ADC Cytotoxin

Early ADCs relied on drugs that were already approved for use as small molecules, such as vinblastine and doxorubicin, and suffered from lack of potency and low clinical activities. Substantially more potent drugs that were too toxic to use in an untargeted manner have been more promising as ADCs. These include auristatins, maytansines, and calicheamicins. Auristatins and maytasines both exert their cytotoxic effects by binding to tubulin, causing G2/M cell cycle arrest, and subsequently leading to apoptosis. Monomethylauristatin E, conjugated through a protease-cleavable dipeptide linker (vcMMAE), and monomethylauristatin F, conjugated directly to mAbs through maleimidocaproic acid (mcMMAF), are synthetic analogs of dolastatin 10, a natural product originally isolated from the Indian ocean sea hare Dolabella ariculara. DM1, conjugated through a disulfide or directly through the heterobifunctional succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC) linker, and DM4, conjugated through a disulfide, are semi-synthetic analogs of maytansine, a natural product originally isolated from the Ethiopian shrub Maytenus ovatus. Calicheamicin, a DNA strand cleaving agent conjugated through an acid-sensitive hydrazone, is a semi-synthetic analog of a Micromonospora echinospora ssp. calichensis fermentation product.