Composition for immunotherapy of cholangiocarcinoma and application thereof
By combining a pharmaceutical composition with an immune checkpoint inhibitor and CD151 antibody, innate immunity and recruitment of CD8+ T cells were solved, and a more significant immune response and a higher therapeutic response rate were achieved.
Patent Information
- Application Number
- CN202510352316.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-25
- Publication Date
- 2025-06-06
AI Technical Summary
The therapeutic effect of cholangiocarcinoma is limited, especially in advanced patients. The existing targeted therapy and immunotherapy are not effective, and drug resistance or side effects may occur, affecting the quality of life of patients.
A pharmaceutical composition is provided, including a therapeutically effective amount of an immune checkpoint inhibitor (such as a PD-1 inhibitor) and a CD151 antibody, through targeting the membrane protein CD151 of tumor-associated fibroblasts, activates a cGAS-sting-mediated type I IFN response, enhances the innate immunity of the cells, and recruits more CD8+ T cells, thereby enhancing the effect of immunotherapy.
Significantly enhance the immune response, overcome immune escape, improve the response rate of cholangiocarcinoma treatment, and provide new treatment options, which are especially effective for patients who are ineffective against single immunotherapy.
Smart Images
Figure CN120093930A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedical technology, and in particular to a composition for immunotherapy of bile duct cancer and its application. Background Art
[0002] Cholangiocarcinoma is a malignant tumor that occurs in the bile ducts of the liver. Surgery remains the main method for treating cholangiocarcinoma, but because cholangiocarcinoma usually has no obvious symptoms in the early stages, many patients are already in the advanced stages when diagnosed and lose the opportunity for surgery. Therefore, targeted therapy and immunotherapy have gradually become emerging treatment options for cholangiocarcinoma. However, due to the severe fibrosis and hard matrix of cholangiocarcinoma, an "immune barrier" is formed, resulting in poor immunotherapy effects. The overall efficacy of using PD-1 inhibitors alone (such as carrelizumab and tislelizumab) to treat cholangiocarcinoma is still relatively limited, and many patients cannot obtain significant survival benefits from it.
[0003] Although the treatment of cholangiocarcinoma is constantly being updated, the overall efficacy is still limited, especially in advanced patients. Existing targeted therapies and immunotherapies are not effective, and drug resistance or side effects may occur in some patients, affecting the quality of life of patients. Therefore, the treatment of cholangiocarcinoma still faces great challenges, and new targeted therapy strategies need to be developed to further enhance the treatment effect and improve patient prognosis. Summary of the invention
[0004] 1. Technical issues to be solved
[0005] In view of this, one of the main purposes of the present invention is to provide a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of an immune checkpoint inhibitor and a CD151 antibody; (2) a pharmaceutically or immunologically acceptable carrier or excipient. By targeting the membrane protein CD151 of tumor-associated fibroblasts, the cGAS-sting-mediated type I IFN response is activated, the cell's own innate immunity is enhanced, and more CD8 + T cells. By combining CD151 targeted inhibitors with PD-1 immune checkpoint inhibitors, immunotherapy can enhance the effects of low immune cell infiltration and low function in cholangiocarcinoma, solve the problems of poor efficacy of existing immunotherapy, immune escape and insufficient immune cell function, and ultimately improve the treatment effect of cholangiocarcinoma and patient prognosis.
[0006] (II) Technical solution
[0007] In order to achieve the above-mentioned object, the present invention provides a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of an immune checkpoint inhibitor and a CD151 antibody; and (2) a pharmaceutically or immunologically acceptable carrier or excipient.
[0008] In one embodiment, the CD151 antibody is administered prior to, concurrently with, or after administration of the immune checkpoint inhibitor.
[0009] In one embodiment, the immune checkpoint inhibitor includes 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.
[0010] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor.
[0011] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody.
[0012] In one embodiment, the PD-1 antibody includes one or a combination of nivolumab, pembrolizumab, toripalimab, sintilimab and carrelizumab.
[0013] In one embodiment, the PD-1 antibody is Anti-PD1 mAb (BE0146) from Bioxcel.
[0014] In one embodiment, the CD151 inhibitor comprises one or a combination of antibodies, siRNA, miRNA, gRNA and antisense oligonucleotides against CD151 or a nucleic acid molecule encoding the protein.
[0015] In one embodiment, the CD151 inhibitor is a CD151 antibody.
[0016] In one embodiment, the CD151 antibody includes one or a combination of 5C11, H193, M-20, EPR series, EPR3202, TS151r, 1A5 and RM1001.
[0017] In one embodiment, the CD151 antibody is Anti-CD151 mAb (A2793) from Selleck Chemicals.
[0018] In another aspect, the present invention also provides use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating bile duct cancer and / or diseases and / or symptoms associated with bile duct cancer.
[0019] In another aspect, the present invention also provides a pharmaceutical preparation, which comprises the above-mentioned pharmaceutical composition.
[0020] In another aspect, the present invention also provides the use of the above-mentioned pharmaceutical preparation in the preparation of a drug for preventing and / or treating bile duct cancer and / or diseases and / or symptoms associated with bile duct cancer.
[0021] In one embodiment, the cholangiocarcinoma in the above application includes one or a combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and extrahepatic cholangiocarcinoma.
[0022] In one embodiment, the ratio of the immune checkpoint inhibitor dosage to the CD151 inhibitor dosage in the above application is 2:1-1:2.
[0023] In one embodiment, the immune checkpoint inhibitor is administered at a dose of 5-15 mg / kg.
[0024] In one embodiment, the immune checkpoint inhibitor in the above application is administered at a dosage of 10 mg / kg.
[0025] In one embodiment, the CD151 inhibitor is administered at a dose of 5-15 mg / kg.
[0026] In one embodiment, the CD151 inhibitor in the above application is administered at a dose of 10 mg / kg.
[0027] In one embodiment, the total administration dose of the immune checkpoint inhibitor and CD151 antibody in the above application is 10 mg / kg; the administration dose of the immune checkpoint inhibitor is 5 mg / kg; and the administration dose of the CD151 inhibitor is 5 mg / kg.
[0028] In one embodiment, the immune checkpoint inhibitor and CD151 inhibitor in the above application are administered by intraperitoneal injection.
[0029] In one embodiment, the administering subject is healthy.
[0030] In one embodiment, the administering subject is non-healthy.
[0031] In one embodiment, the subject of administration has cholangiocarcinoma.
[0032] In one embodiment, the administering subject does not have cholangiocarcinoma.
[0033] In one embodiment, the subject includes mammals and non-mammals.
[0034] 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.
[0035] In one embodiment, the subject is a mouse.
[0036] (III) Beneficial effects
[0037] The present invention provides a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of an immune checkpoint inhibitor and a CD151 antibody; and (2) a pharmaceutically or immunologically acceptable carrier or excipient. Compared with the prior art, the pharmaceutical composition has the following beneficial effects:
[0038] 1. Enhanced immune response: Compared with the use of PD-1 inhibitors alone, targeting CD151 activates the innate immunity of tumor-associated fibroblasts and recruits CD8 + T cell infiltration significantly enhances the immune system's ability to kill cholangiocarcinoma.
[0039] 2. Overcome immune escape: By improving fibrosis, reshape the microenvironment of the "immune desert" of cholangiocarcinoma, break the immune barrier, enhance the infiltration of other immune cells, and enhance the effect of immunotherapy.
[0040] 3. Novel combination therapy: The combination of CD151 inhibitors and immune checkpoint inhibitors (PD-1 inhibitors) can improve the response rate of treatment and provide new treatment options for patients who are ineffective with single immunotherapy.
[0041] 4. Easy to promote and apply: This treatment method is simple and low-cost, and is suitable for most bile duct cancer patients, especially those with weak immune function.
[0042] (IV) Terms and Definitions
[0043] 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.
[0044] 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, mini antibodies, 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. It also includes immune fragments of antibodies (e.g., Fab, Fab', F(ab')2, or scFv), regardless of whether such antibodies are produced in whole or in part by immunization, by recombinant technology, by in vitro synthesis, or by other methods. Thus, as used herein, the term "antibody" includes those antibodies prepared, expressed, generated or isolated by recombinant means, such as (a) antibodies isolated from transgenic animals (e.g., mice) for human immunoglobulin genes or 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, generated or isolated by any other means involving splicing of immunoglobulin gene sequences to other DNA sequences. These antibodies have variable and constant regions derived from germline immunoglobulin sequences of two different animal species. However, in certain embodiments, these antibodies may have undergone in vitro mutagenesis (or, when transgenic animals for human immunoglobulin sequences are used, 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., humans), may not be sequences that naturally occur in vivo within the antibody germline repertoire of that species. Unless otherwise indicated, the term "antibody" includes derivatives, variants, fragments, and muteins thereof in addition to antibodies comprising two full-length heavy chains and two full-length light chains. In some cases, an "antibody" may include fewer chains, such as antibodies that naturally occur in camels that may only contain heavy chains.
[0045] As used herein, the term "inhibitor" or "inhibitor of CD151 or its encoding nucleic acid molecule" is used interchangeably and refers to a substance that can reduce the level or activity of CD151 or its encoding nucleic acid molecule. Inhibitors that can be used in the present disclosure include, but are not limited to, antibodies, siRNA, miRNA, gRNA, antisense oligonucleotides, antagonists, and blockers against CD151 or nucleic acid molecules encoding the protein.
[0046] 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.
[0047] As used herein, the term "pharmaceutical composition" refers to a composition comprising an immune checkpoint inhibitor and / or a histone acetyltransferase inhibitor formulated together with one or more pharmaceutically acceptable carriers.
[0048] 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 to provide quick, continuous or delayed release of the active ingredient after administration to a mammal.
[0049] The dosage form of the pharmaceutical composition disclosed in the present invention can be granules, tablets, lyophilized powder, suppositories, capsules, sublingual tablets, liquid solutions, nasal drops, sprays, and quantitative sprays.
[0050] The pharmaceutical compositions of the present invention may be administered using any known method.The term "administering" or "applying" a substance, compound or agent to a subject may be performed using one of a variety of methods known to those skilled in the art.
[0051] For example, the compound or agent can be administered intranasally (e.g., by inhalation), intrathecally (into the spinal canal or subarachnoid space), intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intracerebrally, and transdermally (by absorption, e.g., through a skin catheter). The compound or agent can also be suitably introduced by a rechargeable or biodegradable polymeric device or other device (e.g., a patch and a pump or formulation) that provides extended, slowed, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.
[0052] As used herein, the term "pharmaceutically acceptable" ingredients are substances that are suitable for use in humans and / or animals without excessive adverse reactions (such as toxicity, irritation, and allergic response), ie, at a reasonable benefit / risk ratio.
[0053] 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. The term refers to such pharmaceutical carriers: they are not necessary active ingredients themselves and are not overly toxic after administration. 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., NJ 1991).
[0054] In the composition, pharmaceutically acceptable carriers 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 pharmaceutically active 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 low temperature storage media, comprising components that scavenge free radicals, provide pH buffering, osmotic / osmotic support, energy substrates and ion concentrations, which can balance the intracellular state at low temperatures; and mixtures of organic solvents and water.
[0055] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level includes the type and severity of the subject, age, sex, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant medications, and other factors well known in the medical field.
[0056] As used herein, the term "treating" a condition or 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, or eliminating, substantially inhibiting, slowing, 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 harmful or annoying symptoms. Treatment also refers to accomplishing one or more of the following: (a) lessening the severity of the condition; (b) limiting the development of symptoms characteristic of the condition being treated; (c) limiting the worsening of symptoms characteristic of the condition being treated; (d) limiting the recurrence of the condition in patients who previously had the condition; and / or (e) limiting the recurrence of symptoms in patients who were previously free of symptoms of the condition.
[0057] As used herein, the term "prevent" or "preventing" refers to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptoms. BRIEF DESCRIPTION OF THE DRAWINGS
[0058] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0059] Figure 1 It is a comparative bar graph of T cell activity and effector function in different treatment groups.
[0060] Figure 2 Figure 2 is the tumor growth curve of mice in different treatment groups.
[0061] Figure 3 Figure 2 is the tumor growth curve of mice in different treatment groups.
[0062] Figure 4 is the synergy combination index (CI) value. DETAILED DESCRIPTION
[0063] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0064] As used herein, “containing,” “having,” or “including” include “comprising,” “mainly consisting of,” “substantially consisting of,” and “consisting of;” “mainly consisting of,” “substantially consisting of,” and “consisting of” are subordinate concepts of “containing,” “having,” or “including.”
[0065] The experimental methods used in the following examples are all conventional methods unless otherwise specified, and the reagents, methods and equipment used are all conventional reagents, methods and equipment in the technical field unless otherwise specified.
[0066] Example 1
[0067] In vitro cell experiments:
[0068] 1) Primary fibroblasts were isolated from mouse liver samples using mouse fibroblast magnetic bead sorting method. The cells were resuspended in fibroblast culture medium and plated for in vitro culture.
[0069] 2) CD151-overexpressing fibroblast cell lines and CD151-knockdown fibroblast cell lines were constructed in primary fibroblasts, and the conditioned medium was collected.
[0070] 3) Isolation of CD8 from mouse spleen using mouse CD8 magnetic bead isolation method + T cells. + Anti-CD3 antibody (usually 2 μg / mL) and anti-CD28 antibody (usually 2 μg / ml) were added to T cells to activate T cells.
[0071] 4) On the second day of T cell activation, conditioned medium and T cell medium were added in a 1:1 ratio to establish fibroblast conditioned medium overexpressing CD151, fibroblast conditioned medium with CD 151 knockdown, and a control group, respectively. During the co-culture process, an appropriate amount of IL-2 (100 IU / mL) was supplemented to promote T cell proliferation and differentiation.
[0072] 4) On the fourth day of co-culture, T cell activity and the secretion of cytokines granzyme B and interferon-γ were detected by flow cytometry.
[0073] The results are as follows Figure 1 As shown, compared with the control group, the fibroblast group with CD151 knockdown significantly promoted the secretion of T cell cytokines granzyme B and interferon γ, while the fibroblast group with CD151 overexpression significantly inhibited the secretion of T cell cytokines granzyme B and interferon γ.
[0074] Example 2
[0075] In vivo animal experiments:
[0076] 1) Mouse cholangiocarcinoma cell line LTP-39 was mixed with primary fibroblasts or CD151 knockdown fibroblasts at a ratio of 1:1, washed twice with sterile PBS, and the cell concentration was adjusted to 5×10 6 Cells / 100μL. Use a sterile syringe to subcutaneously inject 100μL of the cell suspension into the right armpit of C57BL / 6 mice. Observe the condition of the mice every day and wait for tumor formation (usually takes 5-7 days, and the tumor is considered formed when the diameter reaches 5mm).
[0077] 2) Use a caliper 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×W2) / 2. Record the mean tumor volume of each group for subsequent data analysis.
[0078] The survival status of the mice was observed every day and the survival time was recorded. When the mice were unable to eat or move, had a sharp drop in weight, or had a tumor volume exceeding 1500mm 3 When euthanasia is performed.
[0079] The results are as follows Figure 2 As shown, compared with the control group, the fibroblast group with CD151 knockdown significantly inhibited the growth of subcutaneous tumors in mice.
[0080] Example 3
[0081] Effect of combination therapy on tumor growth in mice:
[0082] 1) Mouse cholangiocarcinoma cell line LTP-39 was mixed with primary fibroblasts at a ratio of 1:1, washed twice with sterile PBS, and the cell concentration was adjusted to 5×10 6 Cells / 100μL. Use a sterile syringe to subcutaneously inject 100μL of the cell suspension into the right armpit of C57BL / 6 mice. Observe the condition of the mice every day and wait for tumor formation (usually takes 5-7 days, and the tumor is considered formed when the diameter reaches 5mm).
[0083] 2) After tumor formation, the mice in the primary fibroblast group were randomly divided into the following four groups (5 mice in each group):
[0084] Control group: injected with 10 mg / kg normal saline, once every 3 days, for 2 weeks.
[0085] PD-1 treatment group: 10 mg / kg Anti-PD1 mAb (BE0146) was intraperitoneally injected every 3 days for 2 weeks.
[0086] CD151 targeted treatment group: 10 mg / kg Anti-CD151 mAb (A2793) was intraperitoneally injected every 3 days for 2 weeks.
[0087] Combined treatment group: 5 mg / kg Anti-PD1 mAb (BE0146) and 5 mg / kg Anti-CD151 mAb (A2793) were intraperitoneally injected every 3 days for 2 weeks.
[0088] 2) Use a caliper 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×W2) / 2. Record the mean tumor volume of each group for subsequent data analysis.
[0089] The survival status of the mice was observed every day and the survival time was recorded. When the mice were unable to eat or move, had a sharp drop in weight, or had a tumor volume exceeding 1500mm 3 When euthanasia is performed.
[0090] The results are as follows Figure 3 As shown in the figure, the tumor volume of mice in the control group has been increasing, and compared with the group treated with PD-1 monoclonal antibody alone, the growth rate of the tumor in the group treated with PD-1 and CD151 combined was significantly slowed down and the tumor volume was significantly reduced. This shows that the combined treatment has the effect of reducing the tumor volume and ultimately achieves the purpose of treatment.
[0091] Example 4
[0092] Verification of synergistic effects of combined therapeutic drugs:
[0093] 1) CD8 + T cells were co-cultured with primary mouse Caf, and 10uM CD151 monoclonal antibody and PD-1 monoclonal antibody were added (concentration ratio was 1:1), and T cell activity and the secretion of cytokines granzyme B and interferon y were detected by flow cytometry. The activity of primary mouse Caf was detected by CCK8, and the combination index (CI) value was calculated.
[0094] The results are as follows Figure 4 As shown, the combination index (CI) value was recalculated using the Chou-Talalay method. The results confirmed that there was a synergistic interaction between CD151 monoclonal antibody and PD1 monoclonal antibody in primary mouse Caf, rather than an additive effect, with a CI of 0.61032 at ED50.
[0095] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.
[0096] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions 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 CD151 antibodies; (2) A pharmaceutically or immunologically acceptable carrier or excipient.
2. The pharmaceutical composition according to claim 1, characterized in that The CD151 antibody is administered before, simultaneously with, or after the immune checkpoint inhibitor.
3. The pharmaceutical composition according to claim 1 or 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 1 or 2, characterized in that The CD151 inhibitor includes one or a combination of antibodies, siRNA, miRNA, gRNA and antisense oligonucleotides against CD151 or nucleic acid molecules encoding the protein.
6. The pharmaceutical composition according to claim 5, characterized in that The CD151 inhibitor is a CD151 antibody.
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 for use according to claims 1-6 or 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.