Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody

Eifion Robinson; João P. M. Nunes; Vessela Vassileva; Antoine Maruani; João C. F. Nogueira; Mark E. B. Smith; R. Barbara Pedley; Stephen Caddick; James R. Baker; Vijay Chudasama

doi:10.1039/C7RA00788D

Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody†

Eifion Robinson,‡^a João P. M. Nunes,‡^a Vessela Vassileva,^b Antoine Maruani,

^a João C. F. Nogueira,^a Mark E. B. Smith,^a R. Barbara Pedley,^b Stephen Caddick,^a James R. Baker*^a and Vijay Chudasama

*^a

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* Corresponding authors

^a Department of Chemistry, University College London, London, WC1H 0AJ, UK
E-mail: j.r.baker@ucl.ac.uk, v.chudasama@ucl.ac.uk
Tel: +44 (0)20 7679 2653

^b UCL Cancer Institute, 72 Huntley Street, London, UK

Abstract

Herein we report the use of pyridazinediones to functionalise the native solvent accessible interstrand disulfide bonds in trastuzumab with monomethyl auristatin E (MMAE). This method of conjugation delivers serum stable antibody–drug conjugates (ADCs) with a controlled drug loading of 4. Moreover, we demonstrate that the MMAE-bearing ADCs are potent, selective and efficacious against cancer cell lines in both in vitro and in vivo models.

RSC Advances

Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody†

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Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody

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