ADC Cytotoxin

Antibody-drug conjugates (ADCs) represent a novel class of cancer therapeutics. Their design involves a tumor-specific antibody, a linker and a cytotoxic payload. The payload in ADCs are highly potent cytotoxins, exerting their effects on critical cellular processes required for survival. Typically, the cytotoxins used in ADCs are a 100-1000 times more potent than regular chemotherapeutics and preferably have sub-nanomolar potency. Most compounds in current clinical testing utilize either maytansine derivatives (DM1/DM4) or auristatins (MMAE/ MMAF), which are both microtubule inhibitors. These typically induce apoptosis in cells undergoing mitosis by causing cell cycle arrest at G2/M. More recent work shows that microtubule inhibitors may also disrupt non-dividing cells in interphase. Other classes of cytotoxins used in ADCs include enediynes (Calicheamicin ), duocarmycin derivatives, pyrrolobenzodiazepines (PBDs) and indolinobenzodiazepines, all of which target the minor groove of DNA, and quinoline alkaloids (SN-38), which inhibit topoisomerase. For example, the potent cytotoxic drug doxorubicin and daunorubicin may interact with DNA by intercalation.