Other requirements of ADC for connected toxins include: 1, sufficient water solubility, and stability in serum, because ADC may circulate in the body for days; 2, there must be functional groups that can be used to associate to Linker; 3, must be insensitive to enzymatic degradation of lysosomes; 4, Reduce polymerization effects (lipophilic substances readily occur) and alter the interaction of ADC and the pGp (permeability glycoprotein, drug efflux pump, prone to lipophilic binding), which is the main cause of multi-directional resistance (MDR) in tumor cells.In addition, for the side of the cleavable linker ADC, effect to require the toxin to kill the target cells and then enter the cell membrane to kill the surrounding cells, the toxin is required to have a certain lipid and water distribution coefficient (LogP) and a positive / neutral charge.
The common points of the toxins used by ADC drugs are extremely high toxicity and small selectivity, which makes them difficult to use as small-molecule drugs alone.These toxins have often been studied as chemical agents in the past, but were abandoned due to too small TI and later onset of toxicity (late emerging toxicity).The current most clinically used cytotoxic drugs can be divided into two major categories according to their mechanism of action:
DNA damaging agent: calicheamicin (C L M, alkinedinylene antimicrobial) acting on DNA, leads to DNA lysis and cell death by binding to the DNA and double spiral groove.
Tubulin inhibitor: To block microtubule polymerization, to block the cell cycle, and then to induce tumor cell apoptosis.Tubulin inhibitors are divided into two main categories: rabbit toxin and its orestatine derivatives auristatins (MMAE, MMAF, M M A F, MMAD) and Medand derivatives maytansinoids (DM1, DM2, DM3, DM4).Currently, the vast majority of tubulin inhibitors are used in the ADCs project, and both subtoxins have approved marketed products (Adcetris uses MMAE,Kadcyla of orestatin using Meddentin derivative DM1).Oriastatin dominates, accounting for about more than 50% of ADC drugs under development.
Selection of the ILinker(linker)
Linkers are a bridge linking antibodies to cytotoxic drugs.Ideal conjugation must be stabilized in vitro or in blood circulation in case of systemic toxicity due to early release of cytotoxic drugs, while enabling rapid release of effective cytotoxic drugs to kill cancer cells after entering cancer cells.