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Cysteine ​​engineered antibody-toxin conjugates

A cysteine ​​and conjugate technology, applied in drug combination, anti-tumor drugs, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the problem of limited clinical dosage and poor drug uniformity , patient side effects, etc.

Active Publication Date: 2021-10-19
BAILI-BIO (CHENGDU) PHARM CO LTD
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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 ​​engineered antibody-toxin conjugates
  • Cysteine ​​engineered antibody-toxin conjugates
  • Cysteine ​​engineered antibody-toxin conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] The synthesis of embodiment 1 mc

[0013]

[0014] 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

[0015] Synthesis of Example 2 Mc-OSu

[0016]

[0017] 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

[0018] Synthesis of Example 3 Fmoc-Val-OSu

[0019]

[0020] 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

The 235-position serine (S) of the target antibody is transformed into cysteine ​​(C), and the 205-position valine (V) of the light chain is transformed into cysteine ​​(C), and the modified cysteine The free sulfhydryl group (‑SH) of amino acid is coupled with the mc‑vc‑PAB‑OH linker coupled with a small molecule highly active cytotoxin (Payload) to form a cysteine-engineered antibody‑ with excellent homogeneity. Toxin conjugates with a toxin to antibody ratio (DAR) of 3.2-4.0. This antibody-toxin conjugate has the general formula: 2C3-HC-S235C-LC-V205C-mc-vc-PAB-payload. At the same time, the present invention also discloses the preparation and purification method of the TDC medicine, and its application in the treatment of tumors expressing EGFRvIII and overexpressing EGFRwt.

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 t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/68A61P35/00C07K16/28
CPCA61K47/6817A61P35/00C07K16/2863
Inventor 朱义王一茜卓识李杰陈澜余永国万威李
Owner BAILI-BIO (CHENGDU) PHARM CO LTD
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