CN114191545B - Application of PD1 antibody in medicine for treating obesity and fatty liver - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
- C07K16/2818—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 against CD28 or CD152
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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Abstract
The invention provides application of a PD1 antibody in a medicament for treating obesity and fatty liver, and belongs to the technical field of medicaments for treating obesity and fatty liver. The invention (1) constructs a high-fat diet induced obese mouse non-alcoholic fatty liver model; (2) The induction model was intervened by intraperitoneal injection of anti-PD 1 antibodies during the high-fat diet; (3) Various physiological indexes of mice are tracked, and the effect between PD1 antibody and fatty liver of obese mice is studied. The PD1 antibody is proved to have remarkable curative effect on treating obesity and fatty liver, and the novel application of the PD1 antibody in medicaments for treating obesity and fatty liver is found. Provides a new component for developing the medicines for obesity and fatty liver.
Description
Technical Field
The invention belongs to the technical field of fatty liver treatment medicines, and particularly relates to application of a PD1 antibody in medicines for treating obesity and fatty liver.
Background
Obesity is a major problem in public health worldwide, and is closely related to insulin resistance, diabetes, atherosclerosis, hypertension and certain cancers, obesity and the occurrence and development of these diseases are all known to have inflammation, researchers generally consider obesity as a low-grade chronic inflammatory state, and research results indicate that inflammatory proteins are high in circulating levels in obese individuals, and these inflammation results in changes in the number and types of various molecules that activate immune cells as endogenous ligands.
Visceral lipid accumulation is particularly prominent in obese patients in the liver, an important organ for cholesterol synthesis and storage of excess fat. Non-alcoholic fatty liver disease (NAFLD) is caused by liver hyperlipidemia, and combines inflammation and hepatocyte injury to define non-alcoholic hepatitis steatosis (NASH), and various liver inflammation suggests that fatty liver has a close relationship with immune response. For example, cytokines of T cells can serve as biomarkers of NAFLD, human NASH is characterized by increased frequency of intra-hepatic IL-17+ cells and intra-hepatic cd4+ T cells; NKT cells are able to regulate liver inflammation, and accumulation of NKT cells (not a specific NKT subset) stimulates liver fibrosis, exacerbating NAFLD to NASH development and promoting cirrhosis.
Programmed cell death protein (PDCD 1/PD 1) is an immunosuppressive receptor expressed in activated T cells, which is involved in regulating the function of T cells, effector CD8+ T cells, and in addition, which promotes differentiation of cells into T regulatory cells. Systemic lupus erythematosus and multiple sclerosis were found to be closely related to PD1, and this protein was expressed in a variety of tumors including melanoma, and has been demonstrated to play a role in anti-tumor immunity.
Recent clinical analyses indicate that obesity is associated with increased response and survival in cancer patients receiving targeted therapy and checkpoint blocking immunotherapy treatment. Obesity increases T cell senescence, leading to higher PD1 expression and dysfunction driven in part by leptin signaling, however, PD 1-mediated T cell dysfunction in obesity makes patient tumors more pronounced in response to checkpoint blockade, and importantly, data indicate a significant improvement in prognosis for obese cancer patients treated with PD1 inhibitors. More researchers have found that in vivo PD1 blockade can improve tissue homeostasis in obese mice, and that inhibition of PD1 signaling significantly increases the proportion of IL-13 expressing ILC2 s. Standard diet fed mice were treated with anti-PD 1, which restored the expression control levels of IL-5 and IL-13mRNA and increased mRNA levels encoding uncoupling protein 1 (UCP 1) through the vascular matrix fraction; anti-PD 1 treatment of obese mice improved glucose tolerance and adaptation to environmental cold in lean and obese mice, data indicating that PD1 blocking partially restored the function of the type 2 congenital axis, beneficial effects on adipose tissue homeostasis and adipose tissue.
Currently, no publications report the role of PD1 antibodies in the treatment of obesity and fatty liver.
Disclosure of Invention
The invention aims to provide an application of a PD1 antibody in a medicament for treating obesity and fatty liver, and aims to solve the problem that the conventional medicament for treating obesity and fatty liver with remarkable curative effect is lacking.
The aim of the invention is realized by the following technical scheme:
the embodiment of the invention constructs a high-fat diet induced mouse non-alcoholic fatty liver model by (1); (2) Intraperitoneal injection of PD1 antibody during high-fat diet, and intervention on the induction model; (3) Various physiological indexes of mice are tracked, and the effect between PD1 antibodies and obesity and fatty liver of the mice is studied.
Experiments prove that the PD1 antibody can obviously reduce the accumulation of liver triglyceride and obviously improve obesity, and has obvious curative effect in preventing and treating obesity and fatty liver.
Use of PD1 antibodies in medicaments for the treatment of obesity and fatty liver.
The treatment also includes prophylaxis during the formation of obesity and fatty liver.
The fatty liver is preferably an obese non-alcoholic fatty liver.
In this patent, the PD1 antibody mainly acts as a PD1 inhibitor; the preventive and therapeutic effects of the PD1 antibodies can also be extended to the use of other PD1 inhibitors; namely the application of PD1 inhibitor in the medicine for treating fatty liver.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
the invention researches the relation between the administration of PD1 antibody and the symptoms of obesity and fatty liver for the first time, and experiments prove that the PD1 antibody can obviously reduce the accumulation of liver triglyceride and obviously improve the fatty liver obvious characters such as obesity, and the like, and prove that the PD1 antibody has obvious curative effect in the aspects of preventing and treating obesity and fatty liver, thereby providing a new strategy for the development of obesity and fatty liver medicines.
Drawings
FIG. 1 is a graph showing the results of weight monitoring in example 1 of the present invention;
FIG. 2 is a graph showing the results of monitoring body fat rate according to example 1 of the present invention;
FIG. 3 is a bar graph of the results of subcutaneous fat/body weight ratio in example 1 of the present invention;
FIG. 4 is a bar graph showing the results of epididymal fat/body weight ratio in example 1 of the present invention;
FIG. 5 is a bar graph showing the results of hepatic triglyceride levels in example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to solve the existing medicine for treating fatty liver with obvious curative effect, the invention verifies that the PD1 antibody has obvious curative effect through the experiment of the embodiment, and the PD1 antibody is applied to the medicine for treating obesity and fatty liver.
Example 1
The invention constructs a high-fat diet induced mouse non-alcoholic fatty liver disease model by the method of the embodiment 1; (2) The induction model was intervened by intraperitoneal injection of anti-PD 1 antibodies during the high-fat diet; (3) Various physiological indexes of mice are tracked, and the effect between PD1 antibodies and obesity and fatty liver of the mice is studied. Experiments prove that the PD1 antibody has remarkable curative effect in treating obesity and fatty liver. The specific experimental scheme is as follows:
1. experimental animal feeding and drug treatment:
the experimental animals were five-week-old C57BL/6 male mice purchased from the university of medical university laboratory animal center, guangxi. The experimental environment temperature is 24+/-2 ℃ and the humidity is 40% -60%, and 12 hours of illumination/darkness simulate day-night alternation, so that drinking water and feed can be freely obtained. Mice were randomly divided into two groups, a high-fat diet group (60% kcal fat) and a high-fat diet PD1 antibody intervention group, feed purchased from Yu Teluo phenanthrene corporation; each group of 6 mice was fed (10% kcal fat) for the first three weeks to adapt to the new environment, high-fat diet induction was started on the fourth week, drug injection was started on the sixth week for a total of six weeks, the high-fat diet group was injected with polyclonal antibody IgG (Abcam, ab 37361) twice a week, the high-fat diet PD1 antibody intervention group was injected with anti-PD 1 antibody (Bio-cell, CD 279) each at 0.25mg.
The weight and fat percentage of the mice are continuously monitored in the experimental animal feeding process, and after five weeks of injection, the triglyceride level of liver tissues of the mice is detected, and the subcutaneous fat and epididymal fat are measured by weighing, wherein the specific experimental method is as follows:
(1) The method for monitoring the fat percentage of the mice comprises the following steps: the mice were fixed for detection after weighing by small animal nuclear magnetism (QMR-23-060H-I, N.Y. analytical instruments Co., ltd.).
(2) Liver tissue Triglyceride (TG) detection method: after the preparation of the lysate (RIPA: pmsf=100:1), adding 1mL to 2mL centrifuge tubes, adding 6 small steel balls into each tube, crushing liver tissues by a tissue crusher, placing the liver tissues on a 4-degree homogenizer overnight, centrifuging for 5 minutes after 12 hours, taking the supernatant, diluting five times the volume, placing the supernatant in a dry bath for 10 minutes at 70 ℃, centrifuging for 12000 turns again, centrifuging for 5 minutes, taking the supernatant, adding a corresponding sample and working solution into an ELISA plate according to a TG kit, standing for 10 minutes at 37 ℃, detecting the numerical value under the light absorption value of 510 by the ELISA, converting the TG content of the liver tissues according to a formula, and calibrating by using the measured protein concentration.
(3) Protein concentration detection: firstly, preparing protein detection working solution according to the proportion of A: B=49:1 by using a BCA protein concentration detection kit (Biyun Tian, product number: P0011), adding 10 mu L of liver lysate sample into each hole in a 96-hole ELISA plate, adding 190 mu L of working solution, standing at 37 ℃ for 10 minutes, detecting light absorption value at 562nm, and calculating the protein concentration corresponding to each other according to a protein standard curve.
Experimental results:
as can be seen from the results shown in fig. 1, the body weight of the high-fat diet group was significantly higher than that of the high-fat diet group injected with the PD1 antibody at the tenth and eleventh weeks, indicating that the anti-PD 1 antibody resisted the high-fat diet-induced weight gain to some extent. While the body fat rate of mice was tracked, the results are shown in figure 2, where the body fat rate of mice in the high fat diet group were intervened with PD1 antibody had a significant down-regulation trend compared to the high fat diet group. By measuring body weight and body fat rate, it can be seen that the high fat diet group obtained a mouse non-alcoholic fatty liver model.
Figures 3 and 4 show the ratio of subcutaneous fat to testicular fat to body weight, and as a result, the PD1 antibody can significantly reduce the content of subendothelial fat and testicular fat, and can alleviate and prevent the accumulation of fat in mice.
Fig. 5 shows that the content of triglyceride accumulation in liver is detected, and the experimental result shows that the PD1 antibody can relieve the triglyceride accumulation in liver in the induction process of high-fat diet to a certain extent, and the PD1 antibody can relieve fatty liver symptoms and has remarkable effects on preventing and treating fatty liver.
In conclusion, the experimental results prove that the PD1 antibody can reduce the accumulation of liver triglyceride and other obvious fatty liver characteristics, and has obvious curative effect in preventing and treating fatty liver.
The application of PD1 antibody in the medicine for treating fatty liver.
The treatment also includes prophylaxis during the formation of fatty liver.
The fatty liver is preferably a non-alcoholic fatty liver.
In this patent, the PD1 antibody mainly acts as a PD1 inhibitor; the preventive and therapeutic effects of the PD1 antibodies can also be extended to the use of other PD1 inhibitors; namely the application of PD1 inhibitor in the medicine for treating fatty liver.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
the invention researches the relation between the administration of PD1 antibody and the symptoms of obesity and fatty liver for the first time, and experiments prove that the PD1 antibody can obviously reduce the accumulation of liver triglyceride and obviously improve the fatty liver obvious characters such as obesity, and the like, and prove that the PD1 antibody has obvious curative effect in the aspects of preventing and treating obesity and fatty liver, thereby providing a new strategy for the development of obesity and fatty liver medicines.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (2)
- The application of the PD1 antibody in preparing the medicine for treating obesity is characterized in that: the obesity is obesity induced by high fat diet.
- 2. Use of a PD1 antibody according to claim 1 for the manufacture of a medicament for the treatment of obesity, characterized in that: the treatment includes prophylaxis during the development of obesity.
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| CN104365543A (en) * | 2014-10-28 | 2015-02-25 | 华中科技大学同济医学院附属同济医院 | Method for establishing mouse model of non-alcoholic fatty liver disease combined with viral hepatitis |
| WO2020085644A1 (en) * | 2018-10-25 | 2020-04-30 | 주식회사 바이오톡스텍 | Pharmaceutical composition comprising hydroquinone derivative for preventing or treating obesity or nonalcoholic steatohepatitis |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104365543A (en) * | 2014-10-28 | 2015-02-25 | 华中科技大学同济医学院附属同济医院 | Method for establishing mouse model of non-alcoholic fatty liver disease combined with viral hepatitis |
| WO2020085644A1 (en) * | 2018-10-25 | 2020-04-30 | 주식회사 바이오톡스텍 | Pharmaceutical composition comprising hydroquinone derivative for preventing or treating obesity or nonalcoholic steatohepatitis |
Non-Patent Citations (2)
| Title |
|---|
| Yuzuru Sakamoto等.Increased Frequency of Dysfunctional Siglec-7-CD57+PD-1+ Natural Killer Cells in Patients With Non-alcoholic Fatty Liver Disease.Front Immunol.2021,第第12卷卷(第第603133期期),摘要. * |
| 内脏脂肪堆积更易致病有原因;广州医科大学学报;第66卷(第6期);第75页倒数第2、4段 * |
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