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Anti-tumour vaccine molecule, and preparation method and application thereof

An anti-tumor and vaccine technology, applied in the field of anti-tumor vaccines, can solve the problems of poor immunogenicity of tumor-associated antigens, and achieve strong cellular immunity, good immune performance, and good thermal stability

Inactive Publication Date: 2021-03-19
HUAZHONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to overcome the problem of poor immunogenicity of tumor-associated antigens in the prior art

Method used

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  • Anti-tumour vaccine molecule, and preparation method and application thereof
  • Anti-tumour vaccine molecule, and preparation method and application thereof
  • Anti-tumour vaccine molecule, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1: Preparation of TLR7 agonists

[0131]

[0132] Synthesis of compound 2: 2-chloroadenine (5.4g, 31.8mmol) and sodium (5.0g, 217mmol) were mixed in ethylene glycol monomethyl ether (235mL, 3.1mol), and the mixture was stirred and refluxed at 140°C for 10h . Then add 25 mL of water, add 1 mol / L hydrochloric acid until the pH value = 7, concentrate, wash with water and filter with suction to obtain compound 2, which is directly carried out to the next step without purification.

[0133] Synthesis of compound 3: Compound 2 (0.7g, 3.34mmol), potassium carbonate (3.2g, 23.44mmol), methyl 4-bromomethylbenzoate (1.5g, 6.68mmol) were added to 10mL of dry N,N-di Methylformamide (DMF), stirred and refluxed at 60°C for 8h. Then add a 5% aqueous solution of citric acid until no bubbles are generated, extract with chloroform, wash with brine, and MgSO 4 After drying, filtration, concentration, the reaction mixture was purified by column chromatography to give 3 as a w...

Embodiment 2

[0136] Example 2: Preparation of TLR7 agonist coupled with carrier protein BSA

[0137]

[0138] Synthesis of compound 14: under argon protection, compound 5 (0.03mmol) and EDCI (0.09mmol) were dissolved in DMF (1mL), and finally NHS (N-hydroxysuccinimide) (0.09mmol) was added, 25 Stirring at °C for 3 h; then the resulting mixture was spin-dried with an oil pump to obtain compound 13.

[0139] BSA (0.3μmol, purchased from Wuhan Chucheng Zhengmao Science and Technology Engineering Co., Ltd., brand name CC1050003) was dissolved in PBS (2mL), compound 13 (0.006mmol) was added to DMF and dissolved, the two solutions were mixed, and placed on a shaker at 25°C Reaction 48h. The obtained compound 14 (defined as TLR7a-BSA) was purified by centrifugal filtration with an ultrafiltration tube (Millipore UFC910096 15M, 10KD) and lyophilized. Tested by MALDI-TOF-MS, the average number of covalent linkages between TLR7a and BSA was calculated to be 6 to 7.

Embodiment 3

[0140] Example 3: Preparation of antigen MUC1

[0141]

[0142]

[0143] Compound 8 was synthesized by manual solid phase, and the operation steps were as follows:

[0144] (1) Activation of Rink Amide AM (purchased from Jill Biochemical (Shanghai) Co., Ltd.) resin

[0145] Weigh 306 mg (0.2 mmol) of Rink Amide AM resin into a solid-phase synthesis reaction tube, and use dry dichloromethane (DCM) (4 mL) to swell for 30 min under nitrogen protection. Wash: use dry DCM (3 x 3 mL) and dry ( Spherical molecular sieve dried) N,N-dimethylformamide (DMF) (3 × 3mL) alternately washed repeatedly.

[0146] (2) Fmoc group deprotection

[0147] Under nitrogen agitation, 20% piperidine / DMF solution (3 mL, 3×5 min) was added to the reaction tube, and washing: the resin was washed alternately and repeatedly with DCM (3×3 mL) and DMF (3×3 mL).

[0148] (3) Kaiser-test

[0149] Kaiser-test judges whether the amino group is deprotected by observing the color development of the resin...

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Abstract

The invention relates to the field of anti-tumour vaccines, and discloses an anti-tumour vaccine molecule, and a preparation method and application thereof. The anti-tumour vaccine molecule in the invention has a structure shown as a formula (I); in the formula (I), A is an adjuvant; B is an antigen; furthermore, m A are covalently connected with the protein through covalent connecting arms respectively; and n B are covalently connected with the protein through covalent connecting arms respectively. The anti-tumour vaccine disclosed by the invention is a new anti-tumour molecule, is good in immune performance, can generate an IgG antibody with relatively high titer and relatively strong cellular immunity, is good in thermal stability, and is easy to store and transport. A<m>-protein-B<n> is of formula (I).

Description

technical field [0001] The invention relates to the field of anti-tumor vaccines, in particular to an anti-tumor vaccine molecule and its preparation method and application. Background technique [0002] Extensive studies in cell biology and biochemistry have shown that tumor-associated antigens (TACAs, such as the MUC1 glycoprotein) are ideal targets for immunotherapy and are vigorously pursued in the development of immunotherapeutic anticancer strategies. [0003] To date, immunotherapy has proven to be one of the most promising cancer treatments, offering many possibilities. [0004] However, due to the commonly used tumor-associated antigens as self-antigens, the antigenicity is poor and the immune regulation tolerance is poor, resulting in the inability to elicit an effective immune response. Therefore, improving the immunogenicity of tumor-associated antigens has become an urgent problem to be solved. [0005] A great deal of research has been devoted to better immun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/385A61K39/39A61K39/00A61P35/00C07K19/00
CPCA61K39/385A61K39/39A61K39/00A61K39/0011A61K39/001153A61K39/00117A61K39/001188A61K39/001186A61K39/001192A61P35/00C07K14/4748C07K14/4727A61K2039/6037A61K2039/6081A61K2039/55511C07K2319/31C07K2319/00
Inventor 郭军杨光富杜晶晶王昌伟
Owner HUAZHONG NORMAL UNIV
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