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A Versatile Chemo-Enzymatic Conjugation Approach Yields Homogeneous and Highly Potent Antibody-Drug Conjugates.


ABSTRACT: The therapeutic efficacy of antibodies can be successfully improved through targeted delivery of potent cytotoxic drugs in the form of antibody-drug conjugates. However, conventional conjugation strategies lead to heterogeneous conjugates with undefined stoichiometry and sites, even with considerable batch-to-batch variability. In this study, we have developed a chemo-enzymatic strategy by equipping the C-terminus of anti-CD20 ofatumumab with a click handle using Sortase A, followed by ligation of the payload based on a strain-promoted azide-alkyne cycloaddition to produce homogeneous conjugates. The resulting antibody-drug conjugates fully retained their antigen binding capability and proved to be internalized and trafficked to the lysosome, which released the payload with a favorable efficacy in vitro and in vivo. Thus, this reported method is a versatile tool with maximum flexibility for development of antibody-drug conjugates and protein modification.

SUBMITTER: Xu Y 

PROVIDER: S-EPMC5713254 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A Versatile Chemo-Enzymatic Conjugation Approach Yields Homogeneous and Highly Potent Antibody-Drug Conjugates.

Xu Ying Y   Jin Shijie S   Zhao Wenbin W   Liu Wenhui W   Ding Ding D   Zhou Jie J   Chen Shuqing S  

International journal of molecular sciences 20171031 11


The therapeutic efficacy of antibodies can be successfully improved through targeted delivery of potent cytotoxic drugs in the form of antibody-drug conjugates. However, conventional conjugation strategies lead to heterogeneous conjugates with undefined stoichiometry and sites, even with considerable batch-to-batch variability. In this study, we have developed a chemo-enzymatic strategy by equipping the C-terminus of anti-CD20 ofatumumab with a click handle using Sortase A, followed by ligation  ...[more]

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