SMCC (thioether, non-cleavable)

aka thioether linker, MCC

SMCC is the non-cleavable thioether linker in Kadcyla: the payload is freed only when the whole antibody is digested, so nothing leaks to neighbours.

SMCC couples DM1 to lysines. After lysosomal degradation the released species is lysine-SMCC-DM1, a charged catabolite that cannot cross membranes. This gives excellent plasma stability and low bystander killing, which is why T-DM1 needs high, homogeneous HER2 expression.