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Straightforward Glycoengineering Approach to Site-Specific Antibody-Pyrrolobenzodiazepine Conjugates.


ABSTRACT: Antibody-drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody's native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobenzodiazepine dimer payload (SG3364) using copper-catalyzed click chemistry yielded a site-specific ADC with a drug-to-antibody ratio (DAR) of four. This ADC was compared with a glycoengineered DAR two site-specific ADC, and both were found to be highly potent against EphA2-positive human prostate cancer cells in both an in vitro cytotoxicity assay and a murine tumor xenograft model.

SUBMITTER: Thompson P 

PROVIDER: S-EPMC5108038 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Straightforward Glycoengineering Approach to Site-Specific Antibody-Pyrrolobenzodiazepine Conjugates.

Thompson Pamela P   Ezeadi Ebele E   Hutchinson Ian I   Fleming Ryan R   Bezabeh Binyam B   Lin Jia J   Mao Shenlan S   Chen Cui C   Masterson Luke L   Zhong Haihong H   Toader Dorin D   Howard Philip P   Wu Herren H   Gao Changshou C   Dimasi Nazzareno N  

ACS medicinal chemistry letters 20160920 11


Antibody-drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody's native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobe  ...[more]

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