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Cysteine-modified antibody drug conjugate

A technology of cysteine ​​and conjugates, applied in the field of compounds and their preparation, can solve the problems of poor drug uniformity, toxic and side effects of patients, and limitation of clinical dosage, and achieve the effect of less side effects and good drug uniformity

Active Publication Date: 2017-03-01
СЫЧУАНЬ БАЙЛИ ФАРМ КО ЛТД
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The ADC drug ABT-414, which targets EGFRvIII through interchain disulfide bond sulfhydryl non-specific coupling, has undergone clinical phase II trials in the United States, showing certain clinical effects. However, due to its non-specific coupling method, its Poor drug uniformity, causing serious side effects to patients, limiting its clinical dosage, directly affecting its clinical therapeutic effect

Method used

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  • Cysteine-modified antibody drug conjugate
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Examples

Experimental program
Comparison scheme
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Embodiment 1

[0029] The synthesis of embodiment 1 mc

[0030]

[0031] 3.9 g (0.03 mol) of 6-aminocaproic acid and 3.5 g (0.036 mol) of maleic anhydride 1.2 eq were added to 30 ml of glacial acetic acid. The reaction solution was stirred at 120°C for 4-6 hours. After the reaction was completed, the heating was stopped, and it was naturally cooled to room temperature. Concentrate under reduced pressure at 60°C to remove most of the acetic acid. The resulting brown-yellow viscous liquid was poured into water, and 20ml×3 ethyl acetate was added for extraction, and the organic layers were combined. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brownish-yellow oil, which was stirred with 50ml of water, and an off-white solid was precipitated, filtered, and the target product 5.08 was dried under reduced pressure at 50°C g, yield 80%. mp: 89-92°C....

Embodiment 2

[0032] Synthesis of Example 2 Mc-OSu

[0033]

[0034]Add 4.7g (22mmol) MC and 25g (22mmol) HOSu to 50ml acetonitrile under nitrogen protection. Another 4.5 g (22 mmol) of DCC was dissolved in 25 ml of acetonitrile, and the internal temperature was kept at about 0° C., and slowly dropped into the reaction solution. The reaction solution was reacted at 0°C for 2 hours, and then reacted overnight at room temperature. After filtering, the filter cake was washed with acetonitrile 10ml×3, and the filtrate was concentrated to dryness under reduced pressure. The obtained oil was dried under reduced pressure at room temperature for 6 h to obtain 6.4 g of a light brown solid with a yield of 95%. (Directly put into the next reaction without purification) m / z: 309.2[M+H]+. 1HNMR (400Mz, CDCl3): 1~2(m, 6H, CCH2CH2CH2C), 2.68(t, 2H, CH2CO), 2.95(s, 4H, COCH2CH2CO), 3.68(t, 2H, CH2N), 6.81(s, 2H ,CH=CH).

Embodiment 3

[0035] Synthesis of Example 3 Fmoc-Val-OSu

[0036]

[0037] 10 g of Fmoc-Val and 3.4 g of HOSu were added to 100 ml of THF. Another 6 g of DCC was dissolved in 50 ml of acetonitrile, and the internal temperature was kept at about 0°C, and slowly dropped into the reaction solution. The reaction solution was stirred at room temperature for 24 hours. After filtration, the filter cake was washed with THF, and the filtrate was concentrated under reduced pressure to obtain a transparent oil. The oil was directly used for the next reaction without purification. m / z: 437.4[M+H]+

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Abstract

According to the invention, light-chain 205-locus valine (V) of a target antibody is modified into cysteine (C); free sulfhydryl group (-SH) of the modified cysteine is subjected to fixed-point conjugation with mc-vc-PAB-OH connexon conjugated with small-molecular high-activity cytotoxin (Payload), such that the cysteine-modified antibody drug conjugate with excellent homogeneity is formed. The drug-antibody ratio (DAR) of the conjugate is 1.6-2.0. The antibody drug conjugate has a general formula 2C1-LC-V205C-mc-vc-PAB-payload. Also, the invention discloses a preparation method and a purification method of the TDC drug, and the application of the drug in treatments of EGFRvIII-expressing and EGFRwt-overexpressing tumors.

Description

technical field [0001] The present invention relates to a compound and its preparation method and use, in particular to a class of cysteine ​​modified antibody-toxin conjugate (TDC) and its preparation method and use. Background technique: [0002] Epidermal Growth Factor Receptor EGFR (Epidermal Growth Factor Receptor) is a glycoprotein that belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). EGFR is the epithelial growth factor (EGF) receptor for cell proliferation and signal transduction, which penetrates the cell membrane, has a molecular weight of 170KDa, and is activated by binding to ligands. Upon activation, EGFR is converted from a monomer to a dimer. EGFR may also be activated by aggregation with other members of the ErbB receptor family, such as ErbB2 / Her2 / neu. [0003] EGFR is usually expressed in a low amount in a variety of normal tissue cells, including skin, liver, etc., and is related ...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K47/68A61P35/00
Inventor 朱义王一茜卓识李杰陈澜余永国
Owner СЫЧУАНЬ БАЙЛИ ФАРМ КО ЛТД
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