Application of Aldometanib in preparation of medicine for preventing and treating immune-related adverse reactions and diseases

Abstract

The invention provides an application of a compound Aldometanib in preparation of a medicine for preventing and treating immune-related adverse reactions and diseases. Based on the first discovered prevention and treatment effects of Aldometanib on fatal immune hepatitis, immune myocarditis, pneumonia and enteritis, the invention specifically discloses application of Aldometanib in preparation of drugs for prevention and treatment of immune-related adverse reactions and diseases, and the main mechanism is that Aldometanib activates immune cells AMPK, enhances catabolism of immune cells, promotes immune cell apoptosis, promotes immune cell apoptosis, and improves immune cell apoptosis. The anabolism of the immune cells is inhibited, so that the expression of effector factors of the immune cells is controlled, and inflammatory factor storm is inhibited. Aldometanib has the effects of preventing the occurrence of immune-related adverse reactions and diseases, and inhibiting the attack levels of the immune-related adverse reactions and diseases, so that non-lethal and lethal injuries caused by an immune system to body organs are reduced.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals, and particularly to the use of Aldometanib in the preparation of drugs for preventing and treating immune-related adverse reactions and diseases. Background Art

[0002] Immune-related adverse reactions and diseases impose a burden on patients' lives, are harmful to health, and even endanger life. On the one hand, the indication ratio of immune checkpoint inhibitors in the treatment of malignant tumors has increased from 1.54% in 2011 to 55.47% in 2023. With the widespread application of immune checkpoint inhibitors such as PD-1 monoclonal antibodies, PD-L1 monoclonal antibodies, and CTLA4 monoclonal antibodies, the incidence of immune-related adverse reactions brought about by immunotherapy has increased significantly, mainly including pneumonia, myocarditis, hepatitis, and enteritis, etc. Although the incidence of fatal irAEs is relatively low, the mortality rate is extremely high, and the case fatality rate of severe myocarditis is as high as 50%. On the other hand, other drugs that are not immune checkpoint inhibitors can also cause immune-related adverse reactions. The immune-related adverse reactions and diseases caused by the onset and treatment of genetic factors, allergic reactions, organ transplant rejection reactions, graft-versus-host disease, autoimmune diseases, etc. endanger the health of a wider population.

[0003] Up to now, the types of drugs for treating immune-related adverse reactions and diseases are limited, and there are serious risks of toxic and side effects. They mainly include glucocorticoids such as prednisone and dexamethasone, which increase the risk of infection and may cause osteoporosis and elevated blood sugar after long-term use; calcineurin inhibitors such as cyclosporine and tacrolimus, which may cause liver and kidney toxicity, neurotoxicity such as leukoencephalopathy, hyperglycemia, and electrolyte disorders; antimetabolites such as azathioprine and methotrexate, which may cause bone marrow suppression, gastrointestinal ulcers, liver fibrosis, and liver function damage; alkylating agents such as cyclophosphamide, which may cause hemorrhagic cystitis and bone marrow suppression; and antilymphocyte globulin, which may cause allergic reactions or an increased risk of infection. Therefore, it is very urgent to develop new drugs with low toxic and side effects for highly effective prevention and treatment of immune-related adverse reactions and diseases. Summary of the Invention

[0004] The object of the present invention is to provide the use of a compound Aldometanib in the preparation of drugs for preventing and treating immune-related adverse reactions and diseases. The main mechanism is that Aldometanib activates AMPK in immune cells, enhances the catabolism of glucose by immune cells, inhibits the anabolism of immune cells, thereby controlling the expression of effector factors of immune cells and inhibiting the cytokine storm. Aldometanib has the effect of preventing the occurrence of immune-related adverse reactions and diseases, and inhibiting the morbidity level of immune-related adverse reactions and diseases, thereby reducing the non-lethal and lethal damage caused by the immune system to the body organs.

[0005] To achieve the above object, the present invention adopts the following technical solutions: Use of Aldometanib in the preparation of drugs for preventing and treating immune-related adverse reactions and diseases.

[0006] Preferably, the immune-related adverse reactions include immune-related adverse reactions caused by immune checkpoint inhibitor therapy, immune-related adverse reactions caused by other drugs except immune checkpoint inhibitors, and immune-related adverse reactions and diseases caused by the onset and treatment of genetic factors, allergic reactions, organ transplant rejection reactions, graft-versus-host disease, autoimmune diseases, etc.

[0007] Preferably, the immune-related adverse reactions include immune hepatitis, immune myocarditis, immune pneumonia, and immune enteritis.

[0008] Preferably, the immune checkpoint inhibitors include, but are not limited to, inhibitors and functional blocking antibodies targeting PD-1, PD-L1, and CTLA4.

[0009] Preferably, use of Aldometanib in the preparation of drugs for preventing and treating immune hepatitis or immune myocarditis or immune pneumonia or immune enteritis caused by immune checkpoint inhibitors.

[0010] Preferably, Aldometanib is used to prepare a pharmaceutical composition containing Aldometanib and a pharmaceutical carrier.

[0011] Preferably, the pharmaceutical composition contains 0.0001 wt% - 99.99 wt% of Aldometanib, and the rest is a pharmaceutical carrier.

[0012] Preferably, the Aldometanib has the following structural formula: CAS: 2904601-67-6; Compound CID: 165413044 The advantages of the present invention are: When the inventors studied autoimmune diseases and immune-related adverse reactions induced by immune activators and immune checkpoint inhibitors, they found that Aldometanib effectively prevented the occurrence of fatal immune hepatitis, effectively treated multi-organ inflammatory damage caused by immune checkpoint inhibitors, improved the tumor immune microenvironment. In addition, Aldometanib could also enhance the anti-cancer effect of PD-1 monoclonal antibody. Mechanistically, Aldometanib targets lysosomal AMPK, enhances catabolism, inhibits anabolism, controls the efficiency of immune cells expressing inflammatory factors, regulates the intensity of the inflammatory response, and prevents the immune system from damaging its own organ tissues.

[0013] There has been no report on the application of Aldometanib in the preparation of drugs for preventing and treating immune-related adverse reactions and diseases. Brief Description of the Drawings

[0014] Figure 1 : Aldometanib improves the damage to the cardiac function of mice caused by the combination of PD1 Ab and IL12. Among them: (A) The inventors induced immune adverse reactions in AJ mice by tail vein injection of PD1 antibody (PD1Ab) combined with IL12, and detected the cardiac function of the mice by echocardiography, with a typical two-dimensional echocardiogram.

[0015] (B) The inventors detected the left ventricular ejection fraction of the hearts of the above mice by echocardiography.

[0016] (C) The inventors detected the left ventricular fractional shortening of the hearts of the above mice by echocardiography.

[0017] (D) The inventors detected the left ventricular cardiac output of the hearts of the above mice by echocardiography.

[0018] (E) The inventors detected the left ventricular stroke volume of the hearts of the above mice by echocardiography.

[0019] Figure 2 : Aldometanib inhibits the inflammatory infiltration of the heart, lungs and liver in mice caused by the combination of PD1 Ab and IL12. Among them: (A) The inventors induced immune adverse reactions in AJ mice by tail vein injection of PD1 antibody (PD1Ab) combined with IL12, and detected the inflammatory cell infiltration in myocardial tissue by H&E staining.

[0020] (B) The inventors induced immune adverse reactions in AJ mice by tail vein injection of PD1 antibody (PD1Ab) combined with IL12, and detected the inflammatory cell infiltration in lung tissue by H&E staining.

[0021] (C) The inventors induced immune adverse reactions in AJ mice by injecting PD1 antibody (PD1Ab) via the tail vein in combination with IL12, and detected inflammatory cell infiltration in liver tissues by H&E staining.

[0022] Figure 3 : Aldometanib inhibits dextran sulfate sodium (DSS)-induced inflammatory bowel disease. Among them: (A) The inventors induced inflammatory bowel disease (IBD) in mice by providing them with drinking water containing dextran sulfate sodium (DSS), and after treatment with Aldometanib, took pictures of the cecum - colon - rectum at the end point of treatment.

[0023] (B) The inventors induced inflammatory bowel disease (IBD) in mice by providing them with drinking water containing dextran sulfate sodium (DSS), and after treatment with Aldometanib, measured the length of the cecum - colon - rectum.

[0024] (C) The inventors induced inflammatory bowel disease (IBD) in mice by providing them with drinking water containing dextran sulfate sodium (DSS), and after treatment with different doses of Aldometanib, statistically analyzed the survival rate.

[0025] (D) The inventors induced inflammatory bowel disease (IBD) in mice by providing them with drinking water containing dextran sulfate sodium (DSS), and after treatment with different doses of Aldometanib, statistically analyzed the changes in the body weight of the mice.

[0026] Figure 4 : Aldometanib inhibits concanavalin A (ConA)-induced inflammatory liver injury. Among them: (A) The inventors induced ConA-induced inflammatory liver injury (CIH) and detected alanine aminotransferase ALT.

[0027] (B) The inventors induced ConA-induced inflammatory liver injury (CIH) and detected aspartate aminotransferase AST.

[0028] (C) The inventors induced ConA-induced inflammatory liver injury (CIH) and after treatment with different doses of Aldometanib, statistically analyzed the survival time of the mice.

[0029] (D) The inventors constructed an orthotopic liver tumor model by injecting Hepa1-6 cells into the liver, and on this basis, injected concanavalin A (ConA) to induce ConA-induced inflammatory liver injury (CIH), and after treatment with Aldometanib, statistically analyzed the survival time of the mice.

[0030] Figure 5 : The effect of Aldometanib in synergistically treating liver cancer with PD1 antibody. Among them: (A) The inventors constructed an orthotopic transplantation tumor model by injecting Hepa1-6 cells into the liver, and administered vehicle, Aldometanib alone, PD1 antibody alone, and the combination of Aldometanib and PD1 antibody respectively, and took pictures of the tumor-bearing liver tissues.

[0031] (B) The inventors quantitatively counted the weights of the tumor-bearing livers of the mice in the above model.

[0032] (C) The inventors quantitatively counted the body weights of the mice in the above model.

[0033] (D) The inventors quantitatively analyzed the ratio of the weight of the tumor-bearing liver to the body weight of the mice in the above model.

[0034] Figure 6 : The molecular structural formula of the Aldometanib compound. Detailed implementation manners

[0035] To make the above features and advantages of the present invention more obvious and understandable, specific embodiments are hereinafter given for detailed description. Unless otherwise specified, the methods of the present invention are all conventional methods in the art.

[0036] Example 1 Aldometanib improves the damage of PD1 Ab combined with IL12 to the cardiac function of mice.

[0037] For the immune-related adverse reaction model induced by PD1 Ab combined with IL12, AJ male 7-8-week-old mice were purchased from Jicui Yakang. By the method of tail vein injection, each mouse was injected with 150 μg PD1 Ab and 120 ng IL12, once every three days, for a total of three injections. Starting from the day of each injection of PD1 Ab combined with IL12, Aldometanib treatment was given intraperitoneally for two consecutive days, once a day, at a dose of 0.0625 mg / kg. 48 hours after the third injection of PD1 Ab combined with IL12, the left ventricular function indexes of the mice were detected by echocardiography, including: typical two-dimensional echocardiogram ( Figure 1 in A), left ventricular ejection fraction ( Figure 1 in B), left ventricular fractional shortening ( Figure 1 in C), left ventricular cardiac output ( Figure 1 in D), left ventricular stroke volume ( Figure 1 in E), etc. Aldometanib treatment significantly improved the damage of PD1 Ab combined with IL12 to the cardiac function of mice.

[0038] Example 2 Aldometanib inhibits the inflammatory infiltration of the heart, lungs and liver caused by PD1 Ab combined with IL12.

[0039] For the immune-related adverse reaction model induced by PD1 Ab combined with IL12, AJ male mice aged 7-8 weeks were purchased from Jicuiyaokang. By means of tail vein injection, each mouse was injected with 150 μg PD1 Ab and 120 ng IL12, once every three days, for a total of three injections. Starting from the day of each injection of PD1 Ab combined with IL12, Aldometanib treatment was given intraperitoneally for two consecutive days, once a day, at a dose of 0.0625 mg / kg. 48 hours after the third injection of PD1 Ab combined with IL12, organs such as the heart, lungs, liver, spleen, lymph nodes, thymus, pancreas, stomach, duodenum, small intestine, cecum, colon, rectum, and prostate of the mice were collected for H&E staining and photographed to analyze inflammatory infiltration.

[0040] Compared with the healthy control group (Isotype + vehicle), a large number of immune cell infiltrations were observed in the myocardium of the model non-treatment group (PD1 Ab + IL12 + vehicle), and the immune infiltration in the myocardium of the Aldometanib treatment group (PD1 Ab + IL12 + Aldometanib) was significantly reduced and comparable to that of the healthy control group ( Figure 2 in A). Compared with the healthy control group (Isotype + vehicle), a large number of immune cell infiltrations were observed in the lung tissue of the model non-treatment group (PD1 Ab + IL12 + vehicle), and the immune infiltration in the lung tissue of the Aldometanib treatment group (PD1 Ab + IL12 + Aldometanib) was significantly reduced and comparable to that of the healthy control group ( Figure 2 in B). Compared with the healthy control group (Isotype + vehicle), a large number of immune cell infiltrations were observed in the liver tissue of the model non-treatment group (PD1 Ab + IL12 + vehicle), and the immune infiltration in the liver tissue of the Aldometanib treatment group (PD1 Ab + IL12 + Aldometanib) was significantly reduced and comparable to that of the healthy control group ( Figure 2 in C). The immune infiltration and immune-related damage in many other organs were improved by Aldometanib, and the data are not shown here. Therefore, Aldometanib inhibits immune-related adverse reactions by reducing abnormal infiltration of immune cells in organ tissues.

[0041] Example 3 Aldometanib inhibits dextran sulfate sodium (DSS)-induced inflammatory bowel disease.

[0042] For the dextran sulfate sodium (DSS)-induced inflammatory bowel disease model, C57BL / 6J male mice aged 7 - 8 weeks were purchased from Jicuiyaokang. The mice were treated with DSS (3 g DSS: 100 ml drinking water) by free drinking, and at the same time, Aldometanib was administered by intraperitoneal injection at a dose of 0.0625 mg / kg, every other day. The initial body weight of the mice was recorded on the first day. On the 6th day after starting to feed DSS, the mice were euthanized by cervical dislocation, and the cecum - colon - rectum of the mice was dissected and photographed ( Figure 3 in A), and the length of the cecum - colon - rectum was measured ( Figure 3 in B).

[0043] For the dextran sulfate sodium (DSS)-induced inflammatory bowel disease model, C57BL / 6J male mice aged 7 - 8 weeks were purchased from Jicuiyaokang. The mice were treated with DSS (3 g DSS: 100 ml drinking water) by free drinking, and at the same time, Aldometanib was administered by intraperitoneal injection at doses of 0.0625 mg / kg, 0.125 mg / kg, 0.25 mg / kg, 0.5 mg / kg, and 1 mg / kg, every other day. On the 10th day after starting to feed DSS, the survival rate of the mice was counted ( Figure 3 in C), and the change in the body weight of the mice before the 6th day relative to the initial body weight before feeding DSS was counted ( Figure 3 in D).

[0044] Aldometanib significantly reduced the inflammatory damage to the mouse intestine caused by DSS, manifested as longer colorectal length, longer survival time, and slower body weight loss rate.

[0045] Example 4 Aldometanib inhibits concanavalin A (ConA)-induced inflammatory liver injury.

[0046] For the concanavalin A (ConA)-induced immune hepatitis model, C57BL / 6J male mice aged 7 - 8 weeks were purchased from Jicuiyaokang. The mice were treated with ConA at a mass body weight ratio of 25 mg / kg by tail vein injection. At 6 hours after injecting ConA, the mouse serum was collected, and alanine aminotransferase ALT ( Figure 4 in A), aspartate aminotransferase AST ( Figure 4 in B) were detected using a kit.

[0047] For the concanavalin A (ConA)-induced immune hepatitis model, C57BL / 6J male mice aged 7-8 weeks were purchased from Jicui Yaokang. By means of tail vein injection of ConA, mice were treated with ConA at a mass body weight ratio of 25 mg / kg, and immediately after injecting ConA, different doses of Aldometanib were injected through the tail vein, and the survival time of the mice was recorded ( Figure 4 in C).

[0048] For the hepatocellular carcinoma combined with concanavalin A (ConA)-induced immune hepatitis model, C57BL / 6J male mice aged 7-8 weeks were purchased from Jicui Yaokang. The mice were anesthetized with chloral hydrate, and a 5-mm-long window was made on the right side of the midline of the mouse abdomen near the xiphoid process using ophthalmic scissors to expose the left liver lobe of the mouse. 1×10 6 Hepa1-6 hepatoma cells were injected under the liver capsule, and then pressed with a cotton swab for 2-5 seconds to avoid overflow of tumor cells from the liver. The surgical incision was sutured with medical suture. On the 10th day after modeling, by means of tail vein injection of ConA, mice were treated with ConA at a mass body weight ratio of 12.5 mg / kg, and immediately after injecting ConA, Aldometanib at a mass body weight ratio of 0.25 mg / kg was injected through the tail vein, or Dexamethasone at a mass body weight ratio of 20 mg / kg was injected through the tail vein. Subsequently, for two consecutive days, Aldometanib at a mass body weight ratio of 0.25 mg / kg was injected intraperitoneally every day, or Dexamethasone at a mass body weight ratio of 20 mg / kg was injected through the tail vein, and the survival time of the mice was recorded ( Figure 4 in D).

[0049] Aldometanib significantly reduced the serum distribution of ALT and AST, inhibited ConA-induced inflammatory liver injury, prolonged the survival time of mice with ConA-induced inflammatory liver injury, and prolonged the survival time of mice with intrahepatic tumor-bearing after experiencing ConA-induced inflammatory liver injury. Although Dexamethasone could inhibit ConA-induced inflammatory liver injury, it accelerated the progression of liver tumors and ultimately shortened the survival period of mice.

[0050] Example 5 Effect of Aldometanib in synergistically treating liver cancer with PD1 antibody.

[0051] For the intrahepatic transplanted tumor model, C57BL6 / J male mice aged 7-8 weeks were purchased from Jicui Yaokang (the same below). The mice were anesthetized with chloral hydrate, and a 5-mm-long window was made on the right side of the midline of the mouse abdomen near the xiphoid process using ophthalmic scissors to expose the left liver lobe of the mouse. 1×10 6Hepa1-6 hepatoma cells were used, and then the area was pressed with a cotton swab for 2-5 seconds to prevent tumor cells from overflowing from the liver. The surgical incision was sutured with medical suture. Starting from the 6th day after modeling, Aldometanib monotherapy (dose: 0.0625 mg / kg) was administered intraperitoneally, PD1 Ab monotherapy (dose: 4 mg / kg) was administered via the tail vein, or Aldometanib combined with PD1 Ab treatment (dose: 0.0625 mg / kg + 4 mg / kg) was given, once every 3 days. The mice were euthanized 21 days after modeling, and the tumor-bearing livers were collected. Photos of the tumor-bearing livers were taken ( Figure 5 as shown in A), the weight of the tumor-bearing liver was measured ( Figure 5 as shown in B), the body weight of the tumor-bearing mice was recorded ( Figure 5 as shown in C), and the ratio of the weight of the tumor-bearing liver to the body weight was calculated (Figure 5D). It was found that Aldometanib significantly reduced the liver tumor burden, and its efficacy was comparable to that of the PD1 monoclonal antibody. The combination of Aldometanib and the PD1 monoclonal antibody showed a synergistic anti-tumor effect.

[0052] Combined with Figures 1 - 5 , Aldometanib showed significant inhibitory effects on the immune-related adverse reaction model induced by PD1 Ab combined with IL12, the inflammatory bowel disease model induced by DSS, the inflammatory liver injury model induced by ConA, and the orthotopic liver cancer model accompanied by liver injury. Especially in comparison with dexamethasone, Aldometanib did not cause tumor overprogression and was safer. Given that the core principle of the above models is the damage caused by immune cells to their own organs and tissues, and Aldometanib effectively inhibited these models, it can be seen that Aldometanib effectively acts on other immune-related adverse reactions and diseases, including immune-related adverse reactions caused by immune checkpoint inhibitor therapy, immune-related adverse reactions caused by other drugs, and immune-related adverse reactions caused by the onset and treatment of genetic, allergic reactions, organ transplant rejection, graft-versus-host disease, autoimmune diseases, etc.

[0053] The above are only the preferred embodiments of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims

1. Application of Aldometanib in the preparation of drugs for preventing and treating immune-related adverse reactions and diseases.

2. The use according to claim 1, characterized in that: The immune-related adverse reactions and diseases include immune-related adverse reactions caused by immune checkpoint inhibitor treatment, immune-related adverse reactions caused by drugs other than immune checkpoint inhibitors, and immune-related adverse reactions caused by genetics, allergic reactions, organ transplant rejection, graft-versus-host disease, and the onset and treatment of autoimmune diseases.

3. The use according to claim 1, characterized in that: Immune-related adverse reactions include immune hepatitis, immune myocarditis, immune pneumonia, and immune enteritis.

4. The use according to claim 2, characterized in that: The immune checkpoint inhibitors include but are not limited to inhibitors and function-blocking antibodies targeting PD-1, PD-L1 and CTLA4.

5. The use according to any one of claims 1 to 4, characterized in that: Aldometanib is used to prepare a pharmaceutical composition containing Aldometanib and a pharmaceutically acceptable carrier.

6. The use according to claim 5, characterized in that: The pharmaceutical composition contains 0.0001wt%-99.99wt% of Aldometanib, and the rest is a pharmaceutical carrier.

7. The use according to claim 1, characterized in that: The structural formula of Aldometanib is as follows: 。

Images