The first generation of ADC, including Adcetris® and Kadcyla®, employed site-nonspecific conjugation methods and the payloads are conjugated to cysteines of interchain disulfide bonds (Adcetris) or lysines (Kadcyla). But higher stability and efficacy of ADC require site-specific conjugation and many companies are endeavoring to develop a next generation ADC technology by employing site-specific conjugation method.
In NexMab™ ADC technology, metal ion binding motif is used for site-specific conjugation. C-terminal introduced metal ion binding motif could protect the cysteine residues during the oxidation process by coordinate bond with metal ion. Conventional cysteine conjugation method demands a reduction of cysteine residues to increase the conjugation yield. But use of reducing agents, DTT or TCEP, inevitably leads to non-specific conjugation to the cysteines of disulfide bonds. But, in NexMab™ ADC technology, those reduced cysteines of disulfide bonds could be selectively oxidized while the cysteines in NexMab™ peptides are protected from oxidation by participating metal ion coordination, enabling a site-specific conjugation.