CN117281902A - Application of pharmaceutical composition in preparation of melanoma treatment products - Google Patents
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Classifications
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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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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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
-
- 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
- A61K2039/507—Comprising a combination of two or more separate antibodies
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses an application of a pharmaceutical composition in preparing a product for treating melanoma, wherein the pharmaceutical composition comprises LAG-3 monoclonal antibody and sapalimumab, and the mass ratio of the LAG-3 monoclonal antibody to the sapalimumab is 1:0.9-3; 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. Compared with a similar medicine composition with the same target point, namely, a composition with the ratio of Relalimab to Nivolumab 1:3, the composition with the ratio of GLS-012 to Sipulizumab (Zimbereimab) 1:1 has stronger tumor inhibiting effect on melanoma, and has lower dosage and better safety.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of a pharmaceutical composition comprising LAG-3 monoclonal antibody and sirolimus or a pharmaceutical preparation containing the pharmaceutical composition 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.
LAG-3 and PD-L1/PD-1 both negatively regulate T cell function. Sequencing results of various tumor tissues (including 1400 cases of breast cancer, colon cancer, lung cancer and the like) show that the PD-L1 gene is highly expressed and has positive correlation with the LAG-3 gene, which indicates that the two genes are simultaneously expressed in tumor patients, and in addition, research shows that the PD-1 protein is highly expressed on the surface of TIL cells in non-small cell lung cancer patients and has positive correlation with the LAG-3 protein expression; 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. The above studies clearly show the feasibility and potential synergistic efficacy of targeting both PD-1/PD-L1 and LAG-3 as therapeutic approaches.
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 incidence rate in recent years, has high malignancy degree, early metastasis occurrence and high death rate, and therefore has an unmet clinical treatment demand.
In summary, aiming at the clinical rigid treatment requirement of melanoma, a novel safe and effective antibody drug for resisting LAG-3 target spot is developed, and particularly, the PD-1/PD-L1 inhibitor is combined, so that the problems of low effective rate, drug resistance and the like of the PD-1/PD-L1 inhibitor can be further improved, and the novel antibody drug 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 a pharmaceutical composition or application of a pharmaceutical preparation containing the pharmaceutical composition in preparation of a product for treating melanoma aiming at the defects of the prior art.
In order to solve the technical problems, the invention discloses the following technical scheme:
use of a pharmaceutical composition or a pharmaceutical formulation comprising said pharmaceutical composition for the preparation of a product for the treatment of melanoma.
Wherein the pharmaceutical composition comprises LAG-3 mab and sapalimumab; the LAG-3 monoclonal antibody is fully human anti-LAG-3 monoclonal antibody GLS-012, is an innovative anti-tumor biological agent which is independently developed by a Yu Heng organism and has complete independent intellectual property rights, has a heavy chain region shown as SEQ ID NO.1 and a light chain region shown as SEQ ID NO.2, and is disclosed in 1.53.3-uAb-IgG4k of Chinese patent application ZL 201910146172.2. The sapalimumab has a heavy chain region shown as SEQ ID NO.3 and a light chain region shown as SEQ ID NO. 4.
In some embodiments, the LAG-3 mab and the sapalimab are in a mass ratio of 1:0.9-3.
In some embodiments, the LAG-3 mab and the sapalimab are in a mass ratio of 1:0.9-2.
In some embodiments, the LAG-3 mab and the sapalimab are in a mass ratio of 1:0.9-1.5.
In some embodiments, the LAG-3 mab and the sapalimab are in a mass ratio of 1:1.
wherein the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.
Wherein the product comprises medicines and kits.
Wherein the therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation is 400-560 mg/time, such as 480 mg/time, 280-440 mg/time, such as 360 mg/time, of LAG-3 mab.
Wherein the LAG-3 mab is administered 1 time every 2-4 weeks, such as 1 time every 3 weeks.
Advantageous effects
Compared with a similar medicine composition with the same target point, namely, a composition with the ratio of Relalimab to Nivolumab 1:3, the composition with the ratio of GLS-012 to Sipulizumab (Zimbereimab) 1:1 has stronger tumor inhibiting effect on melanoma, and has lower dosage and better safety.
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 shows the body weight change curve of each group of mice.
FIG. 2 is a graph showing the inhibition effect of the composition of each proportion on tumor growth.
FIG. 3 is a comparison of tumor inhibition rates for compositions of each blend.
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 experiments in mice of the inhibition of melanoma growth by the fully human anti-LAG-3 monoclonal antibody GLS-012 and the fully human anti-PD-1 Silapachob 1:1 composition
1. Purpose(s)
Compared with the composition of the prior art of the mixture ratio of the anti-LAG-3 and the anti-PD-1 target drug Relalimab+Nivolumab 1:3, the anti-melanoma effect and the mixture ratio advantage of the composition of the fully human anti-LAG-3 monoclonal antibody GLS-012 and the fully human anti-PD-1 siroli monoclonal antibody 1:1 are explored.
2. Method of
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 Left and right time group dosing, total 4 groups of 8 animals each, goup1 (negative control): isotype control hIgG4 20mg/kg; goup2 (positive control 1:3 ratio group): relalimab 20mg/kg+Nivoluamb 60mg/kg; goup3 (experimental 1:3 proportioning): fully human anti-GLS-012 20 mg/kg+Zimbereliamb 60mg/kg; goup4 (experimental group 1:1 proportioning group): fully human anti-GLS-012 20 mg/kg+Zimbereliamb 20mg/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 analogues, relatlimab and Nivoluamb, are anti-LAG-3 and anti-PD-1 monoclonal antibodies marketed in the first global lot, respectively.
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 can normally ingest drinking water in a general state after administration, and besides obvious weight reduction of Goup3 mice, the other groups are stable in body weight without stopping administration and death. It is suggested that the other proportioning dose groups have no obvious adverse reaction except that Goup3 can cause the obvious reduction of the weight of the mice due to the adverse reaction. The weight change curves of the mice in each group are shown in figure 1.
3.2 Effectiveness of the method
Compared with the negative control group, the composition groups with various proportions have obvious effect of inhibiting the growth of melanoma cells, and have the effect of inhibiting the tumor growth rate TGI RTV (%) was Goup2:61%, goup3:88%, goup4:84% compared to the negative control groupPAre all<0.01. Second, goup compared to the Goup2 positive drug 1:3 composition3. Goup4 has stronger tumor inhibition activity, but compared with two groups of Goup3 and Goup4, the tumor inhibition rates have no obvious differenceP>0.05 See fig. 3 for details). The two groups of the GLS-012+saparlizumab 1:3 and 1:1 ratio composition have close curative effects, but the 1:1 ratio composition has obviously better safety and lower dosage. The relevant data experiments are shown in table 1 and fig. 2 and 3. The results of this study show that the therapeutic effect of the composition of different proportions of GLS-012 and sirolimus does not increase linearly with increasing dose, possibly related to the saturation of T lymphocyte receptor occupancy at a given dose.
TABLE 1 tumor inhibiting effect (tumor volume) of compositions of different proportions of GLS-012 and Sipalizumab on melanoma B16F10 subcutaneously transplanted tumor mouse model
Note that: data = mean ± standard deviation; comparison with negative control groupP<0.01; compared with the positive control group, the #P<0.05。
4. Conclusion(s)
From the above, it is clear that the fully humanized anti-LAG-3 monoclonal antibody GLS-012 combined anti-PD-1 sapalizumab 1:3 composition and the 1:1 ratio composition have the effect of remarkably inhibiting the growth of melanoma, wherein the 1:1 ratio composition has the similar curative effect as the 1:3 ratio composition, but has better safety, lower using dosage and more clinical application advantages.
EXAMPLE 2 clinical study of safety and efficacy of fully human anti-LAG-3 monoclonal antibody GLS-012 in combination with anti-PD-1 sirolimus monoclonal antibody for treatment of melanoma
1. Purpose(s)
The safety and efficacy of the fully human anti-LAG-3 monoclonal antibody GLS-012 in combination with the anti-PD-1 sirolimus monoclonal antibody regimen for treating melanoma patients was initially explored.
2. Method of
2.1 Patient general condition: all 12 melanoma patients, 7 men, 5 women, average age 56.6±14.7 years (28-73 years), ECOG score: 0 divided into 8 cases and 1 divided into 4 cases; 1 case of acromelasma, 3 cases of mucous membrane melanoma, 5 cases of skin melanoma and 3 cases of unknown primary focus of melanoma are diagnosed; in the past, 12 cases of tumor surgery treatment, 7 cases of chemotherapy, 7 cases of targeted drug treatment, 9 cases of immunotherapy, 3 cases of interferon treatment and 2 cases of radiotherapy are accepted.
2.2 Dosing regimen: GLS-012 480 mg+Cepalizumab 360mg intravenous drip, once every 3 weeks (q 3 w).
2.3 The evaluation method comprises the following steps: efficacy evaluation was performed using RECIST v1.1 and safety evaluation was performed using CTCAE v5.0.
3. Results
3.1 Safety of
Dose Limiting Toxicity (DLT) was not observed during all 12 patients treatment, and severe and immune related adverse events did not occur, with no patient death. Wherein, 1 case has 3 adverse events, the occurrence rate is only 8.3%, the rest are all adverse events of 1-2 levels, and all the adverse events are recovered to be normal (see Table 2 for details). Therefore, the GLS-012 combined with the saparhizomib has better clinical safety and tolerance.
TABLE 2 incidence of adverse events of melanoma with GLS-012 in combination with sirolimus
3.2 Effectiveness of the method
Of all 12 patients, 2 cases with Complete Remission (CR), 6 cases with Partial Remission (PR), 2 cases with Stable Disease (SD), and 2 cases with Progression of Disease (PD). The GLS-012 combined with the saprolipram has 66.7 percent of objective effective rate (ORR) for treating melanoma, 83.3 percent of clinical benefit rate (DCR) and obvious curative effect.
4. Conclusion(s)
In summary, the clinical study results preliminarily show that 360mg of the LAG-3 inhibitor GLS-012 480mg combined with the anti-PD-1 inhibitor sirolimus has an objective effective rate (ORR) of 66.7% for treating melanoma, a clinical benefit rate (DCR) of 83.3%, a 3-4 serious adverse event occurrence rate of only 8.3%, and the rest of 1-2 adverse events. The composition GLS-012 combined with the sirolimus has stronger anti-tumor activity, good safety and tolerance, and is worthy of further 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 within the scope of the invention. Accordingly, the scope of the invention should be determined from the following claims.
Claims (8)
1. The application of a pharmaceutical composition or a pharmaceutical preparation containing the pharmaceutical composition in preparing a product for treating melanoma is characterized in that the pharmaceutical composition comprises LAG-3 monoclonal antibody and sapalimumab, and the mass ratio of the LAG-3 monoclonal antibody to the sapalimumab is 1:0.9-3; 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 mass ratio of LAG-3 mab to saparlizumab is 1:0.9-2.
3. The use according to claim 1, wherein the mass ratio of LAG-3 mab to saparlizumab is 1:0.9-1.5.
4. The use according to claim 1, wherein the mass ratio of LAG-3 mab to saparlizumab is 1:1.
5. the use of claim 1, wherein the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.
6. The use according to claim 1, wherein the product comprises a medicament, a kit.
7. The use according to claim 1, wherein the therapeutically effective amount of the pharmaceutical composition or pharmaceutical formulation is LAG-3 mab 400-560 mg/time and sapalimumab 280-440 mg/time.
8. The use of claim 1, wherein the LAG-3 mab is administered 1 time every 2-4 weeks.
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| CN114206386A (en) * | 2019-08-05 | 2022-03-18 | 小野药品工业株式会社 | Determining biomarkers for effectiveness of immune checkpoint inhibitors |
| US20230330081A1 (en) * | 2020-10-28 | 2023-10-19 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumors |
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