CN113713092A - Application of chemokine receptor CCR6 in preparation of antitumor drugs - Google Patents
Application of chemokine receptor CCR6 in preparation of antitumor drugs Download PDFInfo
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Abstract
The invention relates to application of a chemokine receptor CCR6 in preparation of an anti-tumor medicament. In the invention, chemokine receptor CCR6 is used as a tumor immunotherapy target. The chemokine receptor CCR6 is: modified with Tn sugar-modified glycine building blocks linked in parallelT cell partial epitope sequence (TT) linked with tetanus toxin protein947‑967) The chemokine receptor CCR 6. The invention discloses a chemotactic factor receptor CCR6 as a tumor immunotherapy target for the first time, which can effectively activate an organism immune system and generate antibodies to cause specific anti-tumor response and realize efficient tumor therapy, can be applied to the preparation of different anti-tumor drugs such as lung cancer, colorectal cancer, liver cancer, gastric cancer, breast cancer, pancreatic cancer and the like, and has wide application and industrialization prospect.
Description
Technical Field
The invention relates to application of a chemokine receptor CCR6 in preparation of an antitumor drug, and belongs to the technical field of biological medicines.
Background
The incidence of tumors rises year by year under the influence of multiple factors such as aging of social population, change of life style of people, deterioration of ecological environment and the like, and the tumors become main diseases seriously threatening human health at present. The ideal approach for tumor therapy is to specifically kill tumor cells in vivo without damaging normal cells. Compared with traditional tumor treatment modes such as surgical treatment, chemical treatment, radiation treatment and the like, the tumor immunotherapy has the advantages of strong specificity, small side effect, high safety and the like, so that the tumor immunotherapy is one of the most advanced and hottest tumor treatment methods in the world at present.
Tumor vaccines are important branches of tumor immunotherapy that cannot be ignored, and the traditional vaccines mainly include heat-inactivated or chemical-inactivated virus vaccines, attenuated vaccines, toxoid vaccines, subunit vaccines and the like. Compared with the traditional vaccine, the chemical method is adopted to synthesize the vaccine, which is a novel vaccine preparation strategy, the chemical synthesis method is adopted to covalently couple the immune active components with different functions to form an effective vaccine structure, and the vaccine has the advantages of definite components, definite functions, high purity, small side effect and the like, is widely used for preventing and treating various diseases at present, and is also widely applied to the aspect of tumor prevention and treatment.
The tumor-associated antigen can be recognized by the immune system of the body to cause immune response, and is widely used for early detection, diagnosis and tumor immunotherapy targets of tumors, however, the immunogenicity of the existing tumor-associated antigen is low, and the body is difficult to cause strong anti-tumor immune response. Therefore, the search for new immunotherapeutic targets is pressing. According to a plurality of preclinical researches, the chemokine receptor CCR6 is highly expressed on the surfaces of T cells and B cells and participates in a plurality of inflammatory reactions, and in addition, the CCR6 is obviously up-regulated in the surface expression of a plurality of tumor cells such as liver cancer, primary stomach cancer, pancreatic cancer, colorectal cancer and the like. However, no report on the utilization of the chemokine receptor CCR6 for the treatment of immune tumors has been found. In conclusion, few anti-tumor studies aiming at the chemokine receptor CCR6 are carried out, and the anti-tumor drugs and products aiming at the chemokine receptor CCR6 are not mature yet and have great development prospects.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of the chemokine receptor CCR6 in preparing antitumor drugs.
The technical scheme of the invention is as follows:
the application of a chemokine receptor CCR6 in preparing an antitumor drug is characterized in that the amino acid sequence of the chemokine receptor CCR6 is as follows:
Met-Ser-Gly-Glu-Ser-Met-Asn-Phe-Ser-Asp-Val-Phe-Asp-Ser-Ser-Glu-Asp-Tyr。
preferably, according to the invention, the chemokine receptor CCR6 is: modified with Tn sugar-modified glycine structural unit and connected with tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The chemokine receptor CCR 6;
the tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The amino acid sequence of (a) is as follows:
Phe-Asn-Asn-Phe-Thr-Val-Ser-Phe-Trp-Leu-Arg-Val-Pro-Lys-Val-Ser-Ala-Ser-His-Leu-Glu。
according to the invention, the Tn sugar modified saccharopine structural unit is prepared by the following steps:
with AgClO4And Ag2CO3Reacting a glycosyl donor with a glycosyl acceptor under strictly anhydrous conditions to form intermediate 1 for a mixed catalyst; then under the action of activated zinc powder and acetic anhydride, the intermediate product 1 is converted into N-acetamido by C2 azido, and trifluoroacetic acid is used for cutting the protecting group of carboxyl, namely tert-butyl ester, to obtain a structure unit of the tryptophan modified by Tn sugar;
preferably according to the invention, the glycosyl donor is 3,4, 6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranosyl bromide and the glycosyl acceptor is N- (9H-fluoren-9-yl) methoxycarbonyl-L-serine tert-butyl ester or N- (9H-fluoren-9-yl) methoxycarbonyl-L-threonine tert-butyl ester.
Preferably, the tetanus toxin protein helper T cell partial epitope sequence (TT) is947-967) Is linked to the chemokine receptor CCR6 through a tripeleneglycolic acid linker arm.
According to the invention, the preferable preparation method of the tripeglycolic acid connecting arm is as follows:
taking polyethylene glycol (PEG) as an initial raw material, controlling the reaction dosage and the dropping speed to enable the PEG to have Michael addition reaction with tert-butyl acrylate under the catalysis of sodium metal, then activating the hydroxyl at the other end of the PEG through methanesulfonyl chloride, and directly performing substitution reaction with sodium azide to obtain a compound modified by azido, continuously adding a Pd/C catalyst and introducing hydrogen to perform catalytic hydrogenation reaction to reduce the azido into amino to obtain an intermediate product 2, and further protecting the amino of the intermediate product 2 with Fmoc group; finally, removing the protecting group tert-butyl ester of carboxyl by using trifluoroacetic acid to obtain a tripeleneglycolic acid connecting arm;
preferably, the structural unit of the tryptophan modified with the Tn sugar is modified and connected with a tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The chemokine receptor CCR6 is TT-CCR6 glycopeptide, and the preparation method is as follows:
using Wang resin pre-loaded with amino acid as an initiator, synthesizing CCR6 polypeptide by using a standard Fmoc polypeptide solid phase synthesis method, and then carrying out glycosylation modification on CCR6 polypeptide by using Tn sugar modified glycine structural unitDecorating to obtain CCR6 glycopeptide; then a section of helper T cell epitope sequence (TT) of the tetanus toxin protein is connected by a tripolyethylene glycol alanine connecting arm947-967) And connecting with CCR6 glycopeptide to obtain TT-CCR6 glycopeptide.
Preferably according to the invention, the tumor is lung cancer, colorectal cancer, liver cancer, stomach cancer, breast cancer or pancreatic cancer.
The invention also provides an anti-tumor vaccine which comprises the chemokine receptor CCR6 or TT-CCR6 glycopeptide.
Preferably according to the invention, the vaccine further comprises an adjuvant; the adjuvant is chitosan/polyglutamic acid nanoparticles.
According to a preferred embodiment of the present invention, the preparation method of the anti-tumor vaccine comprises the following steps:
(1) dissolving chitosan in acetic acid to prepare a chitosan solution with the concentration of 0.5-1.5 mg/mL, adjusting the pH to 4-6, and slowly adding a polyglutamic acid solution into the chitosan solution under the condition of continuous stirring to ensure that the ratio of positive charges to negative charges in the solution is (2-10): 1, obtaining a chitosan/polyglutamic acid nanoparticle suspension, centrifuging the suspension at 4000-6000 rpm for 35-45 min, removing supernatant, and suspending precipitates in double distilled water with the same amount to obtain a chitosan/polyglutamic acid nanoparticle solution;
(2) preparing 1-5mg/mL solution of chemokine receptor CCR6 or TT-CCR6 glycopeptide, and then uniformly mixing the solution with the chitosan/polyglutamic acid nanoparticle solution prepared in the step (1) to obtain the chitosan nanoparticle CCR6 glycopeptide tumor vaccine;
wherein the volume ratio of the chemokine receptor CCR6 solution or TT-CCR6 glycopeptide solution to the chitosan/polyglutamic acid nanoparticle solution is 1: (8-10).
The invention has the beneficial effects that:
1. the invention discloses a chemotactic factor receptor CCR6 as a tumor immunotherapy target for the first time, which can effectively activate an organism immune system and generate antibodies to cause specific anti-tumor response and realize efficient tumor therapy, can be applied to the preparation of different anti-tumor drugs such as lung cancer, colorectal cancer, liver cancer, gastric cancer, breast cancer, pancreatic cancer and the like, and has wide application and industrialization prospect.
2. The anti-tumor vaccine provided by the invention firstly takes a chemokine receptor CCR6 as a tumor immunotherapy target, and glycosylation modification is carried out on the chemokine receptor CCR6 by using a Tn sugar-modified glycine structural unit to obtain CCR6 glycopeptide; secondly, to enhance the immunogenicity of CCR6 glycopeptides, the tetanus toxin protein helper T cell epitope sequence (TT) was chemically modified947-967) Coupling with CCR6 glycopeptide to obtain TT-CCR6 glycopeptide; subsequently, chitosan/polyglutamic acid (CS/gamma-PGA) nanoparticles are prepared as an adjuvant by using a polyelectrolyte complex method; and finally, physically mixing the chitosan/polyglutamic acid nanoparticles with TT-CCR6 glycopeptide to prepare the chitosan nanoparticle CCR6 glycopeptide tumor vaccine. The immunogenicity of the chemokine receptor CCR6 is enhanced, the specific immune response is enhanced, and the titer of antibodies is enhanced by modifying and constructing a multivalent structure.
Drawings
FIG. 1 is a schematic diagram of the structure of TT-CCR6 glycopeptide.
FIG. 2 is a graph showing the analysis of the antibody titer in mouse serum.
Detailed Description
The invention will now be further illustrated by means of specific examples and figures, without however limiting the scope of the invention as claimed.
The raw materials used in the examples are conventional raw materials, and the equipment used is conventional equipment, all of which are commercially available.
The 3,4, 6-tri-O-acetyl-2-azido-2-deoxy- α -D-galactopyranosyl bromide in the following examples was prepared using D- (+) -galactose molecules as starting material.
Example 1
The preparation of the anti-tumor vaccine by using the chemokine receptor CCR6 specifically comprises the following steps:
(1) synthesis of structural unit of glycine containing Tn sugar modification
With AgClO4And Ag2CO3Reacting a glycosyl donor with a glycosyl acceptor under strictly anhydrous conditions to form intermediate 1 for a mixed catalyst; then the intermediate product 1 is reacted with activated zinc powder and acetic anhydrideConverting C2 azido into N-acetamido, and then using trifluoroacetic acid to cut off the protecting group of carboxyl, namely tert-butyl ester, to obtain a tryptophan structural unit modified by Tn sugar;
the glycosyl donor is 3,4, 6-tri-O-acetyl-2-azide-2-deoxy-alpha-D-galactopyranosyl bromide, and the glycosyl acceptor is N- (9H-fluoren-9-yl) methoxycarbonyl-L-serine tert-butyl ester or N- (9H-fluoren-9-yl) methoxycarbonyl-L-threonine tert-butyl ester;
(2) synthesis of tripeglycolic acid linking arm
Taking polyethylene glycol (PEG) as an initial raw material, controlling the reaction dosage and the dropping speed to enable the PEG to have Michael addition reaction with tert-butyl acrylate under the catalysis of sodium metal, then activating the hydroxyl at the other end of the PEG through methanesulfonyl chloride, and directly performing substitution reaction with sodium azide to obtain a compound modified by azido, continuously adding a Pd/C catalyst and introducing hydrogen to perform catalytic hydrogenation reaction to reduce the azido into amino to obtain an intermediate product 2, and further protecting the amino of the intermediate product 2 with Fmoc group; finally, removing the protecting group tert-butyl ester of carboxyl by using trifluoroacetic acid to obtain a tripeleneglycolic acid connecting arm;
(3) synthesis of TT-CCR6 glycopeptides
Using Wang resin loaded with amino acid in advance as an initiator, synthesizing a chemokine receptor CCR6 by adopting a standard Fmoc polypeptide solid-phase synthesis method, and then carrying out glycosylation modification on the chemokine receptor CCR6 by using the Tn sugar-modified glycine structural unit prepared in the step (1) to obtain a CCR6 glycopeptide; and then the tetanus toxin protein helper T cell epitope sequence (TT) is connected with the tripolyethylene glycol alanine connecting arm prepared in the step (2)947-967) Connecting with CCR6 glycopeptide to obtain TT-CCR6 glycopeptide; the concrete structure is shown in figure 1Shown in the specification;
wherein, the amino acid sequence of the chemokine receptor CCR6 is as follows:
Met-Ser-Gly-Glu-Ser-Met-Asn-Phe-Ser-Asp-Val-Phe-Asp-Ser-Ser-Glu-Asp-Tyr；
tetanus toxin protein helper T cell epitope sequence (TT)947-967) The nucleotide sequence of (a) is as follows:
Phe-Asn-Asn-Phe-Thr-Val-Ser-Phe-Trp-Leu-Arg-Val-Pro-Lys-Val-Ser-Ala-Ser-His-Leu-Glu；
(4) preparation of chitosan/polyglutamic acid nanoparticles
Dissolving 0.01g of chitosan in 10mL of acetic acid, adjusting the pH value to 5, and slowly adding a polyglutamic acid solution into the chitosan solution under the condition of continuous stirring to ensure that the ratio of positive charges to negative charges in the solution is 2: 1, obtaining chitosan/polyglutamic acid nanoparticle suspension, centrifuging the suspension at 5000rpm for 40min, removing supernatant, and suspending precipitate in double distilled water with the same amount to obtain pure chitosan/polyglutamic acid nanoparticle solution;
(5) preparation of chitosan nanoparticle CCR6 glycopeptide tumor vaccine
Preparing the TT-CCR6 glycopeptide prepared in the step (3) into a 1mg/mL solution, then adding 100 muL of TT-CCR6 glycopeptide solution into 900 muL of the chitosan/polyglutamic acid nanoparticle solution prepared in the step (4), uniformly mixing, and combining the TT-CCR6 glycopeptide with the chitosan/polyglutamic acid nanoparticles through electrostatic interaction to obtain the chitosan nanoparticle CCR6 glycopeptide tumor vaccine.
Example 2
The preparation of an antitumor vaccine using the chemokine receptor CCR6 was performed in the same manner as described in example 1, except that in step (5), TT-CCR6 glycopeptide was formulated as a 2mg/mL solution.
Example 3
The preparation of the anti-tumor vaccine by using the chemokine receptor CCR6 is the same as that in example 1, except that in the step (4), a polyglutamic acid solution is slowly added into a chitosan solution under the condition of continuous stirring, so that the ratio of positive charges to negative charges in the solution is 10: 1.
example 4
An antitumor vaccine was prepared using the chemokine receptor CCR6, as described in example 1, except that the chemokine receptor CCR6 was not modified and linked, the chemokine receptor CCR6 was directly prepared as a 1mg/mL solution, and then mixed with the chitosan/polyglutamic acid nanoparticle solution at a ratio of 1: 9 to obtain the chitosan nanoparticle CCR6 polypeptide tumor vaccine.
Test examples
16 female BALB/C mice with the age of 6-8 weeks are taken and divided into an experimental group A, an experimental group B, an experimental group C and a control group, wherein each group comprises 4 mice, the experimental group A is injected with unmodified chemokine receptor CCR6 in the abdominal cavity of each mouse, the experimental group B is injected with the chitosan nanoparticle CCR6 polypeptide tumor vaccine prepared in example 4 in the abdominal cavity of each mouse, the experimental group C is injected with the chitosan nanoparticle CCR6 glycopeptide tumor vaccine prepared in example 1 of the invention in the abdominal cavity of each mouse, and the control group is injected with sterile PBS in the abdominal cavity of each mouse, and the conditions are kept consistent except for different immunogenic components.
Each mouse was immunized 5 times in total, and every other week. One week after the fifth immunization, the mouse was bled from the cheek and the titer of IgG antibodies in serum was measured by indirect ELISA, as shown in fig. 2.
As can be seen from fig. 2, the chemokine receptor CCR6 in the experimental group a can be used as a tumor immunotherapy target, can effectively activate the immune system of the organism and generate antibodies to elicit specific anti-tumor responses, can be applied to the preparation of anti-tumor drugs, particularly to tumor vaccines, is expected to be applied to the treatment of different tumor diseases such as lung cancer, colorectal cancer, liver cancer, gastric cancer, breast cancer, pancreatic cancer, and the like, and has a wide application and industrialization prospect. Then chitosan nano-particles are used as an adjuvant to be matched with chemokine receptor CCR6 for use, the titer of IgG antibodies in serum can be improved, and the immunostimulating component TT is further prepared by the method947-967Introduced into a tumor vaccine system, enhances the immunogenicity of chemokine receptor CCR6 by modifying and constructing a multivalent structure, so that compared with the chemokine receptor CCR6, the chitosan nanoparticle CCR6 glycopeptide tumor vaccine prepared in the example 1,the IgG antibody titer in serum is improved by more than 10 times; compared with the chitosan nanoparticle CCR6 polypeptide tumor vaccine prepared in the embodiment 4, the IgG antibody titer in serum is improved by 2-2.5 times, and the immunogenicity is obviously enhanced.
Claims (10)
1. The application of a chemokine receptor CCR6 in preparing an antitumor drug is characterized in that the amino acid sequence of the chemokine receptor CCR6 is as follows:
Met-Ser-Gly-Glu-Ser-Met-Asn-Phe-Ser-Asp-Val-Phe-Asp-Ser-Ser-Glu-Asp-Tyr。
2. the use according to claim 1, wherein the chemokine receptor CCR6 is: modified with Tn sugar-modified glycine structural unit and connected with tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The chemokine receptor CCR 6;
the tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The amino acid sequence of (a) is as follows:
Phe-Asn-Asn-Phe-Thr-Val-Ser-Phe-Trp-Leu-Arg-Val-Pro-Lys-Val-Ser-Ala-Ser-His-Leu-Glu。
3. the use of claim 2, wherein the Tn sugar modified saccharopine building block is prepared by the following method:
with AgClO4And Ag2CO3Reacting a glycosyl donor with a glycosyl acceptor under strictly anhydrous conditions to form intermediate 1 for a mixed catalyst; then under the action of activated zinc powder and acetic anhydride, the intermediate product 1 is converted into N-acetamido by C2 azido, and trifluoroacetic acid is used for cutting the protecting group of carboxyl, namely tert-butyl ester, to obtain a structure unit of the tryptophan modified by Tn sugar;
4. use according to claim 3, wherein the glycosyl donor is 3,4, 6-tri-O-acetyl-2-azido-2-deoxy- α -D-galactopyranosyl bromide and the glycosyl acceptor is N- (9H-fluoren-9-yl) methoxycarbonyl-L-serine tert-butyl ester or N- (9H-fluoren-9-yl) methoxycarbonyl-L-threonine tert-butyl ester.
5. The use of claim 2, wherein the tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) Is linked to the chemokine receptor CCR6 through a tripeleneglycolic acid linker arm.
6. The use of claim 5, wherein the tripeleneglycolic acid linker arm is prepared by the following method:
taking polyethylene glycol (PEG) as an initial raw material, controlling the reaction dosage and the dropping speed to enable the PEG to have Michael addition reaction with tert-butyl acrylate under the catalysis of sodium metal, then activating the hydroxyl at the other end of the PEG through methanesulfonyl chloride, and directly performing substitution reaction with sodium azide to obtain a compound modified by azido, continuously adding a Pd/C catalyst and introducing hydrogen to perform catalytic hydrogenation reaction to reduce the azido into amino to obtain an intermediate product 2, and further protecting the amino of the intermediate product 2 with Fmoc group; finally, removing the protecting group tert-butyl ester of carboxyl by using trifluoroacetic acid to obtain a tripeleneglycolic acid connecting arm;
7. the use of claim 2, wherein the Tn sugar-modified glycine building block is modified and ligated with a tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The chemokine receptor CCR6 is TT-CCR6 glycopeptide, and the preparation method is as follows:
using Wang resin pre-loaded with amino acid as an initiator, synthesizing CCR6 polypeptide by adopting a standard Fmoc polypeptide solid phase synthesis method, and then inoculatingCarrying out glycosylation modification on CCR6 polypeptide by using a Tn sugar-modified glycine structural unit to obtain CCR6 glycopeptide; then a section of helper T cell epitope sequence (TT) of the tetanus toxin protein is connected by a tripolyethylene glycol alanine connecting arm947-967) And connecting with CCR6 glycopeptide to obtain TT-CCR6 glycopeptide.
8. An anti-tumor vaccine comprising the chemokine receptor CCR6 of claim 1 or the Tn sugar-modified glycine building block of claim 2 and linked to a tetanus toxin protein helper T cell partial epitope sequence (TT)947-967) The chemokine receptor CCR 6.
9. The anti-tumor vaccine of claim 8, further comprising an adjuvant; the adjuvant is chitosan/polyglutamic acid nanoparticles.
10. The anti-tumor vaccine of claim 8, which is prepared by the following steps:
(1) dissolving chitosan in acetic acid to prepare a chitosan solution with the concentration of 0.5-1.5 mg/mL, adjusting the pH to 4-6, and slowly adding a polyglutamic acid solution into the chitosan solution under the condition of continuous stirring to ensure that the ratio of positive charges to negative charges in the solution is (2-10): 1, obtaining a chitosan/polyglutamic acid nanoparticle suspension, centrifuging the suspension at 4000-6000 rpm for 35-45 min, removing supernatant, and suspending precipitates in double distilled water with the same amount to obtain a chitosan/polyglutamic acid nanoparticle solution;
(2) preparing a chemokine receptor CCR6 or TT-CCR6 glycopeptide into a 1-5mg/mL solution, and then uniformly mixing the solution with the chitosan/polyglutamic acid nanoparticle solution prepared in the step (1) to obtain a chitosan nanoparticle CCR6 glycopeptide tumor vaccine;
wherein the volume ratio of the chemokine receptor CCR6 solution or TT-CCR6 glycopeptide solution to the chitosan/polyglutamic acid nanoparticle solution is 1: (8-10).
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