WO2019042170A1 - Combined drug for treating diseases related to tumor necrosis factor family - Google Patents

Abstract

A combination drug for treating a tumor necrosis factor family-related disease, which comprises chlorogenic acid for simultaneous or separate administration of a unit preparation of the same or different specifications, and a medicament for treating a tumor necrosis factor family-related disease, and is pharmaceutically acceptable Carrier. The combination of chlorogenic acid and drugs for treating tumor necrosis factor family-related diseases can play a synergistic effect on tumor necrosis factor family-related diseases, improve the efficacy of TNF-α inhibitor alone, and reduce the joint cavity of patients with rheumatoid arthritis. Inflammatory infiltration and erosion of articular cartilage; enhance the efficacy of urelumab in inhibiting tumor development; increase the inhibition rate of TARIL on cancer cells; and make synergistic increase in the combination of chlorogenic acid and tumor necrosis factor family-related drugs The effect of the effect is excellent, the toxicity is small, and the clinical application prospect is good.

Description

A combined drug for treating tumor necrosis factor family related diseases Technical field

The present invention relates to a combination drug for treating a tumor necrosis factor family related disease.

Background technique

Since Aggarwal et al. isolated and identified the first tumor necrosis factor (TNF) in 1984, the protein family has nearly 20 members. TNF plays a key role in the occurrence and development of autoimmune diseases, bacterial and viral infections, tumors, diabetes, osteoporosis and other diseases through its interaction with TNF receptor (TNFR). Therefore, in recent years, TNFα/TNFR, Fas/FasL and TRAIL/TRAILR, important members of the TNF/TNFR family, have become important drug targets, and a number of related targeted drugs have been developed, especially biopharmaceuticals, some of which are clinically effective and Business has been a huge success.

At present, most of the drugs for treating tumor necrosis factor family related diseases are still in the pre-clinical and clinical stages, and only a small amount of drugs have been on the market. Different drug-related disorders have been developed for different TNF/TNFR family members, such as TNFα inhibitors mainly for the treatment of rheumatoid arthritis, segmental enteritis, ankylosing spondylitis, psoriatic arthritis and other diseases; The TRAIL/TRAILR related drugs are mainly anti-tumor drugs.

The US Food and Drug Administration (FDA) has approved the listing of five TNFα inhibitors, which have shown good results in the treatment of inflammatory and autoimmune diseases, but the risks they pose are gradually gaining attention. Common adverse reactions that have been reported for TNFα inhibitors include causing malignant tumors, causing infections of bacteria, viruses, fungi, drug immune responses, skin allergic reactions, and the like. Therefore, based on the good efficacy of TNFα inhibitors and the coexisting safety hazards, it is particularly important to reduce the adverse effects of TNFα inhibitors without increasing the dose of TNFα inhibitors. In addition, TRAIL/TRAILR-related drugs have been clinically proven to have anti-tumor effects, but TRAIL alone as an anti-tumor drug is difficult to achieve satisfactory results and needs to be used in combination with other chemotherapeutic drugs.

Chlorogenic acid is a natural substance with strong biological activity. Current clinical trials have confirmed that chlorogenic acid is a safe, non-toxic, broad-spectrum anti-tumor drug that can be used for lung cancer, glioma, The treatment of various malignant tumors such as hepatocellular carcinoma and lymphocyte tumor, and mechanistic studies show that chlorogenic acid plays an anti-tumor role mainly by regulating the cellular immune process mediated by the body T cells.

Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a combination for treating a tumor necrosis factor family-related disease for improving the therapeutic effect of a medicament for treating a tumor necrosis factor family-related disease alone.

The present invention provides a combination medicament for treating a tumor necrosis factor family-related disease, which comprises chlorogenic acid for simultaneous or separate administration of a unit preparation of the same or different specifications, and a tumor necrosis factor-related disease. The drug, as well as a pharmaceutically acceptable carrier.

Among them, the drug for treating a tumor necrosis factor family-related disease includes a TNFα inhibitor, a TNFR-related drug, or a TRAIL/TRAILR-related drug.

Wherein, the TNFα inhibitor comprises adalimumab, infliximab, etanercept;

And/or, TNFR related drugs include Ureurumb;

And/or, TRAIL/TRAILR related drugs include TRAIL.

Wherein, the weight ratio of chlorogenic acid and TNFα inhibitor or TNFR related drug is 400:1 to 1.5:1;

And/or, the molar ratio of chlorogenic acid to TRAIL/TRAILR related drugs is 100:0.025-100:0.3.

Wherein, the weight ratio of chlorogenic acid to TNFα inhibitor or TNFR-related drug is 400:1.

The present invention also provides the use of the aforementioned combination drug for the preparation of a medicament for treating a tumor necrosis factor family related disease.

The tumor necrosis factor family-related diseases are rheumatoid arthritis, segmental enteritis, ankylosing spondylitis, psoriatic arthritis, cancer, solid tumors.

The present invention also provides the use of chlorogenic acid and a medicament for treating a tumor necrosis factor family-related disease in the preparation of a medicament for treating a tumor necrosis factor family-related disease.

The present invention also provides the use of chlorogenic acid for the preparation of a medicament for enhancing the therapeutic effect of a TNF-α inhibitor, urelumab or TARIL alone.

Wherein the drug is a drug for improving the therapeutic effect of the TNF-α inhibitor on reducing the degree of inflammatory infiltration and articular cartilage erosion in the joint cavity of patients with rheumatoid arthritis;

And/or, the drug is a drug that enhances the efficacy of urelumab in inhibiting tumor progression;

And/or, the drug is a drug that increases the inhibition rate of TARIL on cancer cells.

The present invention also provides a method for treating a tumor necrosis factor family-related disease, which is a chlorogenic acid and a medicament for treating a tumor necrosis factor family-related disease, which are simultaneously or separately administered to the same or different unit preparations, and a pharmaceutically acceptable one. Carrier.

Among them, the drug for treating a tumor necrosis factor family-related disease includes a TNFα inhibitor, a TNFR-related drug, or a TRAIL/TRAILR-related drug.

Wherein, the TNFα inhibitor comprises adalimumab, infliximab, etanercept;

And/or, TNFR related drugs include Ureurumb;

And/or, TRAIL/TRAILR related drugs include TRAIL.

Wherein, the weight ratio of chlorogenic acid and TNFα inhibitor or TNFR related drug is 400:1 to 1.5:1;

And/or, the molar ratio of chlorogenic acid to TRAIL/TRAILR related drugs is 100:0.025-100:0.3.

Wherein, the weight ratio of chlorogenic acid to TNFα inhibitor or TNFR-related drug is 400:1.

The Urelumab provided by the present invention is a fully human IgG4 monoclonal antibody for treating cancer and solid tumors targeting CD137 family member CD137, and is currently in clinical trial stage, and is provided by the National Key Laboratory of Biotechnology of Sichuan University.

The combination of chlorogenic acid and the medicament for treating tumor necrosis factor family related diseases can play a synergistic effect on the treatment of tumor necrosis factor family related diseases, improve the curative effect of TNF-α inhibitor alone, and alleviate rheumatoid arthritis patients. Inflammatory infiltration in the joint cavity and the degree of erosion of articular cartilage; enhance the efficacy of urelumab in inhibiting tumor development; increase the inhibition rate of TARIL on cancer cells; and make medicinal drugs related to chlorogenic acid and tumor necrosis factor family Synergistic effect, excellent efficacy, low toxicity, good clinical application prospects.

The present invention will be further described in detail below, but is not intended to limit the scope of the present invention, and in accordance with the above-described basic technical idea of the present invention, Other various modifications, substitutions or changes can be made.

DRAWINGS

Figure 1 shows chlorogenic acid combined with tumor necrosis factor inhibitor drug, local inflammatory cell infiltration score of the joint cavity of mice in different administration groups.

Figure 2 is a graph of chlorogenic acid combined with tumor necrosis factor inhibitor drugs, articular cartilage erosion scores of mice in different administration groups.

Figure 3 shows the results of inhibition of MCF-7 stem cells by different chlorogenic acids in combination with TRAIL (%).

Detailed ways

Example 1 Inhibitory effect of chlorogenic acid combined with TNF-α inhibitor on proliferation of human synovial cells

1, material

Drugs: adalimumab (Xiumeile); etanercept (Enli); infliximab (like grams); chlorogenic acid bulk drug (Sichuan Jiuzhang Biotechnology Co., Ltd., purity 99.3%)

Tissue/cell: Synovial tissue, from patients with orthopedic fractures in West China Hospital of Sichuan University, obtained fibroblast-like synoviocytes after isolation and culture, and used.

2, experimental methods

2.1 single drug and combination drug MTT experiment

The synovial cells were cultured by tissue block transplantation, and digested with 0.25% trypsin. After serial passage for 2-3 times, a cell suspension was prepared using DMEM complete medium to make the cell concentration 5×10 ⁵ /mL, and This was inoculated into a 96-well plate at 100 μL per well, and conventional culture was continued for 24 hours. After the cells are completely attached, the plate is taken out, and the medium is discarded, and then divided into 1) chlorogenic acid monotherapy group; 2) adalimumab single drug group; 3) etanercept monotherapy group; 4) Infuli Single antibody group; 5) chlorogenic acid combined with adalimumab group; 6) chlorogenic acid combined with etanerceptuzumab group; 7) chlorogenic acid combined with infliximab group; 8) negative control Group (only cells, no drugs); 9) blank control group (no cells); and add different experimental drugs in the corresponding group, the specific experimental group and drug concentration are shown in Table 1, 3 duplicate holes in each group . After continuing to culture for 48 hours, MTT was added to each well. After the end, the supernatant was discarded, and DMSO was added to shake well, and the absorbance (A) was measured at 490 nm with a microplate reader.

Table 1 Concentration and combination table of experimental drugs

2.2 Evaluation of the combined effects of drugs

(1) Inhibition rate = 1 - (experimental group A - blank control group A) / (negative control group A - blank control group A) × 100%

(2) Rheumatoid arthritis is an autoimmune disease involving multiple joints. Synovial cells are stimulated by various inflammatory factors, and tumor-like hyperproliferation is one of the important processes of the disease. Inhibition of proliferation of fibroblast-like synoviocytes is one of the main therapeutic strategies for this disease, and it is also an important in vitro indicator for examining related therapeutic drugs.

3. Experimental results

After measuring the value-added condition of each group of cells, the inhibition of the proliferation of synovial cells by different drugs and drug combinations was calculated. The results showed that the chlorogenic acid combined with the drug group (chlorogenic acid combined with adalim and chlorogenic acid) The inhibition rate of the proliferation of fibroblast-like synoviocytes was significantly higher than that of the corresponding single-drug group, and the inhibitory rate of cyanoxine and chlorogenic acid combined with infliximab was significantly higher. The results showed that there was a significant difference (p<0.05), and the experimental results are shown in Table 2:

Table 2 Effect of different administration groups on proliferation of fibroblast-like synoviocytes

**p<0.01 compared with the adalim group; ##p<0.01 compared with the etoposide group; ΔΔp<0.01 compared with the infliximab group.

The results of the experiment showed that chlorogenic acid combined with TNF-α inhibitors (adalimumab, etanercept and infliximab) can significantly increase the inhibition of this type of cells compared with the single drug group, demonstrating the combination. The drug has synergistic effect.

Example 2 Evaluation of in vivo efficacy of chlorogenic acid combined with tumor necrosis factor inhibitor in the treatment of arthritic mice

1, material

Drugs: adalimumab (Xiumeile); chlorogenic acid bulk drug (Sichuan Jiuzhang Biotechnology Co., Ltd., purity 99.3%)

Animal: DBA/1 mice

2, experimental methods

2.1 Establishment of a mouse model of rheumatoid arthritis

(1) Preparation of collagen-adjuvant mixed emulsion

1 The bovine type II collagen was dissolved in 0.1 M glacial acetic acid solution at a concentration of 2 mg/mL, and placed at 4 ° C for 12 h;

2 Take 1 mL of type II collagen and 1 mL of adjuvant, respectively;

3 Push and pull the above mixture back and forth with a syringe to mix the type II collagen and the adjuvant thoroughly, which is milky white, and the process must be carried out on an ice bath.

(2) Establishment of mouse model

The mice were fixed in a self-made fixture, and the back skin was sterilized with 75% ethanol, and each mouse was subcutaneously injected with 200 μL of collagen-complete Freund's adjuvant mixed emulsion. After 3 weeks, the incomplete Freund's adjuvant and the bovine type II collagen solution were mixed in equal amounts and emulsified, and subcutaneously injected into the tail root of each mouse for a total of 100 μL to be boosted to obtain rheumatoid arthritis. Mouse. The control mice were injected with the same amount of physiological saline at the same time as described above.

2.2 Animal grouping and treatment

Twenty-four of the above-mentioned model mice were randomly divided into 4 groups, which were named as 1 model control group; 2 chlorogenic acid monotherapy group; 3 adalim monotherapy group; 4 chlorogenic acid combined with adalim treatment group. A total of 4 groups started on the second day of modeling success, including: 1 model control group was injected with normal saline for 4 weeks in a row; 2 chlorogenic acid monotherapy group was administered intraperitoneally for 4 weeks; 3 adamu monotherapy group , subcutaneous injection every 2 weeks, a total of 2 injections; 4 chlorogenic acid combined with adalim treatment group, chlorogenic acid continuous injection for 4 weeks, and adalim injection every 2 weeks, a total of 2 times, specific grouping and administration The scheme is shown in Table 3.

Table 3 Administration schedules of mice in different administration groups

2.3 Histological assessment

After the end of the experiment (week 4), the histology of each of the administered mice was evaluated as follows.

1 Hematoxylin-eosin staining was used to observe the degree of inflammatory cell infiltration in the joint cavity. The scoring criteria are shown in Table 4:

Table 4 Joint cavity inflammatory cell infiltration scores

2 Toluidine blue staining was used to observe the degree of articular cartilage erosion. The scoring criteria are as shown in Table 5:

Table 5 Articular cartilage erosion degree scoring standard

3. Experimental results

(1) The results of local inflammatory cell infiltration in the joint cavity showed that the chlorogenic acid combined with the adalimin treatment group can significantly reduce the local inflammatory cell infiltration of the joint cavity compared with other groups, compared with the data of the adamu group alone. The ratio was significantly different (p<0.05), and the specific experimental results are shown in Fig. 1.

(2) Experimental results of articular cartilage destruction and bone erosion showed that chlorogenic acid combined with adalim group can significantly alleviate the degree of joint bone erosion in model mice, and achieve good therapeutic effect. Compared with adalimin group, combined The study data of the drug group had significant difference (p<0.05), and the specific experimental results are shown in Fig. 2.

The experimental results show that the chlorogenic acid combined with the adalim group can significantly reduce the inflammatory infiltration in the joint cavity of the model mice, and can reduce the degree of erosion of the articular cartilage, and has a good synergistic effect.

Example 3 Evaluation of the therapeutic effect of chlorogenic acid combined with urelumab on head and neck squamous cell carcinoma in mice

1, material

Drugs: 4-nitroquinoline-1-oxide (4NQO); chlorogenic acid bulk drug (99.2% purity, Sichuan Jiuzhang Biotechnology Co., Ltd.), urelumab (provided by National Key Laboratory of Biotechnology, Sichuan University)

Animal: Balb/c mice (20-25g) 60

2, experimental methods

2.1 Establishment and experimental grouping of mouse models of head and neck squamous cell carcinoma

4NQO was prepared as a reserve solution with a concentration of 0.05% in distilled water, stored at 4 ° C in the dark, and mixed with ordinary tap water to a concentration of 0.005% to the dark, allowing the mice to drink freely and changing the drinking water twice a week. At the beginning of the 16th week, the mice were randomly divided into 4 groups, 15 mice in each group, respectively, 1 model control group; 2 chlorogenic acid monotherapy group; 3urelumab group; 4 chlorogenic acid combined with urelumab treatment group; The chlorogenic acid monotherapy group started at the 16th week, and continued intraperitoneal injection of chlorogenic acid for 5 days, rest for 2 days, and shared the drug until the 36th week; the urelumab monotherapy group started at the 16th week. 4 weeks intravenous injection of urelumab, a total of 5 injections, a shared drug to the 36th week; combined medication group, intravenous injection of urelumab every 4 weeks, a total of 5 times, weekly intraperitoneal injection of chlorogenic acid for 5 days rest for 2 days, a total of Until the 36th week. Specific grouping and dosing schedules are shown in Table 6.

Table 6 Dosing schedules for mice in different dose groups

2.2 Experimental observation

The activity of each group of animals was observed every day during the experiment, and the amount of drinking water, the amount of food and the body weight were summarized once a week. At the end of the experiment (week 36), all mice were weighed and all mice were sacrificed. Mucosal changes in the tongue and other parts of the mouth were observed and recorded. HE staining histopathology was performed to evaluate mice in different dose groups. Abnormal mucosal hyperplasia of the tongue.

3. Experimental results

3.1 The average daily drinking water, body weight and sensitivity at the end of the experiment for different groups of mice are shown in Table 7:

Table 7 Average daily drinking water, end-of-experiment weight, sensitivity of mice in different administration groups

It can be seen from Table 7 that by observing the water consumption, body weight and sensitivity of mice in different administration groups, it was shown that chlorogenic acid combined with urelumab can effectively inhibit the decreased sensitivity of drinking water, body weight and stimulating response in mice.

3.2 Detection results of tongue and mucous membrane disease in mice of different drug administration groups

The experimental results are shown in Table 8:

Table 8 Concentrations and combinations of different drugs set in 96-well plates of each cell

It can be seen from Table 8 that after the end of the experiment, the tongue mucosal diseases of the mice in different administration groups were tested, and the results showed that the chlorogenic acid combined with urelumab was significantly improved compared with the model control group and the urelumab single drug group. The incidence of mucosal lesions in the tongue, the proportion of severe dysplasia and invasive carcinoma was significantly lower than that in the urelumab group alone, and the total number of mice with lesions decreased from 10 (66.7%) to 4 in urelumab alone (26.7). %).

The experimental results show that the combination of chlorogenic acid and urelumab can effectively maintain the normal function of the body, inhibit the development of tumors, and has synergistic effect.

Example 4 Inhibitory effect of chlorogenic acid combined with TRAIL on breast cancer stem cells

1, material

Drugs: TRAIL (Shanghai Minmin); chlorogenic acid raw materials (99.2% purity, Sichuan Jiuzhang Biotechnology Co., Ltd.)

Cell line: MCF-7 cells (human breast cancer cells)

2, experimental methods

2.1 MCF-7 tumor stem cell sorting and obtaining

MCF-7 cells were cultured normally in 1640 complete medium. When the number of cells reached 1×10 ⁸ cells/ml, the cells were digested with trypsin and thoroughly blisted into cell suspension. The cells were labeled with CD44-APC before sorting. CD24-PE, ESA-FITC antibody, cells of CD44+/CD24/low/ESA+ were sorted by flow cytometry and sorted into culture flasks or 96-well plates. Serum-free stem cell-specific medium is used to prevent differentiation of breast cancer stem cells.

2.2 MTT assay to investigate the inhibitory effect of different drug-administered groups on the proliferation of breast cancer stem cells

Different concentrations of different drugs diluted in a stem cell-specific medium were added to a 96-well plate and cross-combined according to the different concentrations in Table 9, and the corresponding control group (without drug) was set. Three replicate wells were set in each group. After incubation for 48 hours, 20 μL of MTT solution was added to each well. Incubation was continued for 4 h. The supernatant was aspirated, 150 μL of DMSO was added to each well, and then shaken on a horizontal shaker for 10 min at low speed to fully dissolve crystals. Hole absorbance value (A). The inhibition rates of the respective drug-added groups were calculated separately.

Table 9 Concentrations and combinations of different drugs set in 96-well plates of each cell

2.3 Evaluation of the combined effects of drugs

(1) According to the above experimental results, the inhibition rate of different drugs on different cells was calculated. The inhibition rate was calculated as follows: inhibition rate = 1 - (experimental group A - blank control group A) / (negative control group A - blank control group A) ×100%;

(2) plot the tumor cell inhibition rate by different concentrations of the same drug, and obtain a dose effect curve;

(3) Calculate the half inhibitory concentration (IC50 value) using the Logit IC50 calculation software according to the drug concentration and the corresponding tumor cell inhibition rate;

(4) The combined use of the formula Q = E (a + b) / (Ea + Eb - Ea × Eb) to calculate the synergy. Where E(a+b) is the inhibition rate of the two drugs, that is, the combined effect of the test, Ea and Eb are the inhibition rates when the two drugs are used alone, the denominator (Ea+Eb-Ea×Eb) is the desired combined effect, and Q is two. Ratio. When the Q value is between 0.85 and 1.15, the combined effect of the two drugs is additive (+), the Q value is synergistic (++) when the value is 1.15-20, the Q value is >20 is the obvious synergy (+++), and the Q value is 0.05. Antagonism at ~0.85, and significant inhibition of Q value <0.05;

3. Experimental results

3.1 Inhibition of MCF-7 stem cells by combination therapy

The inhibitory effects of different concentrations of drug combinations on MCF-7 stem cells were calculated. The results are shown in Figure 3. The inhibitory effect of chlorogenic acid combined with TRAIL on MCF-7 stem cells is generally higher than that of the monotherapy group (chlorogenic acid monotherapy or TRAIL single). medicine). After the above experimental results were analyzed according to the combined drug index method, the Q value of the combination drug was calculated, and chlorogenic acid combined with TARIL had a synergistic effect, and the intensity of this synergistic effect was different under different drug concentration combinations. The results are shown in Table 10:

Table 10 Joint index of different concentrations of chlorogenic acid combined with TRAIL for MCF-7 stem cells

The experimental results show that chlorogenic acid combined with TARIL has significant inhibitory effect on MCF-7 stem cells, thus achieving synergistic effect.

In summary, the combination of the chlorogenic acid of the present invention and a medicament for treating a tumor necrosis factor family-related disease can synergistically enhance the tumor necrosis factor family-related diseases, improve the efficacy of the TNF-α inhibitor alone, and reduce the rheumatoidity. Inflammatory infiltration in the joint cavity of arthritis patients and the degree of erosion of articular cartilage; enhance the efficacy of urelumab in inhibiting tumor development; increase the inhibition rate of TARIL on cancer cells; and make medicinal drugs related to chlorogenic acid and tumor necrosis factor family It has obvious synergistic effect, excellent curative effect, low toxicity and good clinical application prospect.

Claims (15)

A combination medicament for treating a tumor necrosis factor family-related disease, which comprises a chlorogenic acid for simultaneous or separate administration of a unit preparation of the same or different specifications, and a medicament for treating a tumor necrosis factor family-related disease, and A pharmaceutically acceptable carrier. The combination drug according to claim 1, wherein the drug for treating a tumor necrosis factor family-related disease comprises a TNFα inhibitor, a TNFR-related drug, or a TRAIL/TRAILR-related drug. The combination according to claim 2, wherein said TNFα inhibitor comprises adalimumab, infliximab, etanercept; And/or, TNFR related drugs include Ureurumb; And/or, TRAIL/TRAILR related drugs include TRAIL. The combination drug according to any one of claims 1 to 3, wherein the weight ratio of chlorogenic acid to TNFα inhibitor or TNFR-related drug is 400:1 to 1.5:1; And/or, the molar ratio of chlorogenic acid to TRAIL/TRAILR related drugs is 100:0.025-100:0.3. The combination according to claim 4, wherein the weight ratio of chlorogenic acid to TNFα inhibitor or TNFR-related drug is 400:1. The use of the combination according to any one of claims 1 to 5 for the preparation of a medicament for treating a tumor necrosis factor family-related disease. The use according to claim 6, characterized in that the tumor necrosis factor family-related diseases are rheumatoid arthritis, segmental enteritis, ankylosing spondylitis, psoriatic arthritis, cancer, solid tumors. The use of chlorogenic acid and a medicament for treating a tumor necrosis factor family-related disease in the preparation of a medicament for treating a tumor necrosis factor family-related disease. The use of chlorogenic acid for the preparation of a medicament for enhancing the therapeutic effect of a TNF-α inhibitor, urelumab or TARIL alone. The use according to claim 9, wherein the drug is a drug for enhancing the therapeutic effect of the TNF-α inhibitor on reducing the degree of inflammatory infiltration and articular cartilage erosion in the joint cavity of a patient with rheumatoid arthritis; And/or, the drug is a drug that enhances the efficacy of urelumab in inhibiting tumor progression; And/or, the drug is a drug that increases the inhibition rate of TARIL on cancer cells. A method for treating a tumor necrosis factor family-related disease, which is characterized in that it is a chlorogenic acid which is administered simultaneously or separately to a unit preparation of the same or different specifications, and a medicament for treating a tumor necrosis factor family-related disease, and a pharmaceutically acceptable carrier . The method according to claim 11, wherein said drug for treating a tumor necrosis factor family-related disease comprises a TNFα inhibitor, a TNFR-related drug or a TRAIL/TRAILR-related drug. The method according to claim 12, wherein said TNFα inhibitor comprises adalimumab, infliximab, etanercept; And/or, TNFR related drugs include Ureurumb; And/or, TRAIL/TRAILR related drugs include TRAIL. The method according to any one of claims 11 to 13, wherein the weight ratio of chlorogenic acid to TNFα inhibitor or TNFR-related drug is 400:1 to 1.5:1; And/or, the molar ratio of chlorogenic acid to TRAIL/TRAILR related drugs is 100:0.025-100:0.3. The method according to claim 14, wherein the weight ratio of chlorogenic acid to TNFα inhibitor or TNFR-related drug is 400:1.

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