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Bioconjug Chem. 2018 Nov 21;29(11):3503-3508. doi: 10.1021/acs.bioconjchem.8b00630. Epub 2018 Oct 22.

Site-Specific Antibody Drug Conjugates Using Streamlined Expressed Protein Ligation.

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ProteoDesign , C/Baldiri Reixach 10 , Barcelona 08028 , Spain.
LEITAT Technological Center , Biomed Division , C/Baldiri Reixach 15-21 , Barcelona 08028 , Spain.


Antibody-Drug Conjugates (ADCs) have been shown to produce clinical benefit in cancer patient thanks to their ability to target highly cytotoxic small molecules to tumor cells. However, the development of these complex molecules faces significant challenges due to the need to combine a large biologic drug with a small molecule drug to generate the desired bioconjugate. We describe here the use of a protein ligation methodology, based on the native chemical ligation reaction to generate site-specific Antibody-Drug Conjugates, which does not require the incorporation of unnatural modifications into the antibody. Fully native antibodies, with only the desired cytotoxic molecules attached, can be generated, thus minimizing the risk that additional modifications required for the site-specific conjugation pose a risk to the antibody activity. We demonstrate that our approach can be used to generate site-specifically modified ADCs, with potent in vitro and in vivo antitumor activity in a breast cancer tumor model.

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