ADCs Cytotoxin

ADCs Cytotoxin

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Antibody-drug conjugate (ADC) combines the high specificity of monoclonal antibody drugs with the high activity of small molecule cytotoxic drugs to improve the targeting of cancer drugs and reduce toxic side effects. The mechanism of action involves using monoclonal antibodies to specifically target cancer cells, and kill the cancer cells by coupled small molecule drugs.

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More information About ADCs Cytotoxin

Requirements for ADC linked toxins include: 1. Sufficient water solubility and stability in serum, because ADC may circulate in the body for several days; 2. Toxins must have functional groups that can be used to couple with the Linker;3. Toxins must be insensitive to enzymatic degradation reactions of lysosomes; 4. Toxins can reduce the aggregation effect (lipophilic substances tend to occur) and alter the interaction between ADC and pGp (permeability glycoprotein), which is the main cause of multipotent drug resistance (MDR) in tumor cells. In addition, for cleavable linker ADC, the side effect is that the toxin kills the target cells and then enters and exits the cell membrane to kill the surrounding cells. Such cleavable linker ADC requires a toxin with a certain lipid-water partition coefficient (LogP) and a positive / neutral charge.

ADCs Cytotoxin

Common toxins used in ADC drugs are extremely toxic and with little selectivity, which makes them difficult to use alone as small molecule drugs. These toxins have often been studied as chemical drugs in the past but have been abandoned due to their later emerged toxicity. At present, the most commonly used cytotoxic drugs can be divided into two categories according to their mechanism of action: (1) DNA damaging agents: these drugs act on calicheamicin (CLM, an alkene diyne antibacterial drug) of DNA, causing DNA cleavage and cell death by binding to the DNA double helix groove. (2) Tubulin inhibitors: by binding to microtubules, they prevent the polymerization of microtubules, block the cell cycle, and induce tumor cell apoptosis. Tubulin inhibitors can also be divided into two major categories: dolastatin and its auristatin derivatives (MMAE, MMAF, MMAD); and maytansin and maytansinoid derivatives (DM1, DM2, DM3, DM4). At present, majority of clinical research involving ADCs projects use tubulin inhibitors, and both subtoxoids have approved products on the market (Adcetris uses oristatin MMAE and Kadcyla uses maytansinoid DM1). Auristatin is dominating the market, accounting for more than 50% of ADC drugs under investigation.

References:

  1. Nirnoy Dan, Saini Setua, Vivek K. Kashyap.Antibody-Drug Conjugates for Cancer Therapy:Chemistry to Clinical Implications.Pharmaceuticals. 2018, 11, 32,1-22.
  2. Siler Panowksi,Sunil Bhakta,Helga Raab.Site-specific antibody drug conjugates for cancer therapy.Landes Bioscience.2014,6:1, 34–45.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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