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Issue 1, 2017
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Decoupling stability and release in disulfide bonds with antibody-small molecule conjugates

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Abstract

Disulfide bonds provide a bioactivatable connection with applications in imaging and therapy. The circulation stability and intracellular release of disulfides are problematically coupled in that increasing stability causes a corresponding decrease in cleavage and payload release. However, an antibody offers the potential for a reversible stabilization. We examined this by attaching a small molecule directly to engineered cysteines in an antibody. At certain sites this unhindered disulfide was stable in circulation yet cellular internalization and antibody catabolism generated a disulfide catabolite that was rapidly reduced. We demonstrated that this stable connection and facile release is applicable to a variety of payloads. The ability to reversibly stabilize a labile functional group with an antibody may offer a way to improve targeted probes and therapeutics.

Graphical abstract: Decoupling stability and release in disulfide bonds with antibody-small molecule conjugates

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Publication details

The article was received on 26 Apr 2016, accepted on 10 Aug 2016 and first published on 22 Aug 2016


Article type: Edge Article
DOI: 10.1039/C6SC01831A
Citation: Chem. Sci., 2017,8, 366-370
  • Open access: Creative Commons BY license
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    Decoupling stability and release in disulfide bonds with antibody-small molecule conjugates

    T. H. Pillow, J. D. Sadowsky, D. Zhang, S. Yu, G. Del Rosario, K. Xu, J. He, S. Bhakta, R. Ohri, K. R. Kozak, E. Ha, J. R. Junutula and J. A. Flygare, Chem. Sci., 2017, 8, 366
    DOI: 10.1039/C6SC01831A

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