CN113599527B - Application of APOE inhibitor and PD-1 monoclonal antibody in preparation of medicine for treating digestive tract tumor - Google Patents
Application of APOE inhibitor and PD-1 monoclonal antibody in preparation of medicine for treating digestive tract tumor Download PDFInfo
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Abstract
The invention discloses an application of APOE inhibitor and PD-1 monoclonal antibody in preparation of a medicament for treating digestive tract tumor, belonging to the technical field of medicines. The inventor researches and finds that compared with the prior art that the PD-1 monoclonal antibody is used for treating the digestive tract tumor, the APOE inhibitor and the PD-1 monoclonal antibody can be used together to further inhibit the digestive tract tumor and improve the treatment efficiency, and especially for patients with low treatment sensitivity of the PD-1 monoclonal antibody, the APOE inhibitor and the PD-1 monoclonal antibody have important significance for treating the digestive tract tumor.
Description
Technical Field
The invention relates to an application of APOE inhibitor and PD-1 monoclonal antibody in preparation of a medicament for treating digestive tract tumor, belonging to the technical field of medicines.
Background
Digestive tract tumors are one of the most common malignant tumors in China, the incidence rate of the digestive tract tumors is increased year by year, the onset age of the digestive tract tumors also tends to be younger, and the health and the life of people are seriously threatened. Because of the specificity and complexity of the etiology and pathogenesis of the digestive tract tumor, the clinical cure rate is low, and the effective rate of targeted therapy and immunotherapy is about 20%, so that the improvement of the effective rate is extremely important.
At present, the effective rate of the PD-1 monoclonal antibody for treating the digestive tract tumor is 15-20 percent, and the effective rate is lower. The anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies function depending on their expression on the cell surface. Antibodies do not work well for tumors that express low and no corresponding substances. Studies have shown that at least 70% of cancer patients respond poorly to PD-1 antibody therapy. Therefore, single drug therapy does not meet the clinical needs and combination therapy is considered to improve the efficacy.
In recent years, immune checkpoint combination therapies have found widespread use. Although these immune checkpoint inhibitors improve the efficacy of treatment in cancer patients, previous clinical trial data suggest that immune checkpoint treatment does not achieve the expected positive response rate, and many of the previously proposed hypotheses are consequently clinically questioned. Nevertheless, a large number of immune checkpoint antibody combination therapies do have a very good therapeutic effect in controlling disease progression in certain advanced cancers. With the intensive study of the mechanisms of primary and acquired tolerance of immune checkpoint inhibitors, combination therapy regimens will be applied in more clinical trials. In addition to the combination therapy with CTLA-4 and PD-1 antibodies, the combination therapy further comprises: immune interference factors of the tumor microenvironment such as toll-like receptor antagonists, oncolytic viruses, antibodies blocking T cell rejection, suppressive immune cells such as regulatory T cells (Tregs) or macrophage M. These immune factor combination therapies enhance the tumor cell clearance of T cells on the one hand and increase the number of T cells surrounding tumor tissue on the other hand, thereby synergizing immune checkpoint antibodies to inhibit tumor progression. In addition, the combined application of other treatment modes such as radiotherapy, chemotherapy, tumor targeted therapy, cancer vaccine and the like also shows that the activity of immune factors in the tumor microenvironment can be regulated and controlled, and the immune factors and the immune check points generate synergistic action, so that the effect of enhancing the anti-tumor curative effect is achieved. However, there is no systematic study on the mechanism of combination therapy. Further elaborating the intrinsic molecular mechanism, and is important for improving the effective rate of tumor immunotherapy.
Disclosure of Invention
The invention aims to solve the problem of low effective rate of the PD-1 monoclonal antibody for treating the digestive tract tumor in the prior art, provides the application of the combination of the APOE inhibitor and the PD-1 monoclonal antibody in preparing the medicament for treating the digestive tract tumor, and tests prove that the combination of the APOE inhibitor and the PD-1 monoclonal antibody can further inhibit the digestive tract tumor and improve the treatment effective rate.
Technical scheme
The APOE inhibitor and PD-1 monoclonal antibody are used in combination for preparing medicine for treating digestive tract tumor.
Further, the APOE inhibitor is COG133TFA. COG133TFA is a fragment of an apolipoprotein E (APOE) peptide. COG133TFA competes with APOE holoprotein for binding to LDL receptors, and has potent anti-inflammatory and neuroprotective effects. The inventor researches to find that the APOE inhibitor can activate the immunogenicity of cancer patients, enhance the expression of PD-1 in CD8+ T cells, and enhance the sensitivity of medicaments by combining the PD-1 inhibitor.
Furthermore, in the medicine for treating the digestive tract tumor, the APOE inhibitor and the PD-1 monoclonal antibody are main active ingredients.
The invention has the beneficial effects that: compared with the prior art that the PD-1 monoclonal antibody is used for treating the digestive tract tumor, the APOE inhibitor and the PD-1 monoclonal antibody can be used for further inhibiting the digestive tract tumor, improving the treatment efficiency, and particularly aiming at a patient with low treatment sensitivity of the PD-1 monoclonal antibody. The method has important significance for treating digestive tract tumors.
Drawings
FIG. 1 shows the test results of the APOE inhibitor and PD-1 monoclonal antibody alone or in combination for treating mice of a model of subcutaneous tumor of liver cancer;
FIG. 2 shows the test results of APOE inhibitor and PD-1 monoclonal antibody alone or in combination for treating subcutaneous tumor model mice with intestinal cancer;
FIG. 3 shows the results of a test on mice model of subcutaneous carcinoma model treated with APOE inhibitor and PD-1 monoclonal antibody alone or in combination.
Detailed Description
The technical solution of the present invention is further explained with reference to the accompanying drawings and specific embodiments. In the examples below, COG133TFA was purchased from sigmaldrich; PD-1 mAb was purchased from Bioxcell.
Example 1
Establishing wild mouse C57BL/6 subcutaneous liver cancer, intestinal cancer and gastric cancer transplantation tumor model
C57BL/6 mice (purchased from Witonglihua)) At the age of 4 weeks, cell strains (MC 38-intestinal cancer, hepa 1-6-liver cancer and MFC-gastric cancer, all purchased from Shanghai cell biology institute of Chinese academy of sciences) are used for establishing subcutaneous liver cancer, intestinal cancer and gastric cancer transplantation tumor models by injecting at inguinal position. The specific method comprises the following steps: selecting cells (MC 38-intestinal cancer, hepa 1-6-liver cancer or MFC-stomach cancer cells) in a good growth state, pouring out the culture solution in the bottle, adding 2ml of D-Hanks solution, slightly shaking and then pouring out, adding 3ml of digestive juice mixed by 0.25% pancreatin and O.02% EDTA (1:1) into the bottle, slightly shaking the culture bottle to enable the digestive juice to flow over the surfaces of all the cells, and digesting for 3 minutes at room temperature of 25 ℃. The digestion was carried out under an inverted microscope, and when cytoplasmic contraction and increase in intercellular space were observed, the digestion solution was poured off, and 3ml of the culture solution was added to the flask to terminate the digestion. Repeatedly blowing and beating the cells on the bottle wall by using a suction pipe until all the cells are flushed down, slightly blowing, beating and uniformly mixing to form a cell suspension according to the proportion of 1:2, distributing, inoculating into two culture bottles, supplementing the culture solution to 5ml in each bottle, and continuing to culture. The culture was terminated when the cell adherence was 80% as observed under an inverted microscope. At room temperature, 0.25% pancreatin was digested, the cells were detached, and 2ml of RPMI-1640 medium was added to terminate digestion. Collecting cell suspension in 50ml centrifuge tube, centrifuging for 8min at 800 rpm, discarding supernatant, resuspending with RPMI-1640 culture solution, gently blowing and beating into single cell suspension, sucking 9 microliters of cell suspension in EP tube, adding 1 microliter trypan blue, mixing, placing 10 microliters of suspension on blood cell counting plate, counting under inverted microscope, and adjusting cell suspension density to lxl0 if cell viability reaches above 95% 7 And (4) each ml for standby. Disinfecting the skin of the right inguinal region of the mouse, taking the cells in the logarithmic growth phase, and adjusting the cell concentration to lxl0 7 Piece/ml, 0.2ml (2X 10) was aspirated with a syringe 6 One) the cell suspension was inoculated subcutaneously in the right groin of the mice and the injection site was pressed with a cotton swab for several seconds after injection. After inoculation, the animals were returned to the rearing room for further rearing and examined daily for tumor growth. Obtaining the liver cancer, intestinal cancer or gastric cancer transplantation tumor model mouse.
Example 2
APOE inhibitor and PD-1 monoclonal antibody combined treatment digestive tract tumor
1. Taking a liver cancer transplantation tumor model mouse,the test subjects were divided into four groups, i.e., a control group, a PD1 mab-only group (α PD-1), a COG133 TFA-only group (α APOE), and a PD1 mab-and COG133 TFA-combined group (α APOE + α PD-1), and each group consisted of 4 mice, and four groups of mice were treated according to the groups, wherein the PD1 mab-only group: injecting 6.6mg/kg in the abdominal cavity on the eighth day, and injecting every three days later; COG133TFA alone group: injecting 1mg/kg of the abdominal cavity on the next day, and injecting every five days later; combination of PD1 mab and COG133 TFA: injecting COG133TFA1mg/kg intraperitoneally the next day, injecting every five days later, injecting PD1 monoclonal antibody 6.6mg/kg intraperitoneally the eighth day, and injecting every three days later; control group: injecting 100ul PBS into the abdominal cavity on the next day, and injecting every five days later; the activity, spirit, diet and other conditions of the mice were observed daily before and after the experiment. The long diameter a (mm) and the short diameter b (mm) of the tumor were measured every 4 days with a vernier caliper, and the tumor volume (V) of the mouse was calculated according to the following formula: v = ab 2 And/2, the tumor growth curve is plotted. Mice were sacrificed 20 days after dosing by cervical dislocation. The test results are shown in FIG. 1.
Fig. 1 shows the test results of the APOE inhibitor and PD-1 mab used alone or in combination for treating the hepatoma subcutaneous tumor model mouse, and it can be seen from fig. 1 that both COG133TFA and PD1 mab used alone can slow down the growth of hepatoma, and PD1 mab has better effect than COG133TFA in inhibiting cancer, but the combination of both can significantly slow down the growth of hepatoma and even disappear.
2. Taking intestinal cancer transplantable tumor model mice, dividing the mice into four groups, and setting the mice into a control group, a PD1 monoclonal antibody single-use group, a COG133TFA single-use group, a PD1 monoclonal antibody and COG133TFA combined group, wherein each group comprises 4 mice, and the four groups of mice are respectively treated according to corresponding groups, wherein the PD1 monoclonal antibody single-use group comprises: injecting 6.6mg/kg in the abdominal cavity on the eighth day, and injecting every three days later; COG133TFA alone group: injecting 1mg/kg of the abdominal cavity on the next day, and injecting every five days later; combination of PD1 mab and COG133 TFA: injecting COG133TFA1mg/kg intraperitoneally the next day, injecting every five days later, injecting PD1 monoclonal antibody 6.6mg/kg intraperitoneally the eighth day, and injecting every three days later; control group: injecting 100ul PBS into the abdominal cavity on the next day, and injecting every five days later; the activity, spirit, diet and other conditions of the mice were observed daily before and after the experiment. Used every 4 daysThe slide caliper measures the long diameter a (mm) and the short diameter b (mm) of the tumor, and calculates the tumor volume (V) of the mouse according to the following formula: v = ab 2 And/2, the tumor growth curve is plotted. Mice were sacrificed 20 days after dosing by cervical dislocation. The test results are shown in FIG. 2.
Fig. 2 shows the test results of the APOE inhibitor and PD-1 monoclonal antibody used alone or in combination for treating subcutaneous tumor model mice with intestinal cancer, and it can be seen from fig. 2 that either APOE inhibitor COG133TFA or PD1 monoclonal antibody can slow down intestinal cancer growth, and PD1 monoclonal antibody has better effect than that of APOE inhibitor COG133TFA, but the combination of the two can significantly slow down intestinal cancer growth and even disappear.
3. Taking the gastric cancer transplantable tumor model mice, dividing the mice into four groups, and setting the mice into a control group, a PD1 monoclonal antibody single-use group, a COG133TFA single-use group, a PD1 monoclonal antibody and COG133TFA combined group, wherein each group comprises 4 mice, and the four groups of mice are respectively treated according to corresponding groups, wherein the PD1 monoclonal antibody single-use group comprises: injecting 6.6mg/kg in the abdominal cavity on the eighth day, and injecting every three days later; COG133TFA alone group: injecting 1mg/kg of the abdominal cavity on the next day, and injecting every five days later; combination of PD1 mab and COG133 TFA: injecting COG133TFA1mg/kg intraperitoneally the next day, injecting every five days later, injecting PD1 monoclonal antibody 6.6mg/kg intraperitoneally the eighth day, and injecting every three days later; control group: injecting 100ul PBS into the abdominal cavity on the next day, and injecting every five days later; the activity, spirit, diet and other conditions of the mice were observed daily before and after the experiment. The tumor major diameter a (mm) and minor diameter b (mm) were measured with a vernier caliper every 4 days, and the tumor volume (V) of the mice was calculated according to the following formula: v = ab 2 And/2, the tumor growth curve is plotted. The mice were sacrificed 20 days after the drug administration by cervical dislocation. The test results are shown in FIG. 3.
Fig. 3 shows the test results of a gastric carcinoma subcutaneous tumor model mouse treated with APOE inhibitor and PD-1 monoclonal antibody alone or in combination, and it can be seen from fig. 3 that either APOE inhibitor COG133TFA or PD1 monoclonal antibody alone can slow down the growth of gastric carcinoma, and PD1 monoclonal antibody has better effect than that of APOE inhibitor COG133TFA, but the combination of the two can significantly slow down the growth of gastric carcinoma.
Claims (2)
- The application of the APOE inhibitor and the PD-1 monoclonal antibody in preparing a medicament for treating the digestive tract tumor; the APOE inhibitor is COG133 TFA; the digestive tract tumor is liver cancer, intestinal cancer or gastric cancer.
- 2. The use as claimed in claim 1, wherein the medicament for the treatment of gastrointestinal tumours comprises as active ingredients an APOE inhibitor and PD-1 mab.
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| CN114796482A (en) * | 2022-05-31 | 2022-07-29 | 江苏省人民医院（南京医科大学第一附属医院） | Application of gsk3 beta inhibitor in preparation of medicine for improving curative effect of resisting hepatocellular carcinoma |
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