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Conjugate of monophosphate A (MPLA) and carbohydrate antigen Globo H and preparation method and application thereof

A technology of monophosphate esters and conjugates, applied in the field of anti-tumor sugar vaccine development, can solve problems such as suppression, difficult immune response, and difficult confirmation of protein coupling site structure

Inactive Publication Date: 2019-03-08
广州粤美医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the Globo H anti-tumor vaccine on the surface of tumor cells has been used in recent years, it still suffers from the following two points: 1) The uncertainty of the protein coupling site makes its structure complex and difficult to confirm, and the carrier protein will also produce a strong immune response Lead to the suppression of the immune response of Globo H sugar antigen; 2) Since Globo H is a T cell non-resistance antigen, it has poor immunogenicity and is difficult to arouse a strong immune response

Method used

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  • Conjugate of monophosphate A (MPLA) and carbohydrate antigen Globo H and preparation method and application thereof
  • Conjugate of monophosphate A (MPLA) and carbohydrate antigen Globo H and preparation method and application thereof
  • Conjugate of monophosphate A (MPLA) and carbohydrate antigen Globo H and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of sugar vaccine GL-01

[0042]

[0043] 1) Preparation of Compound 4

[0044]

[0045] Dissolve compound 3 (42 mg, 0.02 mmol) in 10 mL of dichloromethane, add appropriate amount of active zinc powder and acetic acid, react at room temperature for 6 h, remove the solid by filtration, remove dichloromethane and acetic acid under reduced pressure, and then extract the obtained oil Dissolve in 10mL dichloromethane containing adipic anhydride (5mg, 0.04mmol), add an appropriate amount of N-methylmorpholine to make the pH of the reaction solution greater than 7, react at room temperature for 12h, dilute with an appropriate amount of dichloromethane, and use saturated NaHCO 3 Washed and extracted 3 times, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (methanol:dichloromethane=1:4) to obtain compound 4 (36 mg, yield 82%). ESI-MS(m / z):2281.5[M+H] + . 1H-NMR(CDCl3,400MHz):7.35-7....

Embodiment 2

[0055] Embodiment 2: the preparation of sugar vaccine GL-02

[0056] 1) Preparation of Compound 9

[0057] Compound 9 (9 mg, 63%) was prepared by reacting compound 5 (12 mg, 5 μmol) with Globo H derivative 7 (6 mg, 8 μmol) using a method similar to step 3 of Example 1. ESI-MS(m / z):3364.0 [M+H] + . 1 H NMR (600MHz, CDCl 3 :CD 3 OD:D 2 O=3:3:1):δ:7.33-7.12(m,25H, ArH),5.51(m,1H,lipid-H-3'),5.37-5.29(m,1H,lipid-H-3) ,5.28-5.19(m,3H,2H of lipid,,H-1""'),5.17-5.00(m,4H,(Ph CH 2 O) 2 P),1.99(s,3H,NH Ac); 1.63-1.40 (m, 12H, lipid), 1.36-1.09 (br, 98H, 48x CH 2 ,lipid),0.98-0.78(18H,6x CH3,lipid).

[0058]

[0059] 2) Preparation of sugar vaccine GL-02

[0060] Prepared by a method similar to step 4 of Example 1, compound 9 (7 mg, 2.2 μmol) was reacted with hydrogen to prepare Globo H sugar vaccine GL-02 (5 mg, 83%). ESI-MS(m / z):2913.7[M+H] + . 1 H NMR (600MHz, CDCl 3 :CD 3 OD:D 2 O=5:3:1):δ:1.98(s,3H,NH Ac ); 1.82-1.57(m,12H,lipid),1.52-1.12(br,98H,48x CH 2 ...

Embodiment 3

[0062] Embodiment 3: the determination of the immune antibody titer of Globo H sugar vaccine GL-01 and GL-02

[0063] 1) Mouse immunization experiment: 6-8 week old mice were taken and divided into immunization group and control group (PBS), 5 mice in each group. The sugar vaccines GL-01 and GL-02 prepared in Example 1 and Example 2, as well as Compound 1 as a positive control, were prepared into liposomes, and the immune test was carried out by subcutaneous injection in mice, using an initial Immunization and three booster immunization schemes, inject the prepared vaccine on days 0, 14, 21, and 28 respectively, and take 0.1ml to 0.2ml of blood from each mouse on days 0, 27, and 38, and place it at 37 degrees for half an hour , placed at 4 degrees for half an hour, centrifuged at 5000 rpm, and the clear serum in the upper layer was separated for ELISA detection and analysis. (Org.Biomol.Chem.,.2014,12,3238; Chem.Sci.,2015,6,7112)

[0064] 2) ELISA immunoassay: 96-well plate,...

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Abstract

The invention relates to a conjugate of monophosphate A (MPLA) and carbohydrate antigen Globo H and capable of serving as an antitumor vaccine and a preparation method and application thereof. The conjugate can be prepared through a chemical method and has the advantages of definite structure, clear composition and adjuvant needlessness. In addition, the invention further provides the applicationof the conjugate in preparing drug for treating or preventing cancer.

Description

technical field [0001] The invention relates to a conjugate of monophosphate ester A (MPLA) and tumor-associated carbohydrate antigen Globo H that can be used as an anti-tumor vaccine, a preparation method and application thereof, and belongs to the technical field of anti-tumor carbohydrate vaccine development. Background technique [0002] At present, tumor vaccines mainly include protein, nucleic acid and sugar vaccines, among which glycoprotein vaccines have become one of the research hotspots at home and abroad. Cell migration and signal transduction play a key role, among which the Globo H carbohydrate antigen is the most prominent (Accounts of Chemical Research 2015, 48, 643Accounts of Chemical Research 201548(3), 643). Therefore, sugar tumor vaccines have the advantages of high specificity, few side effects, and the potential to improve or cure tumors, and are ideal targets for therapeutic anti-tumor vaccines. [0003] However, Globo H, like other carbohydrate antig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/385A61K39/00A61P35/00
CPCA61K39/385A61K39/0011A61K2039/6018A61K2039/627A61P35/00
Inventor 郭忠武郝玲花仲伯华郑俊霞
Owner 广州粤美医药科技有限公司
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