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Next generation maleimides enable the controlled assembly of antibody-drug conjugates via native disulfide bond bridging

Schumacher, FF; Nunes, JP; Maruani, A; Chudasama, V; Smith, ME; Chester, KA; Baker, JR; (2014) Next generation maleimides enable the controlled assembly of antibody-drug conjugates via native disulfide bond bridging. Organic & Biomolecular Chemistry , 12 (37) pp. 7261-7269. 10.1039/c4ob01550a. Green open access

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Abstract

The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody-drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody.

Type: Article
Title: Next generation maleimides enable the controlled assembly of antibody-drug conjugates via native disulfide bond bridging
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1039/c4ob01550a
Publisher version: http://dx.doi.org/10.1039/c4ob01550a
Additional information: This journal is © The Royal Society of Chemistry 2014. This Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported Licence
Keywords: Antibodies, Antibodies, Monoclonal, Humanized, Disulfides, Doxorubicin, Maleimides, Molecular Structure, Trastuzumab
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1437589
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