Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment

Bryden, Francesca; Maruani, Antoine; Savoie, Huguette; Chudasama, Vijay; Smith, Mark E. B.; Caddick, Stephen; Boyle, Ross W.

Abstract

The rapidly increasing interest in the synthesis of antibody–drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin–antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case.

Citation

Bryden, F., Maruani, A., Savoie, H., Chudasama, V., Smith, M. E. B., Caddick, S., & Boyle, R. W. (2014). Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment. Bioconjugate chemistry, 25(3), 611-617. https://doi.org/10.1021/bc5000324

• Acceptance Date: Feb 19, 2014
• Online Publication Date: Mar 7, 2014
• Publication Date: 2014-02
• Deposit Date: Aug 28, 2015
• Publicly Available Date: Nov 23, 2017
• Journal: Bioconjugate chemistry
• Print ISSN: 1043-1802
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 3
• Pages: 611-617
• DOI: https://doi.org/10.1021/bc5000324
• Keywords: Photodynamic sensitisers; Photodynamic therapy; HER2
• Public URL: https://hull-repository.worktribe.com/output/378259
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/bc5000324
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Bioconjugate chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/bc5000324
• Contract Date: Nov 23, 2017