CN116120381A - Monophosphate A (MPLA) conjugated saccharide antigen Tn anti-tumor vaccine and application thereof - Google Patents
Monophosphate A (MPLA) conjugated saccharide antigen Tn anti-tumor vaccine and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of development of anti-tumor sugar vaccines, and particularly relates to preparation and application of a total synthesis anti-tumor sugar vaccine by taking monophosphate ester A (MPLA) as an embedded adjuvant to conjugate tumor-associated sugar antigen Tn. The anti-tumor vaccine is prepared by coupling the MPLA and the Tn through the covalent bond, and has the advantages of definite structure and controllable quality. In addition, the anti-tumor vaccine disclosed by the invention can improve the immunogenicity of the Tn sugar antigen without the action of an external adjuvant, and induce the generation of immune response aiming at the sugar antigen Tn, so that the purpose of specifically killing tumor cells is achieved.
Description
Technical Field
The invention relates to the technical field of chemistry and medicine, in particular to a conjugate of monophosphate A (MPLA) and a saccharide antigen Tn, and a preparation method and application thereof.
Background
The saccharide antigen Tn (Thomsen-nonveau, neu5 Ac. Alpha.2-6 GalNAc. Alpha. -O-Ser/Thr) is a tumor-associated carbohydrate antigen (TACA), which is abnormally overexpressed in multiple tumors such as breast cancer, colon cancer, prostate cancer, lung cancer, etc., and is positively correlated with the deterioration and metastasis of tumor cells, while being hardly expressed in normal cells. Thus, tn is one of the excellent targets for the design of a glycoantigen tumor vaccine.
However, like most TACAs, tn is poorly immunogenic and cannot be recognized and presented by the immune system. In order to improve the immunogenicity of Tn saccharide antigens, conventional strategies have been to prepare glycoprotein conjugate vaccines by coupling Tn with carrier proteins (e.g., KLH, CRM197, tetanus toxoid TT, etc.). However, glycoprotein vaccines prepared from Tn antigen and carrier protein (such as Tn-CRM 197) have uncertain coupling sites, complex composition and need to be used together with an adjuvant during immunization. In addition, glycoprotein conjugate vaccines belong to biological products, and have difficult quality control, poor stability, harsh storage conditions and the like.
Monophosphoryl ester a (MPLA) is a hydrophobic moiety of bacterial Lipopolysaccharides (LPS), is an agonist of Toll-like receptor 4 (Toll like receptor, TLR 4), and can target TLR4 and generate an immune response. The invention takes the MPLA as a vaccine carrier, and is connected with an antigen Tn through an amide bond to prepare Tn-MPLA total synthetic vaccines, such as TM01 and TM02, and the vaccine has the advantages of definite chemical structure, single constituent components, relatively easy quality control, no need of carrier protein or external adjuvant and the like, and meanwhile, the total synthetic vaccine belongs to non-protein medicines, and has the advantages of good stability, simple preservation condition and the like.
Disclosure of Invention
The invention aims to provide a total synthesis anti-tumor sugar vaccine of TLR4 receptor agonist mono-phosphorylated lipid A (MPLA) conjugated sugar antigen Tn. The embedded adjuvant MPLA of the sugar vaccine can improve the immunogenicity of the sugar antigen Tn, induce the specific immune response mediated by T cells, generate high-concentration high-affinity IgG antibodies, and achieve the purpose of specifically killing tumor cells.
It is another object of the present invention to provide a method for preparing the conjugate of mono-phosphorylated lipid a (MPLA) and saccharide antigen Tn.
It is a further object of the present invention to provide the use of the conjugate of mono-phosphorylated lipid a (MPLA) and saccharide antigen Tn in the preparation of an anti-tumour vaccine.
It is a further object of the present invention to provide the use of the conjugate of mono-phosphorylated lipid a (MPLA) and saccharide antigen Tn in the preparation of an antitumor drug.
The above object of the present invention is achieved by the following means:
the present invention provides a compound of formula I, or all possible isomers, pharmaceutically acceptable salts, hydrates or solvates thereof:
MPLA—Tn；
i is a kind of
Wherein, the monophosphoryl ester A (MPLA) is shown in the following formula:
R 1 ，R 2 ，R 3 and R is 4 Selected from the group consisting of optional- (CH) 2 ) n CH 3 ，-CH 2 -CH(OH)-(CH 2 ) n CH 3 ，-CH 2 -CH(O-CO-R 5 )-(CH 2 ) n CH 3 Wherein n is selected from integers from 6 to 14; r is R 5 Optionally substituted C 8-14 An alkyl group; m is selected from integers from 1 to 10.
The Tn is shown as the following formula:
x is selected from the group consisting of optionally-NHC (O) -, -CH 2 -，-NH-，-O-，-C(O)-，-S-，
a is an integer selected from 1-8.
The invention also provides a compound MPLA-Tn of the general formula:
wherein R is 1 ，R 2 ，R 3 And R is 4 Selected from the group consisting of optional- (CH) 2 ) n CH 3 ，-CH 2 -CH(OH)-(CH 2 ) n CH 3 ，-CH 2 -CH(O-CO-R 5 )-(CH 2 ) n CH 3 Wherein n is selected from integers from 6 to 14; r is R 5 Optionally substituted C 8-14 An alkyl group; m is selected from integers from 1 to 10; a is any integer from 1 to 8.
The present invention also provides a compound MPLA-Tn of the structural formula:
the present invention also provides suitable pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I, wherein the pharmaceutically acceptable salts include, but are not limited to, pharmaceutically acceptable salts formed by reaction with bases such as sodium, potassium, magnesium, calcium, lithium and the like. Some of the compounds of the present invention may be crystallized or recrystallized from water or an organic solvent, in which case various solvates may be formed.
The preparation method of the compound of the general formula I comprises the following steps:
the preparation of the above starting compounds 2 and 3 is referred to patent CN201810845422.7; tn antigens and Tn-CRM197 are prepared in the literature (Acta Pharmaceutica Sinica B,2022, https:// doi.org/10.1016/j.apsb.2022.05.028). The synthetic routes for representative compounds TM-01 and TM-02 of the compounds of formula I are as described above: and (3) respectively carrying out condensation reaction on the MPLA derivatives 2 and 3 and Tn derivatives containing amino groups to obtain fully-protected compounds 4 and 5, and carrying out hydrogenation under the catalysis of palladium carbon and palladium hydroxide to obtain fully-synthesized vaccines TM-01 and TM-02.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention aims to overcome the defects of the prior art and provide a total synthesis anti-tumor vaccine of TLR4 receptor agonist mono-phosphorylated lipid A (MPLA) conjugated saccharide antigen Tn, which has the advantages of definite chemical structure, stable physicochemical property, simple quality control, no need of additional adjuvant and the like.
(2) The preparation method of the conjugate provided by the invention has the advantages of short synthetic route, mild reaction condition, high yield and convenient operation, and can be widely applied to industrial preparation.
(3) The anti-tumor vaccine provided by the invention can improve the immunogenicity of the Tn saccharide antigen without the action of an external adjuvant, and induces an immune response aiming at the saccharide antigen Tn, so that the purpose of specifically killing tumor cells is achieved.
Drawings
FIG. 1 is a graph of IgG immunocompetence assessment for glycoprotein vaccines TM-01, TM-02 and glycoprotein vaccine Tn-CRM 197;
FIG. 2 is a graph of complement-dependent cytotoxicity assays for saccharide vaccines TM-01, TM-02 and glycoprotein vaccine Tn-CRM 197.
Detailed Description
In order to better understand the technical scheme of the present invention, the technical scheme of the present invention will be described in further detail with reference to the following examples, but the scope of the present invention is not limited thereto.
Example 1: preparation of sugar vaccine TM-01
1) Preparation of Compound 2
Compound 5 (40.0 mg, 16.8. Mu. Mol) and Tn derivative (5.3 mg, 20.0. Mu. Mol) were dissolved in DMF, the pH was adjusted to 8 with an appropriate amount of N-methylmorpholine under ice bath, warmed to room temperature, reacted for 20h, DMF was removed under reduced pressure, and purified by TLC on silica gel plate chromatography (MeOH/CH 2 Cl 2 1:15, v/v) to give compound 4 (25.0 mg, 59.4%). 1 H NMR(400MHz,CDCl 3 ):δ:7.30-7.11(m,30H),6.81(s,1H,NH),6.73(t,J＝4.8Hz,1H,NH),5.70(d,J＝7.8Hz,1H,NH),5.58-5.45(m,3H,H-3’,2×NH),5.19(t,J＝9.1Hz,1H,H-3),5.08-5.03(m,3H,H-1’),4.90-4.82(m,4H,2×PhCH 2 ),4.52-4.42(m,7H,3×PhCH 2 ,H-4’),4.38(d,J＝10.0Hz,1H,H-1),4.17-3.46(m,27H),2.45-1.95(m,19H),1.58-1.47(m,12H),1.25(b,104H,52×CH 2 ),0.90-0.80(m,18H,3×CH 3 ).ESI-MS(m/z):2499.6[M+H] + 。
4) Preparation of sugar vaccine TM-01
Compound 4 (10.0 mg, 4.0. Mu. Mol), 9.3mg of 10% Pd-C and 9.2mg Pd (OH) 2 Added to 16mL of CH 2 Cl 2 MeOH (4:1, v/v), reacted at room temperature under hydrogen for 20h, the solids removed by filtration, and concentrated under reduced pressure to give sugar vaccine TM-01 (5.4 mg, 65.8%). 1 H NMR(400MHz,CDCl 3 :CD 3 OD＝5:1):δ:5.48-5.13(m,4H),4.67-4.38(m,2H),4.17-3.49(m,26H),2.43-1.95(m,19H),1.50-1.40(m,12H),1.25(b,104H,52×CH 2 ),0.90-0.80(m,18H,3×CH 3 ). 31 P NMR(400MHz,CDCl 3 :CD 3 OD＝3:1):δ:-2.69.ESI-MS(m/z):2049.4[M+H] + 。
Example 2: preparation of sugar vaccine TM-02
1) Preparation of Compound 8
Compound 3 (30.0 mg, 12.6. Mu. Mol) and Tn derivative (4.0 mg, 15.2. Mu. Mol) were dissolved in DMF, the pH was adjusted to 8 with an appropriate amount of N-methylmorpholine under ice bath, warmed to room temperature, reacted for 20h, DMF was removed under reduced pressure, and purified by TLC on silica gel plate chromatography (MeOH/CH 2 Cl 2 1:15, v/v) to give the compound5(15.6mg,49.1％)。 1 H NMR(400MHz,CDCl 3 ):δ:7.34-7.11(m,30H),6.81(s,1H,NH),6.73(t,J＝4.8Hz,1H,NH),5.70(d,J＝7.8Hz,1H,NH),5.58-5.45(m,3H,H-3’,2×NH),5.16(t,J＝9.1Hz,1H,H-3),5.02-4.99(m,3H,H-1’),4.92-4.82(m,4H,2×PhCH 2 ),4.52-4.42(m,7H,3×PhCH 2 ,H-4’),4.38(d,J＝10.0Hz,1H,H-1),4.17-3.46(m,27H),2.45-1.95(m,19H),1.58-1.47(m,12H),1.25(b,108H,54×CH 2 ),0.90-0.80(m,18H,3×CH 3 ).ESI-MS(m/z):2527.6[M+H] + 。
2) Preparation of sugar vaccine TM-02
Compound 5 (10.0 mg, 4.0. Mu. Mol), 10.8mg of 10% Pd-C and 10.2mg of Pd (OH) 2 Added to 16mL of CH 2 Cl 2 MeOH (4:1, v/v), reacted at room temperature under hydrogen for 20h, filtered to remove solids, and concentrated under reduced pressure to give sugar vaccine MS-02 (7.1 mg, 85.5%). 1 H NMR(400MHz,CDCl 3 :CD 3 OD＝5:1):δ:5.47-5.02(m,4H),4.50-4.31(m,5H),4.17-3.45(m,27H),2.50-1.94(m,19H),1.52-1.41(m,12H),1.25(b,108H,54×CH 2 ),0.92-0.85(m,18H,3×CH 3 ). 31 P NMR(400MHz,CDCl 3 :CD 3 OD＝3:1):δ:-2.70.ESI-MS(m/z):2077.5[M+H] + 。
Experimental example 1: evaluation of immunocompetence of saccharide vaccines TM-01 and TM-02
This experimental example the conjugates prepared in example 1 and example 2 (fully synthetic sugar vaccine) were immunized mice, and their immunization was primarily evaluated by ELSA experiments, and antibody serum was shown to have the ability to specifically kill tumor cells under the mediation of complement by antibody-mediated Complementary Dependent Cytotoxicity (CDC) experiments.
1) Preparation of vaccine
The synthesized conjugate was prepared as follows: distearoyl phosphatidylcholine (DSPC): cholesterol=1:6.5:5 dissolved in DCM-MeOH-H 2 In O (5:5:1, v/v,2 mL) mixed solution, spin-dryingAnd (3) a solvent. 3.0mL of hydroxyethylpiperazine ethyl sulfate (HEPES) buffer (20 mM, pH=7.5) was added. The sugar vaccines TM-01 and TM-02 are obtained by ultrasonic treatment for 10-20 minutes. The concentration of Tn in the 2 vaccine solutions formulated was 6 μg/0.1mL.
Dissolving Tn-CRM197 in PBS buffer salt solution, adding aluminum adjuvant, stirring for 30 min, mixing to obtain milky white liquid, and standing at 4deg.C for adsorption overnight. The Tn dose was 1.7 μg/0.1 mL/mouse.
2) Immunization protocol for mice
The 18 female 6-8 week old BALB/c mice were divided into 3 groups of 6 mice each, TM-01, TM-02 and Tn-CRM197, respectively. The preparation is administrated by means of abdominal subcutaneous injection, and 4 times of subcutaneous injection are carried out on days 0, 14, 21 and 28, wherein the injection amount is 0.1mL each time, blood is taken from the eye orbit on days 0, 21, 27 and 38, whole blood is placed on ice for 1h, and centrifugation is carried out at 4000 rpm for 15min at 4 ℃, and supernatant clear serum is taken for ELISA detection analysis. .
3) ELISA immunoassay
0.1M carbonate buffer (pH 9.6) dissolved Tn-HSA, formulated as a 2.0. Mu.g/mL solution, added to 96-well plates at 100.0. Mu.L per well, and incubated overnight at 4 ℃; incubating in a 37 ℃ incubator for 1 hour the next day; PBST wash plates. Adding a milk sealing liquid; add 250.0 μl per well; incubate at room temperature for 1 hour, wash the plates with PBST. Serum samples from 6 mice from the same group were diluted 300, 900, 2700, 8100, 24300, 72900, 218700 and 656100 fold with PBS, respectively; adding 100.0 mu L of diluted serum into a 96-well plate; incubate at 37℃for 2 hours and wash the plate 3 times. HRP (horseradish peroxidase) -labeled IgG (2000-fold dilution) was added, 100.0. Mu.L per well and incubated for 1 hour at room temperature; washing the plate. TMB solution was added, 100.0. Mu.L was added to each well, and the mixture was developed at room temperature in the dark for 20 minutes. Adding 0.5. 0.5M H 2 SO 4 Solution, 100.0 μl/well. The absorbance was immediately detected with a microplate reader at 450nm and 570nm as background wavelengths.
Absorbance (OD) values were plotted against antisera dilution values and a best fit line was obtained. The equation for this line was used to calculate the dilution at which the OD reached 0.2, and the IgG antibody titer was calculated from the inverse of the dilution as shown in fig. 1.
Experimental results: as can be seen from FIG. 1, both the carbohydrate vaccines TM-01 and TM-02 induced mice to produce IgG antibodies against Tn carbohydrate antigen, and the antibody titer increased with increasing number of immunizations; the IgG titer generated by the glycoprotein vaccines TM-01 and TM-02 is basically equivalent, but is obviously higher than that generated by the glycoprotein vaccine Tn-CRM197 of the control group, which shows that the MPLA is used as an endogenous adjuvant, effectively enhances the immunogenicity of the Tn saccharide antigen and induces the specific immune response against the Tn saccharide antigen.
4) Antibody-mediated Complementary Dependent Cytotoxicity (CDC)
Taking breast cancer cells MCF-7 which specifically express Tn sugar antigens and tumor cells MDA-231 which do not express Tn sugar antigens, and respectively culturing in DMEM culture medium containing 10% Fetal Bovine Serum (FBS); configuring cells in logarithmic growth phase to 1.0X10 5 cell suspensions at cell/mL density were seeded into 96-well plates at 100. Mu.L per well, about 10000 cells, and cultured overnight in an incubator. The medium was removed, washed three times with serum-free MEM medium, MEM diluted mouse serum was added and incubated for 2 hours at 37 ℃. Serum-free MEM was washed three times, and a complement solution diluted in the ratio (1:10) was added thereto and incubated at 37℃for 1 hour. Both low reference (serum-free medium alone) and high reference (5% triton-100 treated) groups were set. After the incubation, the cells were centrifuged, 20. Mu.L of the cell supernatant was diluted to 100. Mu.L with PBS, and developed with 100. Mu.L of LDH cytotoxicity detection reagent for 30 minutes. Absorbance was measured at 490nm and cell lysis was calculated from the low and high reference wells.
Experimental results: MCF-7 is breast cancer cell over-expressing Tn antigen, and MDA-231 tumor cell not expressing Tn antigen is used as negative control. Under the same conditions, the antiserum mediated MCF-7 cell lysis rate of the antibody serum induced by the synthesized saccharide vaccines TM-01 and TM-02 of the invention in examples 1 and 2 on mice is significantly higher than that of the blank serum. The MDA-231 cells which do not express the Tn antigen are not cytotoxic, so that the antibodies aiming at the Tn antigen can kill tumor cells containing the Tn antigen, particularly the toxicity effect of serum of the saccharide vaccines TM-01 and TM-02 on MCF-7 is obviously superior to that of glycoprotein vaccine Tn-CRM197, and the conclusion that the antibody titer aiming at Tn generated by the TM-01 and the TM-02 is obviously superior to that of glycoprotein vaccine Tn-CRM197 is consistent with the conclusion that the saccharide vaccines TM-01 and TM-02 have more development potential than that of glycoprotein vaccine Tn-CRM197, so that the vaccine is a very promising anti-tumor vaccine.
Finally, it should be noted that the foregoing examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the foregoing examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principles of the present invention should be made and all equivalent substitutions are intended to be included in the scope of the present invention.
Claims (5)
1. A conjugate of monophosphate a (MPLA) and a saccharide antigen Tn, having the structural formula:
MPLA—Tn；
i is a kind of
Wherein, the monophosphoryl ester A (MPLA) is shown in the following formula:
R 1 ，R 2 ，R 3 and R is 4 Selected from the group consisting of optional- (CH) 2 ) n CH 3 ，-CH 2 -CH(OH)-(CH 2 ) n CH 3 ，-CH 2 -CH(O-CO-R 5 )-(CH 2 ) n CH 3 Wherein n is selected from integers from 6 to 14; r is R 5 Optionally substituted C 8-14 An alkyl group; m is selected from integers from 1 to 10;
the Tn is shown as the following formula:
x is selected from the group consisting of optionally-NHC (O) -, -CH 2 -，-NH-，-O-，-C(O)-，-S-，
a is an integer selected from 1-8;
or a pharmaceutically acceptable salt thereof.
2. The MPLA-Tn conjugate vaccine of claim 1, wherein the structural general formula of the anti-tumor MPLA-Tn conjugate vaccine is one of:
wherein R is 1 ，R 2 ，R 3 And R is 4 Selected from the group consisting of optional- (CH) 2 ) n CH 3 ，-CH 2 -CH(OH)-(CH 2 ) n CH 3 ，-CH 2 -CH(O-CO-R 5 )-(CH 2 ) n CH 3 Wherein n is selected from integers from 6 to 14; r is R 5 Optionally substituted C 8-14 An alkyl group; m is selected from integers from 1 to 10; a is any integer from 1 to 8;
or a pharmaceutically acceptable salt thereof.
3. The MPLA-Tn conjugate vaccine of claims 1 and 2, which has the structural formula as follows:
or a pharmaceutically acceptable salt thereof.
4. A method of treating cancer comprising administering to a patient a therapeutically or prophylactically effective dose of a compound of monophosphate a (MPLA) conjugated Tn saccharide antigen of any one of claims 1 to 3.
5. The method of claim 4, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, bowel cancer, melanoma, liver cancer, lung cancer, renal cell carcinoma, uterine cancer, ovarian cancer, cellular lymphoma, brain cancer, stomach cancer, pancreatic cancer, thyroid cancer, and leukemia.
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