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Monoclonal antibody-antigen binding segment-T-2 toxin conjugate

A technology of monoclonal antibodies and binding fragments, which can be used in the field of pharmaceuticals to solve problems such as skin irritation and breakage

Inactive Publication Date: 2013-10-02
济南环肽医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, T-2 toxin has a strong toxic effect, can directly stimulate the skin and mucous membrane, penetrate epithelial tissue, affect almost all subcellular activities, and inhibit thymus, bone marrow, liver, spleen, lymph node, gonad and gastrointestinal mucosa Synthesis of protein and DNA in other organ cells, and can cause DNA single-strand breaks in lymphocytes

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 Preparation of anti-human hepatocellular carcinoma monoclonal antibody HAb18 Fab-T-2 toxin conjugate

[0020] Anti-human hepatocellular carcinoma monoclonal antibody HAb18 Fab fragment according to literature (Sui Yanfang, He Fengchang, Chen Zhinan. 131 In vivo radioimmunoimaging study of iodine-liver cancer monoclonal antibody Fab fragment conjugates. Chinese Medical Journal. 1998; No. 7; pp. 537-539.) Preparation:

[0021] HAb18 was digested with papain, dialyzed, purified on a fast protein liquid chromatography (FPLC) diethylaminoethyl (DEAE)-40HR chromatography column, and the first elution peak was collected, then concentrated, filtered, and sterilized to obtain HAb18 Fab Fragments were stored at -20°C for future use.

[0022] Dissolve 50mol of T-2 toxin in 200ml of dichloromethane, then add 1-hydroxybenzotriazole, cool in an ice bath, add 50mol of phenylalanine-glycine dipeptide under electromagnetic stirring, and adjust the pH value to 8.0 with sodium...

Embodiment 2

[0024] Example 2 Study on tissue distribution and antitumor pharmacodynamics of anti-human hepatocellular carcinoma monoclonal antibody HAb18 Fab-T-2 toxin conjugate

[0025] SD rats, male, weighing 180-220g, fed freely, fed under SPF conditions for 2 weeks, and started intraperitoneal injection of aflatoxin B1 in the third week, and injected three times a week from the 3rd to 16th week, each dose was 200 μg / kg; Week 22-30: Inject twice a week, 100 μg / kg each time; Week 35-45, inject once a week, 100 μg / kg each time.

[0026] In the 60th week, 30 rats with successful modeling were taken and randomly divided into 3 groups, 10 rats in each group. Group A was the blank group, which was injected with normal saline intraperitoneally; group B was the control group, which was given T-2 toxin 2 mg / kg; Group C is the drug administration group administered intraperitoneally with 2 mg / kg of the anti-human hepatocellular carcinoma monoclonal antibody HAb18 Fab-T-2 toxin conjugate obtain...

Embodiment 3

[0034] Example 3 Preparation of anti-human liver cancer monoclonal antibody 3A5 Fab′-T-2 toxin conjugate and its anti-tumor pharmacodynamics experiment

[0035] Anti-human liver cancer monoclonal antibody 3A5 Fab'-fragment according to the literature (Liu Xiaoyun, Shang Boyang, Liu Xiujun, Zhen Yongsu. Application of pingyangmycin and monoclonal antibody Fab' fragment conjugates to inhibit liver cancer growth and tumor liver metastasis. Chinese Medical Journal; 2001 2010; Issue 4; pp. 201-204.) Prep.

[0036] 50mol of T-2 toxin, dissolved in 200ml of dimethylformamide, adjust the pH value to 5.7-6.5 with phosphate buffer, slowly add 50mol of 1,4-butanediol diglycidyl ether dropwise to T-2 toxin under electromagnetic stirring The secondary methylformamide solution was stirred at 37°C for 4 hours after the dropwise addition, left to stand overnight, and centrifuged to obtain the T-2 toxin modified by the cross-linking agent.

[0037] Take 20 mol of the anti-human liver cancer m...

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PUM

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Abstract

The invention discloses a monoclonal antibody-antigen binding segment-T-2 toxin conjugate which is formed by connecting a monoclonal antibody-antigen binding segment with T-2 toxin by using one of a peptide chain, 1,4-butanediol diglycidyl ether, N-hydroxy succinimido-3-(2-pyrazolyl dithio)-propionate as a cross-linking agent. The invention further provides a preparation method of the monoclonal antibody-antigen binding segment-T-2 toxin conjugate and application of the monoclonal antibody-antigen binding segment-T-2 toxin conjugate in preparation of a targeted anti-tumor drug. According to the experiments, the conjugate disclosed by the invention has an obvious targeting performance for tumor tissues, and can be used for lowering the toxicity of the T-2 toxin and improving the inhibiting effect of the conjugate on the tumors.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a monoclonal antibody antigen-binding fragment-T-2 toxin conjugate, a preparation method thereof and an application in preparation of targeted antitumor drugs. Background technique [0002] T-2 toxin is a trichothecene substance produced by a variety of fungi. It has been found to have broad-spectrum anti-tumor activity. Nanogram-level T-2 toxin can significantly inhibit liver cancer SMMC-7721 cell line and lung cancer A549. Growth of tumor cells such as cell lines, colon adenocarcinoma LS174-T and LOVO strains. [0003] Domestic invention patents CN200910019618.1 (inventor Li Baoqiu, applicant Shandong University, public announcement date July 22, 2009, public announcement number CN101485653A), CN200910014633.7 (inventor Li Baoqiu, applicant Shandong University, authorization announcement date 2011 March 30, authorized announcement number CN101491518B), CN200910014627.1 (inv...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K47/48A61P35/00A61K31/352
Inventor 厉保秋厉凌子李娜高继友
Owner 济南环肽医药科技有限公司
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