Antibody core fucosylation reducing method and composition

A technology of fucosylation and antibodies, applied in the field of a method and compounds used, can solve the problems of reducing core fucosylation, improving immunogenicity, and high price of raw material fucose, so as to reduce core rock Effects of glycosylation and low price

Pending Publication Date: 2019-10-25
SHANGHAI HAOZHE INFORMATION TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The patent reduces the core fucosylation level by adding fucose analogues in the host cell production process. This method can reduce the core fucosylation of antibodies, but the price of raw material fucosylation is very high, and using this method reduces Concomitant core fucosylation increases the proportion of high-mannose glycoforms of antibody N-linked glycans
IgG molecules containing high mannose residues have a shorter serum half-life than IgG molecules containing a double-antennary core structure, which may cause increased immunogenicity, which is not conducive to drug treatment

Method used

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  • Antibody core fucosylation reducing method and composition
  • Antibody core fucosylation reducing method and composition
  • Antibody core fucosylation reducing method and composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: Synthesis of 2-fluoro-mannose analogs, namely 2-deoxy-2-fluoro-1,3,4,6-tetra-oxo-acetyl-D-mannose

[0067]

Embodiment 11

[0069] Under nitrogen protection, D-mannose (50 g, 0.278 mol) was added into pyridine (500 mL), stirred and dissolved. Cool to 0°C, add acetic anhydride (500g, 4.09mol), heat up to 25°C and react for 16 hours. Concentrate under reduced pressure to remove pyridine and acetic anhydride, dissolve the residue with ethyl acetate (500mL), and successively wash with 1mol / L dilute hydrochloric acid (500mL*2), saturated sodium bicarbonate solution (500mL) and saturated sodium chloride solution (500mL) After washing, the organic phase was concentrated under reduced pressure to obtain 97.5 g of off-white solid, with a yield of 90%.

Embodiment 12

[0071] Under nitrogen protection, the compound prepared in Example 1.1 (97.5 g, 0.25 mol) was added into dichloromethane (1500 mL), stirred and dissolved, and cooled to 0°C. 40% hydrobromic acetic acid solution (400 mL) was slowly added, and the temperature was raised to 25°C to react for 3 hours. Washed successively with ice water (1500mL*2), saturated sodium bicarbonate solution (1500mL) and saturated sodium chloride solution (1500mL), the organic phase was concentrated under reduced pressure to obtain 82g of yellow oil with a yield of 80%.

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Abstract

The invention provides a micromolecular mannose analogue for manufacturing a recombinant antibody with complex N-linked glycan and reduced core fucosylation. The mannose analogue is normally taken inby hose cells (through active transport or passive diffusion) to inhibit GDP fucose generation. The method has advantages that due to adoption of mannose in a synthesis substrate, low cost is realized; by adoption of the method, influences on high-mannose type proportion of N-linked glycan is avoided while core fucosylation is reduced.

Description

technical field [0001] The present invention relates to a method for reducing the core fucosylation of an antibody and the technical field of the compound used. Background technique [0002] Recombinant therapeutic proteins are produced by many different methods. A preferred method is the production of recombinant proteins from mammalian host cell lines. Cell lines such as Chinese Hamster Ovary (CHO) cells are engineered to express therapeutic proteins of interest. Different cell lines have different advantages and disadvantages when recombining proteins, including protein characteristics and yield. Monoclonal antibodies or antibody derivatives are a type of recombinant protein. When selecting production cells, it is necessary to balance high yield and product consistency. [0003] The Fc fragment exerts effector function by binding to the receptor through the active region. The N-glycosylation of IgG is located in the consensus sequence of the CH2 region of the Fc fragm...

Claims

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Application Information

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IPC IPC(8): C12N5/071C07H13/04
CPCC12N5/0602C07H13/04C12N2500/34
Inventor 张莹肖志华
Owner SHANGHAI HAOZHE INFORMATION TECH LTD
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