CN115845051B - Pharmaceutical composition and pharmaceutical preparation and application thereof in treating liver cancer - Google Patents
Pharmaceutical composition and pharmaceutical preparation and application thereof in treating liver cancer Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition and a pharmaceutical preparation and application thereof in treating liver cancer, wherein the pharmaceutical composition comprises LAG-3 monoclonal antibody and sapalimumab, and the composition has more remarkable effect of inhibiting the growth of liver cancer tumor compared with the single-drug treatment of LAG-3 monoclonal antibody or sapalimumab.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition, a pharmaceutical preparation and application thereof in treating liver cancer.
Background
Malignant tumor is a serious disease seriously threatening human health, and patients with advanced malignant tumor have short life span and poor life quality, and the adoption of drug treatment is the main treatment method of most patients with advanced tumor. Tumor immunotherapy has gained a great breakthrough in recent 10 years. Different from the traditional chemotherapeutic drugs which directly kill or inhibit the action mechanism of tumor cells, the tumor immunotherapy is to identify and kill the tumor cells through the human body autoimmune system by improving the functions and activities of the body immune system, so that the tumor immune therapy is more in line with the functions of the human body and has smaller adverse reaction.
LAG-3 (lymphocyte activation gene, LAG 3) belongs to the immunoglobulin superfamily and consists of three parts, namely an extracellular region, a transmembrane region and a cytoplasmic region, which are mainly expressed on the surfaces of activated T lymphocytes, partial natural killer cells and the like, and negatively regulate and control the immune function of an organism. LAG-3 shares about 20% homology with CD4 molecules, and the ligand common to both is a major histocompatibility complex class II molecule (Majorhistocompatibility complex class II, MHC II). Recent studies have now found that FGL1 (Fibrinogen-like Protein 1) is also the major ligand molecule for LAG-3. Other ligands for LAG-3 also include LSECtin and Galectin-3, both of which may be associated with immune function suppression in the immune microenvironment. LAG-3 has now become a potential target for tumor immunotherapy and provides a possible approach to tumor immunotherapy in addition to CTLA-4, PD-1.
At present, a plurality of foreign pharmaceutical enterprises are carrying out clinical tests of anti-LAG-3 monoclonal antibodies, including BMS, novartis, regeneron, immuntep and the like. The 2016 BMS published a clinical study of LAG-3 antibody (BMS-986016) for hematological and solid tumors, and after 89 patients received single drug treatment (climbing dose from 20mg to 800mg per person), no serious adverse effects related to the drug occurred, and 800mg alone did not reach MTD. The results of clinical studies on the development of LAG-3 antibodies (LAG-525) for treating 119 solid tumors (climbing dose from 1 to 15 mg/kg) were published in North 2018, and the adverse reactions related to treatment were seen in two stages (including fatigue, diarrhea and nausea) and were not reached with MTD by 15mg/kg alone. Clinical trial results published by LAG-3 antibody (MK-4280) developed in merck in 2018 showed that 18 patients received single drug therapy and that the treatment-related adverse reactions were mainly fatigue and joint pain (climbing dose from 7mg-700 mg/person) with 700mg alone did not reach MTD. The results indicate that the LAG-3 monoclonal antibody has better safety.
LAG-3 and PD-L1/PD-1 both negatively regulate T cell function. Sequencing results of various tumor tissues (1400 cases including breast cancer, liver cancer, lung cancer and the like) show that the high expression of the PD-L1 gene and the LAG-3 gene are positively correlated, which suggests that the two genes are simultaneously expressed in tumor patients, and in addition, research shows that the high expression of the PD-1 protein on the TIL cell surface and the expression of the LAG-3 protein are positively correlated in non-small cell lung cancer patients; these two negative regulatory T cell functional proteins (LAG-3 and PD-L1/PD-1) co-express and synergistically inhibit T cell function, resulting in a poor prognosis for the patient. These findings suggest the feasibility of targeting PD-1/PD-L1 and LAG3 simultaneously as therapeutic approaches and potential synergistic efficacy. At present, a plurality of LAG-3 monoclonal antibodies combined with PD-L1/PD-1 monoclonal antibodies are being developed for clinical trial research. Clinical studies of North developed LAG-3 antibody (LAG-525) in combination with Spartalizumab (PD-1 mab) for solid tumors were also reported in ASCO at 6 months 2018, with 11 PR and 1 CR (ORR 9.9%) in 121 patients after combination. ASCO at 6 months 2021 reports the results of phase II studies of eftilagimod alpha LAG-3 antibodies in combination with pembrolizumab for first-line treatment of metastatic non-small cell lung cancer, with 13 PR and 2 PR (42 ORR) after 36 patients were combined, and with 8.2 months of median PFS. ASCO at month 6 of 2021 also reported phase III results of BMS-986016 (Relatlimab) LAG-3 antibody in combination with Nivolumab versus Nivolumab first line treatment of advanced malignant melanoma, the Relatlimab+Nivolumab group had significantly longer median PFS (10.1 months [95% CI, 6.4-15.7 ]) than the Nivolumab group (4.6 months [95% CI, 3.4-5.6 ]; HR 0.75[95% CI, 0.6-0.9 ]; P=0.0055). The compound preparation is approved by the FDA to be marketed in the 3 rd month of 2022.
Therefore, the LAG-3 monoclonal antibody combined with the PD-L1/PD-1 monoclonal antibody is a new research hot spot, but the research stage is still the initial stage, and a plurality of blanks exist in the research on the aspects of medication safety, drug effect and indication.
Disclosure of Invention
In order to solve or partially solve the problems in the related art, the present application provides a pharmaceutical composition and a pharmaceutical preparation and an application thereof in treating liver cancer.
The first aspect of the present application provides a pharmaceutical composition comprising: LAG-3 mab and sai-herborist Li Shan.
Further, the LAG-3 monoclonal antibody is GLS-012.
Further, the molar concentration ratio of the LAG-3 monoclonal antibody to the saparhizomib was 131:1.
The second aspect of the application provides a pharmaceutical preparation, which comprises the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
Furthermore, the dosage form of the pharmaceutical preparation is injection, tablet, capsule, granule, suspension, emulsion, solution, sol, freeze-dried powder injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained-release preparation or controlled-release preparation.
The above pharmaceutical formulations may be prepared according to conventional methods in the pharmaceutical arts.
The pharmaceutical preparation can also comprise pharmaceutically acceptable carriers and/or auxiliary materials.
The carrier and/or adjuvant may include at least one of a diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier, and lubricant.
The third aspect of the application provides application of the pharmaceutical composition or the pharmaceutical preparation in preparation of drugs for treating liver cancer.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
The beneficial technical effects of the invention are as follows:
the invention provides a medicine composition for treating liver cancer by combining LAG-3 with saprolipram, which has more remarkable effect of inhibiting the growth of liver cancer tumors compared with LAG-3 or saprolipram.
Drawings
FIG. 1 shows the body weight change of mice in each group of pharmacodynamic tests in the present application;
FIG. 2 is a graph showing the tumor volume change of each group of mice in the pharmacodynamic test in the application of the present invention;
FIG. 3 is a graph showing the change in tumor weight of mice in each group in the pharmacodynamic test in the present application;
FIG. 4 is a photograph showing tumor of each group of mice in the pharmacodynamic test in the present application;
Detailed Description
Alternative embodiments of the present application will be described in more detail below with reference to the accompanying drawings. While the drawings illustrate alternative embodiments of the present application, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any or all possible combinations of one or more of the associated listed items.
The pharmaceutical composition and the pharmaceutical preparation of the present invention and the application thereof in treating liver cancer are described in detail below with reference to the accompanying drawings, and the details are as follows:
a pharmaceutical composition comprising: LAG-3 mab and sai-herborist Li Shan.
In one embodiment of the invention, the LAG-3 mab is GLS-012.
The recombinant fully human anti-LAG-3 monoclonal antibody injection (research and development code: GLS-012) is a class 1 biological new drug independently researched and developed by I company, and has complete independent property, wherein the invention patent of 'anti-human LAG-3 monoclonal antibody, its preparation method and application (patent number: ZL 201910146172.2)' is authorized.
GLS-012 is an IgG4 monoclonal antibody having an intact molecular weight of about 145kDa, a heavy chain molecular weight of about 49kDa, and a light chain molecular weight of about 23kDa. The product has strong binding capacity with human LAG-3 on cell surface, can block the binding of the target spot on lymphocyte surface with ligand Galectin-3, LSECtin, MHC-II, FGL-1, etc., and can enhance secretion of IFN-gamma and IL-2 and function of CD4+ T cell, thereby activating killing function of immune system on tumor cell. The research and development of the product has very important significance for the field of malignant tumor treatment.
In one embodiment of the invention, the molar concentration ratio of LAG-3 mab to saparhizomab is 131:1.LAG-3 mab 20 mg/kg+sirolimus 0.15mg/kg,20 x 145:0.15 x 148 = 131:1
A pharmaceutical preparation comprises the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
In one embodiment of the invention, the pharmaceutical preparation is in the form of injection, tablet, capsule, granule, suspension, emulsion, solution, sol, freeze-dried powder injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained release preparation or controlled release preparation.
The application of the pharmaceutical composition or the pharmaceutical preparation in preparing medicines for treating liver cancer.
And (3) effect verification:
the test method comprises the following steps: PBS resuspended tumor cells were inoculated subcutaneously in the right flank of the experimental animalsAt the time of tumor growth to 112mm 3 The animals are grouped for administration in groups of 4, 8 animals in each group, 20mg/kg of the isotype control group G1, 0.15mg/kg of the sapalizumab group G2 and G3: GLS-012 group 20mg/kg, G4 group: GLS-012 was used in combination with sirolimus. The administration volume was 10. Mu.l/g based on the animal body weight. Once every 3 days, and 7 times, with respect to relative tumor inhibition rate, tumor weight inhibition rate (TGI) RTV And TGI TW ) Evaluation was performed.
Table 1 tumor inhibiting effect (tumor volume) of the test substance on liver cancer Hepa1-6 model
Note that: a. mean ± standard error; b. comparing to the Isotype control group; c. comparing with anti-hPD-1+anti-huLAG3 group; d. comparison with anti-huLAG3 group.
Table 2 tumor inhibiting effect (tumor weight) of the test substance on liver cancer Hepa1-6 model
Note that: a. mean ± standard error; b. comparing to the Isotype control group; c. comparing with anti-hPD-1+anti-huLAG3 group; d. comparison with anti-huLAG3 group.
Results:
1) Animal weights in the test are shown in fig. 1, and each group of mice generally has good state after administration, normally ingests drinking water, and has stable body weight without stopping administration and death.
2) The tumor volume results of each group are shown in Table 1 and FIG. 2, and the tumor growth inhibition rates TGI of the single-drug, GLS-012 and combined injection GLS-012 groups RTV (%) 42.7% respectivelyPercent, 40.9%, 66.6%, the tumor volumes of the combination group compared to the isotype IgG control group animals were statistically different (P)<0.05). There were cases where tumors disappeared in each of the administration groups (see fig. 3).
3) The tumor weight results of each group are shown in Table 2 and FIG. 3, and the tumor weight inhibition rate TGI of the combination of 20mg/kg of the single-drug combination of the sirolimus, the single-drug combination of the GLS-012, the GLS-012 and the 0.15mg/kg of the combined-drug combination of the sirolimus TW (%) 53.4%, 48.6%, 72.3% respectively, both the single and combined sirolimus antibodies were statistically different from the tumor weights of animals of the isotype IgG control group (P<0.05 and P<0.001)。
4) Comparison of tumor volume and tumor weight both indicate that GLS-012 single drug has certain anti-tumor effect, and can enhance anti-tumor effect by combining with sapalimumab.
The foregoing description of the embodiments of the present application is illustrative, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described. The terminology used herein was chosen in order to best explain the principles of the embodiments, the practical application, or the improvement of technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Claims (3)
1. The application of the pharmaceutical composition in preparing medicines for treating liver cancer is characterized in that: the pharmaceutical composition consists of GLS-012 and saprolipram, and the molar concentration ratio of the GLS-012 and the saprolipram is 131:1.
2. The application of the pharmaceutical preparation in preparing medicaments for treating liver cancer is characterized in that: the pharmaceutical preparation comprises a pharmaceutical composition and pharmaceutically acceptable auxiliary materials; the pharmaceutical composition consists of GLS-012 and saprolipram, and the molar concentration ratio of the GLS-012 and the saprolipram is 131:1.
3. The use according to claim 2, wherein the pharmaceutical formulation is in the form of an injection, tablet, capsule, granule, suspension, emulsion, solution, sol, lyophilized powder for injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained release formulation or controlled release formulation.
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| CN115845051A (en) | 2023-03-28 |
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