Stable and homogeneous drug conjugation by sequential bis-alkylation at disulphide bonds using bis-sulphone reagents

Antibody drug conjugates (ADCs) have begun to have a tremendous impact on the treatment of cancer and other pathological conditions. A current limitation in ADC development is that much effort and time is needed to fully optimise the combination of antibody, linker and drug. New linker strategies are required to ensure that more homogeneous and stable ADCs can be produced with more predictable in vivo behaviour without the need for extensive re-optimisation, especially if one component of the ADC is changed. In order to improve both the homogeneity and the stability of ADCs, we have developed linkers that allow sitespecific drug conjugation based on bis-sulphones that covalently re-bridge reduced disulphide bonds. The bis-sulphone reagents comprise a drug, a linker and a bis-reactive conjugating moiety that is capable of undergoing reaction with both sulphur atoms derived from a reduced disulphide bond in antibodies and antibody fragments. We have demonstrated that the bis-sulphone-derived conjugates retain antigen-binding, are stable in serum and exhibit potent and antigen-selective cell killing in both in vitro and in vivo cancer models. Disulphide re-bridging conjugation is a general approach to prepare stable ADCs, which does not require the antibody to be recombinantly re-engineered for site-specific conjugation. The bis-sulphone linker-platform is being developed by Abzena plc under the trade name ThioBridge™.