Table 1.
Documented resistance mechanisms for FDA-approved antibody-drug conjugates (ADCs).
| 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.