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Issue 8, 2018
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Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones

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Abstract

Due to their exquisite cysteine-selectivity, excellent stability, and ability to functionally rebridge disulfide bonds, dibromopyridazinediones are emerging as an exciting new class of bioconjugation reagents, particularly in the field of antibody conjugation. Despite this, relatively little work has been performed on the optimisation of their synthesis and subsequent reaction with immunoglobulins. Herein we present a novel synthetic route towards functionalised dibromopyridazinediones, proceeding via an isolatable dibromopyridazinedione-NHS ester. Reaction of this activated intermediate with a variety of amines produces functional dibromopyridazinediones in good to excellent yields. The disulfide rebridging capacity of these reagents was optimised on the clinically relevant IgG1 trastuzumab, resulting in a general method which allows for the generation of site-selectively modified native trastuzumab with over 90% homogeneity (no disulfide scrambling) without the need for protein engineering or enzymatic conjugation.

Graphical abstract: Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones

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Supplementary files

Article information


Submitted
19 Dec 2017
Accepted
29 Jan 2018
First published
29 Jan 2018

This article is Open Access

Org. Biomol. Chem., 2018,16, 1359-1366
Article type
Paper

Highly homogeneous antibody modification through optimisation of the synthesis and conjugation of functionalised dibromopyridazinediones

C. Bahou, D. A. Richards, A. Maruani, E. A. Love, F. Javaid, S. Caddick, J. R. Baker and V. Chudasama, Org. Biomol. Chem., 2018, 16, 1359
DOI: 10.1039/C7OB03138F

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