Synthesis of precision antibody conjugates using proximity-induced chemistry

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dc.citation.firstpage9107en_US
dc.citation.issueNumber18en_US
dc.citation.journalTitleTheranosticsen_US
dc.citation.lastpage9117en_US
dc.citation.volumeNumber11en_US
dc.contributor.authorCao, Yu J.en_US
dc.contributor.authorYu, Chenfeien_US
dc.contributor.authorWu, Kuan-Linen_US
dc.contributor.authorWang, Xuechunen_US
dc.contributor.authorLiu, Dongen_US
dc.contributor.authorTian, Zeruen_US
dc.contributor.authorZhao, Lijunen_US
dc.contributor.authorQi, Xuexiuen_US
dc.contributor.authorLoredo, Axelen_US
dc.contributor.authorChung, Annaen_US
dc.contributor.authorXiao, Hanen_US
dc.date.accessioned2021-09-23T17:11:38Zen_US
dc.date.available2021-09-23T17:11:38Zen_US
dc.date.issued2021en_US
dc.description.abstractRationale: Therapeutic antibody conjugates allow for the specific delivery of cytotoxic agents or immune cells to tumors, thus enhancing the antitumor activity of these agents and minimizing adverse systemic effects. Most current antibody conjugates are prepared by nonspecific modification of antibody cysteine or lysine residues, inevitably resulting in the generation of heterogeneous conjugates with limited therapeutic efficacies. Traditional strategies to prepare homogeneous antibody conjugates require antibody engineering or chemical/enzymatic treatments, processes that often affect antibody folding and stability, as well as yield and cost. Developing a simple and cost-effective way to precisely couple functional payloads to native antibodies is of great importance. Methods: We describe a simple proximity-induced antibody conjugation method (pClick) that enables the synthesis of homogeneous antibody conjugates from native antibodies without requiring additional antibody engineering or post-synthesis treatments. A proximity-activated crosslinker is introduced into a chemically synthesized affinity peptide modified with a bioorthogonal handle. Upon binding to a specific antibody site, the affinity peptide covalently attaches to the antibody via spontaneous crosslinking, yielding an antibody molecule ready for bioorthogonal conjugation with payloads. Results: We have prepared well-defined antibody-drug conjugates and bispecific small molecule-antibody conjugates using pClick technology. The resulting conjugates exhibit excellent in vitro cytotoxic activity against cancer cells and, in the case of bispecific conjugates, superb antitumor activity in mouse xenograft models. Conclusions: Our pClick technology enables efficient, simple, and site-specific conjugation of various moieties to the existing native antibodies. This technology does not require antibody engineering or additional UV/chemical/enzymatic treatments, therefore providing a general, convenient strategy for developing novel antibody conjugates.en_US
dc.identifier.citationCao, Yu J., Yu, Chenfei, Wu, Kuan-Lin, et al.. "Synthesis of precision antibody conjugates using proximity-induced chemistry." <i>Theranostics,</i> 11, no. 18 (2021) Ivyspring: 9107-9117. https://doi.org/10.7150/thno.62444.en_US
dc.identifier.digitalv11p9107en_US
dc.identifier.doihttps://doi.org/10.7150/thno.62444en_US
dc.identifier.urihttps://hdl.handle.net/1911/111408en_US
dc.language.isoengen_US
dc.publisherIvyspringen_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleSynthesis of precision antibody conjugates using proximity-induced chemistryen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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