Antibody drug conjugate and application thereof

A technology of antibody drugs and conjugates, applied in the field of biomedicine, can solve problems such as failure, low quantity of small molecule drugs, and low drug efficacy

Pending Publication Date: 2020-04-10
MABPLEX INT LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, if a small molecule drug with low toxicity is selected, the drug effect is too low due to the low amount of small molecule drug loaded, which leads to clinical failure.

Method used

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  • Antibody drug conjugate and application thereof
  • Antibody drug conjugate and application thereof
  • Antibody drug conjugate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment

[0172] Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not indicate specific conditions are usually carried out according to conventional conditions or according to the conditions suggested by the manufacturer, and the reagents that do not indicate specific sources are conventional reagents purchased in the market. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

[0173] The unit of weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of solute in 100 ml of solution.

[0174] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in...

Embodiment 1

[0175] The preparation of embodiment 1 compound 1

[0176]

[0177] Dissolve 145.4mg maleimide caproic acid in 10mL DMF, add 244.7mg HATU and 226uLDIPEA, and stir at room temperature. 201.9mgMMAF was dissolved in 5mL DMF, slowly added dropwise to the above reaction system, and stirred at room temperature for 16h. The solvent was distilled off under reduced pressure and purified by preparative liquid phase to obtain 90.3 mg of the product (maleimidecaproyl-MMAF, Mc-MMAF) with a yield of 36%. LC-MS: (M+H) + 924.8, (M-H) - 923.2.

[0178] Dissolve 36.1mg of maleimidocaproyl-MMAF in 1.5mL DMF, add 5.6mg of Cys-Cys and 2.1uLDIPEA, stir at room temperature for 3h, then add 1.1mg of Cys-Cys, and stir at room temperature for 2h. Add 17.7 mg of 6-(maleimido) hexanoic acid succinimidyl ester and 25 uL DIPEA, and stir at room temperature for 15 h. The solvent was distilled off under reduced pressure and purified by preparative liquid phase method to obtain 120.0 mg of compound wi...

Embodiment 2

[0179] The preparation of embodiment 2 compound 2

[0180]

[0181] According to the preparation method of Example 1, maleimide caproyl-MMAF was prepared. Dissolve 40.1mg maleimide caproyl-MMAF in 1.5mL DMF, add 4.4mg Cys-Cys-Cys and 2.1uLDIPEA, stir at room temperature for 2h, then add 1.8mgCys-Cys-Cys, react at room temperature for 2h, then add 0.9mg Cys-Cys-Cys, react at room temperature for 2h. Add 13.5 mg 6-(maleimido) hexanoic acid succinimide ester and 21 uLDIPEA, and stir at room temperature for 15 h. The solvent was distilled off under reduced pressure and purified by preparative liquid phase method to obtain 223.1 mg of compound with a yield of 49%. LC-MS: (M+3H) 3+ 1648.4, (M-3H) 3- 1646.3.

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Abstract

According to the invention, one or more cysteine residues or cysteine derivative residues are used as a drug connection carrier; one or more drugs are coupled to limited connecting sites of the antibody at the same time, so that drugs with higher drug loading capacity are prepared or drugs with lower toxicity can be selected to prepare ADC products, and ADC products with larger treatment windows are obtained. Furthermore, since a plurality of drug molecules can be coupled at one connection site, the ADC product obtained by the method provided by the invention has better uniformity under the condition of preparing antibody drug conjugates with the same DAR value. The use amount of the antibody required in production can be greatly reduced, so that the production cost is effectively reduced.Compared with the antibody drug conjugate of which the same site can only be connected with one drug molecule, the antibody drug conjugate prepared by adopting the method disclosed by the invention still has the same inhibiting or killing effect on tumor cells under the condition that the total amount of the coupled drug molecules is greatly reduced.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to an antibody-drug conjugate based on one or more cysteine ​​residues or cysteine ​​derivative residues as a drug-linked carrier and its application. The carrier can be coupled with one or more drugs at the limited linking sites of the antibody as needed. Background technique [0002] Antibody-drug conjugate (ADC) refers to a type of biological drug that connects a biologically active drug (Drug) and antibody (Antibody) through a chemical linker (Linker). ADC is like a precision-guided weapon system, in which biologically active drugs are used as lethal ammunition to precisely strike diseased cells under the guidance of antibodies. Therefore, ADCs combine the dual advantages of high potency of cytotoxic drug molecules and high targeting of antibodies. As of July 2019, only 6 antibody-drug conjugates have been approved globally (Table 1). [0003] Table 1 Marketed Antibody Drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61K45/00A61P35/00
CPCA61P35/00A61K47/65A61K47/6803A61K47/6849C07K16/32A61K47/6855A61K47/6889A61K47/6801
Inventor 李乐乐黄长江孙友祥刘丽娜
Owner MABPLEX INT LTD
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