A kind of antibody conjugate containing boron ester unit polymer and its construction method

A conjugate and conjugation technology, applied in the field of biomedicine, can solve the problems of reducing the therapeutic effect, failing to achieve the effect of targeted therapy, and the reduction of antibody-antigen binding rate, etc., to achieve clear and concise preparation process and excellent tumor targeting effect , Excellent biocompatibility effect

Active Publication Date: 2021-06-04
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The part on the antibody that recognizes the antigen is the antigen-binding fragment (Fab, fragment of antigen binding). When the antibody is oriented correctly, it can bind to the antigen. Otherwise, the antibody-antigen binding rate will be significantly reduced, and effective targeted therapy cannot be achieved. An important reason why targeted therapies have not become routine in clinical practice
Combining chemotherapy drugs with antibodies to form antibody-drug conjugates (Antibody-Drug Conjugates, ADCs) can solve the problem of antibody orientation to a certain extent, but these conjugation techniques still have the following problems: (1) The preparation process is cumbersome, and the antibody There is a possibility of denaturation during the preparation process, resulting in loss of targeting function; (2) In the obtained antibody-drug conjugates, the drug / antibody ratio is not uniform, and the conjugates with unconjugated or less drugs are less effective. Low, it will compete with effectively coupled products to bind to cancer cell surface antigens, reducing the therapeutic effect; (3) It is impossible to flexibly adjust the types of antibodies or drugs according to different types of cancer cells, and the universality is poor

Method used

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  • A kind of antibody conjugate containing boron ester unit polymer and its construction method
  • A kind of antibody conjugate containing boron ester unit polymer and its construction method
  • A kind of antibody conjugate containing boron ester unit polymer and its construction method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Preparation of polymethacrylic acid (PMAA) nanogel microspheres-transferrin (Tf) conjugate

[0024] Step 1: Preparation of PMAA Microspheres

[0025] Monomer methacrylic acid (MAA), crosslinking agent N,N-methylenebisacrylamide (MBA) and initiator azobisisobutyronitrile (AIBN) are added to acetonitrile in a certain proportion and mixed evenly, heated to 95°C, Reflux the solvent for 2 hours, centrifuge to remove the solvent and unreacted monomers, wash with ethanol and deionized water three times, and freeze-dry for 24 hours;

[0026] Step 2: Modification of 2-(hydroxymethyl)phenylboronic acid cyclic monoester unit on the surface of PMAA microspheres

[0027] A certain amount of PMAA nanogel microspheres is dispersed in phosphate buffer solution (pH=7.4, the same below), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ) and N-hydroxysuccinimide (NHS), reacted at room temperature for 1 hour to activate the carboxyl groups of the microsphe...

Embodiment 2

[0030] Example 2: Preparation of PMAA nanogel microspheres-vascular endothelial growth factor receptor antibody (Anti-VEGF Receptorantibody) conjugate

[0031] Disperse PMAA-BB microspheres (preparation method is the same as in Example 1) in phosphate buffer solution, add a certain amount of vascular endothelial growth factor receptor antibody phosphate buffer solution, mix well and let stand for 10 min until it fully reacts for subsequent applications.

Embodiment 3

[0032] Example 3: Preparation of polyaspartic acid drug-loaded micelles-Tf conjugates

[0033] Step 1: Preparation and Alkynylation of Polyaspartic Acid

[0034] L-aspartic acid powder, 85% phosphoric acid (H 3 PO 4 ), sulfolane and mesitylene were mixed evenly, after microwave reaction, washed with water and ethanol for several times, and the polysuccinimide obtained after vacuum drying and 2-[2-(2-propynyloxy)ethoxy ]Ethylamine was dissolved in dimethylformamide (DMF), reacted at room temperature for 12 hours, after several times of DMF dissolution-ether precipitation and centrifugation, and vacuum-dried to obtain alkyne-modified polyaspartic acid;

[0035] Step 2: Polyaspartic acid grafted with polyethylene glycol, cyclic monoester of 2-(hydroxymethyl)phenylboronic acid and drug molecule

[0036] Dissolve the alkyne-modified polyaspartic acid in DMF, add azide polyethylene glycol monomethyl ether (mPEG-N) dissolved in DMF 3 ) and azide 2-(hydroxymethyl)phenylboronic aci...

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Abstract

The invention belongs to the technical field of medicine, and specifically relates to an antibody conjugate containing a boron ester unit polymer and a construction method thereof. In the present invention, the cyclic monoester unit of 2-(hydroxymethyl)phenylboronic acid on the polymer carrier reacts with the adjacent diol group of the sugar chain on the crystallizable segment at the Y-shaped lower end of the antibody to form a five The boroester ring is used to couple the polymer and its derivatives with 2-(hydroxymethyl)phenylboronic acid cyclic monoester unit to the antibody. The antibody conjugate obtained by the present invention can retain the integrity of the antibody and the recognition function of the Y-shaped upper arm antigen-binding fragment of the antibody to the greatest extent; Combining polymers and their derivatives with different drugs or drug carriers, and then coupling with different antibodies, can achieve the purpose of targeted treatment of different types of cancer. In view of the excellent biocompatibility and tumor targeting effect, as well as the universality for different types of cancer, this antibody conjugate has broad development prospects in clinical application.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a class of antibody conjugates and a preparation method thereof. Background technique [0002] Traditional chemotherapy has poor selectivity, and severe side effects can lead to death of patients. Therefore, targeted therapy is one of the ways to achieve this goal while reducing the systemic toxicity of chemotherapy drugs and enhancing the effect on tumors. Compared with normal tissue cells, different antigens are overexpressed on the surface of cancer cells, and the use of antibodies corresponding to certain antigens to specifically direct therapeutic agents to cancer cells is a research direction in the field of targeted therapy. The part on the antibody that recognizes the antigen is the antigen-binding fragment (Fab, fragment of antigen binding). When the antibody is oriented correctly, it can bind to the antigen. Otherwise, the antibody-antigen binding rate wi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/68A61K47/69
CPCA61K47/68A61K47/6801A61K47/6849A61K47/6907
Inventor 汪长春万家勋李永婧
Owner FUDAN UNIV
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