[0007] (II) Technical Solutions
[0008] To achieve the above object, the present invention provides a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of an immune checkpoint inhibitor and a PCAF inhibitor; (2) a pharmaceutically or immunologically acceptable carrier or excipient.
[0009] In one embodiment, the PCAF antibody is administered before, simultaneously with, or after the administration of the immune checkpoint inhibitor.
[0010] In one embodiment, the immune checkpoint inhibitor comprises one or a combination of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a TIGIT inhibitor, a VISTA inhibitor, and an IDO inhibitor.
[0011] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor.
[0012] In one embodiment, the PD-1 inhibitor comprises one or a combination of nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, and InVivoMAb anti-mouse PD-1.
[0013] In one embodiment, the PD-1 inhibitor is InVivoMAb anti-mouse PD-1.
[0014] In one embodiment, the PCAF inhibitor comprises one or a combination of curcumin, curcumin, CPTH2, C646, GSK525762A, WP1130, MG149, E64d, MB-3, H3-CoA-20, PCAF-IN-1, PCAF-IN-2, AAU-22, malic acid, and Isothiazolones.
[0015] In one embodiment, the PCAF inhibitor is PCAF-IN-1.
[0016] On the other hand, the present invention also provides the use of the above pharmaceutical composition in the preparation of a drug for preventing and / or treating cholangiocarcinoma and / or diseases and / or symptoms related to cholangiocarcinoma.
[0017] On the other hand, the present invention also provides a pharmaceutical preparation, which comprises the above pharmaceutical composition.
[0018] On the other hand, the present invention also provides the use of the above pharmaceutical preparation in the preparation of a drug for preventing and / or treating cholangiocarcinoma and / or diseases and / or symptoms related to cholangiocarcinoma.
[0019] In one embodiment, the cholangiocarcinoma in the above application includes one or a combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and extrahepatic cholangiocarcinoma.
[0020] In one embodiment, the mass ratio of the dosages of the immune checkpoint inhibitor and the PCAF inhibitor in the above application is 1:10 - 10:1.
[0021] In one embodiment, the mass ratio of the dosages is 1:1.
[0022] In one embodiment, the dosage of the immune checkpoint inhibitor in the above application is 5 mg / kg.
[0023] In one embodiment, the dosage of the PCAF inhibitor in the above application is 5 mg / kg.
[0024] In one embodiment, the immune checkpoint inhibitor and the PCAF inhibitor in the above application are administered by intraperitoneal injection.
[0025] In one embodiment, the subject to be administered is healthy.
[0026] In one embodiment, the subject to be administered is non - healthy.
[0027] In one embodiment, the subject to be administered has cholangiocarcinoma.
[0028] In one embodiment, the subject to be administered does not have cholangiocarcinoma.
[0029] In one embodiment, the subjects include mammals and non - mammals.
[0030] Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non - human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, etc. Examples of non - mammals include, but are not limited to, birds, fish, or other non - mammals, etc.
[0031] In one embodiment, the subject is a mouse.
[0032] Beneficial effects
[0033] The present invention provides the use of an immune checkpoint inhibitor and a PCAF inhibitor in the preparation of a drug for preventing and / or treating cholangiocarcinoma and / or diseases and / or symptoms related to cholangiocarcinoma. Compared with the prior art, the following beneficial effects are achieved:
[0034] 1. Enhance CD8 +T cell immune function: Existing immunotherapy mainly focuses on the single use of PD-1 immune checkpoint inhibitors, but the effect is often limited due to insufficient immune cell function. The present invention significantly enhances CD8 + The immune function of T cells improves their ability to kill tumors, overcoming the problem of insufficient immune cell activity in traditional treatments.
[0035] 2. Solve the immune escape mechanism: Cholangiocarcinoma has a complex immune escape mechanism, which allows the tumor to escape immune surveillance. Existing immune checkpoint inhibitors have limited efficacy in this context. The present invention enhances the anti-tumor effect of T cells through the combined use of PCAF inhibitors, and at the same time, by eliminating the immune escape mechanism, tumor cells are more easily recognized and attacked by the immune system, thereby effectively improving the treatment effect.
[0036] 3. Significant improvement in immunotherapy effect: Compared with the use of PD-1 inhibitors alone, the combined treatment strategy of the present invention has shown a stronger anti-tumor effect in the treatment of cholangiocarcinoma. The combination of PCAF inhibitors and PD-1 inhibitors can not only improve the function of T cells, but also break through the barrier of tumor immune escape, significantly improve the comprehensive effect of treatment, and enhance the patient's treatment response.
[0037] 4. Improve patient prognosis: A major challenge of immunotherapy is the uncertainty of treatment effect and drug resistance in some patients. By combining with PCAF inhibitors, the present invention helps to increase the response rate of cholangiocarcinoma patients to immunotherapy and reduce the occurrence of drug resistance, thereby significantly improving the prognosis of patients.
[0038] 5. Clinical application potential: This invention provides a new idea and solution for the immunotherapy of cholangiocarcinoma, solving the problems of poor effect of existing immunotherapy and immune escape. This combined treatment method has good clinical application potential and can bring higher survival rate and better quality of life to cholangiocarcinoma patients.
[0039] Terms and Definitions
[0040] As used herein, the term "immune checkpoint inhibitor" refers to a molecule that reduces, inhibits, interferes with, or modulates one or more checkpoint proteins in whole or in part. Checkpoint proteins regulate T cell activation or function. A variety of checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD1 and its ligands PDL1 and PDL2 (Pardoll, Nature Reviews Cancer 12: 252-264, 2012). These proteins are responsible for the co-stimulatory or inhibitory interactions of T cell responses. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.
[0041] As used herein, the term "antibody" includes glycosylated and non-glycosylated immunoglobulins of any isotype or subclass mentioned, or antigen-binding regions thereof that compete with intact antibodies for specific binding, including monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies, antibody mimetics, chimeric antibodies, humanized antibodies, human antibodies, antibody fusions, antibody conjugates, single-chain antibodies, antibody derivatives, antibody analogs, and their corresponding fragments. Also included are immunological fragments of antibodies (e.g., Fab, Fab’, F(ab’)2 or scFv), whether such antibodies are produced in whole or in part by immunization, by recombinant techniques, by in vitro synthetic means or by other methods. Thus, as used herein, the term "antibody" includes antibodies prepared, expressed, produced or isolated by recombinant means, such as (a) antibodies isolated from transgenic animals (e.g., mice) with respect to human immunoglobulin genes or from hybridomas prepared from human immunoglobulin genes; (b) antibodies isolated from host cells transfected to express antibodies (e.g., from transfectomas); (c) antibodies isolated from recombinant combinatorial antibody libraries; and (d) antibodies prepared, expressed, produced or isolated by any other means involving splicing of immunoglobulin gene sequences to other DNA sequences. These antibodies have variable and constant regions of germline immunoglobulin sequences from two different animal species. However, in certain embodiments, these antibodies may undergo in vitro mutagenesis (or, when using transgenic animals with respect to human immunoglobulin sequences, in vivo somatic mutagenesis), and thus, the amino acid sequences of the VH and VL regions of these antibodies, although derived from and related to the germline VH and VL sequences of a particular species (e.g., human), may not be sequences that occur naturally in the antibody germline repertoire of that species in vivo. Unless otherwise indicated, the term "antibody" includes derivatives, variants, fragments and mutant proteins thereof in addition to antibodies comprising two full-length heavy chains and two full-length light chains. In some instances, an "antibody" may include fewer chains, such as antibodies that may contain only heavy chains and that occur naturally in camels.
[0042] As used herein, the terms "patient" or "subject" are used interchangeably and refer to mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish or other non-mammals, etc.
[0043] As used herein, the term "pharmaceutical composition" refers to a composition comprising an immune checkpoint inhibitor and a PCAF inhibitor formulated together with one or more pharmaceutically acceptable carriers.
[0044] The formulation of the pharmaceutical composition can be adjusted according to the application. In particular, the pharmaceutical composition can be formulated using methods known in the art so as to provide rapid, continuous or delayed release of the active ingredient after administration to a mammal.
[0045] The dosage forms of the pharmaceutical composition disclosed in the present invention can be granules, tablets, lyophilized powders, suppositories, capsules, sublingual tablets, liquid solutions, nasal drops, sprays, metered spray forms.
[0046] Any known method can be used to administer the pharmaceutical composition of the present invention. One of the various methods known to those skilled in the art can be used to "administer" or "apply" a substance, compound or agent to a subject.
[0047] For example, the compound or agent can be administered intranasally (e.g., by inhalation), intrathecally (into the intraspinal or subarachnoid space), intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intracerebrally, and transdermally (by absorption, e.g., through a skin catheter). The compound or reagent can also be suitably introduced through a rechargeable or biodegradable polymeric device or other device (e.g., patches and pumps or formulations) that provides extended, slowed or controlled release of the compound, reagent. Administration can also be carried out, for example, once, multiple times and / or over one or more extended periods.
[0048] As used herein, the term "pharmaceutically acceptable" ingredient is a substance that is suitable for use in humans and / or animals without undue adverse reactions (such as toxicity, irritation and allergic reactions), i.e., a substance having a reasonable benefit / risk ratio.
[0049] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is a carrier for the administration of therapeutic agents, including various excipients and diluents. This term refers to those pharmaceutical carriers which are not necessarily the active ingredient itself and which are not unduly toxic when administered. Suitable carriers are well known to those of ordinary skill in the art, and a full discussion of pharmaceutically acceptable excipients can be found in Remington’s Pharmaceutical Sciences, Mack Pub. Co., N.J. 1991.
[0050] Pharmaceutically acceptable carriers in the composition include any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, surfactants, fillers, disintegrants, binders, diluents, lubricants, glidants, pH regulators, buffers, enhancers, wetting agents, solubilizers, surfactants, antioxidants, etc. that are compatible with drug administration. The use of such media and agents for active pharmaceutical substances is well known in the art. The composition may contain other active compounds that provide supplementary, additional or enhanced therapeutic functions. Solid carriers or excipients, such as lactose, starch or talc, or liquid carriers, such as water, fatty oils or liquid paraffin. Other examples of the carrier include culture media, such as DMEM or RPMI; and cryopreservation media, containing components that scavenge free radicals, provide pH buffering, osmotic / osmolarity support, energy substrates and ion concentrations, which can balance the intracellular state at low temperatures; and mixtures of organic solvents and water.
[0051] As used herein, the term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level includes factors such as the type and severity of the subject, age, gender, drug activity, sensitivity to the drug, administration time, administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field.
[0052] As used herein, the term "treating" a condition or a patient means taking steps to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results include, but are not limited to, alleviating, substantially inhibiting, slowing down or reversing the progression of a disease, condition or disorder, substantially improving or alleviating the clinical or aesthetic symptoms of a condition, substantially preventing the clinical or aesthetic symptoms of a disease, condition or disorder, and avoiding adverse or undesirable symptoms. Treatment also refers to accomplishing one or more of the following: (a) reducing the severity of a disorder; (b) limiting the development of the characteristic symptoms of the disorder being treated; (c) limiting the worsening of the characteristic symptoms of the disorder being treated; (d) limiting the recurrence of the disorder in patients previously suffering from the disorder; and / or (e) limiting the recurrence of symptoms in patients previously without symptoms of the disorder.
[0053] As used herein, the term "preventing" means reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition or associated symptoms (e.g., diabetes or cancer). Description of the Drawings
[0054] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.
[0055] Figure 1 It is a bar chart comparing the T cell activities and effector functions of different treatment groups.
[0056] Figure 2 It is the combination index (CI) value of the anti-PD-1 monoclonal antibody combined with the PCAF inhibitor.
[0057] Figure 3 It is the tumor growth curve of mice in different treatment groups.
[0058] Figure 4 It is a bar chart showing the statistics of T cell infiltration and effector functions in tumor tissues after the treatment of murine cholangiocarcinoma.
[0059] Figure 5 It is the tumor growth curve of mice in different treatment groups in Example 3.
[0060] Figure 6 It is a bar chart showing the statistics of T cell infiltration and effector functions in tumor tissues after the treatment of murine cholangiocarcinoma in Example 3. Detailed implementation manners
[0061] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.
[0062] As used herein, "comprising", "having", or "including" includes "containing", "consisting essentially of...", "consisting substantially of...", and "consisting of..."; "consisting essentially of...", "consisting substantially of...", and "consisting of..." are subordinate concepts of "comprising", "having", or "including".
[0063] The experimental methods used in the following embodiments are all conventional methods unless otherwise specified. The reagents, methods, and equipment used are all conventional reagents, methods, and equipment in the technical field unless otherwise specified.
[0064] Example 1
[0065] In vitro cell experiments:
[0066] 1) PBM Cs were isolated from peripheral blood samples using Ficoll-Paque density gradient centrifugation. PBMCs were taken from the separation layer and washed with PBS (phosphate buffer solution) to remove plasma and other impurities.
[0067] 2) PBMCs were seeded into T cell medium, and anti-CD3 antibody (usually 2 μg / mL) and anti-CD28 antibody (usually 2 μg / ml) were added to activate T cells.
[0068] 3) PBMCs were placed in an incubator at 37 °C and 5% CO 2 and cultured. During the culture process, an appropriate amount of IL-2 (100 IU / mL) was supplemented to promote T cell proliferation and differentiation. The induced CD8 + T cells could be used for subsequent experiments.
[0069] 4) CD8 + T cells were co-cultured with cholangiocarcinoma cell line RBE, and DMSO at a concentration of 10 μM, PCAF inhibitor (PCAF-IN-1) at a concentration of 10 μM, PD-1 inhibitor (InVivoMAb anti-mouse PD-1) at a concentration of 10 μM, PCAF inhibitor (PCAF-IN-1) at a concentration of 10 μM and PD-1 inhibitor (InVivoMAb anti-mouse PD-1) at a concentration of 10 μM were added respectively. After 24 h of culture, flow cytometry was used to detect T cell activity and the secretion of cytokines granzyme B and interferon γ.
[0070] The results were as Figure 1 shown. Compared with the control and single drug treatment, the combination of PD-1 and PCAF inhibitor significantly promoted T cell activity and the secretion of T cell cytokines granzyme B and interferon γ.
[0071] The activity of cholangiocarcinoma cell line RBE was detected by CCK8, and the combination index (CI) value was calculated. The results were as Figure 2 shown. Using the Chou-Talalay method to calculate the combination index (CI) value, there was a synergistic interaction between PCAF inhibitor and PD1 monoclonal antibody in cholangiocarcinoma cell line RBE, rather than an additive effect, and the CI was 0.63232 at ED50.
[0072] Example 2
[0073] In vivo animal experiment:
[0074] 1) The mIC-22 mouse cholangiocarcinoma cells were washed twice with sterile PBS, and the cell concentration was adjusted to 5×10 6Cells / 100 μL. Using a sterile syringe, subcutaneously inject 100 μL of the cell suspension into the right axilla of C57BL / 6 mice. Observe the mice's condition daily and wait for tumor formation (usually takes 5 - 7 days, and tumor formation is considered when the diameter reaches 5 mm 3 ).
[0075] 2) After tumor formation, randomly divide the mice into the following four groups (5 mice in each group)
[0076] Control group: Inject an equal volume of normal saline, with the same method and frequency as other groups.
[0077] PD-1 treatment group: Intraperitoneally inject 5 mg / kg of PD-1 inhibitor (InVivoMAb anti-mouse PD-1) every 3 days for 2 weeks.
[0078] PCAF inhibitor treatment group: Intraperitoneally inject 5 mg / kg of PCAF inhibitor (Anacardic Acid, AA) once a day for 2 weeks.
[0079] Combined treatment group: Intraperitoneally inject 5 mg / kg of InVivoMAb anti-mouse PD-1 and 5 mg / kg of AA, with the same administration method and frequency as above.
[0080] 3) Use calipers to measure the long diameter (L) and short diameter (W) of the tumor every 3 days, and calculate the tumor volume according to the formula: V = (L × W 2 ) / 2, and record the mean tumor volume of each group for subsequent data analysis.
[0081] 4) Observe the survival status of the mice daily and record the survival time. When the mice show inability to eat or move, a sharp weight loss, or the tumor volume exceeds 1500 mm 3 , perform euthanasia. And collect fresh tumor tissues for subsequent flow cytometry analysis of the proportion of immune cells in the tumor tissues.
[0082] As Figure 3 shown, compared with the control and single-drug treatments, the combination of PD-1 and PCAF inhibitor significantly inhibited the growth of subcutaneous tumors in mice.
[0083] As Figure 4 shown, compared with the control and single-drug treatments, the combination of PD-1 and PCAF inhibitor significantly promoted the infiltration of CD8+ T cells and the secretion of cytokines granzyme B and interferon γ in mouse tumors.
[0084] Example 3
[0085] Animal experiment in vivo with half the dose:
[0086] 1) Wash the mIC-22 mouse cholangiocarcinoma cells twice with sterile PBS, and adjust the cell concentration to 5×10 6 cells / 100 μL. Using a sterile syringe, subcutaneously inject 100 μL of the cell suspension into the right axilla of C57BL / 6 mice. Observe the mice's condition daily and wait for tumor formation (usually takes 5 - 7 days, and tumor formation is considered when the diameter reaches 5 mm 3 ).
[0087] 2) After tumor formation, randomly divide the mice into the following four groups (5 mice in each group)
[0088] Control group: Inject an equal volume of normal saline, with the same method and frequency as other groups.
[0089] PD-1 treatment group: Intraperitoneally inject 5 mg / kg PD-1 inhibitor once every 3 days for 2 weeks.
[0090] PCAF inhibitor treatment group: Intraperitoneally inject 5 mg / kg PCAF inhibitor (Anacardic Acid, AA) once a day for 2 weeks.
[0091] Combined treatment group: Inject a combination of 2.5 mg / kg PD-1 inhibitor and 2.5 mg / kg AA, with the same administration method and frequency as above.
[0092] 3) Use calipers to measure the long diameter (L) and short diameter (W) of the tumor every 3 days, and calculate the tumor volume according to the formula: V = (L×W 2 ) / 2, record the mean tumor volume of each group for subsequent data analysis.
[0093] 4) Observe the survival status of the mice daily and record the survival time. When the mice show inability to eat or move, a sharp weight loss, or the tumor volume exceeds 1500 mm 3 , perform euthanasia. And collect fresh tumor tissues for subsequent flow cytometry analysis of the proportion of immune cells in the tumor tissues
[0094] It should be noted that, in this text, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising an..." does not exclude the existence of additional identical elements in the process, method, article or device comprising the said element.
[0095] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) Therapeutically effective amounts of immune checkpoint inhibitors and PCAF inhibitors; (2) A pharmaceutically or immunologically acceptable carrier or excipient.
2. The pharmaceutical composition according to claim 1, characterized in that The PCAF antibody is administered prior to, concurrently with, or after administration of the immune checkpoint inhibitor.
3. The pharmaceutical composition according to claim 2, characterized in that The immune checkpoint inhibitor includes one or a combination of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, VISTA inhibitors and IDO inhibitors.
4. The pharmaceutical composition according to claim 3, characterized in that The immune checkpoint inhibitor is a PD-1 inhibitor.
5. The pharmaceutical composition according to claim 2, characterized in that The PCAF inhibitor includes one or a combination of garcinia, curcumin, CPTH2, C646, GSK525762A, WP1130, MG149, E64d, MB-3, H3-CoA-20, PCAF-IN-1, PCAF-IN-2, AAU-22, anacardic acid and isothiazolones.
6. The pharmaceutical composition according to claim 5, characterized in that The PCAF inhibitor is PCAF-IN-1.
7. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for preventing and / or treating cholangiocarcinoma and / or diseases and / or symptoms associated with cholangiocarcinoma.
8. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 1 to 6 or the use according to claim 7.
9. Use of the pharmaceutical preparation according to claim 8 in the preparation of a medicament for preventing and / or treating cholangiocarcinoma and / or diseases and / or symptoms associated with cholangiocarcinoma.
10. The use according to claim 7 or 9, characterized in that: The cholangiocarcinoma includes one or a combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and extrahepatic cholangiocarcinoma.