CN117547605A - Application of LAG-3 monoclonal antibody in preparation of melanoma treatment products - Google Patents
Application of LAG-3 monoclonal antibody in preparation of melanoma treatment products Download PDFInfo
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- CN117547605A CN117547605A CN202311570843.0A CN202311570843A CN117547605A CN 117547605 A CN117547605 A CN 117547605A CN 202311570843 A CN202311570843 A CN 202311570843A CN 117547605 A CN117547605 A CN 117547605A
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- 201000001441 melanoma Diseases 0.000 title claims abstract description 30
- 102000017578 LAG3 Human genes 0.000 title claims abstract description 26
- 101150030213 Lag3 gene Proteins 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title description 5
- 239000003814 drug Substances 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 abstract description 24
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 229940121484 relatlimab Drugs 0.000 abstract description 5
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 15
- 230000000694 effects Effects 0.000 description 8
- 238000009169 immunotherapy Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010008570 Chloasma Diseases 0.000 description 2
- 208000003351 Melanosis Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003127 anti-melanomic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000000385 effect on melanoma Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 230000006641 stabilisation Effects 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/876—Skin, melanoma
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses an application of LAG-3 monoclonal antibody in preparing a melanoma treatment product, wherein the LAG-3 monoclonal antibody is GLS-012. Compared with similar medicine Relatlimab with LAG-3 target, GLS-012 has obvious tumor inhibiting effect on melanoma, and has the clear characteristics of low dosage, high anticancer activity and high safety. GLS-012 can be used as a single medicament for treating melanoma, and has clinical value for treating melanoma by single medicament.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of LAG-3 monoclonal antibody in preparation of a melanoma treatment product.
Background
Patients with advanced malignant tumor have short life cycle and poor life quality, and the adoption of drug treatment is the main treatment method for most patients with advanced tumor. The traditional antitumor drugs are combined chemotherapy by adopting a plurality of cytotoxic drugs, the chemotherapy drugs have poor targeting property and obvious side effects, and have great damage to normal tissue cells while killing tumor cells, so that great clinical demands for novel antitumor drugs exist.
In recent years, tumor immunotherapy is becoming a research and development hotspot, and a great breakthrough is continuously obtained. Different from the traditional chemotherapeutic drugs which directly kill or inhibit the action mechanism of tumor cells, the tumor immunotherapy is to activate the human body autoimmune system to identify and kill the tumor cells 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. Tumor immunotherapy has become a hotspot in the field of tumor therapy today, where T cell tumor immunotherapy is in the core position.
LAG-3 belongs to immunoglobulin superfamily, and is composed of three parts of extracellular region, transmembrane region and cytoplasmic region, and is mainly expressed on the surface of activated T lymphocyte and partial natural killer cell, etc., and can negatively regulate and control body immunity function. Numerous studies have demonstrated that by inhibiting the binding of LAG-3 to its ligand molecules, T cell activation and killing of tumor cells by the immune system can be promoted, LAG-3 has become a potential tumor immunotherapeutic target and provides a potential route for tumor immunotherapy in addition to CTLA-4, pd-1.
Malignant melanoma is a tumor produced by melanocytes of skin and other organs, belongs to a high-grade malignant tumor, is one of the most rapid malignant tumors with high malignant degree and early metastasis and high death rate in recent years, and therefore, clinical unmet therapeutic needs exist.
In summary, aiming at the clinical rigid treatment requirement of melanoma, the development of a safe and effective novel antibody drug for resisting the LAG-3 target is one of important ways for further improving the curative effect of melanoma.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of providing an application of anti-LAG-3 monoclonal antibody in preparation of melanoma treatment products aiming at the defects of the prior art.
In order to solve the technical problems, the invention discloses the following technical scheme:
LAG-3 monoclonal antibody can be used as the only active ingredient in preparing a product for treating melanoma, namely GLS-012 can be independently used as a medicament for treating melanoma.
Wherein the LAG-3 monoclonal antibody is a fully human anti-LAG-3 monoclonal antibody GLS-012, which is an innovative anti-tumor biological agent with complete independent intellectual property independently developed by Yu Heng organisms, has a heavy chain region shown as SEQ ID NO.1 and a light chain region shown as SEQ ID NO.2, and has been disclosed in Chinese patent application ZL201910146172.2 'anti-human LAG-3 monoclonal antibody, a preparation method and application thereof'.
Wherein the product comprises medicines and kits.
Wherein the therapeutically effective amount of LAG-3 mab is in the range of 20-1200 mg/time in some embodiments, 30-1000 mg/time in some embodiments, 40-800 mg/time in some embodiments, 40 mg/time, 60 mg/time, 80 mg/time, 160 mg/time, 240 mg/time, 360 mg/time, 480 mg/time, 600 mg/time, or 800 mg/time.
Wherein the LAG-3 mab is administered 1 time every 2-4 weeks in some embodiments, and 1 time every 3 weeks in some embodiments.
Currently, the mainstream knowledge of LAG-3 single drugs cannot be prepared, and combined treatment is required to have clinical value. Preliminary results of animal experiments and human clinical experiments indicate that the LAG-3 monoclonal antibody GLS-012 has therapeutic value of single-drug patent medicine.
The beneficial effects are that:
compared with similar medicine Relatlimab with LAG-3 target, GLS-012 has obvious tumor inhibiting effect on melanoma, and has the clear characteristics of low dosage, high anticancer activity and high safety. GLS-012 can be used as a single medicament for treating melanoma, and has clinical value for treating melanoma by single medicament.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.
FIG. 1 is a graph showing the change in body weight of mice in each experimental group.
FIG. 2 is a graph showing the inhibition of tumor growth by each experimental group.
FIG. 3 is a comparison of tumor inhibition rates for each experimental group.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are commercially available.
Example 1: in vivo experimental study of mice with full-human anti-LAG-3 monoclonal antibody GLS-012 on inhibiting melanoma growth
1 purpose
The tumor inhibiting effect of the fully human anti-LAG-3 monoclonal antibody candidate drug GLS-012 in a melanoma B16F10 subcutaneous transplantation tumor mouse model and the relation between the dosage and the curative effect are explored.
2 method
2.1 PBS-resuspended melanoma cells B16F10 were inoculated subcutaneously in the right flank of female B6-hLAG-3 mice and grown to 74mm in tumors 3 The animals were dosed in groups of 5 groups of 8 animals each. Goup1: isotype control group (hIgG 4) 20mg/kg; goup2: GLS-012 (fully human anti-LAG-3, 8 mg/kg); goup3: middle dose of GLS-012 (fully human anti-LAG-3, 20 mg/kg); goup4: high dose trial GLS-012 (fully human anti-LAG-3, 50 mg/kg); goup5: positive control (fully human anti-LAG-3, rayleigh Li Shan anti-analog delatlimab 20 mg/kg). The administration volume was 10. Mu.L/g based on the animal body weight. Grouping when the astronomical was D0, 2 doses per week for 4 times total, for relative Tumor Growth Inhibition (TGI) RTV ) Evaluation was performed. Wherein, the positive control drug Relatlimab is an anti-lag-3 target monoclonal antibody which is marketed in the first batch worldwide.
2.2 relative tumor growth inhibition Rate TGI RTV (%) = (1-T/C) ×100%, wherein: T/C = treatment/control RTV mean, RTV is relative tumor volume, i.e. TV ratio after treatment to before treatment.
3. Results
3.1 Safety of
The mice in each group generally have good state after administration, normally ingest drinking water, have generally stable weight, have no drug withdrawal and death, and have detailed animal weight changes in the experiment shown in figure 1. The experiment groups of each dose are indicated that no obvious adverse reaction occurs.
3.2 availability
The tumor volume results in the experiment are shown in Table 1, FIG. 2 and FIG. 3, and GLS-012 low dose 8mg/kg group, medium dose 20mg/kg group, high dose 50mg/kg group and Relatlimab analog medium dose 20mg/kg group have remarkable inhibiting effect on melanoma growth, and the tumor growth inhibition rate TGI thereof RTV (%) 51%, 73%, 77% and 38%, respectively, were statistically significantly different from the isotype control group (P-average)<0.01). Wherein, compared with the low dose group of the GLS-012 and the medium dose group of the positive control drug Relatlimab analog mg/kg, the low dose group of the GLS-012 has stronger anti-melanoma activity (the tumor inhibition rate is 51% vs.38%, and the comparison between the two groups is P)<0.05). The absolute value of the tumor inhibition rate tends to increase compared with the medium dose group of 20mg/kg in the GLS-012 high dose group of 50mg/kg, but there is no statistical difference in the comparison between the 2 groups (P>0.05 Suggesting that on an effective dose basis GLS-012 does not increase linearly with increasing dose, possibly associated with saturation of T lymphocyte receptor occupancy.
TABLE 1 tumor inhibiting effect (tumor volume) of GLS-012 single drug on melanoma B16F10 subcutaneously transplanted tumor mouse model
Note that: b. comparing to the Isotype control group; c. compared with GLS-012 low dose (8 mg/kg);
d. comparison with the GLS-012 dose (20 mg/kg) group; e. compared to the GLS-012 high dose (50 mg/kg) group.
Conclusion 4
The research results clearly show that the fully human anti-LAG-3 monoclonal antibody GLS-012 has a remarkable effect of inhibiting the growth of melanoma, especially the fully human anti-LAG-3 monoclonal antibody GLS-012 shows an excellent curative effect (P < 0.01) which is remarkably higher than that of a positive control drug at a dosage of 20mg/kg at a low dosage of 8mg/kg, and has good safety, lower use dosage and huge potential in clinical value.
EXAMPLE 2 safety and efficacy clinical study of fully human anti-LAG-3 monoclonal antibody GLS-012 for treatment of melanoma
1 purpose
The safety and effectiveness of the fully human anti-LAG-3 monoclonal antibody GLS-012 in treating melanoma patients were initially explored.
2 method
2.1 patient general cases: 17 melanoma patients, of which men 4 and women 13, had an average age of 53.5+ -13.2 years (33-75 years), ECOG score: 0 divided into 12 cases and 1 divided into 5 cases. The diagnosis was 9 cases of acromelasma, 5 cases of mucosal melasma, 1 case of cutaneous melasma and 2 cases of melanoma primary foci. In the past, 16 cases of tumor surgery treatment, 12 cases of chemotherapy and 14 cases of targeted drug treatment are received, and all 17 cases of patients are subjected to immunotherapy.
2.2 dosing regimen: GLS-012 was administered by single intravenous drip once every 3 weeks. Of these, 40mg dose group 1, 80mg dose group 3, 240mg dose group 7, 480mg dose group 3, 800mg dose group 3.
2.3 evaluation method: efficacy evaluation was performed using RECIST v1.1 and safety evaluation was performed using CTCAE v5.0.
3 results
3.1 Security
No grade 3 adverse events, serious adverse events and immune related adverse events and no death cases occur in all 17 patients during treatment. GLS-012 adverse event occurrence rates are shown in Table 2, all belong to the 1-2 grades, all recover to normal, and no serious 3-4 grades of adverse events occur. Therefore, the GLS-012 has better clinical safety and tolerance.
TABLE 2 incidence of adverse events of GLS-012 on melanoma treatment with single drug
3.2 availability
Of all 17 patients, 8 (47.1%) subjects reached disease Stabilization (SD), 6 (35.3%) were disease Progression (PD), and the other 3 (17.6%) had not reached the evaluation time. Preliminary research results indicate that the objective effective rate (ORR) of GLS-012 for treating melanoma by single drug is 47.1%, and the curative effect is remarkable.
Conclusion 4
In conclusion, on the basis of preclinical pharmacodynamics study, the clinical study initially shows that GLS-012 single drug has outstanding curative effect on melanoma, and good safety and tolerance. In particular, the single medicine has the clinical function of treating melanoma, and is worthy of further research and development.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be determined from the following claims.
Claims (8)
1. Application of LAG-3 monoclonal antibody in preparing melanoma treating product; the LAG-3 monoclonal antibody is GLS-012; GLS-012 has a heavy chain region as shown in SEQ ID NO.1 and a light chain region as shown in SEQ ID NO. 2.
2. The use according to claim 1, wherein the product comprises a medicament, a kit.
3. The use according to claim 1, wherein the therapeutically effective amount of LAG-3 mab is
20-1200 mg/time.
4. The use according to claim 1, wherein the therapeutically effective amount of LAG-3 mab is
30-1000 mg/time.
5. The use according to claim 1, wherein the therapeutically effective amount of LAG-3 mab is
40-800 mg/time.
6. The use of claim 1, wherein the therapeutically effective amount of LAG-3 mab is 40 mg/time, 80 mg/time, 240 mg/time, 480 mg/time, or 800 mg/time.
7. The use according to claim 1, wherein the LAG-3 mab is administered 1 time every 2-4 weeks.
8. The use of claim 1, wherein the LAG-3 mab is administered 1 time every 3 weeks.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311570843.0A CN117547605A (en) | 2023-11-23 | 2023-11-23 | Application of LAG-3 monoclonal antibody in preparation of melanoma treatment products |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311570843.0A CN117547605A (en) | 2023-11-23 | 2023-11-23 | Application of LAG-3 monoclonal antibody in preparation of melanoma treatment products |
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| Publication Number | Publication Date |
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| CN117547605A true CN117547605A (en) | 2024-02-13 |
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| CN202311570843.0A Withdrawn CN117547605A (en) | 2023-11-23 | 2023-11-23 | Application of LAG-3 monoclonal antibody in preparation of melanoma treatment products |
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| CN (1) | CN117547605A (en) |
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- 2023-11-23 CN CN202311570843.0A patent/CN117547605A/en not_active Withdrawn
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Application publication date: 20240213 |