To overcome stability and heterogeneity issues of
antibody-drug conjugates (ADCs) produced with existing bioconjugation technologies incorporating a
maleimide motif, we developed McSAF Inside, a new technology based on a trifunctionalized di(bromomethyl)
pyridine scaffold. Our
solution allows the conjugation of a linker-payload to previously reduced interchain cysteines of a native antibody, resulting in
disulfide rebridging. This leads to highly stable and homogeneous ADCs with control over the
drug-to-antibody ratio (DAR) and the linker-payload position. Using our technology, we synthesized an ADC, MF-BTX-MMAE, built from anti-CD30 antibody cAC10 (brentuximab), and compared it to
Adcetris, the first line treatment against CD30-positive
lymphoma, in a CD30-positive
lymphoma model. MF-BTX-MMAE displayed improved DAR homogeneity, with a solid batch-to-batch reproducibility, as well as enhanced stability in thermal stress conditions or in the presence of a free
thiol-containing
protein, such as
human serum albumin (HSA). MF-BTX-MMAE showed
antigen-binding, in vitro cytotoxicity, in vivo efficacy, and tolerability similar to
Adcetris. Therefore, in accordance with current regulatory expectations for the development of new ADCs, McSAF Inside technology gives access to relevant ADCs with improved characteristics and stability.