Straightforward Glycoengineering Approach to Site-Specific Antibody–Pyrrolobenzodiazepine Conjugates
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 mamm...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2016-11, Vol.7 (11), p.1005-1008 |
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| creator | Thompson, Pamela Ezeadi, Ebele Hutchinson, Ian Fleming, Ryan Bezabeh, Binyam Lin, Jia Mao, Shenlan Chen, Cui Masterson, Luke Zhong, Haihong Toader, Dorin Howard, Philip Wu, Herren Gao, Changshou Dimasi, Nazzareno |
| description | 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. |
| doi_str_mv | 10.1021/acsmedchemlett.6b00278 |
| format | Article |
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Chem. Lett</addtitle><description>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. 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Chem. Lett</addtitle><date>2016-11-10</date><risdate>2016</risdate><volume>7</volume><issue>11</issue><spage>1005</spage><epage>1008</epage><pages>1005-1008</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><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. 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| subjects | Letter |
| title | Straightforward Glycoengineering Approach to Site-Specific Antibody–Pyrrolobenzodiazepine Conjugates |
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