Galactose Oxidase Enables Modular Assembly of Conjugates from Native Antibodies with High Drug-to-Antibody Ratios**

被引：4

作者：

Angelastro, Antonio ^{[1
,2
]}

Barkhanskiy, Alexey ^{[1
,2
]}

Mattey, Ashley P. ^{[1
,2
]}

Pallister, Edward G. ^{[1
,2
]}

Spiess, Reynard ^{[1
,2
]}

Goundry, William ^{[3
]}

Barran, Perdita ^{[1
,2
]}

Flitsch, Sabine L. ^{[1
,2
]}

机构：

[1] Univ Manchester, Sch Chem, 131 Princess St, Manchester M1 7DN, Lancs, England

[2] Univ Manchester, Manchester Inst Biotechnol, 131 Princess St, Manchester M1 7DN, Lancs, England

[3] AstraZeneca, Dept Pharmaceut Sci, Silk Rd Business Pk, Macclesfield SK10 2NA, Cheshire, England

来源：

CHEMSUSCHEM | 2022年 / 15卷 / 09期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

antibodies; antibody-drug conjugates; biocatalysis; glycoengineering; medicinal chemistry; SITE; PHARMACOKINETICS; EFFICACY;

D O I：

10.1002/cssc.202102592

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The potential of antibody conjugates with high drug loading in anticancer therapy has recently been highlighted by the approval of Trastuzumab deruxtecan and Sacituzumab govitecan. These biopharmaceutical approaches have spurred interest in bioconjugation strategies with high and defined degrees of drug-to-antibody ratio (DAR), in particular on native antibodies. Here, a glycoengineering methodology was developed to generate antibody drug conjugates with DAR of up to eight, by combining highly selective enzymatic galactosylation and oxidation with biorthogonal tandem Knoevenagel-Michael addition chemistry. This four-step approach offers a selective route to conjugates from native antibodies with high drug loading, and thus illustrates how biocatalysis can be used for the generation of biopharmaceuticals using mild reaction conditions.

引用

页数：4

共 43 条

[1] A strain-promoted [3+2] azide-alkyne cycloaddition for covalent modification of blomolecules in living systems [J].