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Antibody Drug Conjugates with Two Different Drugs

A technology of drug conjugates and antibodies, which is used in drug combinations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc. It is difficult to determine the coupling position, and the selectivity of amino coupling is poor.

Active Publication Date: 2022-07-22
BAILI-BIO (CHENGDU) PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the limitation of its coupling method, the DAR obtained by C-LOCK technology is often 2-4, and K-LOCK technology also has obvious limitations: when the lysine-linked drug-antibody coupling ratio (DAR) > 2 , since a single antibody molecule contains about 88 lysines, such a large number of lysines leads to poor selectivity of amino coupling, and it is difficult to determine the number and position of coupling, although it can be controlled to a certain extent by coupling conditions, But it poses great challenges when preparing complex antibody conjugates with two different drugs
And the patent CN106132431 did not give the report of the drug efficacy data and plasma stability in animals

Method used

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  • Antibody Drug Conjugates with Two Different Drugs
  • Antibody Drug Conjugates with Two Different Drugs
  • Antibody Drug Conjugates with Two Different Drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-6

[0076]

Embodiment 1

[0077] Example 1 Synthesis of Compound 1

[0078]

[0079] Fmoc-Lys(mmt)-OH (2g, 3.2mmol, 1eq), PABA (788.16mg, 6.4mmol, 2eq), HATU (1.34g, 3.52mmol, 1.1eq), DIEA (1.24g, 9.6 mmol, 3eq) and 20ml DMF, stir and dissolve, nitrogen protection, reaction at 25°C; dot plate detection, lysine reaction is complete. 200ml of water was added to the reaction solution, a large amount of solid was precipitated, extracted with EA (60ml×3), the organic phase was washed three times with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.85g of yellow oil. The intermediate of the previous step was dissolved with 20 ml of diethylamine, and the reaction was carried out at 25°C under nitrogen protection; The solvent was spin-dried, 100 ml of EA was added to dissolve, washed with brine three times, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.58 g of a light brown oily product. Purification by column chromatography: gradient elution was carried out with D...

Embodiment 2

[0081] Example 2 Synthesis of Compound 2

[0082]

[0083] Compound 1 (300 mg, 0.574 mmol, 1 eq) N was added to a single-necked flask 3 PEG 8 COOH (350mg, 0.631mmol, 1.1eq), HOBT (85mg, 0.631mmol, 1.1eq) DIEA (149mg, 1.15mmol, 2.0eq) and 4ml of dry DMF, nitrogen protection, ice water bath cooling and stirring to dissolve the solution; add HATU (240mg , 0.631mmol, 1.1eq), 25 ℃ reaction; spot plate detection, 005 reaction is complete, post-processing. 50 ml of water was added to the reaction solution, extracted with EA (50 ml×3), the organic phase was washed three times with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 920 mg of light yellow oil. Preparation and purification of thin layer plate: develop once with DCM:MeOH=15:1 as developing solvent, and purify to obtain 500 mg of light yellow oily product.

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Abstract

The invention discloses an antibody-drug conjugate with two different drugs. The invention connects one drug to the cysteine ​​residue of the antibody in a point-specific coupling manner, and combines a second drug with different action mechanisms. Cytotoxic drugs are linked to cysteine ​​residues of the antibody in a non-site-directed manner.

Description

technical field [0001] The present invention relates to an antibody-drug conjugate with two different drugs. Background technique [0002] Antibody-drug conjugates (ADCs), as a new type of targeted drugs, generally consist of three parts: antibodies or antibody-like ligands, small-molecule drugs, and linkers that couple ligands and drugs. Antibody-drug conjugates utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve therapeutic purposes. In August 2011, the U.S. Food and Drug Administration (FDA) approved Adecteis, a new ADC drug developed by Seattle Genetics for the treatment of Hodgkin lymphoma and relapsed anaplastic large cell lymphoma (ALCL). TM The listing and clinical application have proved the safety and efficacy of such drugs. [0003] The main role of ADC drug antibody is the targeted delivery function, and the final drug effect is the coupled drug ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/68A61K45/00A61P35/00
CPCA61K45/00A61K47/6851A61P35/00
Inventor 朱义李杰卓识万维李余永国李刚锐
Owner BAILI-BIO (CHENGDU) PHARM CO LTD