Antibody-drug conjugates (ADCs) are an emerging class of targeted therapeutic, typically for use in the treatment of cancers. These therapeutics consist of an antibody and a cytotoxic payload which are chemically linked, often by a moiety which enables selective release of the drug once the antibody has guided it to the target. In all marketed ADCs, drugs are attached to the antibody via stochastic labelling of lysine or site-selective labelling of cysteine. Re-bridging the native interchain disulfides in an IgG1 antibody is also site-selective and is proposed to confer greater stability to the ADC. However, typically, each disulfide is re-bridged independently, with a linker that can be pre- or post- functionalised, resulting in a mixture of ADC species; full- and half-antibody species are prevalent, with a variety of drug-to-antibody ratios (DARs). Here we present a method for the generation of ADCs with integer DAR. Re-bridging occurs efficiently with low equivalents of linker. Click chemistry enables conversion of the fully re-bridged antibody-linker species to stable bioconjugates containing 1, 2, 3 or 4 payloads, as desired. Analysis of these bioconjugates in HER2-positive cell lines indicates improved efficacy compared to native antibody. This new linker methodology will enable precise, integer drug/fluorophore loading. The possibility of loading odd-integer numbers of drugs, including making an ADC with a DAR of 1, represents an exciting step forward and enables the study of these species as therapeutics.

Novel disulfide re-bridging strategy for the synthesis of antibody-drug conjugates (ADCs)

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ACS Fall 2022

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