Table 1.
ADC | Resistance Mechanisms Directed Against | ||
---|---|---|---|
Targeting Moiety | Linker | Payload | |
Gemtuzumab ozogamicin | CD33 splice variant lacking antibody epitope | drug efflux transporters, | |
PI3K pathway activation, | |||
mTORC1/2 activation, | |||
deficient Bak/Bax activation | |||
Brentuximab vedotin | CD30 down-regulation | drug efflux transporter, | |
MMAE resistance | |||
Trastuzumab emtansine | HER2 down-regulation, | enhanced trafficking to non-lysosomal compartments, reduced V-ATPase activity * | drug efflux transporter, |
SLC46A3 down-regulation, | |||
STAT3 pathway activation, | |||
altered internalization | PTEN/PI3K activation, | ||
PLK1 activation, | |||
failure to induce Cyclin B1 | |||
Inotuzumab ozogamicin | drug efflux transporters |
* non-cleavable linker requires complete antibody degradation by lysosomal enzymes. FDA = Food and Drug Administration; CD = Cluster of Differentiation; PI3K = PhosphatidylInositol-3-Kinase; mTORC = mammalian Target Of Rapamycin Complex; Bak = Bcl-2 antagonist/killer; Bax = Bcl-2-associated x protein; MMAE = MonoMethyl Auristatin E; HER2 = Human Epidermal growth factor Receptor 2; SLC46A3 = SoLute Carrier 46A3; STAT3 = Signal Transducer and Activator of Transcription 3; PTEN = Phosphatase and TENsin homolog; V-ATPase = Vacuolar-type proton pumping Adenosine Tri-Phosphate hydrolyzing enzyme; PLK1 = Polo-Like Kinase 1.