Assembly of high-potency photosensitizer-antibody conjugates through application of dendron multiplier technology

Rodrigues, João M.M.; Cheng, Miffy H.Y.; Bryden, Francesca; Maruani, Antoine; Rodrigues, João M. M.; Cheng, Miffy H. Y.; Savoie, Huguette; Beeby, Andrew; Chudasama, Vijay; Boyle, Ross W.

Abstract

© 2017 American Chemical Society. Exploitation of photosensitizers as payloads for antibody-based anticancer therapeutics offers a novel alternative to the small pool of commonly utilized cytotoxins. However, existing bioconjugation methodologies are incompatible with the requirement of increased antibody loading without compromising antibody function, stability, or homogeneity. Herein, we describe the first application of dendritic multiplier groups to allow the loading of more than 4 porphyrins to a full IgG antibody in a site-specific and highly homogeneous manner. Photophysical evaluation of UV-visible absorbance and singlet oxygen quantum yields highlighted porphyrin-dendron 14 as the best candidate for bioconjugation; with subsequent bioconjugation producing a HER2-targeted therapeutic with average loading ratios of 15.4:1. In vitro evaluation of conjugate 18 demonstrated a nanomolar photocytotoxic effect in a target cell line, which overexpresses HER2, with no observed photocytotoxicity at the same concentration in a control cell line which expresses native HER2 levels, or in the absence of irradiation with visible light.

Citation

Rodrigues, J. M., Cheng, M. H., Bryden, F., Maruani, A., Rodrigues, J. M. M., Cheng, M. H. Y., Savoie, H., Beeby, A., Chudasama, V., & Boyle, R. W. (2018). Assembly of high-potency photosensitizer-antibody conjugates through application of dendron multiplier technology. Bioconjugate chemistry, 29(1), 176-181. https://doi.org/10.1021/acs.bioconjchem.7b00678

• Journal Article Type: Article
• Acceptance Date: Dec 7, 2017
• Online Publication Date: Dec 7, 2017
• Publication Date: Jan 17, 2018
• Deposit Date: Jan 18, 2018
• Publicly Available Date: Dec 8, 2018
• Journal: Bioconjugate chemistry
• Print ISSN: 1043-1802
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 1
• Pages: 176-181
• DOI: https://doi.org/10.1021/acs.bioconjchem.7b00678
• Keywords: Biotechnology; Organic Chemistry; Bioengineering; Pharmacology; Pharmaceutical Science; Biomedical Engineering
• Public URL: https://hull-repository.worktribe.com/output/517283
• Publisher URL: http://pubs.acs.org/doi/10.1021/acs.bioconjchem.7b00678
• 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 https://doi.org/10.1021/acs.bioconjchem.7b00678
• Contract Date: Jan 18, 2018